Chronic fatigue syndrome/Myalgic encephalomyelitis (CFS/ME)
In June 2019, AIM Immunotech reported that the company received import clearance from Argentina's Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica (ANMAT), for rintatoimod, for the treatment of severe chronic fatigue syndrome. This is followed by export clearance issued by the US FDA in September 2019, under the section 802 (b) (2) of the U.S. Federal Food, Drug and Cosmetic Act. ANMAT will conduct a final inspection of the product and release tests before granting final approval to begin commercial sales. Once final approval by ANMAT is obtained, GP Pharma will begin distributing the in Argentina. ANMAT approved rintatolimod for the treatment of patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) in Argentina in August 2016. The approval was based on clinical data from two pivotal trials, AMP-516 and AMP-502. 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. The approval is expected to have a beneficial effect on AIM ImmunoTech's early access program partnerships in Europe and Australia      .
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  . 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  . 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  . 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    . In November 2010, Hemispherx Biopharma filed a request with the US FDA to maintain an active NDA for rintatolimod to treat CFS    . 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   . 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  .
The FDA accepted Hemispherx's NDA filing (originally submitted in October 2007) for review in July 2008  . 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)  . 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  . 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  .
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)   .
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  .
In March 2017, Hemispherx re-initiated its US-based cost recovery programme at the price increase recently approved by the FDA  .
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  .
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  .
In August 2015, Hemispherx Biopharma plan to file for regulatory approval for rintatolimod worldwide, including Europe, Latin America, Australia, New Zealand and the US  . The company also plans to introduce the product in Turkey under an Expanded Access Programme (EAP).
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  .
AIM ImmunoTech plans to initiate a confirmatory phase II trial for rintatolimod in CFS/ME in the US  .
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   . 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  . As at December 2016, 27 patients accessed rintatolimod, under the patient assistance AMP 511 study, authorised by the US FDA in May 1997  . In June 2018, Hemispherx Biopharma expanded its APM 511 programme in the US and expanded patient enrolment  . The US FDA has approved the reimbursement rate of $200 per vial for the direct costs of the drug through EAP  . 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  . In December 2020, IRB granted approval to include patients previously diagnosed with SARS-CoV-2 and now demonstrated post-acute infection chronic fatigue-like symptoms to be included in the expanded access programme  . In a same month, company received IRB approval for a public notification of potential enrollment in the post-COVID-19 “Long Hauler” portion of the active AMP-511 expanded access program (EAP) protocol. Patients in the trial will be treated with Ampligen. AIM is currently preparing the IRB-approved protocol for submission to the US FDA. The Ampligen EAP protocol is authorized to enroll up to 100 active trial participants, 20 of whom may be Long Haulers. All the study participants will receive the same Ampligen treatments   . In January 2020, First COVID-19 “Long Hauler” patient was dosed in expanded access programme  .
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)   . The trial was completed in February 2004. Results of the US-based study were published in the Journal of Applied Research and PLoS ONE  . In September 2015 and October 2016, a retrospective analysis of data from the trial was released   .
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  . 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   .
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  . 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   .
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  .
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  .
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  .
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  .
COVID-2019 infections and other respiratory viral diseases
In May 2021, AIM ImmunoTech announced that it plans a phase I/II inhalation trial for COVID-2019 infections 
In September 2020, Roswell Park Cancer Institute, in collaboration with AIM ImmunoTech and National Cancer Institute initiated a phase I/IIa trial to evaluate the side effects of rintatolimod, in combination with interferon (IFN) alpha-2b, in cancer patients with mild or moderate COVID-19 infection (I659920; NCI2020-02317; P30CA016056; NCT04379518). The open-label, randomised trial intends to enrol approximately 64 patients in the US   . In May 2020, the US FDA approved the first human trial to evaluate the safety and effectiveness rintatolimod, in combination with interferon alfa-2b, in cancer patients with COVID-2019 infections  . In November 2020, first patient was dosed in this study. In March 2021, AIM ImmunoTech announced that the Institutional Review Board of Roswell Park Comprehensive Cancer Center approved a protocol ammendment for the trial for randomisation of additional twenty patients. Ten patients will receive a single dose of rintatolimod, but no interferon treatment, and the other ten will receive best available care only   . Funding for the clinical trial was provided, partly through grants from the National Cancer Institute and AIM, as well as institutional support from Roswell Park  .
In March 2021, AIM ImmunoTech in collaboration with Centre for Human Drug Research (CHDR) initiated the phase I AMP-COV-100 trial to assess the safety, tolerability and biological activity of repeated intranasal administration of rintatolimod as a prophylaxis or treatment for COVID-19 infections and other respiratory viral diseases (CHDR2049; AMP-COV-100). The prospective, double-blind trial intends to enrol approximately 40 healthy volunteers in Netherlands. The trial will randomise volunteers into four cohorts; cohort one, two, three and four will receive 75 μg, 200 μg, 500 μg and 1250 μg of rintatolimod, respectively, compared with placebo  . In February 2021, AIM ImmunoTech received approval from the required Ethics Committee in the Netherlands to commence the phase I trial   . In April 2021, AIM ImmunoTech announced positive safety data from the cohort one, allowing for the dose escalation in the cohort two of the trial  . In April 2021, AIM ImmunoTech announced completion of dosing and positive safety data from the second cohort, allowing for the dose escalation in the third cohort of the trial  . In May 2021, AIM ImmunoTech completed dosing of Cohort three in the phase I trial reporting no serious adverse events 
In August 2020, AIM Immuno Tech reported that it identified an in vitro model in which rintatolimod at intranasal dosage levels resulted in decrease in SARS-CoV-2 infectious viral yields by 90%. The data supported the development of rintatolimod as both prophylaxis and early onset intranasal therapy of COVID-2019 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-2019 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-2019 infections  .
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  .
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  .
In February 2020, AIM Immuno Tech released preclinical pharmacodynamics data for severe acute respiratory syndrome caused due to COVID-2019 infections  . In May 2021, AIM Immuno Tech released preclinical data from animal and in in vitro models  .
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  .
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]  . 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  . 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®  .
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  . 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  . Results from the preclinical mouse model of Ebola virus were released in February 2015   . Additionally, Hemispherx announced that it is developing a protocol for the clinical trial of the drug in Ebola virus infection  . 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   . Rintatolimad was shown to inhibit the Ebola meningenome by investigators at the Howard University  . Biochemical in vitro data was reported later in the same month, by the University of Cagliari, Italy  . 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  .
HIV and HCV infections
A phase IIb study of rintatolimod in HIV was completed in the US (NCT00035581)  . 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)  . 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  . 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   . 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      .
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   .
Pre-clinical studies also showed cross-protection against H5N1 viruses using trivalent seasonal influenza vaccine in mouse models  .
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  .
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.
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  .
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  . 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   .
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   . 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   .
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  .
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  .
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     . In April 2019, the first patient was dosed in the trial  .
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   .
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  . As of August 2019, seven patients were enrolled in the trial and completed treatment    .
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   .
In February 2021, the European Medicines Agency granted orphan drug designation to rintatolimod for the treatment of pancreatic cancer. AIM ImmunoTech announced that NV Hemispherx Biopharma Europe (subsidiary of AIM ImmunoTech), received formal notification from the European Commission (EC) approving the company’s orphan medicinal product application. Earlier in the same month, the Committee for Orphan Medicinal Products (COMP) of the EMA recommended orphan drug designation for rintatolimod  .
In December 2020, the US FDA granted orphan drug designation status to rintatolimod for the treatment of pancreatic cancer  .
In February 2021, the Dutch Health and Youth Care Inspectorate (IGJ) has approved treatment for six pancreatic cancer patients as part of a new, follow-up Early Access Program (EAP) at Erasmus Medical Center in the Netherlands. Based on the authorisations, the company intends to treat up to 16 pancreatic cancer patients with rintatolimod under the EAP  .
In September 2020, AIM announced intention to obtain US FDA's fast-track and breakthrough designations and to obtain IND authorisations to conduct a follow-up phase II/III clinical trial in patients with pancreatic cancer in the Netherlands and in the US. The company also announced intention to file dual orphan drug status applications with the US FDA and the EMA for use of rintatolimod (Ampligen) in the treatment of late-stage pancreatic carcinoma in the US and in the EU  .
Ampligen is available in Europe and in the US under an Early Access Programme  . 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. In February 2021, updated efficacy data from the trial were released by AIM ImmunoTech      . The company intends to expand the early access programme to other European countries and Canada      .
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). In September 2020, positive efficacy data from the programme were reported by AIM ImmunoTech  .
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  .
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  .
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   .
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   .
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  .
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  . 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  .
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  .
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.
Rintatolimod demonstrated synergistic antitumor and antiviral activity when combined with human interferons in various studies  .
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  . The open-label trial intends to enrol approximately 45 patients in the US   .
In September 2020, University of Pittsburgh, in collaboration with Roswell Park Cancer Institute, Hemispherx Biopharma and National Cancer Institute, suspended a phase I/II trial which was investigating the addition of cisplatin to an investigational dendritic cell vaccine with or without an investigational drug combination of rintatolimod, interferon alpha-2b (IFN), and oral celecoxib, to evaluate the effect on recurrent ovarian cancer. The reasons for suspension was not disclosed (NCT02432378; 11-128; 5P01CA132714). The randomised, open-label trial, which was initiated in July 2015, intends to enrol approximately 25 patients in the US. Enrolment in phase II portion is expected to commence in September 2020. In November 2018, the trial had enrolled 10 patients in the phase I portion of the study. 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    .
In preclinical studies of SARS-CoV-1 in mouse models, a protective effect was exhibited by rintatolimod. Virus lung titers were below detectable limits. The drug led to a rapid decline of virus in the lungs compared with untreated animals with a 100% survival outcome versus 100% death rate in the control group  .
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  . In preclinical models and human tumour explants demonstrated that rintatolimod is a TLR3 restricted and targeted modulator of “hot” tumour microenvironments  .
The National Cancer Institute has awarded $US14.5 million to Roswell Park to fund five immuno-oncology clinical trials. 
In October 2019, AIM immunotech raised approximately $US10 million from the public markets to support the clinical development of rintatolimod  .
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  .
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  .
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  . 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  .
In July 2016, Hemispherx entered into an agreement with Avrio Biopharmaceuticals, to serve as an additional contract manufacturer of rintatolimod  .