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Rintatolimod - AIM ImmunoTech

Drug Profile

Rintatolimod - AIM ImmunoTech

Alternative Names: Ampligen; Atvogen; Mismatched double-stranded RNA - AIM ImmunoTech; Poly I:Poly C12U; Poly I:polyC12U; poly(I) poly(C12,U); Rintamod; Vaccine-adjuvant-poly-I-polyC12U; Vaccine-adjuvant-rintatolimod

Latest Information Update: 31 Mar 2020

At a glance

  • Originator Hemispherx Biopharma
  • Developer AIM ImmunoTech; National Cancer Institute (USA); Roswell Park Cancer Institute; United States Army Medical Research Institute of Infectious Diseases; University of Pittsburgh
  • Class Adjuvants; Antineoplastics; Antivirals; Oligonucleotides
  • Mechanism of Action HIV replication inhibitors; Immunostimulants; Interferon stimulants; Ribonuclease stimulants; RNA synthesis inhibitors; Toll-like receptor 3 agonists; VP35 protein inhibitors
  • Orphan Drug Status

    Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.

    Yes - Renal cell carcinoma; Ebola virus infections; HIV infections; Chronic fatigue syndrome; Malignant melanoma
  • New Molecular Entity Yes

Highest Development Phases

  • Registered Chronic fatigue syndrome
  • Phase II Colorectal cancer; Prostate cancer
  • Phase I/II Breast cancer; Influenza virus infections; Ovarian cancer; Peritoneal cancer
  • Phase I Pancreatic cancer
  • Preclinical COVID 2019 infections; Ebola virus infections; West Nile virus infections; Zika virus infection
  • Research Influenza A virus infections
  • Suspended HIV infections
  • No development reported Hepatitis B; Malignant melanoma; Renal cell carcinoma
  • Discontinued Smallpox; Western equine encephalitis virus infections

Most Recent Events

  • 26 Mar 2020 AIM ImmunoTech plans clinical trials for COVID-2019 infections (Early-stage disease) in Argentina, Asia, Europe and USA (IV)
  • 26 Mar 2020 AIM ImmunoTech plans clinical trials for COVID-2019 infections (Prevention) in Argentina, Asia, Europe and USA (Intranasal)
  • 26 Mar 2020 AIM ImmunoTech plans clinical trials for COVID-2019 infections (Prevention) in Argentina, Asia, Europe and USA (PO)

Development Overview

Introduction

Rintatolimod, a mismatched double-stranded RNA nucleic acid that induces interferon production and activates an intracellular enzyme (RNase-L) against viral RNA transcripts, is being developed by AIM ImmunoTech (formerly Hemispherx Biopharma) for the treatment of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), pathogenic infections and cancer. The drug has been shown to activate toll-like receptor 3 (TLR-3), which is involved in the early detection of pathogens and the establishment of early defence mechanisms. Additionally, rintatolimod acts as a non-mitogenic stimulator of the immune system, as it works through cellular molecular cascades and therefore, is not vulnerable to mutational changes. Rintatolimod inhibits replication of the human immunodeficiency virus (HIV). In Canada, rintatolimod has been available since May 1996, under an emergency drug release statute, for the treatment of CFS and AIDS (acquired immunodeficiency deficiency syndrome). Rintatolimod is available for severe chronic fatigue syndrome on a named patient, cost-recovery basis in South Africa and the US. Rintatolimod is available in Europe under an Early Access Programme. Intravenously administered rintatolimod is approved in Argentina as a therapy for chronic fatigue syndrome and is awaiting approval in the US. Clinical development is underway for breast cancer, influenza-A virus infections, colorectal cancer, ovarian cancer, peritoneal cancer, prostate cancer, influenza virus infections in the US and pancreatic cancer in the Netherlands. Preclinical research is underway for Ebola virus infections, West Nile virus and Zika virus infections in Italy and the US. Early research is underway in influenza A virus H7N9 subtype infections and COVID-2019 infections prevention in the US.

Preclinical research for the treatment of western equine encephalitis virus infection and small pox was underway in the US. However, development of the drug for these indications seems to be discontinued. Phase II development in hepatitis B, malignant melanoma and renal cell carcinoma was ongoing in the US, and phase III development in chronic fatigue syndrome was conducted and awaiting regulatory approval in the European Union. As of September 2006, no further drug development was reported in these indications. Phase II development in HIV infections was conducted in the US, but the drug development was suspended in March 2007.

In Ebola virus infections, the viral protein, VP35, binds to dsRNA in the host and activates a signalling cascade that results in neutralisation of the host defence mechanism. AIM ImmunoTech expects that administration of rintatolimod may overcome this action and allow the host defence to counter the infection. The company is working with regulatory authorities to develop intranasal sprays, aimed at preventing the further escalation of the Ebola outbreak.

Preclinical data demonstrated that rintatolimod is active against the flavivirus family of viruses which includes the West Nile virus and Zika virus. The mechanism of action of rintatolimod is useful in application for treatment of multiple sclerosis and as antiviral therapy against flaviviruses, including West Nile virus, and virus classes associated with bioterrorism.

An intranasal formulation of rintatolimod is being referred by AIM ImmunoTech to be used as an influenza vaccine enhancer. Preclinical data showed that the compound also acts as a cancer vaccine adjuvant. Rintatolimod had demonstrated a greater than two fold survival benefit in mice model of western equine encephalitis virus infection in comparison with favipiravir.

Hemispherx reported that it is exploring co-development partnerships with vaccine producers [1] .

Rintatolimod is available for licensing worldwide [2] .

In August 2019, Hemispherx Biopharma changed its name to AIM ImmunoTech [3] .

Company Agreements

In January 2017, Hemispherx extended its rintatolimod European Early Access Program (EAP) agreement with myTomorrows to enable access of Ampligen® to chronic fatigue syndrome/myalgic encephalomyelitis patients as well as pancreatic cancer patients beginning in the Netherlands. Hemispherx, in April 2018, amended its agreement to include management of a Special Access Programme (SAP) in Canada for patients suffering from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). In June 2018, the company announced that the EAP approval was accepted in Netherlands for pancreatic cancer. myTomorrows is Hemispherx’s exclusive service provider in Europe and Turkey and will manage all EAP activities relating to the pancreatic cancer extension of the programme. In May 2016, Hemispherx executed an amended and restated agreement signed earlier in August 2015 with myTomorrows, for the commencement and management of an EAP for rintatolimod in all of Europe and Turkey. Under the collaboration, myTomorrows will conduct EAP activities to include the supply of the drug for the treatment of chronic fatigue syndrome as well as collaborate with the physicians to capture data that may support the regulatory approval worldwide. [4] [5] [6] [7] [8] [9]

In March 2018, University of Nebraska Medical Center (UNMC) and Hemispherx Biopharma entered into an agreement to test the capability of rintatolimod to enhance immune responses. The study will test the capability of rintatolimod when combined with peptide vaccine developed by UNMC for pancreatic cancer. UNMC researchers will immunise mice with pancreatic tumours expressing MUC1. [10]

In June 2016, Hemispherx Biopharma obtained a comprehensive omnibus assignment of intellectual property created by William Carter, the former CEO of Hemispherx, resulting in obtaining complete and irrevocable ownership of intellectual property related to Ampligen® [11] .

Hemispherx Biopharma entered into an exclusive license agreement with Emerge Health for the commercialisation of of rintatolimod for the treatment of chronic fatigue syndrome in Australia and New Zealand. Emerge and Hemispherx will collaborate on seeking approval of the product from Australia's Therapeutic Goods Administration (TGA) and New Zealand's Medicines and Medical Devices Safety Authority (Medsafe) and Emerge will distribute the product in both the countries on a named-patient basis. Emerge will also seek orphan drug designation and Hemispherx will provide support for this. Hemispherx will supply rintatolimod at a predetermined transfer price [12] .

In September 2014, Hemispherx entered into a collaborative agreement with the Swiss Department of Defense, Civil Protection and Sports to evaluate rintatolimod against Ebola virus infections, as part of the DEA (Data Exchange Agreement) Annex for Medical Preparedness and Bio-Defense Agreement between the Swiss Surgeon General and the US Department of Defense [13] . In the same month, Hemispherx entered into five integrated research collaborations to develop therapeutic cocktails against Ebola. These collaborations are with the National Institutes of Allergy and Infectious Diseases, the United States Army Medical Research Institute in Infectious Disease, the Swiss Department of Defense, Howard University and a US-based facility with biosafety level 4. Rintatolimod has shown potential value with respect to inclusion in several therapeutic cocktails under development for Ebola [14] .

In July 2014, Hemispherx Biopharma entered into a strategic alliance with Bioclones, under which the companies agreed to jointly pursue regulatory approval of rintatolimod in South Africa [15] .

Hemispherx entered into an exclusive revenue sharing sales, marketing, distribution and supply agreement for rintatolimod in Argentina with GP Pharm Latino-America, an affiliate of Spanish GP Pharm SA, in June 2010. This agreement expired in June 2015 and was renewed in May 2016 with the same clauses as earlier. Under the terms of the agreement, GP Pharm will be responsible for gaining regulatory approval and for commercialisation of rintatolimod for the treatment of CFS in Argentina. GP Pharm also has been granted expanded rights to sell the therapeutic into other Latin American countries, based upon GP Pharm achieving certain performance milestones. In December 2010, the agreement was amended to immediately include Mexico in the agreed territories and GP Pharm Mexico will be responsible for gaining regulatory approval for rintatolimod for the treatment of CFS in Mexico. Hemispherx will manufacture and supply rintatolimod to GP Pharm [16] [17] [18] .

Hemispherx Biopharma and the Lovelace Respiratory Research Institute (LRRI) entered into a research contract worth more than $US1 million in November 2008 to conduct additional preclinical studies with rintatolimod to enhance the NDA filing status of the product. Projected preclinical studies under the contract are designed to enhance the cellular understanding of the product's molecular actions across various animal species, including humans and should facilitate the filing of additional NDAs for potential treatment of CFS in various countries outside North America [19] .

In December 2007, Hemispherx Biopharma notified Esteve of its intention to terminate the licence agreement between the two companies, as certain contractually required clinical trials had not been performed by Esteve. Esteve has applied for arbitration but Hemispherx intends to counterclaim [20] . In March 2002, Esteve and Hemispherx entered into a collaborative agreement under which Esteve will be the sole distributor of rintatolimod in Spain, Portugal and Andorra for the treatment of CFS. Under this agreement, in addition to other terms, Esteve will also collaborate in the drug product development by conducting clinical studies in Spain in patients co-infected with HIV/HCV. Pertaining to the infection time, the treatment would be split into two sets. the first set would consist of patients co-infected <12 months and the second would include those who have had consistent, chronic HIV-HCV co-infection for >12 months.

Inactive agreements

Hemispherx Biopharma's agreement with BIKEN in Japan expired in September 2010. The two parties were working together to develop a nasally administered influenza vaccine utilising research done by Hemispherx and the Japanese National Institute of Infectious Diseases (NIID). Hemispherx successfully completed its 3-year research programme with the NIID during the second quarter of 2010 [21] [22] .

In February 2004, Fujisawa Deutschland GmbH, a subsidiary of Fujisawa Pharmaceutical Co., entered into an option agreement with Hemispherx Biopharma with the intent of becoming a distributor for rintatolimod for the potential treatment of CFS in Germany, Switzerland and Austria. A fee of €400 000 was paid pursuant to the terms of the option agreement, and upon execution of the Distribution Agreement, Fujisawa was to pay Hemispherx fees and milestone payments with a potential worth of several millions of dollars [23] . However, this agreement has been terminated.

In September 2003, Hemispherx Biopharma entered into an agreement with Guangdong Medicine Group Corporation to organise clinical trials, marketing, sales and distribution for both of its lead compounds, rintatolimod and Alferon N® in the People's Republic of China [see RDI Profile 800006022]. The agreement stipulated that the Guangdong Medicine Group Corporation (GMC) will conduct clinical trials with rintatolimod, for the treatment of HIV. All costs related to the trials were to be covered by GMC. Additionally, GMC had to develop and implement marketing and promotional programmes [24] . It appears that this agreement is no longer active.

In May 2003, Hemispherx Biopharma and the Center for Cell and Gene Therapy entered into a research project agreement that would see rintatolimod implemented in a protocol used in patients with relapsed EBV-positive Hodgkin's lymphoma [25] . This collaboration no longer appears to be active.

Crystaal Corporation (later Biovail Pharmaceuticals Canada) acquired exclusive marketing rights to rintatolimod in Canada in February 2000. However, this agreement no longer appears to be active.

In an arrangement between Hemispherx and Bioclones, Bioclones had certain marketing rights for rintatolimod in the Southern Hemisphere, UK and Ireland. However, the agreement between Hemispherx and Bioclones has ended.

Manufacturing

Hemispherx signed a letter of intent with HollisterStier Laboratories for the contract manufacturing of rintatolimod in October 2005. This agreement will enable Hemispherx to manufacture the active pharmaceutical ingredient for 10 000 doses of rintatolimod per week if initial objectives are achieved, in combination with a polymer production facility which is under construction [26] .

Key Development Milestones

In March 2017, Hemispherx re-initiated its US-based cost recovery programme at the price increase recently approved by the FDA [27] .

In December 2017, Hemispherx Biopharma reported that its Contract Manufacturing Organization for rintatolimod (Ampligen®) completed a commercial scale demonstration or engineering manufacturing run, along with the re-qualifications of analytical methods that were agreed upon during a previous successful Pre-Approval Inspection as necessary prior to the production of commercial lots of rintatolimod [28] .

In October 2016, Hemispherx Biopharma reported that the transfer of technology to Avrio Biopharmaceuticals related to contract manufacturing of rintatolimod for use in the Expanded Access Programme in Turkey and England has been completed. The first cGMP lot is expected to be compounded, filled and finished in November and released in December 2016 [29] .

In August 2015, Hemispherx Biopharma plan to file for regulatory approval for rintatolimod worldwide, including Europe, Latin America, Australia, New Zealand and the US [4] . The company also plans to introduce the product in Turkey under an Expanded Access Programme (EAP).

Chronic fatigue syndrome/Myalgic encephalomyelitis (CFS/ME)

In September 2019, rintatolimod received clearance from US FDA under the section 802 (b) (2) of the U.S. Federal Food, Drug and Cosmetic Act for exportation to Argentina for the treatment of severe chronic fatigue syndrome. In August 2016, Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica (ANMAT) approved rintatolimod for the treatment of patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) in Argentina. The approval was based on clinical data from two pivotal trials, AMP-516 and AMP-502 [30] [31] . In July 2012, Hemispherx Biopharma had submitted the NDA to ANMAT, through its local representative GP Pharm in Argentina, seeking approval of rintatolimod for the treatment of CFS under orphan drug status [32] . The approval is expected to have a beneficial effect on AIM ImmunoTech's early access program partnerships in Europe and Australia [16] .

In December 2017, Hemispherx announced that discussions are ongoing with the US FDA on the next steps regarding a New Drug Application (NDA) for rintatolimod (Ampligen®) in ME/CFS [28] . The US FDA issued a Complete Response Letter (CRL) for Hemispherx Biopharma's NDA for rintatolimod (Ampligen®) in February 2013. In its CRL, the agency declined to approve rintatolimod for the treatment of CFS. The FDA said that the company should conduct at least one additional clinical trial, complete various non-clinical trials and conduct selected data analyses. The agency has also stated that there is no sufficient information on the efficacy and safety of rintatolimod in CFS due to a limited safety database and a number of discrepancies within the data provided [33] . In March 2016, the company announced that it had completed discussions with NIH's National Institute of Neurological Disorders and Stroke to discuss how the NIH’s research may assist the company in closing key questions from the FDA [34] . Hemispherx Biopharma reported in its 2014 annual report that it plans to conduct an end-of-review meeting with the FDA to clarify and narrow the outstanding issues regarding the further development of Ampligen® for the treatment of CFS.

In August 2012, Hemispherx Biopharma filed with the US FDA, its complete response to the agency's 2009 CRL to the NDA for rintatolimod for CFS. The FDA accepted the filing as a complete class 2 response and the PDUFA date was set in February 2013 [35] [36] [37] . In November 2010, Hemispherx Biopharma filed a request with the US FDA to maintain an active NDA for rintatolimod to treat CFS [38] [39] [40] . New analyses from the AMP 516 study published in a PLoS ONE report in March 2012, supplement the original study findings and helped support a re-filing of the NDA [41] [42] . In December 2012, the FDA Advisory Committee made recommendations for an additional controlled clinical trial of rintatolimod prior to approval, as the company had not provided sufficient evidence of efficacy and safety [43] .

The FDA accepted Hemispherx's NDA filing (originally submitted in October 2007) for review in July 2008 [44] . Hemispherx received the CRL in December 2009, stating that the two primary clinical studies submitted did not provide credible evidence of efficacy of rintatolimod and recommended at least one additional study of sufficient size and sufficient duration (6 months) [45] . As part of the NDA submission, the company had requested that complete rodent carcinogenicity studies in two species be waived, but the waiver was not granted. Certain additional non-clinical studies and additional data to support non-clinical studies already submitted were also recommended. Prior to the receipt of the CRL, Hemispherx had already begun many of the additional studies and collection of the requested additional data. Hemispherx submitted preclinical data in January 2010 that showed no evidence of antibodies to rintatolimod, and no increase in certain cytokines, after administration of the drug in primates at doses used in clinical studies. The company believed that the data were sufficient to address certain preclinical issues mentioned in the CRL [46] . In the CRL, the FDA also commented on rintatolimod manufacturing, noting the need to resolve outstanding inspection issues at the facilities producing the drug. Hemispherx submitted new data regarding this matter in December 2009 and believes that all manufacturing concerns have been addressed [47] .

In June 2018, Hemispherx Biopharma completed production of a commercial size batch of more than 8 500 vials of Ampligen®. AIM ImmunoTech intends to generate substantial revenues from this batch through an existing 2 100 vial stock order from myTomorrows for its early access programmes in ME/CFS and pancreatic cancer in Europe and Canada. This vial stock will be utilised to meet projected needs for clinical trials of Ampligen in the US, including the FDA-approved expanded access compassionate care program in ME/CFS, and clinical trials involving various cancers with Ampligen® as a stand-alone therapy as well as in combination with checkpoint blockade technology. Hemispherx Biopharma also reported that it filled and finished production of another batch of 8 000 vials which will supply the initial demand for the anticipated commercial launch of Ampligen in Argentina, for treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) [48] [49] .

In August 2017, Hemispherx Biopharma, in collaboration with Millions Missing Canada, plans advance CFS/ME research and potential treatments in Canada. AIM ImmunoTech and Millions Missing Canada will follow the model that Hemispherx used to obtain approval for rintatolimod in Argentina by seeking a Canadian Pharmaceutical partner to file for regulatory approval in Canada. The existing rintatolimod new drug application database will be used to gain approval of the product [50] .

In March 2014, Hemispherx reported that following the notification of clearance of the Rintamod™ trademark in Chile, Peru and Uruguay, Hemispherx and GP Pharma are preparing to file rintatolimod for approval in these countries for the treatment of CFS [51] .

AIM ImmunoTech plans to initiate a confirmatory phase II trial for rintatolimod in CFS/ME in the US [52] .

In March 1997, Hemispherx Biopharma initiated an expanded access phase III open-label trial to evaluate the safety of rintatolimod in 100 patients with severely debilitating chronic fatigue syndrome in the US (AMP 511; NCT00215813). In November 2010, Hemispherx expanded the enrolment of this trial in conjunction with ongoing analysis of the completed phase III AMP 516 study. The company is conducting analysis into the possible viral aetiology of CFS [53] [40] . In September 2015, Hemispherx reported the approval of patient assistance programme for the AMP 511 study, thereby allowing the patients in the study to receive the drug through March 2016, at a cost-recovery rate, since they entered the study [54] . As at December 2016, 27 patients accessed rintatolimod, under the patient assistance AMP 511 study, authorised by the US FDA in May 1997 [55] . In June 2018, Hemispherx Biopharma expanded its APM 511 programme in the US and expanded patient enrolment [56] . The US FDA has approved the reimbursement rate of $200 per vial for the direct costs of the drug through EAP [57] . In January 2019, Hemispherx reported that the US FDA authorised the AMP 511 protocol to expand compassionate care where there is no commercially approved therapy. New recruits will not be eligible to participate in a future confirmatory trial. Additionally, a plan for a future pivotal confirmatory trial is underway, wherein previously-treated patients will not be eligible for participation [58] .

In May 2004, Hemispherx reported favourable efficacy and safety data from its 40-week, randomised, parallel, placebo-controlled, double-blind, phase III study of rintatolimod in 234 patients with severely debilitating CFS, which was initiated in December 1998 (AMP 516; NCT00215800) [59] [60] . The trial was completed in February 2004. Results of the US-based study were published in the Journal of Applied Research and PLoS ONE [41] . In September 2015 and October 2016, a retrospective analysis of data from the trial was released [52] [61] .

In February 2000, Crystal Corporation (now Biovail Pharmaceuticals Canada) acquired exclusive marketing rights to rintatolimod in Canada. Rintatolimod has been available in Canada since May 1996 under the Canadian Emergency Drug Release Programme for the treatment of CFS and immune dysfunction syndrome from Rivex Pharma (Helix BioPharma).

Rintatolimod has been granted orphan drug status for the treatment of CFS in the US and Europe. Hemispherx had previously applied for approval to use rintatolimod for CFS in Europe [62] . The US FDA also granted orphan drug designation to rintatolimod for the treatment of HIV/AIDS, renal cell carcinoma and malignant melanoma.

Rintatolimod has been evaluated in phase II trials for the treatment of CFS/ME [63] [64] .

Bioclones planned to initiate clinical studies with rintatolimod for the treatment of CFS in Australia; however, no recent development has been reported.

In August 2018, Hemispherx reported that rintatolimod synergistically potentiated anti-tumour activity and median survival of other anti-cancer compounds including checkpoint inhibitors in preclinical studies [65] . In January 2018, Hemispherx released data from preclinical studies and preliminary clinical data on a favourable immune-modulatory activity of rintatolimod on the tumour micro environment, which potentially could help convert cold tumours to tumours that will respond to immunotherapeutic drugs such as checkpoint inhibitors. In addition, rintatolimod in combination with alpha interferon and COX-2 inhibitors uniformly induced attraction of killer T cells into the tumor lesions of multiple human cancer types, rather than healthy tissue, and simultaneously eliminated undesirable Treg cells and local production of other suppressive factors such as interleukin-10 [66] [67] .

Hemispherx Biopharma, in September 2015, reported positive outcome from preclinical studies to evaluate the in vitro exposure of peripheral blood mononuclear cells (PBMCs) from 15 CFS patients [68] .

In January 2015, Hemispherx reported that rintatolimod 400mg bid, in natural killer cells donated by patients with chronic fatigue syndrome, increased the in vitro mean natural killer cell activity [69] .

A preclinical study conducted by Utah State University in collaboration with Yale University, Vanderbilt University, and the Centre d'Immunologie de Marseille-Luminy demonstrated the roll of toll-like receptor 3 (TLR-3) in rintatolimod's mechanism of action. This study, evaluating the mechanism of action in TLR-3 knockout mice, was conducted under a NIH contract [70] .

Viral infections

In September 2013, Hemispherx reported that it intends to undertake major programmes to investigate rintatolimod as a biodefence agent, with a focus on the prevention or treatment of H7N9 pandemic influenza virus infections, alpha virus infections including Venezuelan Equine Encephalomyelitis (VEE), and Middle East Respiratory Syndrome (MERS). The in vitro and in vivo studies have confirmed that rintatolimod is highly active against these virus classes [71] .

Ebola virus infections

In May 2015, rintatolimod received orphan drug designation by the EMA for the treatment of Ebola virus disease. Hemispherx Biopharma reported in March 2015 that rintatolimod had received a positive opinion from the Committee for Orphan Medicinal Products (COMP) regarding its orphan drug application in the EU [72] . The application was supported by the in vitro and in vivo data in appropriate preclinical models relevant to the EVD indication conducted in Italy, as well as, clinical safety data obtained from non-EVD clinical studies. The data suggested that rintatolimod successfully competed with dsRNA for Ebola VP35 binding with a low concentration reflected by an IC50 = 1.1 µg/ml [73] . Results from the preclinical mouse model of Ebola virus were released in February 2015 [74] [75] . Additionally, Hemispherx announced that it is developing a protocol for the clinical trial of the drug in Ebola virus infection [76] . In November 2014, Hemispherx Biopharma and United States Army Medical Research Institute of Infectious Disease (USAMRIID) reported that low concentrations of rintatolimod demonstrated effective protection of human cells against Ebola virus in in vitro studies. Furthermore, USAMRIID reported its plans to continue to collect data and to initiate in vitro synergy studies using rintalimod and interferon alpha n3 [see RDI Profile 800006022]. These studies are being planned to establish a basis for clinical interventions in both preventative and therapeutic settings of Ebola virus disease [77] [78] . Rintatolimad was shown to inhibit the Ebola meningenome by investigators at the Howard University [79] . Biochemical in vitro data was reported later in the same month, by the University of Cagliari, Italy [80] . In September 2014, Hemispherx collaborated with researchers from the USAMRIID to assess rintalimod and interferon alpha n3 as a potential prevention or treatment for Ebola virus infections [81] .

HIV and HCV infections

A phase IIb study of rintatolimod in HIV was completed in the US (NCT00035581) [82] . This trial evaluated the potential effectiveness of rintatolimod to increase the highly active anti-retroviral therapy (HAART)-free time interval before HIV rebound during the strategic therapeutic intervention (STI) of HAART. A phase II study assessing the safety and efficacy of adding rintatolimod to a STI of HAART was also completed in the US (NCT00035893) [83] . Hemispherx also conducted phase II trials in patients with chronic hepatitis B. However, Hemispherx has stated that these studies were not well-controlled, therefore further testing will be necessary. The company's main priority is to the development of rintatolimod in CFS, and it is assumed that trials in other indications will resume when approval has been achieved in CFS.

In July 2004, Esteve Laboratorios in Spain received authorisation from the Spanish Ministry of Health to import rintatolimod for a clinical trial in HIV/HCV coinfected patients. Hemispherx shipped the required number of vials of rintatolimod for the trial [84] . A phase II pilot study was initiated by Hemispherx and Esteve in January 2005 to evaluate the antiretroviral effect of rintatolimod in the treatment of patients infected by HIV-1, with or without HCV co-infection [85] [86] . However, Esteve discontinued this trial due to poor patient recruitment and no further development has been reported.

Influenza virus infections

In August 2017, Hemispherx Biopharma and University of Alabama announced the initiation of full data analysis of the phase I/II trial to assess immunogenicity and safety of FluMist® [see AdisInsight drug profile800004972] with and without rintatolimod (AMP-600; NCT01591473). The full data analysis was commenced following the FDA's evaluation, as communicated in August 2017, of preliminary reports of blinded-study finding. Previously, in February 2017, Hemispherx Biopharma terminated the trial stating that CDC indicated nasal spray flu vaccine should not be used during 2016-2017. The two-staged, randomised, double-blind trial was initiated in April 2012, and enrolled 12 volunteers in the US. The trial assessed the immunogenicity and safety of intranasal FluMist [see AdisInsight RDI profile800004972] administered sequentially with intranasal rintatolimod. The intranasal administration of rintatolimod was well tolerated in healthy volunteers. Immunogenicty data from the trial were released in January 2018. In July 2018, Hemispherx filed positive safety report on this trial [87] [88] [89] [90] [91] .

Hemispherx Biopharma was planning to conduct a placebo-controlled phase II study to investigate the efficacy of adding rintatolimod to standard care in seriously ill patients with influenza virus infections. The company has entered into an agreement with Fountain Medical Development (a Clinical Research Organisation) to prepare, file and gain approval to conduct the trial in China. However, status of this trial is unknown [92] [93] .

Pre-clinical studies also showed cross-protection against H5N1 viruses using trivalent seasonal influenza vaccine in mouse models [89] .

A preclinical study of a nasally delivered H5N1 vaccine containing an inactivated full-particle vaccine, rintatolimod as adjuvant and carboxy vinyl polymer base as vaccine base, was conducted by Japan's National Institute of Infectious Disease, with funding from the country's Ministry of Health, Labor and Welfare. Results showed that, in the group for which rintatolimod 20-fold was used, both IgG and IgA antibody titres had the highest values 2 weeks after final immunisation [94] .

Smallpox

Hemispherx stated in December 2001 that positive results had been obtained from animal studies on rintatolimod for the treatment of smallpox. It had suppressed vaccinia virus lesions at very low doses, but it appears that development for this indication has been discontinued.

Coronavirus infections (SARS coronavirus infections

): In March 2020, AIM Immuno Tech announced intention to conduct clinical trials with intranasal and oral formulation of rintatolimod (Ampligen®) for a protective prophylactic as well as intravenous formulation for early-onset therapy of COVID-1019 infection in Argentina, the Asia, the Europe and the US. The company is also in discussions with myTomorrows and the Erasmus Medical Center in the Netherlands Rotterdam, to explore expedited pre-clinical and clinical trials of Ampligen® for a protective prophylactic as well as early-onset therapy of COVID-1019 infections [95] .

In March 2020 AIM Immuno Tech announced that rintatolimod (Ampligen) will be tested for the potential treatment of COVID-19 by National Institute of Infectious Diseases (NIID) in Japan [96] .

In February 2020, AIM Immuno Tech announced that the company intends to introduce rintatolimod (Ampligen) in China for the treatment of COVID-19 virus infection [97] .

In February 2020, AIM Immuno Tech released preclinical pharmacodynamics data for severe acute respiratory syndrome caused due to COVID-2019 infections [98] .

Hemispherx Biopharma reported in February 2010 that it was holding discussions with clinical research organisations in China with a view to starting clinical antiviral programmes for rintatolimod in that country. The clinical programmes will relate to use of the drug to treat SARS. The company stated that this decision was based on promising results for the drug in an animal model of SARS; the preclinical work was conducted by independent researchers at Utah State University and the University of North Carolina [99] .

In May 2003, Hemispherx initiated a collaboration with the Genome Institute of Singapore (GIS), to evaluate rintatolimod and Alferon® N for the treatment of SARS [see RDI Profile 800006022] [100] . Hemispherx entered into a Research Project Agreement with the Institute for Medical Virology, Johann Wolfgang Goethe University Hospital, Germany, to evaluate the antiviral activity of rintatolimod and Alferon® N, alone and in combination against the SARS coronavirus.

NIH-sponsored studies of potential therapies for SARS identified rintatolimod as having unusually high and consistent antiviral activity against human coronavirus, the pathogen implicated as the causative agent of the disease. Rintatolimod demonstrated very high potency at very low concentrations (0.4 µg/mL) and had a favourable safety profile [101] . In October 2003, Hemispherx announced that, based on these promising new results, the company would stockpile injectable and/or oral formats of rintatolimod and Alferon® [102] .

Zika virus infection

In February 2016, Hemispherx announced its intention to explore the intranasal use of Ampligen® in non-pregnant patients with Zika virus infection. The study aims to establish whether or not Ampligen® could decrease Zika viral load in blood and other body fluids in patients, could shorten the time period during which the virus may be transmitted, and/or could decrease viral related tissue pathology [103] .

Cancer indications

In December 2014, Hemispherx reported that it is developing rintatolimod as a therapeutic complement to a new molecular class of anti-tumour drugs, immune checkpoint inhibitors or PD-1 (Programmed Death) inhibitors. The company is developing on-going antitumor programs in collaboration with Georgia Regents University (GRU) Cancer Centre and the University of Pittsburgh (UP). Preclinical studies conducted at GRU showed that a dsRNA analogue of rintatolimod had significantly increased survival in animal tumours when administered in combination with PD-1 inhibitors and in follow on animal experiments with rintatolimod demonstrated anti-tumour properties similar to those of typical PD-1 inhibitors with a resultant long term survival advantage in mouse melanoma. Rintatolimod and PD-1 treated mice were resistant to re-challenge with viable melanoma cells in the absence of drug (s) indicating a memory effect, which is most likely mediated by anti-melanoma cytotoxic CD8+ cells. Research conducted at UP showed that rintatolimod as a component to help modify the immunological micro environment around tumours to boost anti-tumour response. The data obtained provides basis for the combination of rintatolimod with PDL1 blockers and PD-1 blockers. The company believes that additional clinical trials will be required to establish whether these findings translate to enhanced survival or other clinical benefit in patients with malignant melanoma, metastatic renal cancer or other conditions [104] . As at July 2017, AIM ImmunoTech is planning clinical trials for cancer, including renal cell carcinoma and metastatic melanoma. Ampligen had a positive modulating effect on the PD-1/PD-L1/PD-L2 system in human ovarian and colorectal cancers [1] [105] .

In October 2018, Hemispherx Biopharma signed a clinical trial agreement with Roswell Park, to conduct clinical studies of Ampligen, in combination with checkpoint inhibitors, for the treatment of three solid tumours, including urothelial carcinoma (bladder and associated structures), renal cell carcinoma and melanoma [57] [106] . In June 2018, the company also signed a memorandum of understanding (MoU) with Roswell Park Cancer Center to conduct a planned phase I/II study of Ampligen, in combination with checkpoint inhibitors, in solid tumours [48] [107] .

Hemispherx Pharma has stated that the company is collaborating with several cancer centres that are conducting clinical trials of rintatolimod as an adjuvant in various cancer indications. The centres include the University of Washington, the Abramson Cancer Center at the University of Pennsylvania and the University of Pittsburgh [108] .

Breast cancer

In September 2019, AIM ImmunoTech announced that it has received FDA authorisation to proceed with the phase I study of chemokine modulation plus neoadjuvant chemotherapy in patients with early-stage triple negative breast cancer (TNBC) using rintatolimod. The study will be conducted to evaluate the safety and tolerability of rintatolimod in combination with celecoxib with or without Intron A, and chemotherapy [109] .

In January 2019, Hemispherx Biopharma in collaboration with Roswell Park Cancer Center initiated a phase I study of rintatolimod in combination with pembrolizumab, in patients with metastatic triple negative breast cancer, who will undergo a pre-treatment biopsy (62218; NCT03599453). The trial was designed to evaluate the increase of CD8+ infiltration into tumour microenvironment after pre-treatment CKM regime comprising rintatolimod, celecoxib and recombinant interferon alfa-2b. The trial completed enrolment of six patients and initiated treatment in the US [110] [111] [112] [113] . In April 2019, the first patient was dosed in the trial [114] .

In June 2014 the University of Washington completed the phase I/II study began in the US which is evaluating Ampligen® as an adjuvant (with HER2 vaccination) in breast cancer (NCT01355393). The trial was initiated in August 2011, and enrolled 50 patients in the US [115] [116] .

Colorectal cancer

In March 2018, Roswell Park Cancer Institute, in collaboration with National Cancer Institute (NCI), initiated a phase IIa trial to evaluate the safety and efficacy of rintatolimod, in combination with celecoxib and recombinant interferon alfa-2b [see AdisInsight drug profiles 800006795 and 800009995, respectively], in patients with colorectal cancer, metastatic to the liver (I 52917; NCI-2017-02471; P30CA016056; NCT03403634). The open-label study is enrolling approximately 12 patients in the US [117] . As of August 2019, seven patients were enrolled in the trial and completed treatment [110] [111] [118] .

In January 2018, Hemispherx Biopharma, in collaboration with Roswell Park Cancer Institute, terminated a phase I/II trial of rintatolimod, in combination with celecoxib and interferon, in patients with recurrent colorectal cancer (NCT01545141; 10-131). The open-label, parallel, randomised trial intended to enrol approximately 50 patients in the US [119] [108] .

Pancreatic cancer

As of August 2019, phase I development of rintatolimod for the treatment of pancreatic cancer is underway in Netherlands through early access programme. The candidate was well tolerated during the programme (AIM ImmunoTech pipeline, August 2019).

Ampligen is available in Europe and in the US under an Early Access Programme [120] . In February 2019, company extended its Early Access Program for Ampligen for the treatment of pancreatic cancer at the Erasmus Medical Center in the Netherlands. The EAP is approved for the treatment of pancreatic cancer by the Dutch Health Inspectorate for two year. As of February 2019, 43 patients have been treated under this programme. Early results have been released [111] [121] [105] . The company intends to expand the early access programme to other European countries and Canada [110] [122] [48] [123] [6] .
In August 2018, Hemispherx Biopharma released initial 500 vials of rintatolimod of 2,100 vial stock order from myTomorrows for pancreatic cancer Early Access Program (EAP) in Netherlands [124] .

Prostate cancer

In November 2019, Hemispherx Biopharma in collaboration with National Cancer Institute and Roswell Park Comprehensive Cancer Center initiated a phase II trial to evaluate the safety and immunomodulatory effectiveness of combination of rintatolimod and aspirin with or without recombinant interferon alfa-2b (interferon [IFN]-alpha) in patients with prostate cancer before surgery (I 77318; NCI-2019-01192; P30CA016056; NCT03899987). The randomised open-label trial intends to enrol approximately 45 patients in the US [125] .

In August 2019, Hemispherx Biopharma reported approval of an IND application for a prospective phase II trial of rintatolimod. The trial will be conducted in collaboration with Roswell Park Comprehensive Cancer Center and will evaluate neoadjuvant conditioning of prostate cancer with rintatolimod as a component of chemokine modulation with or without interferon-alpha 2b. The company also received approval from the Institutional Review Board (IRB) to conduct the trial. In March 2019, Hemispherx Biopharma submitted the IND. As at March 2019, preclinical development is underway in the US [110] [121] .

Ovarian/Peritoneal cancer

The University of Pittsburgh initiated a phase I/II trial to evaluate the safety and efficacy of autologous alpha type-1 polarised dendritic cell vaccine in combination with a systemic chemokine modulation regimen, consisting of rintatolimod, celecoxib and interferon-α-2b, as adjuvant therapy, following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, in patients with peritoneal cancer (NCT02151448). The trial will enrol approximately 168 patients from the US. The primary endpoint is to determine whether this combination immunotherapy can increase time-to-progression and whether this treatment regimen is safe. The study has enrolled 45 patients as of February 2019 [111] [126] .

The Abramson Cancer Center at the University of Pennsylvania is conducting a phase I/II trial of an autologous oxidized tumour cell lysate vaccine with rintatolimod as an adjuvant in ovarian, fallopian tube and primary peritoneal cancer (NCT01312389). Enrolment of an estimated 29 patients in the US was completed in April 2012 [127] .

In April 2011, Quest PharmaTech and Hemispherx Biopharma announced a clinical development arrangement for a planned 30-patient trial of oregovomab in combination with rintatolimod as a vaccine enhancer [128] . Under the terms of agreement, the costs will be shared by both companies. The trial was expected to begin in Canada and the US in 2011 but no recent development has been reported [129] .

The University of Washington Tumor Vaccine Group in the USA conducted a preclinical study in a transgenic mouse breast cancer model, which showed that rintatolimod acts as a potent cancer vaccine adjuvant when combined with an antitumour peptide vaccine. The results were reported in April 2011 [130] .

Hemispherx has completed phase II development and received clearance from the US FDA for a phase III study in patients with renal cell carcinoma. Clinical trials have also been conducted in patients with malignant melanoma. However, Hemispherx has stated that certain studies to date have not been well-controlled and additional tests will be necessary.

Preclinical data demonstrated that, in explant culture models, rintatolimod activated the TLR3 pathway and promoted an accumulation of killer T cells. However, unlike the other two TLR3 agonists (poly IC and natural double stranded RNA), it did not accumulate regulatory T cell (Treg). This can aid in creating an enhanced tumour microenvironment for checkpoint blockage therapy [9] . In preclinical models and human tumour explants demonstrated that rintatolimod is a TLR3 restricted and targeted modulator of “hot” tumour microenvironments [112] .

Investigator sponsored trial

In February 2019, the UPMC Hillman Cancer Center (formerly the University of Pittsburgh Cancer Institute) in collaboration with Merck and Hemispherx Biopharma initiated a phase I/II trial to evaluate the efficacy, safety of rintatolimod (IP, 200mg)in combination with cisplatin (IP, 50 mg/m2) and pembrolizumab (IV, 200mg) in patients with recurrent, platinum sensitive ovarian cancer (NCT03734692; HCC 18-087). In June 2019, the first patient was treated in the trial [131] . The open-label trial intends to enrol approximately 45 patients in the US [132] [133] .

In July 2015, University of Pittsburgh, in collaboration with Roswell Park Cancer Institute, Hemispherx Biopharma and National Cancer Institute, initiated a phase I/II trial to investigate if cisplatin in addition to an investigational dendritic cell vaccine with or without an investigational drug combination of rintatolimod, interferon alpha-2b (IFN), and oral celecoxib, has any effect on recurrent ovarian cancer (NCT02432378; 11-128; 5P01CA132714). The randomised, open-label trial intends to enrol approximately 40 patients in the US. As of November 2018, the trial enrolled 10 patients in the phase I portion of the study. As of August 2019, the phase 1 part of the study has been completed. The combination therapy was safe and generally well tolerated with no major toxicities reported, and showed positive survival data in patients with stage 4 ovarian cancer [134] [118] [135] .

Financing information

In October 2019, AIM immunotech raised approximately $US10 million from the public markets to support the clinical development of rintatolimod [136] .

In September 2019, the US Department of Defense granted $US 8.32 million fund in another "Breakthrough Award" to Moffitt Cancer Center for a Phase 2 clinical study of a combination of therapies with rintatolimod in patients with brain-metastatic breast cancer (BMBC). Roswell Park Comprehensive Cancer Center also received its own Department of Defence funded Breakthrough Award of $SU 6.42 million to study Ampligen in the treatment of BMBC [137] .

In February 2017, Hemispherx Biopharma announced the registered direct offering worth $US1 million following the definitive agreements with various investors. The proceeds of the offering will be used to cover expenses related to manufacturing of rintatolimod and for preparation of technology transfer opportunities [138] .

In August 2016, Hemispherx Biopharma entered into definitive agreements with two institutional investors for an offering of shares of common stock with gross proceeds of approximately $US5 million in a registered direct offering. The net proceeds will be used by the company for the expenses related to manufacturing of rintatolimod [139] . In November 2010, Hemispherx was awarded grants totalling $US488 958 through the US Qualifying Therapeutic Discovery Project programme. Part of these funds will be used to support clinical development of rintatolimod in CFS [140] .

Manufacturing agreement

In July 2016, Hemispherx entered into an agreement with Avrio Biopharmaceuticals, to serve as an additional contract manufacturer of rintatolimod [141] .

Patent Information

In February 2020, AIM ImmunoTech announced the filing of three provisional patent applications related to rintatolimod against the Wuhan coronavirus infections. The three provisional patent applications include rintatolimod as a therapy for the Wuhan coronavirus, rintatolimod as part of a proposed intranasal universal coronavirus vaccine that combines rintatolimod with inactivated Wuhan coronavirus, conveying immunity and cross-protection and a high-volume manufacturing process for rintatolimod [98] .

In 2016, Hemispherx Biopharma was granted US patents 9 315 528 B2 and 9 315 538 for the composition of matter patent for rintatolimod in the US [142] [55] .

In September 2015, the European Patent Office granted Hemispherx Biopharma a patent (EP 2 340 307) titled "Double-Stranded Ribonucleic Acids with Rugged Physiochemical Structure and Highly Specific Biologic Activity". In June 2015, the European Patent Office issued a formal notification to grant a patent. This composition of matter patent covers a form of rugged dsRNA, which has reduced tendency to form branched dsRNA enabling high bioactivity and binding affinity to toll-like receptor 3 (TLR3). The patent also covers the formulations of rugged dsRNA and methods of treatment with the same. A total of 28 patents were granted in different countries in the EU, further to which the product will be protected up to 2029 and beyond [55] [143] [144] .

In May 2014, the US Patent and Trademark Office had issued an US patent 8 722 874 to Hemispherx, entitled "Double-stranded Ribonucleic Acids with Rugged Physiochemical Structure and Highly Specific Biologic Activity", covering a novel form of rugged dsRNA, pharmaceutical formulations containing the dsRNA, and methods of treatment using these formulations. The patent provides protection until at least 2029 [145] .

In January 2013, US Patent Office granted one patent in Singapore for the use of Ampligen® to initiate innate immunity and to treat or prevent viral infections and tumours.

In July 2011, Hemispherx Biopharma was granted a US patent no. 7 943 147 for the use of rintatolimod as a seasonal influenza vaccine adjuvant. The patent describes a method using intranasal rintatolimod with a seasonal influenza vaccine to enhance an immune response against a H5N1 avian influenza infection [146] .

The main US CFS/ME treatment patent for rintatolimod, patent number 6 130 206, expired in October 2017. The main patents covering HIV treatment, including patent number 4 820 696, 5 063 209, and 5 091 374, expired in April 2006, November 2008, and February 2009, respectively. The US patent number 5 593 973 covering rintatolimod for the treatment of hepatitis C expired in January 2014. The Ampligen® Trademark number 73/617 87 was renewed through December 2018.

In May 2004, Hemispherx filed an expanded US patent application covering the use of rintatolimod for the potential treatment and prevention of SARS and emerging viruses. Hemispherx has been issued certain patents on the use of rintatolimod alone and rintatolimod in combination with certain other drugs including AZT, ddI, ddC, interferon and/or IL-2, for the treatment of HIV.

The original US composition of matter patent for rintatolimod was issued to the Johns Hopkins University in the early 1970s and was exclusively licensed to Hemisphere Biopharma. This patent has since expired [145] .

Drug Properties & Chemical Synopsis

  • Route of administration Intradermal, Intranasal, Intraperitoneal, IV
  • Formulation Infusion, Spray, unspecified
  • Class Adjuvants, Antineoplastics, Antivirals, Oligonucleotides
  • Target HIV replication; Interferon; Ribonuclease; RNA synthesis; Toll-like receptor 3; VP35 protein
  • Mechanism of Action HIV replication inhibitors; Immunostimulants; Interferon stimulants; Ribonuclease stimulants; RNA synthesis inhibitors; Toll-like receptor 3 agonists; VP35 protein inhibitors
  • WHO ATC code

    J05 (Antivirals for Systemic Use)

    J05A-B (Nucleosides and nucleotides excl. reverse transcriptase inhibitors)

    J05A-X (Other antivirals)

    L03A (Immunostimulants)

    N07 (Other Nervous System Drugs)

  • EPhMRA code

    J5 (Antivirals for Systemic Use)

    J5B1 (Viral hepatitis products)

    J5B4 (Influenza antivirals)

    J5C1 (Nucleoside and nucleotide reverse transcriptase inhibitors)

    L3A (Immunostimulating Agents Excluding Interferons)

    N7 (Other CNS Drugs)

  • Chemical name [(2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate;[(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-oxo-3H-purin-9-yl)oxolan-2-yl]methyl dihydrogen phosphate;[(2R,3S,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate
  • Molecular formula C28 H40 N9 O25 P3
  • Chemical Structure
  • CAS Registry Number 38640-92-5

Biomarkers Sourced From Trials

Indication Biomarker Function Biomarker Name Number of Trials

adenocarcinoma

Outcome Measure

MIP-1 alpha

integrin, alpha X (complement component 3 receptor 4 subunit)

integrin, alpha M (complement component 3 receptor 3 subunit)

IL10

IFN-gamma

IDO1

FOXP3

CXCL9

CXCL12

CXCL10

CD8a

CD4

CD3g

CD3e

CD3d

CCL5

CCL4

C-X-C motif chemokine ligand 11

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

advanced breast cancer

Exclusion

HER2

1

advanced breast cancer

Inclusion

HER2

1

advanced breast cancer

Outcome Measure

IFN-gamma

HER2

CD4

1

1

1

carcinoma

not specified

FOXP3

CXCR4

CXCL9

CXCL12

CXCL10

chemokine (C-C motif) receptor 6

CD8a

CD4

CCR5

C-X-C motif chemokine receptor 3

C-X-C motif chemokine ligand 11

C-C motif chemokine receptor 4

C-C motif chemokine ligand 22

1

1

1

1

1

1

1

1

1

1

1

1

1

carcinoma

Outcome Measure

MIP-1 alpha

integrin, alpha X (complement component 3 receptor 4 subunit)

integrin, alpha M (complement component 3 receptor 3 subunit)

IL10

IFN-gamma

IDO1

FOXP3

CXCL9

CXCL12

CXCL10

CD8a

CD4

CD3g

CD3e

CD3d

CCL5

CCL4

C-X-C motif chemokine ligand 11

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

colorectal cancer

not specified

FOXP3

CXCR4

CXCL9

CXCL12

CXCL10

chemokine (C-C motif) receptor 6

CD8a

CD4

CCR5

C-X-C motif chemokine receptor 3

C-X-C motif chemokine ligand 11

C-C motif chemokine receptor 4

C-C motif chemokine ligand 22

1

1

1

1

1

1

1

1

1

1

1

1

1

colorectal cancer

Outcome Measure

HGPRT

CD8a

1

2

early breast cancer

Exclusion

HER2

1

early breast cancer

Inclusion

HER2

1

early breast cancer

Outcome Measure

IFN-gamma

HER2

CD4

1

1

1

fallopian tube cancer

Outcome Measure

MIP-1 alpha

integrin, alpha X (complement component 3 receptor 4 subunit)

integrin, alpha M (complement component 3 receptor 3 subunit)

IL10

IFN-gamma

IDO1

HER2

FOXP3

CXCL9

CXCL12

CXCL10

CD8a

CD4

CD3g

CD3e

CD3d

CCL5

CCL4

C-X-C motif chemokine ligand 11

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

fallopian tube cancer

Safety

HER2

1

liver metastases

not specified

FOXP3

CXCR4

CXCL9

CXCL12

CXCL10

chemokine (C-C motif) receptor 6

CD8a

CD4

CCR5

C-X-C motif chemokine receptor 3

C-X-C motif chemokine ligand 11

C-C motif chemokine receptor 4

C-C motif chemokine ligand 22

1

1

1

1

1

1

1

1

1

1

1

1

1

ovarian cancer

Outcome Measure

MIP-1 alpha

integrin, alpha X (complement component 3 receptor 4 subunit)

integrin, alpha M (complement component 3 receptor 3 subunit)

IL10

IFN-gamma

IDO1

HER2

FOXP3

CXCL9

CXCL12

CXCL10

CD8a

CD4

CD3g

CD3e

CD3d

CCL5

CCL4

C-X-C motif chemokine ligand 11

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

ovarian cancer

Safety

HER2

1

peritoneal cancer

Outcome Measure

MIP-1 alpha

integrin, alpha X (complement component 3 receptor 4 subunit)

integrin, alpha M (complement component 3 receptor 3 subunit)

IL10

IFN-gamma

IDO1

HER2

FOXP3

CXCL9

CXCL12

CXCL10

CD8a

CD4

CD3g

CD3e

CD3d

CCL5

CCL4

C-X-C motif chemokine ligand 11

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

peritoneal cancer

Safety

HER2

1

sarcoma

Outcome Measure

MIP-1 alpha

integrin, alpha X (complement component 3 receptor 4 subunit)

integrin, alpha M (complement component 3 receptor 3 subunit)

IL10

IFN-gamma

IDO1

FOXP3

CXCL9

CXCL12

CXCL10

CD8a

CD4

CD3g

CD3e

CD3d

CCL5

CCL4

C-X-C motif chemokine ligand 11

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

Biomarker

Drug Name Biomarker Name Biomarker Function
Rintatolimod - AIM ImmunoTech C-C motif chemokine ligand 22 not specified
C-C motif chemokine receptor 4 not specified
C-X-C motif chemokine ligand 11 not specified
C-X-C motif chemokine receptor 3 not specified
CCR5 not specified
CD4 Outcome Measure
CD8a not specified
chemokine (C-C motif) receptor 6 not specified
CXCL10 not specified
CXCL12 not specified
CXCL9 not specified
CXCR4 not specified
FOXP3 not specified
HER2 Exclusion, Inclusion, Outcome Measure
IFN-gamma Outcome Measure
For more detail, check out BiomarkerBase: the leading source of information about biomarkers used in drug development and diagnostic tests, tracking a comprehensive list of biomarker uses worldwide by over 800 companies

Development Status

Summary Table

Indication Qualifier Patient Segment Phase Countries Route / Formulation Developers Event Date
Breast cancer - Adjuvant therapy Phase I/II USA Intradermal / unspecified AIM ImmunoTech 01 Jul 2011
Breast cancer triple-negative breast cancer Combination therapy, Inoperable/Unresectable, Metastatic disease, Second-line therapy or greater Phase I USA IV / unspecified AIM ImmunoTech, Roswell Park Cancer Institute 09 Jan 2019
COVID 2019 infections - - Preclinical USA IV / unspecified AIM ImmunoTech 11 Feb 2020
COVID 2019 infections - Prevention Research USA Intranasal / unspecified AIM ImmunoTech 11 Feb 2020
Chronic fatigue syndrome - - Registered Argentina IV / Infusion AIM ImmunoTech 23 Aug 2016
Chronic fatigue syndrome - - Preregistration USA IV / Infusion AIM ImmunoTech 11 Oct 2007
Chronic fatigue syndrome - - No development reported (Preregistration) European Union IV / Infusion AIM ImmunoTech 05 Sep 2006
Colorectal cancer in combination with celecoxib and interferon alfa-2b Combination therapy, Inoperable/Unresectable, Metastatic disease, Recurrent, Second-line therapy or greater Phase II USA IV / unspecified National Cancer Institute (USA), Roswell Park Cancer Institute 27 Mar 2018
Colorectal cancer - Metastatic disease, Neoadjuvant therapy, Recurrent Phase I/II USA IV / unspecified AIM ImmunoTech, Roswell Park Cancer Institute 01 Oct 2012
Ebola virus infections - - Preclinical USA Intranasal / Spray AIM ImmunoTech, United States Army Medical Research Institute of Infectious Diseases 02 Feb 2015
Ebola virus infections - - Preclinical Italy Intranasal / Spray AIM ImmunoTech 24 Mar 2015
HIV infections - - Suspended (II) USA IV / Infusion AIM ImmunoTech 04 Feb 2011
Hepatitis B - - No development reported (II) USA IV / Infusion AIM ImmunoTech 05 Sep 2006
Influenza A virus infections Biodefence purposes - Research USA IV / unspecified AIM ImmunoTech 12 Sep 2013
Influenza virus infections - Combination therapy, In volunteers, Prevention Phase I/II USA Intranasal / unspecified AIM ImmunoTech 01 Apr 2012
Malignant melanoma - - No development reported (II) USA IV / Infusion AIM ImmunoTech 05 Sep 2006
Ovarian cancer - Adjuvant therapy Phase I/II USA IV / unspecified AIM ImmunoTech 01 Mar 2011
Ovarian cancer - Combination therapy, Neoadjuvant therapy, Recurrent, Second-line therapy or greater Phase I/II USA Intraperitoneal / unspecified AIM ImmunoTech, University of Pittsburgh 01 Jul 2015
Pancreatic cancer Early access programme Late-stage disease Phase I Netherlands IV / unspecified AIM ImmunoTech 13 Aug 2017
Peritoneal cancer - Adjuvant therapy Phase I/II USA IV / unspecified AIM ImmunoTech 01 Jul 2014
Prostate cancer In prostate cancer patients before surgery Combination therapy, Late-stage disease, Neoadjuvant therapy Phase II USA IV / unspecified AIM ImmunoTech, Roswell Park Cancer Institute, National Cancer Institute (USA) 29 Nov 2019
Renal cell carcinoma - - No development reported (II) USA IV / Infusion AIM ImmunoTech 05 Sep 2006
Smallpox - - Discontinued (Preclinical) USA IV / Infusion AIM ImmunoTech 08 Feb 2010
West Nile virus infections - - Preclinical USA unspecified / unspecified AIM ImmunoTech 03 Feb 2016
Western equine encephalitis virus infections - - Discontinued (Preclinical) USA IV / unspecified AIM ImmunoTech 13 Apr 2015
Zika virus infection - - Preclinical USA Intranasal / unspecified AIM ImmunoTech 03 Feb 2016

Orphan Status

Indication Patient Segment Country Organisation Event Date
Chronic fatigue syndrome - USA AIM ImmunoTech 09 Dec 1993
Chronic fatigue syndrome - European Union Hemispherx Biopharma Europe 31 Dec 1995
Ebola virus infections - European Union AIM ImmunoTech 11 May 2015
HIV infections - USA AIM ImmunoTech 01 Dec 2013
Malignant melanoma - USA AIM ImmunoTech 01 Dec 2013
Renal cell carcinoma - USA AIM ImmunoTech 01 Dec 2013

Commercial Information

Involved Organisations

Organisation Involvement Countries
Hemispherx Biopharma Originator USA
AIM ImmunoTech Owner USA
myTomorrows Market Licensee Canada, Europe, Turkey
GP Pharm Market Licensee Argentina, Latin America, Mexico
Emerge Health Market Licensee Australia, New Zealand
University of Alabama Collaborator USA
National Cancer Institute (USA) Collaborator USA
Merck & Co Collaborator USA
University of Washington Collaborator USA
Howard University Collaborator USA
National Institute of Neurological Disorders and Stroke Collaborator USA
University of Pennsylvania Collaborator USA
Roswell Park Cancer Institute Collaborator USA
University of Cagliari Collaborator Italy
National Institute of Allergy and Infectious Diseases Collaborator USA
Swiss Department of Defence, Civil Protection and Sport Collaborator Switzerland
Lovelace Respiratory Research Institute Collaborator USA
United States Army Medical Research Institute of Infectious Diseases Collaborator USA
University of Nebraska Medical Center Collaborator USA
Bioclones Collaborator South Africa
University of Pittsburgh Collaborator USA
Millions Missing Canada Collaborator Canada
Georgia Regents University Collaborator USA

Brand Names

Brand Name Organisations Indications Countries
Ampligen AIM ImmunoTech Chronic fatigue syndrome Argentina, USA
Rintamod GP Pharm Chronic fatigue syndrome Latin America

Scientific Summary

  • Adverse Events Occasional: Chills; Dyspnoea; Fatigue; Fever; Flu-like symptoms; Flushing; Headache; Leucocytosis; Leucopenia; Muscle pain; Nausea; QT interval prolongation

Adverse Events

Cancer indications

The most common adverse events in a clinical trial with metastatic melanoma patients included myalgia, headache and fatigue [165] .

Chronic fatigue syndrome (CFS)

Rintatolimod 400mg twice-daily for 40 weeks was generally well tolerated in a pivotal, multicentre (n = 12), randomised, double-blind, placebo-controlled phase III study in 234 patients with CFS. There were no significant differences in the frequency of missed dosages and withdrawals among patients receiving rintatolimod or placebo; however, a greater proportion of placebo patients had significant prolongation of the EKG QT interval compared with those who received rintatolimod [41] [155] .

HIV infections

During clinical trials in which HIV-infected patients received IV infusions of rintatolimod at dose levels of 10-570 mg/m2/dose, the most frequent adverse events were flushing, chills, fever, tight chest, dyspnoea, flu-like symptoms and nausea. All reactions were self-limiting and generally subsided after the infusion was completed. Infusions were usually accompanied by transient leucopenia and then leucocytosis. One patient who received rintatolimod 570 mg/m2 discontinued therapy after developing flu-like symptoms and fatigue [172] [177] [167] .

During combination therapy with zidovudine and rintatolimod, toxicity was similar to that caused by zidovudine alone [178] .

In a study that compared rintatolimod with placebo in zidovudine recipients, the total number of adverse events did not differ significantly between treatment groups [164] .

In HIV-1-positive patients undergoing structured treatment interruptions (STI) of HAART, adverse events associated with rintatolimod were mild and self-limiting. There was no incidence of insulin resistance, hyperlipidaemia, or adverse changes in lactic acid levels [159] .

Influenza virus infections

Results from a phase I/II trial showed that the intranasal use of rintatolimod and FluMist [see AdisInsight RDI profile800004972] was generally well-tolerated. No evidence of any increase in adverse effects related to higher dosage levels of rintatolimod or to the continued administration of rintatolimod during the second and third dual vaccinations was observed. The two-staged, randomised, double-blind trial assessed the immunogenicity and safety of intranasal FluMist administered sequentially with intranasal rintatolimod [87] [91] .

Pharmacodynamics

Summary

Coadministration of rintatolimod and a peptide cancer vaccine inhibited tumour growth to a significantly greater extent than the vaccine alone (p=0.002) in a transgenic breast cancer mouse model. Administration of rintatolimod with the vaccine inhibited tumour growth to a significantly greater extent than another vaccine adjuvant candidate, CpG ODN 2395 (a toll-like receptor-9 agonist); however, inhibition of tumour growth was not significantly different between rintatolimod plus vaccine and GM-CSF plus vaccine. Compared with the vaccine alone, addition of rintatolimod, CpG and GM-CSF inhibited tumour growth by 60%, 53% and 37%, respectively. In contrast, imiquimod failed to increase the antitumour activity of the vaccine [130] .

In preclinical studies involving rodents and non-human primates (monkeys), rintatolimod enhanced the activity of influenza vaccines by conferring increased cross-reactivity and cross-protection, against deadly viruses, including avian H5N1 influenza virus. The studies showed that the development of a universal vaccine was possible through simply administered nasal immunisation of seasonal vaccines in combination with rintatolimod to achieve immune enhancement by ‘epitope spreading’. The data demonstrated in animals and humans showed the generation of antibodies against highly pathogenic avian influenza viruses with high lethality in humans, ~60% for H5N1 and ~40% for H7N9, with super pandemic potential,with the ability to easily infect humans through antigenic shift obtained with retention of high lethality [88] .

Pancreatic Cancer

Results from a preclinical study conducted in pancreatic cancer mouse model showed that treatment with rintatolimod in combination with an anti-PD-L1 drug showed a significant synergistic increase in median survival over control (p = 0.029) [111] .

Results from in vitro studies demonstrated that in vitro treatment of peripheral blood mononuclear cells (PBMCs) from 15 CFS patients (mean average age 47.5 years and median age 46.1 years, 67% are female) with rintatolimod increased mean NK activity (NKCC) and median NK activity (NKCC) by 178% and 100%, respectively [68] .

Ebola virus infection

In preclinical studies in mouse model of Ebola virus, complete survival (100%) was observed at the lowest dose of 6mg/kg of rintatolimod, which was corresponding to human dose of approximately 400mg, during the 21 day treatment period. The survival rate lowered to 90% at higher dosages. A 100% death rate was observed in placebo-treated animals within seven days of infection [74] [75] .

In in vitro studies, rintatolimod indicated binding to VP35 and displacement of viral dsRNA with 50% inhibition at 1.1 µg/ml. Inhibitory concentrations of 4 µg/ml at 50% viral protection was similar to VP35 binding result. The EC50 of rintatolimod was very low relative to the rintatolimod serum levels achieved [80] .

Influenza virus infections

Preclinical data in macaque monkeys exposed to the most virulent forms of pandemic influenza (H5N1) showed that while standard human seasonal influenza vaccines alone had no benefit on H5N1 virus pathology and clinical status, these were highly effective against H5N1 influenza virus when co-administered with small doses of intranasal rintatolimod in a prophylactic setting. Additionally to increased cross-protection and cross-reactivity, rintatolimod may enhance immunity with higher IgA and IgG levels to provide a survival/therapeutic advantage in animal models, and has potential to protect against a phenomenon known as "antigenic drift" (when the pandemic virus can escape the preventive effect of the vaccine). This is well-established phenomenon with avian H5N1 virus that has mitigated the potential usefulness of various already manufactured influenza vaccines [151] .

Rintatolimod was combined with oseltamivir and with zanamivir and applied to cells in culture which had been infected with an H5N1 strain of highly pathogenic avian influenza (HPAI). Results showed that rintatolimod, oseltamivir, and zanamivir exhibited dose responses in the inhibition of the adverse effects of HPAI on cell cultures. At certain doses, furthermore, the combination of rintatolimod and oseltamivir showed synergistic inhibition of viral-induced cell destruction. Similar synergistic results were seen with the combination of rintatolimod and zanamivir [152] .

Rintatolimod reduced serum and liver viral DNA levels in ducks congenitally infected with duck hepatitis B virus, and had at least additive effects with ganciclovir. Rintatolimod had no effect on circulating duck HBsAg and viral replication returned to baseline levels after treatment discontinuation [173] .

Rintatolimod showed 100% survival rate at clinically achievable human dosage levels for severe acute respiratory syndrome (SARS) in animal experiments [98] .

Antimicrobial Activity

Summary

Rintatolimod induced expression of the physiologically functioning antiviral protection system (2-5A synthetase/RNase L system) in cells.

In vitro

, rintatolimod 9.7 µg/ml inhibited HIV. Rintatolimod is synergistic with multiple anti-HIV drugs. Combination indices were determined for 14 anti-HIV agents alone and in combination with rintatolimod using Dose Effect analyses and the CalcuSyn for Windows software. Rintatolimod was synergistic in combination with abacavir, zidovudine, zalcitabine, didanosine, stavudine, efavirenz, indinavir, ritonavir, nelfinavir and amprenavir. It was synergistic to antagonistic with lamivudine, delavirdine, nevirapine and saquinavir [161] .-related reduction of Molt-3 cell growth rate by 50%. It acted synergistically with a reverse transcriptase inhibitor and with an antisense oligonucleotide directed against the tat gene [179] .

Rintatolimod did not display any synergism against HIV in vitro when used in combination with didanosine. In contrast, synergism was demonstrated between rintatolimod and zidovudine at combination ratios ranging from 100 : 1 to 1 : 50 [166] . Rintatolimod also acted synergistically with zidovudine against zidovudine-resistant strains [178] .

The compound has been shown to inhibit human herpes virus-6 (HHV-6) infection in T lymphocytes at concentrations of 100 and 200 µg/ml [180] [181] , and is also active against rotavirus [169] .

Rintatolimod was equally active against wild-type HIV and HIV resistant to nevirapine, protease inhibitors and nucleoside reverse transcriptase inhibitors [161] .

Rintatolimod is synergistic with multiple anti-HIV drugs. Combination indices were determined for 14 anti-HIV agents alone and in combination with rintatolimod using dose effect analyses and the CalcuSyn for Windows software. Rintatolimod was synergistic in combination with abacavir, zidovudine, zalcitabine, didanosine, stavudine, efavirenz, indinavir, ritonavir, nelfinavir and amprenavir. It was synergistic to antagonistic with lamivudine, delavirdine, nevirapine and saquinavir [161] .

The effect of rintatolimod on duck hepatitis B (DBHV) replication in duck primary hepatocytes was compared with D-FMAU. Rintatolimod and D-FMAU inhibited DBHV DNA replication by 50% at concentrations of 0.34±0.06 and 0.0007±0.0001 µgm/L, respectively. Rintatolimod slightly inhibited the intermediate DBHV DNA at a concentration as high as 1.0 µg m/L. The DBHV replicative form was markedly suppressed in the presence of 0.1 µg m/L of D-FMAU. However, rintatolimod markedly inhibited DHBV RNA transcription, compared with D-FMAU. This inhibitory effect of rintatolimod continued after the compound was removed from the culture medium whereas the efficacy of D-FMAU did not [163] .

Drug Interactions

Summary

Immunogenicity

Summary

When co-administered with vaccine, rintatolimod boosted IgA antibody levels by up to 500%. Of the animals that were administered with rintatolimod, 80% survived viral challenge, while none in the placebo group survived [153] .

In a phase I/II trial, rintatolimod displayed cross-reactivity in healthy volunteers which was also seen earlier against avian influenza strains. The combination therapy utilised in the trial produced specific secretory IgA antibody responses of a minimum 4-fold over baseline against at least one of the homologous vaccine strains in the vaccine in 92% of the volunteers. There was induction of cross-reactive secretory IgA antibodies against highly pathogenic avian influenza strains H5N1, H7N9, and H7N3, all with pandemic potential for humans. Updated results showed that the combination regimen generated antibodies against influenza subtypes not present in the seasonal vaccine. The two-staged, randomised, double-blind trial assessed the immunogenicity and safety of intranasal FluMist [see AdisInsight RDI profile [500004972]] administered sequentially with intranasal rintatolimod [87] [88] [91] .

Therapeutic Trials

Ten patients with metastatic melanoma were treated with rintatolimod in an open-label phase I/II trial. The drug was administered intravenously at a low dose (80mg) to one patient, and at a high dose (200-1000mg) to nine patients, over 30-60 min twice-weekly for 3-111 weeks. Two of the patients receiving high dose therapy achieved a complete response. Both received maintenance therapy for at least 12 months following this and have remained in complete response without further therapy at 21 and 91 months [165] .

Pancreatic cancer:

Results from 26 patients in an early access programme in pancreatic cancer revealed stable disease in six patients and regression of metastasis in two patients. Earlier results from 24 evaluable patients indicated survival of more than one year, for four of 24 patients with locally advanced or metastatic disease, and treated with rintatolimod. An additional four patients on combination therapy of rintatolimod and palliative chemotherapy survived for more than one year. However, there were 15 casualties in this group of patients within seven months of rintatolimod therapy. Of the five resected patients, two died on rintatolimod, 24 and 27 months respectively, following resection. The remaining three patients are still alive with a mean survival of 26 months after resection and adjuvant rintatolimod treatment. Results from the 26 patients treated under the programme [121] [111] .

Chronic fatigue syndrome (CFS)/Myalgic encephalomyelitis (ME)

Relatively more XMRV antibody-positive patients had a >25% increase in exercise tolerance testing (ETT) after treatment with rintatolimod, compared with placebo, than the XMRV antibody-negative patients, in a phase III trial of the drug in patients with CFS. In this placebo-controlled, double-blind trial, patients (n = 208) were randomised to receive rintatolimod 200-400mg or an equivalent volumen of placebo twice-weekly, via IV-infusion, for 40 weeks. Baseline serum samples from all patients were analysed for antibodies directed against XMRV. Results also suggest that the XMRV antibody-negative patients with CFS had a lower activity level and a reduced ability to complete normal daily activities at baseline [150] .

Rintatolimod increased oxygen consumption in parallel with improvements in treadmill performance in patients with CFS in a phase III study. Maximal oxygen consumption (VO2 max) increased 10-fold with rintatolimod compared with placebo, and there was a significant correlation between improvement in exercise duration and increase in VO2 max [154] .

Rintatolimod significantly improved patients physical performance as assessed by Treadmill Exercise Tolerance Testing (ETT) in a 40-week placebo-controlled phase III study in 234 patients with severely debilitating CFS. Rintatolimod 400mg twice-weekly was superior to placebo for improved ETT (19.4 vs 5.1%) for the patient population that completed 40 weeks' treatment and also for the intent-to-treat population (17.7 vs 4.3%) that completed <40 weeks treatment. In intent to treat analysis, rintatolimod 40mg for 40 weeks improved intra-patient placebo adjusted ET 21.3% from baseline. Correction in patients with reduced dosing resulted in increased placebo improvement to 28% (p = 0.022). The proportion of patients with exercise improvements of at least 25% and 50% were 1.7 and 1.9-fold greater, respectively, with rintatolimod versus placebo (p < 0.05). An improvement of exercise tolerance of greater or equal to 25% from baseline (16% placebo-adjusted improvement; p=0.013) was demonstrated in a significantly greater percentage of rintatolimod patients (39%) vs. placebo patients (23%). In addition, rintatolimod also reduced dependence on CFS medications compared with placebo (p < 0.05) [52] [69] [41] [60] [156] . A retrospective analysis of data from the trial showed that, for a subset of patients with baseline exercise tolerance (ET) of >9mins, 33% of patients on rintatolimod improved ET duration by ≥25% versus 12% of patients on placebo (p=0.004). Additionally, 23% of patients on rintatolimod improved by ≥50% in ET duration, compared with 4.5% of patients in placebo (p=0.003). Similar clinically significant improvements for the cohort of study subjects with baseline ET >9mins, as a function of the same ET parameters, were also noted for the Karnofsky Performance Score (KPS) and Vitality (SF-36 subscale) quality of life secondary endpoint. Rintatolimod reduced deterioration in ET compared with placebo in patients who failed to physically improve [61] . In another retrospective analysis of the AMP 516, segmented primarily by disease duration, demonstrated that at least 25% improvement in placebo-adjusted exercise tolerance was observed in 51% of rintatolimod treated patients in a cohort with a disease duration of two to eight years vs. 18% of placebo patients (33% placebo-adjusted improvement, p=0.003). Also, patient subset with less than two years or greater than eight years of disease duration failed to show a clinically-significant response [52] [59] .

Rintatolimod significantly improved cognitive and physical performance in a Belgium clinical study. Physical performance for activities of daily living, measured using the Karnofsky Performance Score, showed an improvement of 43% (from 53 at baseline to 76). Exercise performance was measured by bicycle testing; oxygen uptake improved from 1.16 L/min at baseline to 1.48 L/min after treatment with rintatolimod. The cognitive improvement seen in patients receiving rintatolimod was measured using the cognitive subscale of the SCL 90-R or neuropsychological function tests. Significantly greater improvements were seen in patients receiving rintatolimod compared with placebo. Of patients treated with rintatolimod, about 80% experienced an apparent 'complete clinical recovery' after 6 months' treatment; spontaneous improvement in untreated patients with CFS is about 2%. Patients with CFS were randomised to receive rintatolimod (200-400mg twice-weekly) or placebo for 24 weeks [174] [170] [175] .

The effects of rintatolimod on immune function were compared with those of placebo in a randomised, double-blind, crossover study (ACTG 056) in volunteers. Overall, there were no significant differences between the two treatments in terms of production of interferon and biological markers of interferon, T lymphocytic function, lymphocyte proliferative responses and natural killer cell activity. Symptom scores were greater in rintatolimod recipients than in placebo recipients but symptoms were mild in nature and the between-group difference was only significant on the day after dosing [167] .

In 15 patients with chronic fatigue syndrome, rintatolimod normalised the upregulated 2-5A synthetase/RNase L system and cleared human herpesvirus 6 antigen-positive cells from peripheral blood mononuclear cell cultures [171] .

Pharmacoeconomics

The potential pharmacoeconomic impact of rintatolimod on the treatment of CFS/ME has been investigated. Pharmacoeconomic data, including medication use, and cost and charges of hospitalisation and emergency room visits, were retrospectively collected. Mean annual health-care charges for patients receiving rintatolimod were calculated to be $US2 097, compared with $US8 606 for placebo recipients [162] .

Hepatitis B

Results of a phase I/II study of rintatolimod 400-600mg two to three times/week in eight patients with chronic hepatitis B indicated that the drug may have an antiviral effect. Four patients lost HBV DNA and three patients became HBeAg seronegative during 24 weeks' treatment. None of the patients have relapsed [176] .

HIV infections

The effects of rintatolimod alone or in combination with zidovudine, were investigated in a placebo-controlled study in HIV seropositive patients. Continuous therapy with rintatolimod for at least 2 years prevented the progression of HIV infection in p24 seronegative patients. When administered in combination with zidovudine, CD4+ cell counts were increased compared to those observed in patients receiving each agent alone. Rintatolimod also appeared to restore immune function in HIV-infected patients, as shown by the return or increase in delayed-type hypersensitivity [168] .

Results from a phase I study (ACTG 038) were unable to confirm previous beneficial effects of rintatolimod in HIV infection. A total of 39 HIV-infected patients with asymptomatic disease or early ARC received one to six doses of rintatolimod for 9 or 25 weeks. Rintatolimod had no significant effects on p24 antigenaemia, HIV viraemia or the number of HIV-infected cells. However, the rate of CD4+ cell depletion was reduced; this effect was dose-dependent [177] .

In a study conducted in 36 zidovudine-treated patients, rintatolimod therapy was most effective when initiated earlier in the course of HIV disease. Over a 48-week study period, patients treated with rintatolimod (400 or 700mg twice-weekly) had a mean decrease in CD4+ count of 52 cells/µl compared with 89 cells/µl in placebo recipients. Rintatolimod-treated patients with baseline CD4+ counts ≥300 cells/µl showed a mean increase in CD4+ count of 26 cells/µl which peaked at week 24. Placebo recipients had a consistent decrease from baseline. A change to rintatolimod therapy after 48 weeks of placebo treatment reversed the CD4+ decline in seven patients. Rintatolimod recipients were less likely to progress to AIDS than placebo recipients [164] .

Significantly fewer patients relapsed within the first 30 days of structured treatment interruption (STI) when treated with rintatolimod. In this phase IIb study, the primary endpoint was the mean total time of HAART-free intervals before rebound of plasma HIV-1 RNA. There were two groups of patients: the "Harvard cohort" of eight newly/acutely HIV-infected patients and the "study group", designed to be similar to the referenced Harvard cohort. The similarities being a) HAART was given for ≥9 months; b) CD4 ≥400 cells/mL and c) HIV RNA levels below 50 copies/mL. The main difference between the groups was that the Harvard cohort were studied within weeks or months of initial infection whereas the study group had been infected with HIV for several years. Interim data analysis were performed with a control (non-rintatolimod treated) group obtained from scientific literature "meta-analysis" and a second with a concurrent control (non-rintatolimod treated) group obtained from identical, participating medical institutions. In the meta-analysis, none of the patients relapsed while on rintatolimod within the first 30 days compared with 86% of a control group of patients (p = 0.012). In the second analysis, the median duration of STI in the rintatolimod group was >18 weeks, compared with 7 weeks in the concurrent control, non-rintatolimod group [160] .

In a phase IIb study (AMP 720) of patients with HIV undergoing up to three structured treatment interruptions (STI) of HAART, rintatolimod (400mg IV twice-weekly) therapy resulted in significant prolongation of controlled HIV viraemia, compared with untreated controls. Patients taken off HAART but given rintatolimod (n = 7) continued to show virus levels <5000 copies/mL for a mean of 25 weeks and counting. In the control group, patients (n = 9) taken off HAART and not given rintatolimod, developed an HIV rebound within a mean of 13 weeks. In addition, the rintatolimod group demonstrated an increase in CD8+ cells suggesting induction of immunogenicity [157] [158] [159] .

Future Events

Expected Date Event Type Description Updated
31 Dec 2020 Trial Update Hemispherx Biopharma plans a clinical trial for Breast cancer (Late-stage disease, Metastatic disease) by 2020 [110] 19 Aug 2019
31 Dec 2020 Trial Update Hemispherx Biopharma plans a clinical trial for Pancreatic cancer (Combination therapy) in Netherlands in 2019 [110] 03 Jan 2020
31 Dec 2019 Trial Update Hemispherx Biopharma plans additional clinical trials for Cancer in 2019 [148] 19 Dec 2018
31 Dec 2019 Trial Update Hemispherx Biopharma and Roswell Park Cancer Institute plan a phase II trial for Colorectal cancer (Combination therapy, Late-stage disease; Metastatic disease, Second-line therapy or greater) in USA in 2019 [121] 19 Aug 2019
31 Dec 2019 Trial Update Hemispherx Biopharma and Roswell Park Cancer Institute plan a phase II trial for Bladder cancer, Melanoma and Renal cell carcinoma (Combination therapy, Late-stage disease, Second-line therapy or greater) in USA in 2019 [121] 15 Mar 2019
31 Dec 2019 Trial Update Hemispherx Biopharma and University of Nebraska Medical Center plan a clinical trial for Non-small cell lung cancer (First-line therapy, Combination therapy) in USA in 2019 [121] 15 Mar 2019
31 Dec 2019 Trial Update Hemispherx Biopharma and University of Nebraska Medical Center plan a phase II trial in Pancreatic cancer (Late-stage disease, Combination therapy) in USA in 2019 [121] 15 Mar 2019
31 Dec 2019 Trial Update Hemispherx Biopharma and Roswell Park Cancer Institute plan a clinical trial for Breast cancer (Inoperable/unresectable, Combination therapy, Metastatic disease, Second line therapy or greater) in USA in 2019 [121] 09 Apr 2019
31 Dec 2019 Trial Update Hemispherx Biopharma and Buffett Cancer Center plan a clinical trial for Non-small cell lung cancer and Pancreatic cancer in 2019 (9257508) 15 Mar 2019
07 Dec 2019 Trial Update Hemispherx Biopharma plans a phase I trial for Breast cancer (Combination therapy, Early-stage disease) in USA by 2020 [110] 15 Oct 2019
30 Oct 2019 Trial Update Roswell Park Cancer Institute in collaboration with National Cancer Institute plans a phase IIa trial for Colorectal cancer (Combination therapy, Metastatic disease) in USA in October 2019 (NCT04119830) (700308674) 16 Oct 2019
30 Sep 2019 Trial Update Roswell Park Cancer Institute and National Cancer Institute plan a phase Ib/II trial in Breast cancer (Neoadjuvant therapy, First-line therapy, Combination therapy) in USA (IV), in September 2019 (700311275), (NCT04081389) 16 Sep 2019
30 Jun 2019 Trial Update Hemispherx Biopharma, Roswell Park Cancer Institute, and National Cancer Institute plan a phase II trial in Prostate cancer (Neoadjuvant therapy) in USA in June 2019 (NCT03899987) (700306120) [147] 09 Dec 2019
11 Feb 2019 Trial Update Hemispherx Biopharma plans a phase I/II trial for Ovarian Cancer (Combination therapy, Recurrent, Second-line therapy or greater) in USA (700302125), (NCT03734692) [148] 13 Feb 2019
31 Dec 2018 Regulatory Status Hemispherx Biopharma intends to initiate a Special Access Program (SAP) for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in Canada in May 2018 [8] 29 Oct 2018
31 Dec 2018 Regulatory Status Hemispherx Biopharma announces intention to submit applications for Early Access Programs (EAP) in Europe and additional countries in 2018 [149] 05 Mar 2018
31 May 2018 Regulatory Status Hemispherx Biopharma plans to supply Ampligen® for pancreatic cancer patients in Canada under a Special Access Program (SAP) in May 2018 [120] 20 Jun 2018
01 Feb 2018 Trial Update Roswell Park Cancer Institute and National Cancer Institute plan a early phase IIa trial for Colorectal cancer (Metastatic disease, Combination therapy) in USA in February 2018 (NCT03403634) (700292415) 25 Jul 2018

Development History

Event Date Update Type Comment
26 Mar 2020 Trial Update AIM ImmunoTech plans clinical trials for COVID-2019 infections (Early-stage disease) in Argentina, Asia, Europe and USA (IV) [95] Updated 31 Mar 2020
26 Mar 2020 Trial Update AIM ImmunoTech plans clinical trials for COVID-2019 infections (Prevention) in Argentina, Asia, Europe and USA (Intranasal) [95] Updated 31 Mar 2020
26 Mar 2020 Trial Update AIM ImmunoTech plans clinical trials for COVID-2019 infections (Prevention) in Argentina, Asia, Europe and USA (PO) [95] Updated 31 Mar 2020
11 Feb 2020 Patent Information AIM ImmunoTech files three provisional patent applications for rintatolimod [98] Updated 24 Feb 2020
11 Feb 2020 Phase Change Early research in COVID-2019-infections (Prevention) in USA (Intranasal) [98] Updated 24 Feb 2020
11 Feb 2020 Phase Change - Preclinical Preclinical trials in COVID-2019-infections in USA (IV) before February 2020 [98] Updated 24 Feb 2020
11 Feb 2020 Scientific Update Preclinical pharmacodynamics data in COVID-2019-infections released by AIM ImmunoTech [98] Updated 24 Feb 2020
29 Nov 2019 Phase Change - II Phase-II clinical trials in Prostate cancer (Combination therapy, Late-stage disease, Neoadjuvant therapy) in USA (IV) (NCT03899987) Updated 09 Dec 2019
14 Oct 2019 Trial Update Roswell Park Cancer Institute in collaboration with National Cancer Institute plans a phase IIa trial for Colorectal cancer (Combination therapy, Metastatic disease) in USA in October 2019 (NCT04119830) Updated 16 Oct 2019
24 Sep 2019 Regulatory Status Rintatolimod receives clearance from US FDA for exportation to Argentina for the treatment of Chronic fatigue syndrome [30] Updated 15 Oct 2019
09 Sep 2019 Trial Update Roswell Park Cancer Institute and National Cancer Institute plan a phase Ib/II trial in Breast cancer (Neoadjuvant therapy, First-line therapy, Combination therapy) in USA (IV), in September 2019 , (NCT04081389) Updated 16 Sep 2019
23 Aug 2019 Company Involvement Hemispherx Biopharma is now called AIM ImmunoTech Updated 05 Sep 2019
15 Aug 2019 Trial Update Hemispherx Biopharma plans a clinical trial for Pancreatic cancer (Combination therapy) in Netherlands in 2019 [110] Updated 03 Jan 2020
15 Aug 2019 Trial Update Hemispherx Biopharma plans a phase I trial for Breast cancer (Combination therapy, Early-stage disease) in USA by 2020 [110] Updated 15 Oct 2019
15 Aug 2019 Regulatory Status The US FDA approves IND application for a phase II trial for rintatolimod in Prostate cancer (Combination therapy, Neoadjuvant therapy) [110] Updated 19 Aug 2019
15 Aug 2019 Trial Update Hemispherx Biopharma plans a phase II trial for Ovarian Cancer (Combination therapy, Recurrent, Second-line therapy or greater) (Intraperitoneal) [110] Updated 19 Aug 2019
15 Aug 2019 Trial Update Hemispherx Biopharma plans a clinical trial for Breast cancer (Late-stage disease, Metastatic disease) by 2020 [110] Updated 19 Aug 2019
17 Jun 2019 Trial Update Hemispherx Biopharma, Roswell Park Cancer Institute, and National Cancer Institute plan a phase II trial in Prostate cancer (Neoadjuvant therapy) in USA in June 2019 (NCT03899987) [147] Updated 09 Dec 2019
13 Mar 2019 Trial Update Hemispherx Biopharma and Roswell Park Cancer Institute plan a phase II trial for Colorectal cancer (Combination therapy, Late-stage disease; Metastatic disease, Second-line therapy or greater) in USA in 2019 [121] Updated 19 Aug 2019
13 Mar 2019 Trial Update Hemispherx Biopharma and Roswell Park Cancer Institute plan a clinical trial for Breast cancer (Inoperable/unresectable, Combination therapy, Metastatic disease, Second line therapy or greater) in USA in 2019 [121] Updated 09 Apr 2019
13 Mar 2019 Phase Change - Preclinical Preclinical trials in Prostate cancer in USA before March 2019 (IV) [121] Updated 15 Mar 2019
13 Mar 2019 Regulatory Status Hemispherx Biopharma files an IND application with the US FDA for a planned phase II trial in Prostate cancer (Neoadjuvant therapy) [121] Updated 15 Mar 2019
13 Mar 2019 Trial Update Hemispherx Biopharma and Roswell Park Cancer Institute plan a phase II trial for Bladder cancer, Melanoma and Renal cell carcinoma (Combination therapy, Late-stage disease, Second-line therapy or greater) in USA in 2019 [121] Updated 15 Mar 2019
13 Mar 2019 Trial Update Hemispherx Biopharma and University of Nebraska Medical Center plan a phase II trial in Pancreatic cancer (Late-stage disease, Combination therapy) in USA in 2019 [121] Updated 15 Mar 2019
13 Mar 2019 Trial Update Hemispherx Biopharma and University of Nebraska Medical Center plan a clinical trial for Non-small cell lung cancer (First-line therapy, Combination therapy) in USA in 2019 [121] Updated 15 Mar 2019
28 Feb 2019 Scientific Update Efficacy data from an Early Access Programme in Pancreatic cancer in Netherlands released by Hemispherx Biopharma [111] [121] Updated 19 Mar 2019
28 Feb 2019 Scientific Update Pharmacodynamics data from a preclinical trial in Pancreatic cancer released by Hemispherx Biopharma [111] Updated 07 Mar 2019
11 Feb 2019 Trial Update University of Pittsburgh in collaboration with Merck & Co and Hemispherx Biopharma initiates enrolment in a phase-I/II trial for Ovarian cancer (Combination therapy, Neoadjuvant therapy, Second-line therapy or greater) in USA [132] (NCT03734692) Updated 13 Feb 2019
09 Jan 2019 Phase Change - I Phase-I clinical trials in Breast cancer (Combination therapy, Metastatic disease, Second-line therapy or greater, Inoperable/Unresectable) in USA (IV) (NCT03599453) [114] Updated 09 Apr 2019
08 Jan 2019 Regulatory Status Institutional Review Board approves the initiation of a clinical trial of rintatolimod in Breast cancer [112] Updated 15 Jan 2019
31 Dec 2018 Trial Update Hemispherx Biopharma and Buffett Cancer Center plan a clinical trial for Non-small cell lung cancer and Pancreatic cancer in 2019 Updated 15 Mar 2019
12 Dec 2018 Trial Update Hemispherx Biopharma plans a phase I/II trial for Ovarian Cancer (Combination therapy, Recurrent, Second-line therapy or greater) in USA , (NCT03734692) [148] Updated 13 Feb 2019
12 Dec 2018 Trial Update Hemispherx Biopharma plans additional clinical trials for Cancer in 2019 [148] Updated 19 Dec 2018
13 Aug 2018 Trial Update Hemispherx Biopharma plans a phase I and phase II trials for Cancer in combination with checkpoint inhibitors [65] Updated 20 Aug 2018
09 Jul 2018 Scientific Update Adverse events and immunogenicity data from a phase I/II trial in Influenza virus infections released by Hemispherx Biopharma [87] Updated 11 Jul 2018
24 Jun 2018 Biomarker Update Biomarkers information updated Updated 31 Aug 2018
15 Jun 2018 Trial Update Hemispherx Biopharma plans a phase I/II trial for Solid tumours (Combination therapy) in USA [48] Updated 20 Jun 2018
02 May 2018 Trial Update Hemispherx Biopharma plans phase I/II trial for Cancer (in combination with checkpoint inhibitors) Updated 07 May 2018
17 Apr 2018 Regulatory Status US FDA approves a Compassionate Care Programme for Myalgic encephalomyelitis/Chronic fatigue syndrome before April 2018 [49] Updated 20 Apr 2018
17 Apr 2018 Trial Update Hemispherx Biopharma plans a Compassionate Care Programme for Myalgic encephalomyelitis/Chronic fatigue syndrome (ME/CFS) in USA [49] Updated 20 Apr 2018
04 Apr 2018 Regulatory Status Hemispherx Biopharma intends to initiate a Special Access Program (SAP) for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in Canada in May 2018 [8] Updated 29 Oct 2018
04 Apr 2018 Licensing Status Hemispherx amends its agreement with myTomorrows to expands rintatolimod Early Access Programme for Chronic fatigue syndrome to Canada [8] Updated 09 Apr 2018
27 Mar 2018 Phase Change - II Phase-II clinical trials in Colorectal cancer (Combination therapy, Metastatic disease, Second-line therapy or greater, Recurrent, Inoperable/Unresectable) in USA (IV) (NCT03403634) Updated 07 May 2018
27 Mar 2018 Other Chemical structure information added Updated 27 Mar 2018
14 Mar 2018 Licensing Status University of Nebraska Medical Center and Hemispherx Biopharma agree to test the combined efficacy of rintatolimod and peptide vaccine for Pancreatic cancer [10] Updated 20 Mar 2018
26 Feb 2018 Regulatory Status Hemispherx Biopharma plans to supply Ampligen® for pancreatic cancer patients in Canada under a Special Access Program (SAP) in May 2018 [120] Updated 20 Jun 2018
06 Feb 2018 Trial Update Hemispherx Biopharma terminates a phase I/II trial in Colorectal cancer (Neoadjuvant therapy, Metastatic disease, Recurrent) in USA (IV) (NCT01545141) Updated 06 Feb 2018
31 Jan 2018 Scientific Update Immunogenicity data from a phase I/II trial in Influenza virus infections released by Hemispherx Biopharma [88] Updated 05 Feb 2018
31 Jan 2018 Scientific Update Pharmacodynamics data from a preclinical trial in Influenza virus infections released by Hemispherx Biopharma [88] Updated 05 Feb 2018
23 Jan 2018 Regulatory Status Hemispherx Biopharma announces intention to launch rintatolimod for Chronic fatigue syndrome in Argentina Updated 29 Jan 2018
18 Jan 2018 Trial Update Roswell Park Cancer Institute and National Cancer Institute plan a early phase IIa trial for Colorectal cancer (Metastatic disease, Combination therapy) in USA in February 2018 (NCT03403634) Updated 25 Jul 2018
20 Dec 2017 Active Status Review Rintatolimod is still in preregistration phase for Chronic fatigue syndrome in USA [28] Updated 09 Apr 2018
13 Aug 2017 Phase Change - I Phase-I clinical trials in Pancreatic cancer (Late-stage disease) in Netherlands (IV) (AIM ImmunoTech pipeline, August 2019) Updated 03 Jan 2020
08 Aug 2017 Licensing Status Rintatolimod is available for licensing in Canada as of 08 Aug 2017. http://www.hemispherx.net/ [50] Updated 10 Aug 2017
04 Aug 2017 Regulatory Status Hemispherx Biopharma announces intention to submit applications for Early Access Programs (EAP) in Europe and additional countries in 2018 [149] Updated 05 Mar 2018
11 Jul 2017 Trial Update Hemispherx Biopharma plans clinical trials for Cancer [105] Updated 27 Jul 2017
23 Feb 2017 Trial Update Hemispherx Biopharma terminates a phase I/II trial in Influenza virus infection (Combination therapy, Prevention, In volunteers) in USA as CDC indicated nasal spray flu vaccine should not be used during 2016-2017 (NCT01591473) Updated 02 Nov 2017
11 Jan 2017 Phase Change - Clinical Clinical trials in Pancreatic cancer in Netherlands (IV) [6] Updated 10 Jun 2017
11 Jan 2017 Regulatory Status European Early access programme for rintatolimod has been extended to include pancreatic cancer patients [6] Updated 16 Jan 2017
31 Dec 2016 Patent Information Hemispherx Biopharma has a patent protection for composition of matter of rintatolimod in USA [55] before December 2016 Updated 16 Jun 2017
31 Oct 2016 Scientific Update Updated retrospective analysis of efficacy data from a phase III trial in Chronic fatigue syndrome released by Hemispherx Biopharma [52] Updated 07 Nov 2016
31 Oct 2016 Trial Update Hemispherx Biopharma plans a confirmatory phase III trial for Chronic fatigue syndrome in USA [52] Updated 07 Nov 2016
23 Aug 2016 Phase Change - Registered Registered for Chronic fatigue syndrome in Argentina (IV) - First global approval [31] Updated 25 Aug 2016
25 Jul 2016 Regulatory Status Rintatolimod is available on an Early Access Programme for the treatment of Chronic fatigue syndrome in Europe [5] Updated 28 Jul 2016
06 Jun 2016 Licensing Status Hemispherx irrevocabaly obtains all intellectual property related to Ampligen® under a comprehensive omnibus assignment [11] Updated 09 Jun 2016
31 May 2016 Active Status Review Rintatolimod is still in preregistration for Chronic fatigue syndrome in Argentina Updated 06 Jun 2016
31 May 2016 Licensing Status Hemispherx renews the sales, marketing, distribution and supply agreement with GP Pharm for rintatolimod in Argentina for the treatment of chronic fatigue syndrome [16] Updated 06 Jun 2016
16 Mar 2016 Trial Update Hemispherx complete a phase II trial in Chronic fatigue syndrome before 2016 [63] Updated 16 Mar 2016
09 Feb 2016 Trial Update Hemispherx plans a clinical trial for Zika virus infections [103] Updated 11 Feb 2016
03 Feb 2016 Phase Change - Preclinical Preclinical trials in West Nile virus infections in USA (unspecified route) Updated 17 Feb 2016
03 Feb 2016 Phase Change - Preclinical Preclinical trials in Zika virus infection in USA (Intranasal) Updated 11 Feb 2016
21 Sep 2015 Scientific Update Retrospective analysis of efficacy data from a phase III trial in Chronic fatigue syndrome released by Hemispherx Biopharma [61] Updated 19 Oct 2015
21 Sep 2015 Patent Information Hemispherx Biopharma has patent protection for composition of matter of rintatolimod in the European Union [143] Updated 11 Oct 2015
17 Sep 2015 Regulatory Status Rintatolimod is available on a Named Patient Access Programme, under the AMP-511 study, for the treatment of Chronic fatigue syndrome in USA (IV) [54] Updated 16 Jun 2017
15 Sep 2015 Scientific Update Interim pharmacodynamics data from a Preclinical study in Chronic fatigue syndrome released by hemispherx Biopharma [68] Updated 07 Oct 2015
10 Aug 2015 Licensing Status Rintatolimod licensed to myTomorrows for implementation of Early Access Programme for the treatment of Chronic fatigue syndrome in Europe and Turkey [4] Updated 19 Aug 2015
10 Aug 2015 Regulatory Status Celsion plans for regulatory approval worldwide, including Europe, Latin America, Australia, New Zealand and USA [4] Updated 19 Aug 2015
01 Jul 2015 Phase Change - I/II Phase-I/II clinical trials in Ovarian cancer (Combination therapy, Neoadjuvant therapy, Second-line therapy or greater, Recurrent) in USA (Intraperitoneal) (NCT02432378) Updated 13 Jan 2016
25 Jun 2015 Patent Information Hemispherx Biopharma receives patent allowance for composition of matter of rintatolimod in Europe [144] Updated 27 Jun 2015
11 May 2015 Regulatory Status Rintatolimod receives Orphan Drug status for Ebola virus infections in European Union [72] Updated 13 May 2015
24 Mar 2015 Phase Change - Preclinical Preclinical trials in Ebola virus infections in Italy (Intranasal) [73] Updated 30 Mar 2015
24 Mar 2015 Regulatory Status The Committee for Orphan Medicinal Products (COMP) recommends orphan drug designation for rintatolimod in European Union for Ebola virus infections [73] Updated 30 Mar 2015
23 Mar 2015 Phase Change - Discontinued(Preclinical) Discontinued - Preclinical for Western equine encephalitis virus infections in USA (IV) Updated 13 Apr 2015
09 Mar 2015 Licensing Status Rintatolimod licensed to Emerge Health in Australia and New Zealand [12] Updated 14 Mar 2015
12 Feb 2015 Scientific Update Pharmacodynamics data from a preclinical study in Ebola virus infections released by Hemispherx Biopharma [75] Updated 12 Feb 2015
09 Feb 2015 Scientific Update Updated pharmacodynamics data from a preclinical study in Ebola virus infections released by Hemispherx Biopharma [74] Updated 12 Feb 2015
02 Feb 2015 Phase Change - Preclinical Preclinical trials in Ebola virus infections in USA (Intranasal) prior to February 2015 Updated 04 Feb 2015
12 Jan 2015 Scientific Update Efficacy data from a phase III trial in Chronic fatigue syndrome released by Hemispherx [69] Updated 19 Jan 2015
31 Dec 2014 Active Status Review Rintatolimod is still in preregistration for Chronic fatigue syndrome in USA and Argentina Updated 16 Apr 2015
17 Nov 2014 Scientific Update Pharmacodynamics data from an in vitro study in Ebola virus infection released by Hemispherx [80] Updated 20 Nov 2014
29 Sep 2014 Company Involvement Hemispherx enters into five research collaborations to develop therapeutic cocktails against Ebola virus infections [14] Updated 01 Oct 2014
10 Sep 2014 Phase Change Early research in Ebola virus infections in USA (Intranasal) Updated 03 Nov 2014
10 Sep 2014 Company Involvement Hemispherx establishes a research agreement with Swiss Department of Defense, Civil Protection and Sports for the development of Rintatolimod in Ebola virus infections [13] Updated 15 Sep 2014
14 Jul 2014 Licensing Status Hemispherx Biopharma and Bioclones agree to co-develop rinatatolimod in South Africa [15] Updated 18 Jul 2014
01 Jul 2014 Phase Change - I/II Phase-I/II clinical trials in Peritoneal cancer (Adjuvant therapy) in USA (IV) Updated 25 Nov 2014
28 May 2014 Trial Update University of Pittsburgh plans a phase I/II trial for Peritoneal cancer (adjuvant therapy) in USA (NCT02151448) Updated 29 Jul 2014
10 Mar 2014 Regulatory Status Hemispherx Biopharma announces intention to submit regulatory filings in Chile, Peru & Uruguay for Chronic fatigue syndrome [51] Updated 11 Mar 2014
01 Dec 2013 Regulatory Status Rintatolimod receives Orphan Drug status for HIV infections in USA Updated 02 Jul 2014
01 Dec 2013 Regulatory Status Rintatolimod receives Orphan Drug status for Malignant melanoma in USA Updated 02 Jul 2014
01 Dec 2013 Regulatory Status Rintatolimod receives Orphan Drug status for Renal cell carcinoma in USA Updated 02 Jul 2014
12 Sep 2013 Phase Change Early research in Coronavirus infections in USA (IV) Updated 18 Sep 2013
12 Sep 2013 Phase Change Early research in Influenza-A virus infections in USA (IV) Updated 18 Sep 2013
12 Sep 2013 Phase Change Early research in Alphavirus Infections in USA (IV) Updated 18 Sep 2013
04 Feb 2013 Regulatory Status The US FDA issues a Complete Response Letter declining to approve an NDA for rintatolimod for the treatment of Chronic fatigue syndrome [33] Updated 07 Feb 2013
01 Oct 2012 Phase Change - I/II Phase-I/II clinical trials in Colorectal cancer (Neoadjuvant therapy, Metastatic disease, Recurrent) in USA (IV) (NCT01545141) Updated 25 Nov 2014
14 Aug 2012 Regulatory Status The US FDA sets PDUFA date of February 2013 for NDA review for Chronic fatigue syndrome Updated 15 Aug 2012
01 Aug 2012 Regulatory Status Hemispherix Biopharma files its complete response to the US FDA's Complete Response Letter for rintatolimod in Chronic fatigue syndrome [37] Updated 02 Aug 2012
18 Jul 2012 Phase Change - Preregistration Preregistration for Chronic fatigue syndrome in Argentina (IV) Updated 19 Jul 2012
01 Apr 2012 Phase Change - I/II Phase-I/II clinical trials in Influenza virus infections (Combination therapy, In volunteers, Prevention) in USA (Intranasal) (NCT01591473) Updated 16 Nov 2017
19 Mar 2012 Scientific Update Efficacy and adverse event data from a phase III trial in Chronic fatigue syndrome released by Hemispherx Biopharma [41] Updated 20 Mar 2012
01 Jan 2012 Phase Change - No development reported(Preclinical) No development reported - Preclinical for Western equine encephalitis virus infections in USA (IV) Updated 13 Apr 2015
31 Aug 2011 Phase Change - I/II Phase-I/II clinical trials in Cancer (adjuvant in breast cancer vaccination trial) in USA (Injection) Updated 15 Dec 2011
01 Jul 2011 Phase Change - I/II Phase-I/II clinical trials in Breast cancer (Adjuvant therapy) in USA (Intradermal) Updated 25 Nov 2014
04 Apr 2011 Phase Change - Preclinical Preclinical trials in Cancer in USA (Injection) Updated 08 Apr 2011
04 Apr 2011 Scientific Update Pharmacodynamics data from a preclinical study in Cancer released by Hemispherx Biopharma [130] Updated 08 Apr 2011
01 Mar 2011 Phase Change - I/II Phase-I/II clinical trials in Ovarian cancer (Adjuvant therapy) in USA (IV) Updated 25 Nov 2014
04 Feb 2011 Phase Change - Suspended(II) Suspended - Phase-II for HIV infections in USA (IV) Updated 04 Feb 2011
14 Dec 2010 Regulatory Status The FDA grants Hemispherx a 12 month extension to modify its rintatolimod NDA Updated 20 Dec 2010
09 Dec 2010 Licensing Status Rintatolimod licensed to GP Pharm in Mexico [17] Updated 17 Dec 2010
29 Nov 2010 Regulatory Status Hemispherx files a request with the FDA to maintain an active NDA for rintatolimod to treat Chronic fatigue syndrome [40] Updated 03 Dec 2010
10 Nov 2010 Company Involvement Hemispherx receives grant through the US Qualifying Therapeutic Discovery Project programme for rintatolimod development in Chronic fatigue syndrome [140] Updated 15 Nov 2010
30 Sep 2010 Licensing Status Rintatolimod is available for licensing as of 30 Sep 2010. http://www.hemispherx.net Updated 28 Jan 2011
08 Sep 2010 Scientific Update Topline efficacy data from a phase III trial in chronic fatigue syndrome released by Hemispherx [150] Updated 10 Sep 2010
08 Jul 2010 Active Status Review Rintatolimod is still in preregistration for Chronic fatigue syndrome in USA Updated 08 Jul 2010
17 Jun 2010 Licensing Status Hemispherx enters into a sales, marketing distribution and supply agreement with GP Pharm Latinoamerica for rintatolimod in the treatment of chronic fatigue syndrome in Argentina [18] Updated 17 Jun 2010
08 Apr 2010 Trial Update Hemispherx Biopharma completes phase II trials in HIV infections Updated 15 Apr 2010
08 Feb 2010 Phase Change - Discontinued(Preclinical) Discontinued - Preclinical for Smallpox in USA (IV) Updated 08 Feb 2010
01 Dec 2009 Regulatory Status Hemispherx Biopharma receives complete response letter from the US FDA for rintatolimod in Chronic fatigue syndrome [45] Updated 07 Dec 2009
22 Oct 2009 Scientific Update Pharmacodynamics data from a preclinical study in macaque monkeys in Influenza virus infections released by Hemispherx Biopharma [151] Updated 28 Oct 2009
26 May 2009 Regulatory Status The US FDA advises Hemispherx Biopharma of a possible brief delay in its action report for the NDA filing of rintatolimod for Chronic fatigue syndrome Updated 11 Jun 2009
18 Feb 2009 Regulatory Status The US FDA extends the PDUFA review date for the NDA filing of rintatolimod for Chronic fatigue syndrome Updated 03 Mar 2009
01 Jan 2009 Phase Change - Preclinical Preclinical trials in Western equine encephalitis virus infections in USA (IV) Updated 13 Apr 2015
18 Nov 2008 Company Involvement Hemispherx Biopharma enters into a research contract agreement with Lovelace Respiratory Research Institute to conduct additional preclinical studies with rintatolimod for Chronic fatigue syndrome in USA [19] Updated 03 Dec 2008
08 Jul 2008 Regulatory Status The US FDA accepts Hemispherx Biopharma's NDA filing of rintatolimod for review in Chronic fatigue syndrome Updated 22 Jul 2008
06 Mar 2008 Regulatory Status Hemispherx Biopharma reaches agreement with the US FDA on specific steps to achieve completion of NDA filing for rintatolimod in Chronic fatigue syndrome Updated 18 Mar 2008
09 Jan 2008 Regulatory Status Hemispherx Biopharma formally submits detailed responses to address questions raised by the US FDA concerning the NDA filing for rintatolimod in Chronic fatigue syndrome Updated 23 Jan 2008
10 Dec 2007 Licensing Status Hemispherx Biopharma intends to terminate its licence agreement with Esteve Updated 19 Dec 2007
05 Dec 2007 Regulatory Status Hemispherx Biopharma receives notification from the US FDA that the NDA filing for rintatolimod in Chronic fatigue syndrome is incomplete; FDA review is postponed Updated 19 Dec 2007
11 Oct 2007 Phase Change - Preregistration Preregistration for Chronic fatigue syndrome in USA (IV) Updated 24 Oct 2007
11 Jun 2007 Scientific Update Preclinical data added to the Viral Infections pharmacodynamics section [152] Updated 11 Jun 2007
16 Mar 2007 Phase Change - Suspended(II) Suspended - Phase-II for HIV infections treatment in USA (IV) Updated 27 Sep 2007
05 Sep 2006 Phase Change - No development reported(Clinical) No development reported - Clinical-Phase-Unknown for Chronic fatigue syndrome in Australia (IV) Updated 05 Sep 2006
05 Sep 2006 Phase Change - No development reported(Clinical) No development reported - Clinical-Phase-Unknown for Chronic fatigue syndrome in South Africa (IV) Updated 05 Sep 2006
05 Sep 2006 Phase Change - No development reported(II) No development reported - Phase-II for Chronic fatigue syndrome in Belgium (IV) Updated 05 Sep 2006
05 Sep 2006 Phase Change - No development reported(II) No development reported - Phase-II for Hepatitis B in USA (IV) Updated 05 Sep 2006
05 Sep 2006 Phase Change - No development reported(II) No development reported - Phase-II for HIV infections treatment in Spain (unspecified route) Updated 05 Sep 2006
05 Sep 2006 Phase Change - No development reported(II) No development reported - Phase-II for Malignant melanoma in USA (IV) Updated 05 Sep 2006
05 Sep 2006 Phase Change - No development reported(II) No development reported - Phase-II for Renal cell carcinoma in USA (IV) Updated 05 Sep 2006
05 Sep 2006 Phase Change - No development reported(III) No development reported - Phase-III for HIV infections treatment in European Union (unspecified route) Updated 05 Sep 2006
05 Sep 2006 Phase Change - No development reported(Preclinical) No development reported - Preclinical for Smallpox in USA (IV) Updated 05 Sep 2006
05 Sep 2006 Phase Change - No development reported(Preregistration) No development reported - Preregistration for Chronic fatigue syndrome in Canada (IV) Updated 05 Sep 2006
05 Sep 2006 Phase Change - No development reported(Preregistration) No development reported - Preregistration for Chronic fatigue syndrome in European Union (IV) Updated 05 Sep 2006
03 Mar 2006 Scientific Update Preclinical data from a media release have been added to the Viral infections immunogenicity section [153] Updated 03 Mar 2006
18 Oct 2005 Trial Update Phase III trials have been completed in Chronic fatigue syndrome Updated 18 Oct 2005
17 Aug 2005 Phase Change - II Phase-II clinical trials in HIV infections treatment in USA (IV) Updated 19 May 2009
13 Apr 2005 Scientific Update Data from a media release have been added to the Neurological Disorders therapeutic trials section [154] Updated 13 Apr 2005
06 Jan 2005 Phase Change - II Phase-II clinical trials in HIV infections treatment in patients with or without Hepatitis C virus co-infection in Spain (IV) Updated 06 Jan 2005
13 Oct 2004 Scientific Update Clinical data from a media release have been added to the adverse events section [155] Updated 13 Oct 2004
13 Jul 2004 Regulatory Status Esteve Laboratorios has received import authorisation from the Spanish Ministry of Health for Ampligen® to conduct clinical trials in HIV/HCV coinfected patients Updated 13 Jul 2004
01 Jun 2004 Scientific Update Data presented at the 17th International Conference on Antiviral Research (ICAR-2004) have been added to the Neurological disorders therapeutic trials section [156] Updated 01 Jun 2004
05 May 2004 Scientific Update Data from a media release have been added to the Neurological disorders therapeutic trials section [60] Updated 05 May 2004
04 Feb 2004 Trial Update Hemispherx has completed a phase III trial in CFS in USA Updated 04 Feb 2004
01 Feb 2004 Trial Update Hemispherx Biopharma completes a phase III trial in Chronic Fatigue Syndrome in USA (IV) (NCT00215800) Updated 10 Aug 2017
30 Oct 2003 Phase Change Mismatched double stranded RNA has received Orphan Drug Status for Chronic fatigue syndrome in USA Updated 04 Aug 2004
08 Sep 2003 Licensing Status Hemispherx Biopharma has entered into an agreement with Guandong Medicine Group Corporation to organise clinical trials, market, sell and distribute Interferon-α-n3 in China for HIV infections treatment Updated 08 Sep 2003
12 May 2003 Licensing Status Hemispherx Biopharma has entered into an agreement with the Center for Cell and Gene Therapy to implement Ampligen in relapsed EBV-positive Hodgkins lymphoma [25] . Updated 12 May 2003
06 May 2003 Scientific Update Data presented at the 16th International Conference on Antiviral Research (ICAR-2003) have been added to the Viral infections therapeutic trials section [157] Updated 06 May 2003
23 Dec 2002 Scientific Update Data from a media release have been added to the Viral Infections therapeutic trials section [158] Updated 23 Dec 2002
09 Dec 2002 Trial Update Hemispherx has completed enrolment in a phase III trial for Chronic fatigue syndrome in the US Updated 19 Feb 2003
27 Nov 2002 Scientific Update A study has been added to the adverse events and Viral Infections therapeutic trials sections [159] Updated 27 Nov 2002
31 Mar 2002 Licensing Status Hemispherx Biopharma's mismatched double stranded RNA licensed to Esteve in Spain, Portugal and Andorra for Chronic fatigue syndrome Updated 19 Dec 2007
25 Mar 2002 Scientific Update Preliminary data have been added to the Viral Infections therapeutic trials section [160] Updated 25 Mar 2002
31 Dec 2001 Scientific Update A study has been added to the Viral Infections antimicrobial acivity and drug interactions sections [161] Updated 31 Dec 2001
21 Dec 2001 Phase Change - Preclinical Preclinical development for Smallpox in USA (Unknown route) Updated 21 Dec 2001
21 Feb 2001 Phase Change - III Phase-III clinical trials for HIV infections treatment in European Union (IV) Updated 21 Feb 2001
02 Feb 2001 Trial Update Hemispherx has modified the protocol for its phase II HIV trial Updated 02 Feb 2001
12 Jan 2001 Regulatory Status US FDA approves a phase II trial protocol for patients with early-stage HIV Updated 12 Jan 2001
24 Oct 2000 Phase Change - Preregistration Preregistration for Chronic fatigue syndrome in Canada (IV) Updated 24 Oct 2000
20 Oct 2000 Regulatory Status Hemispherx Europe receives Orphan Drug Status for Mismatched double stranded RNA for the treatment of Chronic fatigue syndrome in the European Union Updated 20 Oct 2000
20 Oct 2000 Regulatory Status Hemispherx has expanded treatment protocols to the European Union Updated 20 Oct 2000
31 Aug 2000 Phase Change Investigation in Chronic fatigue syndrome in South Africa (IV) Updated 31 Aug 2000
30 Jun 2000 Regulatory Status The FDA has approved a phase II/III trial in patients with HIV infection resistant to currently available treatments Updated 30 Jun 2000
26 May 2000 Phase Change Investigation in Chronic fatigue syndrome in Australia (IV) Updated 26 May 2000
25 Feb 2000 Regulatory Status Hemispherx Biopharma has filed an application for expanded access for HIV patients and phase I/II trials with the US FDA Updated 25 Feb 2000
18 Feb 2000 Licensing Status Mismatched double stranded RNA licensed to Biovail Corporation in Canada Updated 18 Feb 2000
10 Dec 1999 Company Involvement An agreement with Schering-Plough has been reached in the US for production of Mismatched double stranded RNA Updated 10 Dec 1999
13 Sep 1999 Scientific Update Pharmacoeconomics data from a Clinical trial in Chronic fatigue syndrome released by Hemispherx Biopharma [162] Updated 21 Oct 1999
10 Dec 1998 Phase Change - Preregistration Preregistration for Chronic fatigue syndrome in European Union (IV) Updated 10 Dec 1998
13 Oct 1998 Scientific Update A study has been added to the Viral infections antimicrobial section [163] Updated 13 Oct 1998
23 Jan 1997 Phase Change - II Phase-II clinical trials for Chronic fatigue syndrome in Belgium (IV) Updated 23 Jan 1997
23 Jan 1997 Phase Change - II Phase-II clinical trials for HIV infections treatment in USA (IV) Updated 23 Jan 1997
05 Dec 1996 Phase Change Investigation in Chronic fatigue syndrome in Belgium (IV) Updated 05 Dec 1996
05 Dec 1996 Phase Change Investigation in Chronic fatigue syndrome in Canada (IV) Updated 05 Dec 1996
21 Oct 1996 Scientific Update A study has been added to the Nervous system disorders therapeutic trials section Updated 21 Oct 1996
17 Oct 1996 Scientific Update A study has been added to the therapeutic trials section [164] Updated 17 Oct 1996
26 Feb 1996 Phase Change - III Phase-III clinical trials for Chronic fatigue syndrome in USA (IV) Updated 26 Feb 1996
16 Feb 1996 Phase Change - II Phase-II clinical trials for Renal cell carcinoma in USA (IV) Updated 16 Feb 1996
28 Apr 1995 Phase Change - II Phase-II clinical trials for Malignant melanoma in USA (IV) Updated 28 Apr 1995
12 Apr 1995 Scientific Update A study has been added to the Cancer therapeutic trials section [165] Updated 12 Apr 1995

References

  1. Hemispherx Highlights Year-To-Date Progress, Outlines Key Objectives.

    Media Release
  2. Hemispherx Biopharma Signs Clinical Trial Agreement with Roswell Park Comprehensive Cancer Center to Study Ampligen in Combination with Checkpoint Inhibitors in a Phase IIa Study in Urothelial Carcinoma, Renal Cell Carcinoma and Melanoma.

    Media Release
  3. Hemispherx Biopharma, Inc. Changes Name to AIM ImmunoTech Inc. Reflecting Ampligen's(Rm) Immuno Modulation Progress in Ongoing Oncology Clinical Trials and ME/CFS.

    Media Release
  4. Hemispherx Enters Into an Agreement With myTomorrows for an Early Access Program for Rintatolimod in Europe.

    Media Release
  5. Hemispherx Announces First Shipment of Rintatolimod (Ampligen(R)) to Early Access Program in Europe.

    Media Release
  6. Hemispherx Biopharma Announces Extension of Rintatolimod European Early Access Program (EAP) to Pancreatic Cancer Patients.

    Media Release
  7. Hemispherx Biopharma Announces Financial Results for the Year Ended December 31, 2016.

    Media Release
  8. Hemispherx Expands Ampligen Early Access Programme to Canada to Treat ME/CFS Patients.

    Media Release
  9. Hemispherx Announces New Data Showing Ampligens Positive Role in Reprograming Tumor Microenvironment.

    Media Release
  10. Hemispherx Biopharma and UNMC Partner to Take on Pancreatic Cancer.

    Media Release
  11. Hemispherx Biopharma Obtains a Comprehensive Carter Omnibus Assignment of Intellectual Property.

    Media Release
  12. Hemispherx Enters a Collaboration with Emerge Health for the Commercialization of Ampligen for Chronic Fatigue Syndrome (CFS) in Australia and New Zealand.

    Media Release
  13. Hemispherx Biopharma and the Swiss Department of Defense, Civil Protection and Sports Expand Their Collaborative Research Agreement to Include the Study of Alferon(Rm) and Ampligen(Rm) Against the Ebola Virus.

    Media Release
  14. Hemispherx Biopharma Expands Research on Potential Ebola Treatments to Five Independent Experts/Institutional Collaborators.

    Media Release
  15. Hemispherx Biopharma and Bioclones, a Leading South African Biotechnology Company, Join Forces on Novel Therapeutic Cancer Vaccine.

    Media Release
  16. Hemispherx Biopharma Renews Sales, Marketing, Distribution and Supply Agreement with GP Pharm.

    Media Release
  17. Hemispherx Biopharma Extends GP Pharm License to Mexico for Ampligen to Treat for Chronic Fatigue Syndrome in Latin America.

    Media Release
  18. Hemispherx Biopharma Licenses Platform Technologies to GP Pharm.

    Media Release
  19. Hemispherx Enters Major Contract With Lovelace Respiratory Institute.

    Media Release
  20. Hemispherx Biopharma Intends to Terminate License to Esteve for the Marketing of Ampigen for Chronic Fatigue Syndrome in Certain Territories.

    Media Release
  21. Hemispherx Biopharma, Inc. 2nd Quarter 2010 Financial Results.

    Media Release
  22. Hemispherx Biopharma, Inc. Releases Financial Results for the Three Months Ended June 30, 2008.

    Media Release
  23. Hemispherx Biopharma Signs Option Agreement for Ampligen with Fujisawa Pharmaceutical Company.

    Media Release
  24. Hemispherx Biopharma Signs Agreement with Guangdong Medicine Group Corporation.

    Media Release
  25. Hemispherx Biopharma Enters Into Therapeutic Agreement for Ampligen(R) With The Center for Cell and Gene Therapy at Baylor College of Medicine.

    Media Release
  26. Hemispherx Biopharma Signs Letter of Intent with HollisterStier Laboratories LLC for the Production of Ampligen(R).

    Media Release
  27. Hemispherx Biopharma, Inc. Meets Ampligen Sales Milestone in the 1st Quarter of 2017.

    Media Release
  28. Hemispherx Successfully Completes Commercial Scale Demonstration Batch of Ampligen(R) at Contract Manufacturer.

    Media Release
  29. Hemispherx Biopharma Announces Completion of Ampligen(R) Manufacturing Technology Transfer Milestone.

    Media Release
  30. AIM ImmunoTech's Ampligen Receives Clearance from FDA for Exportation to Argentina for the Treatment of Severe Chronic Fatigue Syndrome.

    Media Release
  31. Hemispherx Biopharma Announces Major Breakthrough: Approval for Commercial Sale of Rintatolimod (U.S. Tradename: Ampligen(R)) to Treat Severe Cases of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in the Argentine Republic.

    Media Release
  32. Hemispherx Biopharma Announces Filing a New Drug Application in Argentina for Ampligen(R) to Treat Chronic Fatigue Syndrome.

    Media Release
  33. Hemispherx Biopharma Receives Complete Response Letter from FDA on Ampligen(Rm) New Drug Application for Chronic Fatigue Syndrome.

    Media Release
  34. International Stem Cell Corporation to Raise $6.3 Million Through a Private Placement to Fund Phase I Clinical Trial.

    Media Release
  35. Hemispherx Biopharma Announces FDA Advisory Committee Will Review Ampligen(R) for Chronic Fatigue Syndrome

    Media Release
  36. FDA Accepts Complete Response Submission Regarding the Ampligen(R) New Drug Application for Chronic Fatigue Syndrome.

    Media Release
  37. Hemispherx Biopharma Files Complete Response With the FDA Regarding Its Ampligen(R) New Drug Application for Chronic Fatigue Syndrome.

    Media Release
  38. FDA Grants Hemispherx Biopharma Extension in Its Pending New Drug Application (NDA) for the Treatment of Chronic Fatigue Syndrome (CFS).

    Media Release
  39. FDA Grants Hemispherx Biopharma Extension in Its Pending NDA for Treatment of Chronic Fatigue Syndrome (CFS).

    Media Release
  40. Hemispherx Biopharma Files With the FDA a Request to Maintain as Active Hemispherx NDA for Ampligen(R) to Treat Chronic Fatigue Syndrome (CFS).

    Media Release
  41. Hemispherx Publishes Data on the Bioactivity of Ampligen(R) in Chronic Fatigue Syndrome ("CFS").

    Media Release
  42. Hemispherx Biopharma and the FDA Reach Agreement on Filing Requirements for the Company's Complete Response in Support of Ampligen(R) New Drug Application for Chronic Fatigue Syndrome Treatment.

    Media Release
  43. FDA Advisory Committee Makes Recommendations on Ampligen (R) for Chronic Fatigue Syndrome.

    Media Release
  44. Hemispherx Biopharma's Ampligen NDA for Chronic Fatigue Syndrome Accepted for Review by the FDA.

    Media Release
  45. Hemispherx Biopharma Receives Complete Response Letter From FDA on Ampligen(R) New Drug Application for Chronic Fatigue Syndrome.

    Media Release
  46. Hemispherx Biopharma Addresses Ampligen(R) CFS Preclinical Issues.

    Media Release
  47. Hemispherx Biopharma Addresses Ampligen(R) Manufacturing Issues.

    Media Release
  48. Hemispherx Releases First 8,500 Vial Lot of Ampligen to Supply Expanded Access Programs in the United States, Europe and Canada for ME/CFS and Pancreatic Cancer and Announces Successful Finish of Second Commercial Size Lot.

    Media Release
  49. Hemispherx Successfully Completes Production of More Than 8,500 Vials of Ampligen for Commercial Sales and Expanded Clinical Programs.

    Media Release
  50. Hemispherx Biopharma Announces Collaboration with Millions Missing Canada to Bring Medication to Canadians for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

    Media Release
  51. Hemispherx Biopharma Announces Plans to File for Regulatory Approval of Ampligen(Rm) to Treat Chronic Fatigue Syndrome (CFS) in Three Additional Latin America Countries.

    Media Release
  52. Hemispherx Biopharma Announces Identification of High Responder Patient Subgroup from Ampligen(R) Phase III Trial in Patients with CFS/ME.

    Media Release
  53. An Open-Label Study Of Poly I:Poly C12U (AMPLIGEN) in Patients With Severely Debilitating Chronic Fatigue Syndrome (CFS)

    ctiprofile
  54. Hemispherx Biopharma Announces Patient Assistance Program for Chronic Fatigue Syndrome Open Label Study.

    Media Release
  55. Hemispherx Biopharma Form 10-K, March 2017. Internet-Doc 2017;.

    Available from: URL: https://www.sec.gov/Archives/edgar/data/946644/000149315217003242/form10-k.htm
  56. Hemispherx Opens FDA-Approved Reimbursement Based Expanded Access Treatment Program for ME/CFS to New Enrollees at Approved Clinical Sites in Nevada and North Carolina.

    Media Release
  57. Hemispherx Outlines Ampligen Combination Therapy Clinical Study Strategy for the Treatment of Multiple Cancers in Letter to Stockholders.

    Media Release
  58. Hemispherx Biopharma Inc. Announces Advancement in Expanded Access Program for Ampligen in the Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

    Media Release
  59. A Multi-center, Double-blind, Randomized, Placebo-controlled Study of the Safety and Efficacy of Poly I:Poly C12U (Ampligen) 400 mg IV Twice Weekly Versus Placebo in Patients With Severely Debilitating Chronic Fatigue Syndrome (CFS)/Myalgic Encephalomyelitis (ME)

    ctiprofile
  60. Hemispherx Biopharma Announces Phase 3 Chronic Fatigue Syndrome Trial Meets Primary Endpoint.

    Media Release
  61. Hemispherx Biopharma Research Team Identifies Characteristics of Chronic Fatigue Syndrome (CFS) Patients Potentially Predictive of Improved Response to Ampligen.

    Media Release
  62. Hemispherx Biopharma Files New Drug Application for Ampligen as Treatment for Chronic Fatigue Syndrome.

    Media Release
  63. Hemispherx Biopharma Reviews Ampligen(R) Data With National Institute of Neurological Disorders and Stroke (NINDS).

    Media Release
  64. A phase II study of Ampligen (rintatolimod) for the treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

    ctiprofile
  65. Hemispherx Updates Stockholders, Highlighting Ampligens Role in Enhancing Immunotherapeutic Therapies.

    Media Release
  66. Hemispherx Announces Data Presentation on the Potential for Ampligen to Improve Cancer Outcomes with Checkpoint Inhibitors.

    Media Release
  67. Hemispherx Announces Presentation of New-Found Properties of Ampligen at Immuno-Oncology Frontiers Conference, Jan 24.

    Media Release
  68. Hemispherx Biopharma Reports Low NK Cell Activity in Chronic Fatigue Syndrome (CFS) and Relationship to Disease Symptoms.

    Media Release
  69. Low Natural Killer (NK) Activity Observed Across the Chronic Fatigue Syndrome (CFS) Disease Spectrum.

    Media Release
  70. New Report Illuminates Ampligen(Rm)'s Unique Mechanism of Action.

    Media Release
  71. Hemispherx Announces Initial Test Results in Biosecurity/Biodefense Arena.

    Media Release
  72. Hemispherx Biopharma Europe N.V./S.A. Receives Orphan Medicine Designation by the European Medicines Agency for Ampligen to Treat Patients With Ebola Virus Disease (EVD).

    Media Release
  73. Hemispherx Biopharma Europe N.V./S.A. Receives Positive Opinion on Application for Orphan Designation by the European Medicines Agency for Ampligen to Treat Patients With Ebola Virus Disease (EVD).

    Media Release
  74. Hemispherx Biopharma Posts USAMRIID Ebola Study Concluding Ampligen(Rm) Produced 100% Survival Rate in Rodents With 100% Mortality in Placebo.

    Media Release
  75. Hemispherx: U.S. Army Scientists (USAMRIID) Find Ampligen(R) Produces 100% Survival Rate in Ebola Virus Rodent Study.

    Media Release
  76. Hemispherx Biopharma and USAMRIID to Present New Discoveries Concerning the Efficacy of Ampligen(Rm) Against the Ebola Virus at Upcoming International Symposium on Filoviruses.

    Media Release
  77. Hemispherx Biopharma Announces Financial Results for the Nine Months Ended September 30, 2014.

    Media Release
  78. Hemispherx Biopharma and United States Army Medical Research Institute of Infectious Diseases (USAMRIID) Collaborate on Alferon(R) and Ampligen(R) Against the Ebola Virus.

    Media Release
  79. Hemispherx Announces Data Showing Inhibition of Ebola by Ampligen(Rm) Enlarged by Howard University Research.

    Media Release
  80. Ampligen(Rm) Blocks Critical Ebola Viral Disease (EVD) Protein Which is Linked to High Mortality in Man.

    Media Release
  81. Hemispherx Biopharma and United States Army Medical Research Institute of Infectious Diseases (USAMRIID) Agree to Collaborate in Studying Alferon(R) and Ampligen(R) Against the Ebola Virus.

    Media Release
  82. Safety and Efficacy of Ampligen in the Treatment of HIV Patients Failing HAART

    ctiprofile
  83. The Role of Ampligen in Strategic Therapeutic Intervention (STI) of Highly Active Anti-Retroviral Therapy (HAART): A Multi-Center, Randomized, Controlled Study of Ampligen Potentiation of the HAART-Free Interval.

    ctiprofile
  84. Hemispherx Biopharma Initiates HIV/HEP-C Clinical Program; Clinical Trial with Ampligen in Collaboration with Esteve Laboratorios Targets HIV/HEP-C Twin Epidemics.

    Media Release
  85. Clinical Trials Insight: 700009615

    ctiprofile
  86. Hemispherx Biopharma Initiates Enrollment in HIV/HEP-C Clinical Program; Clinical Trial with Ampligen in Collaboration with Esteve Laboratorios Targets HIV/HEP-C Twin Epidemics.

    Media Release
  87. Hemispherx Files Positive Safety Report on Intranasal Use of Ampligen in Combination with FluMist Influenza Vaccine.

    Media Release
  88. Hemispherxs Ampligen Highlighted in Review of Role of TLR3 Agonist Support for Universal Flu Immunization Development Programs.

    Media Release
  89. Hemispherx Human Safety Study of Intranasal Ampligen(R) with Influenza Vaccine Shows Ampligen was Generally Well-Tolerated.

    Media Release
  90. Hemispherx Biopharma, Inc. to Webcast, Live, at VirtualInvestorConferences.com November 2.

    Media Release
  91. A Phase I/II, Two-Staged, Single-Center, Randomized, Double-Blind, Antibody Titer Study to Assess Immunogenicity and Safety of FluMist Intranasal Influenza Vaccine Administered With and Without a TLR-3 Agonist, Ampligen

    ctiprofile
  92. Clinical Trials Insight: 700056402

    ctiprofile
  93. Hemispherx Biopharma Prepares Application to Initiate Phase II Clinical Trials in China With Ampligen(R).

    Media Release
  94. Hemispherx Reports Successful Culmination of Three Year Joint Research Program at Japanese NIID.

    Media Release
  95. AIM ImmunoTech Announces Further Efforts to Establish Clinical Trials Assessing Ampligen as a Potential Protective and Early-Onset Treatment for the Current COVID-19 Pandemic.

    Media Release
  96. AIM ImmunoTech's Drug Ampligen to Be Tested by Japan's National Institute of Infectious Diseases as a Potential Treatment for the New SARS Coronavirus (SARS-CoV-2) Responsible for the New Human Infectious Disease COVID-19.

    Media Release
  97. AIM ImmunoTech Joins with ChinaGoAbroad for an Ampligen China Entry Against COVID-19, the New SARS-like Coronavirus Disease Epidemic.

    Media Release
  98. AIM ImmunoTech Files Three Provisional Patent Applications Surrounding Ampligen(R)for Use Against the SARS-like Wuhan 2019 Novel Coronavirus.

    Media Release
  99. New Animal Model for Evaluating Antiviral Agents Against the SARS Virus Indicates Potential Effect of Ampligen(R), an Experimental Therapeutic.

    Media Release
  100. Hemispherx Initiates Collaboration on SARS with Genome Institute of Singapore.

    Media Release
  101. SARS: Newly NIH Sponsored Studies of Potential Therapies for SARS Now Finds Hemispherx' Ampligen among the Most Active from a Large Pool of 70 -Seventy- Drug Candidates.

    Media Release
  102. Hemispherx Biopharma Expands SARS Prevention/Treatment Initiative; Prior to Anticipated Fall/Winter Outbreak also widens Distribution and Clinical Networks.

    Media Release
  103. Hemispherx Biopharma Exploring Possible Research Programs in Zika Virus Modeled on a Prior Alferon(R)N Clinical Trial on Closely Related Flavivirus (West Nile).

    Media Release
  104. Hemispherx's Ampligen(R) Provides Anti-Tumor Activity Analogous to Emerging Immune Checkpoint Inhibitors.

    Media Release
  105. Hemispherx Updates Status of Immuno-Oncology Program in Pancreatic Cancer.

    Media Release
  106. A Phase IIa trial of Ampligen (rintatolimod) in combination with checkpoint inhibitors for the treatment of advanced urothelial cancer, renal cell carcinoma and Melanoma (Second line therapy or greater, combination therapy)

    ctiprofile
  107. Phase I/II study of rintatolimod to enhance the immune mediated effects of CPIs in patients with advanced solid tumors

    ctiprofile
  108. Hemispherx Biopharma and the University of Pittsburgh Collaborate on a Novel Chemokine-Modulatory Program for Cancer Immunotherapies With Ampligen(Rm) as a Key Component.

    Media Release
  109. AIM ImmunoTech Announces Progress Toward Opening of Breast Cancer Study at Roswell Park Comprehensive Cancer Center.

    Media Release
  110. Hemispherx Issues 2019 Second Quarter Report Citing Strong Steady Progress in Cancer Clinical Trials.

    Media Release
  111. Hemispherx Announces Dutch Health Inspectorate Approval to Extend the Ampligen Pancreatic Cancer Early Access Program Until March 2020.

    Media Release
  112. Hemispherx Biopharma Announces IRB Approval of Clinical Study in Metastatic Triple Negative Breast Cancer in Collaboration with Roswell Park Comprehensive Cancer Center.

    Media Release
  113. Pilot Open Label Clinical Trial Evaluating the Safety and Efficacy of Chemokine Modulation to Enhance the Effectiveness of Pembrolizumab in Patients With Metastatic Triple Negative Breast Cancer

    ctiprofile
  114. Hemispherx Announces the First Participant Received Initial Dosing in Breast Cancer Clinical Trial Using Hemispherx' Ampligen and Pembrolizumab.

    Media Release
  115. Phase I-II Study of HER2 Vaccination With Poly(I) Poly(C12U) (Ampligen) as an Adjuvant in Optimally Treated Breast Cancer Patients

    ctiprofile
  116. Hemispherx Biopharma Announces Financial Results for the Three Months Ended September 30, 2011.

    Media Release
  117. Phase 2a Study Evaluating a Chemokine-Modulatory Regimen in Patients With Colorectal Cancer Metastatic to the Liver

    ctiprofile
  118. Hemispherx Reports 2018 Third Quarter and First Nine Months Financial Results.

    Media Release
  119. Randomized Phase 1/2 Evaluation of Neoadjuvant Administration of a Chemokine-Modulatory Regimen in Patients With Recurrent Resectable Colorectal Cancer

    ctiprofile
  120. Hemispherx To Supply Ampligen for Pancreatic Cancer Patients in Canada Under Special Access Program.

    Media Release
  121. Hemispherx Biopharma Announces Significant Progress in its Ampligen Pancreatic Cancer Program and Multiple Ampligen+Checkpoint Blockade Immuno-Oncology Programs.

    Media Release
  122. Hemispherx Secures Corrections from Two Stock News Organizations Related to Their Inaccurate Reporting of an Equity Distribution Agreement Disclosed in a Recent SEC Filing.

    Media Release
  123. Hemispherx Biopharma Repurposes Ampligen in Immuno-Oncology.

    Media Release
  124. Hemispherx Releases Recently Manufactured Ampligen for Pancreatic Cancer Early Access Program in the Netherlands to Fill Stock Order.

    Media Release
  125. Randomized Phase 2 Study: Neoadjuvant Conditioning of Prostate Cancer Tumor Microenvironment Using a Novel Chemokine-Modulating Regimen

    ctiprofile
  126. A Phase 1/2 Trial Evaluating αDC1 Vaccines Combined With Tumor-Selective Chemokine Modulation as Adjuvant Therapy After Surgical Resection of Peritoneal Surface Malignancies

    ctiprofile
  127. A Phase I/II Randomized Clinical Trial of Autologous Oxidized Tumor Cell Lysate Vaccine For Recurrent Ovarian, Fallopian Tube or Primary Peritoneal Cancer

    ctiprofile
  128. Oregovomab and rintatolimod as adjuvant therapy for cancer

    ctiprofile
  129. Quest PharmaTech Announces Clinical Development Agreement with Hemispherx Biopharma Inc. to evaluate a combinatorial Immunotherapy Technology.

    Media Release
  130. Animal Model Data Presented at AACR Indicate That Hemispherx Biopharma's Ampligen(R) May be a Potent Tumor Vaccine Adjuvant.

    Media Release
  131. Hemispherx Biopharma Announces First Patient Treated in Phase 2 Ovarian Cancer Clinical Trial Evaluating Ampligen in Combination with Pembrolizumab and Cisplatin.

    Media Release
  132. Hemispherx Biopharma Announces Commencement of a New 45 Subject Clinical Trial Combining Ampligen and Mercks Keytruda in the Treatment of Recurrent Ovarian Cancer.

    Media Release
  133. Systemic Immune Checkpoint Blockade and Intraperitoneal Chemo-Immunotherapy in Recurrent Ovarian Cancer

    ctiprofile
  134. Hemispherx Reports Positive Safety and Survival Data in Phase 1 Stage 4 Ovarian Cancer Clinical Study Using Ampligen(Rm).

    Media Release
  135. A Phase 1-2 Neoadjuvant Dose Finding, Safety, and Immunologic Efficacy Trial of Intensive Locoregional Chemoimmunotherapy for Recurrent Ovarian Cancer and Tumor-Specific Intranodal Autologous Alpha-DC1 Vaccines

    ctiprofile
  136. AIM ImmunoTech Provides Comprehensive Clinical Trials Update With Major Inflection Points Identified.

    Media Release
  137. AIM ImmunoTech Inc. Announces a Second DoD Award, This One of $8.3 Million, to Fund Phase 2 Clinical Trial to Study Ampligen as Part of a New Treatment for Brain-Metastatic Breast Cancer at the Moffitt Cancer Center.

    Media Release
  138. Hemispherx Biopharma, Inc. Announces $1 Million Registered Direct Offering.

    Media Release
  139. Hemispherx Biopharma, Inc. Announces $5 Million Registered Direct Offering.

    Media Release
  140. Hemispherx Biopharma Receives Therapeutic Discovery Project Grant From U.S. Department of Treasury.

    Media Release
  141. Hemispherx Biopharma Reaches Agreement with Avrio Biopharmaceuticals for the Accelerated Production of Ampligen(Rm).

    Media Release
  142. HEMISPHERX BIOPHARMA 10-K. Internet-Doc 2019;.

    Available from: URL: https://www.sec.gov/Archives/edgar/data/946644/000149315219004583/form10-k.htm
  143. Hemispherx Biopharma Receives the European Patent Office Grant of New Composition of Matter Patent Covering Ampligen(R) Formulations.

    Media Release
  144. Hemispherx Receives the European Patent Office Examining Division's Notice of Intention to Grant the New Composition of Matter Patent Covering Ampligen(R) Formulations.

    Media Release
  145. Hemispherx Receives New U.S. Composition of Matter Patent Covering Ampligen(Rm) Formulations.

    Media Release
  146. Hemispherx Biopharma Receives U.S. Patent Office Notification of New Patent Granted for the Use of Ampligen(R) as an Influenza Virus Vaccine Adjuvant for Protection Against Pandemic Avian Influenza.

    Media Release
  147. Hemispherx Biopharma Issues Clinical Update for Ampligen Immuno-oncology Program.

    Media Release
  148. Hemispherx Biopharma Issues Letter to Stockholders.

    Media Release
  149. Hemispherx Encouraged by Cytokine Biomarker Discovery Which May Lead to a Diagnostic for Chronic Fatigue Syndrome.

    Media Release
  150. Hemispherx Biopharma to Present New Retrovirus (XMRV) Data at 1st International Workshop on XMRV and Chronic Fatigue Syndrome (CFS).

    Media Release
  151. Japanese NIH Research Reaffirms and Expands Pandemic Flu Protection by Ampligen(R).

    Media Release
  152. Hemispherx Presents Evidence of Ampligen (Rm) Synergies with Existing Antivirals at International Avian Influenza Conference.

    Media Release
  153. 3 New Studies Show Hemispherx Biopharma's Ampligen(R) and Alferon(R) LDO May Provide Defense against Avian Flu.

    Media Release
  154. Hemispherx Biopharma's Investigational Drug Increases Physical Performance in New Chronic Fatigue Syndrome -CFS- Clinical Study; Maximum Oxygen Consumption Increased 10-Fold with Ampligen-R- vs. Placebo.

    Media Release
  155. Hemispherx Biopharma Presents Newphase III Data on Ampligen at the 7th International Conference for Chronic Fatigue Syndrome.

    Media Release
  156. CARTER W, Strayer D, Mitchell W, Stevens S, AMP 516 Investigators. Phase III, randomized, double-blinded clinical trial in chronic fatigue syndrome shows significant improvement in exercise treadmill performance with ampligen compared to placebo. 17th-ICAR-Late 2004;13.

  157. Mitchell W, Blick G, Strayer D, CARTER W, AMP 720 Investigators, et al. A phase IIB prospective, randomized, controlled study evaluating AMPLIGEN during structured treatment interruption of HAART in HIV infection. Antiviral-Res 2003;5741.

  158. Hemispherx Presents New Data from Phase IIB Clinical Trial of RNA-based Ampligen(R) for Structured Treatment Interruption in HIV at DART Conference.

    Media Release
  159. Strayer D, Blick G, Mitchell W, Cimoch P, CARTER W. A phase IIB prospective, randomized, controlled study evaluating the immunomodulatory role of poly I:poly C12U against HIV. 14th-Aids-Suppl 2002;37.

  160. Hemispherx announces poly I: poly C12U increases the control of HIV during strategic treatment interruption in chronically HIV infected patients.

  161. Essey RJ, McDougall BR, Robinson WE. Mismatched double-stranded RNA (PolyI-polyC(12)U) is synergistic with multiple anti-HIV drugs and is active against drug-sensitive and drug-resistant HIV-1 in vitro. Antiviral-Res 2001;51189-202.

    PubMed | CrossRef Fulltext
  162. New study indicates benefits of Ampligen (R) in treatment of severe CFS.

  163. Ijichi K, Mitamura K, Ida S, et al. Comparison of antiviral effects of mismatched double-stranden RNA and 1-(2'deoxy-2'-fluoro-beta-D-arabinofuranosyl) -5-methyl-uracil (D-FAMU) against duck hepatitis B virus in vitro. Antiviral-Chem-Chemother 1997;8537-540.

    PubMed | CrossRef Fulltext
  164. Thompson KA, Strayer DR, Salvato PD, Thompson CE, Klimas N, et al. Results of a double-blind placebo-controlled study of the double-stranded RNA drug polyI:polyC(12)U in the treatment of HIV infection. Eur-J-Clin-Microbiol-Infect-Dis 1996;15580-587.

    PubMed | CrossRef Fulltext
  165. Buzaid AC, Strayer DR, Witman PA, et al. Phase I/II study of poly I:polyC(12)U (Ampligen Rm) shows activity against metastatic melanoma. 30th-ASCO 1994;13399.

    PubMed
  166. O'Marro SD, Armstrong JA, Asuncion C, Gueverra L, Ho M. The effect of combinations of ampligen and zidovudine or dideoxyinosine against human immunodeficiency viruses in vitro. Antiviral-Res 1992;17169-177.

    PubMed
  167. Hendrix CW, Margolick JB, Petty BG, Markham RB, Nerhood L, et al. Biologic effects after a single dose of poly(I):poly(C12U) in healthy volunteers. Antimicrob-Agents-Chemother 1993;37429-435.

    PubMed
  168. Carter WA, Ventura D, Shapiro DE, Strayer DR, Gillespie DH, et al. Mismatched double-stranded RNA, Ampligen (poly(I) : poly(C12U), demonstrates antiviral and immunostimulatory activities in HIV disease. Int-J-Immunopharmacol 1991;13 (Suppl. 1)69-76.

  169. Konishi K, Mukoyama A, Muller WEG, et al. Effect of poly(I) . poly(C12U) (Ampligen) on enteric virus (rotavirus, poliovirus and Coxsackie B3 virus) infections. Lett-Appl-Microbiol 1994;19386-390.

    PubMed
  170. Belgium Clinical Trial Demonstrates that Ampligen(R) is Effective in the Treatment of Chronic Fatigue Syndrome.

    Media Release
  171. Suhadolnik RJ, Reichenbach NL, Hitzges P, Sobol RW, Peterson DL, et al. Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome. Clin-Infect-Dis 1994;18 (Suppl.1)96-104.

  172. McMahon D, Winkelstein A, Huang X-L, Armstrong J, Pazin G, et al. Acute reactions associated with the infusion of ampligen. AIDS 1992;6235-236.

    PubMed
  173. Niu J, Wang Y, Dixon R, et al. The use of ampligen alone and in combination with ganciclovir and coumermycin A1 for the treatment of ducks congenitally-infected with duck hepatitis B virus. Antiviral-Res 1993;21155-171.

    PubMed
  174. Belgian study reports good results, trial is expanded.

    Media Release
  175. Strayer DR, Carter WA, Brodsky I, et al. A controlled clinical trial with a specifically configured RNA drug, poly(I).poly(C12U), in chronic fatigue syndrome. Clin-Infect-Dis 1994;18 (Suppl.1)88-95.

  176. O'Brien CB, Garcia G, Henzel B, et al. Ampligen treatment of chronic hepatitis B. Gastroenterology 1994;106 (Suppl.)952.

  177. Armstrong JA, McMahon D, Huang X-L, Pazin GJ, Gupta P, et al. A phase I study of ampligen in human immunodeficiency virus-infected subjects. J-Infect-Dis 1992;166717-722.

    PubMed
  178. Gillespie D, Hubbell HR, Carter WA, Midgette P, Elsasser W, et al. Synergistic inhibition of AZT-resistant HIV by AZT combined with poly(I):poly(C12U), without synergistic toxicity to bone marrow progenitor cell elements. In-Vivo 1994;8375-381.

    PubMed
  179. Ushijima H, Tsiapalis CM, Daum T, Schroder HC, Matthes E, et al. Synergistic anti-human immunodeficiency viral (HIV-1) effect of the immunomodulator ampligen (mismatched double-stranded RNA) with inhibitors of reverse transcriptase and HIV-1 regulatory proteins. Antiviral-Chem-Chemother 1993;4(6):315-321.

    PubMed
  180. Ablashi DV, Berneman Z, Strayer DR, et al. Poly(I).poly(C12U) inhibits in vitro replication of human herpesvirus type 6. Clin-Infect-Dis 1994;18 (Suppl.1)113.

  181. Ablashi DV, Berneman ZN, Williams M, Strayer DR, Kramarsky B, et al. Ampligen inhibits human herpesvirus-6 in vitro. In-Vivo 1994;8587-591.

    PubMed
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