In November 2014, Hemispherx Biopharma and United States Army Medical Research Institute of Infectious Disease (USAMRIID) reported that interferon-α-n3 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 interferon α n3 and rintalimod [see RDI Profile 800001203]. These studies are being planned to establish a basis for clinical interventions in both preventative and therapeutic settings of Ebola virus disease  . In September 2014, Hemispherx Biopharma collaborated with researchers from the USAMRIID to assess rintalimod and interferon-α-n3 as a treatment for Ebola virus infections  .
AIM ImmunoTech is undertaking major programmes to investigate interferon α n3 as a biodefence agent, with a focus on the prevention or treatment of H7N9 pandemic influenza virus infections, α virus infections including Venezuelan Equine Encephalomyelitis (VEE), and Middle East Respiratory Syndrome (MERS). Data from in vitro studies demonstrated that interferon-α-n3 was highly active against oseltamivir-resistant strains of H7N9 pandemic influenza, and the product has also been shown to be highly active against the other two virus classes of interest. Interferon-α-n3 has also showed inhibition of neuromidase resistant Shanghai/1/H7N9 virus. More recently, Hemispherx reported that research conducted by the NIAID demonstrated that interferon-α-n3 inhibits the replication of MERS coronavirus infection in vitro. The findings were confirmed by studies conducted at the University of Texas Medical Branch     .
Hepatitis C virus (HCV) infections
Interferon α n3, under the brand name Naturaferon®, is approved in Argentina for the treatment of Hepatitis C infections in treatment-experienced patients who fail or become intolerant to recombinant interferon    .
Phase III trials of interferon α n3, or Alferon N® Injection, have been completed in the US and Mexico for the treatment of previously untreated patients with chronic active hepatitis C. A total of 275 patients were treated with interferon-α-n3 for 24 weeks with a further 24 weeks follow-up. After completing the analysis of the results, Interferon Sciences had intended to request a meeting with the FDA to determine the adequacy of the data for filing purposes. However, following the acquisition of the rights to interferon-α-n3 by Hemispherx, the compound appeared to be in phase II/III development with the latter company for hepatitis C. Fujimoto was conducting phase II clinical studies in Japan for hepatitis C. However, no further development has been reported in the US or Japan for this indication. AIM ImmunoTech plans to conduct a phase III study of Alferon N® Injection in hepatitis in China.
Hemispherx and Bioclones intend to initiate a clinical trial in South Africa to assess the safety and biological effects of adding interferon α n3 to a strategic therapeutic intervention protocol. The trial will enrol approximately 30 patients with HIV   .
In March 2004, Hemispherx announced that the US FDA had authorised an IND that enabled the company to initiate a phase II study of Alferon N LDO®, Low Dose Oral natural interferon, in asymptomatic HIV positive patients (NCT00215852). The study was an open-label, dose ranging, outpatient study involving approximately 60 patients who were randomly assigned to each dose level. Patients were administered the assigned Alferon N LDO® dose once each day for 10 consecutive days; the overall duration of the study was 6 weeks. The primary endpoints of the trial were an increase or upregulation in genes known to be mediators of the natural immune response and secondary endpoints included the absolute CD4 count and plasma HIV RNA levels. No recent development on this study has been reported   .
Interferon Sciences previously completed a phase III study of interferon α n3 in 110 HIV-infected patients with CD4 counts ≥250 cells/mm3 and viral loads ≥2000 copies/ml. As the study's primary efficacy variable, reduction in viral load, was not achieved at the end of treatment, the FDA indicated that another trial was necessary to further evaluate the efficacy of interferon-α-n3 injection for this indication.
Human papillomavirus (HPV) infections
An injectable form of interferon α n3, Alferon N Injection® or Altemol®, was marketed in the USA and Mexico for the treatment of genital warts caused by HPV. However, in Mexico its marketing was not active or discontinued. The commercial sales of Alferon N Injection® were halted in March 2008 for reasons relating to the expiration date of the company's finished goods inventory and the need to prepare the company's manufacturing facility for the FDA pre-approval inspection regarding the NDA for Ampligen® [see Adis Insight Drug profile 800001203] (Hemispherx Biopharma Form 10-K, March 2010). The company reported that it was undertaking a major capital improvement programme to upgrade its manufacturing capability, and according to the its website, the product was being marketed in the US in October 2012. In November 2014, Hemispherx reported that it has received a Certificate of Approval from the city of New Brunswick for the work completed to upgrade its manufacturing facility. The company will test the scaled up facility to produce commercial levels of Alferon N Injection®, Alferon N LDO® [see below] and other products  . The facility commenced its operations at the beginning of 2015. The FDA will reaffirm the amended BLA for Alferon N Injection® before the commercial sales of the product anticipated by late 2015. FDA's approval will be required to release the commercial product following the submission of stability and quality release data. Amada Healthcare will distribute the product   .
In August 2015, Hemispherx announced that in an analysis of relapsed and refractory neutralising antibody (NAB) positive patients who switched treatment to interferon α n3 injection, restoration in the clinical response was found to be in 33/40 (82%) of patients  .
Interferon-α-n3 injection was approved in Argentina for the treatment of patients with refractory or recurring HPV, in January 2012. GP Pharm submitted the application for the approval of interferon-α-n3 injection for the treatment of HPV infections in August 2011. In March 2013, the regulatory authorities in Argentina expanded the label for the product to include the treatment of patients that have failed treatment with or become intolerant to recombinant interferon, while receiving treatment for any disease, including multiple sclerosis, hepatitis C, and certain cancers. Hemispherx had applied for an extension of the label, in October 2012, to include patients with hepatitis C who had developed neutralising antibodies to recombinant interferon. The company is awaiting approval from the US FDA for the sale of its existing inventory, and product that is to be manufactured at its facility in New Brunswick, before commencing commercial launch in this market. Alferon N Injection® is being marketed in Argentina under the brand name Naturaferon®     .
Hemispherx conducted clinical trials of Alferon N LDO® in patients with HPV infections in the US and Hong Kong  . Interferon Sciences conducted phase II clinical trials in the US with the gel formulation of interferon-α-n3 (Alferon N Gel®) in women with intravaginal warts caused by human papillomavirus (HPV) who have recurrent, persistent low or high grade cervical dysplasia. However, no recent reports on development of both formulations of interferon-α-n3 identified for this indication.
Influenza virus infections (including influenza A virus infections [pandemic or avian influenza])
In January 2014, Hemispherx reported that the administration of a low dose oral formulation of interferon-α-n3 (Alferon® LDO) in a primate model provided protection from pulmonary tissue damage associated with infection by highly pathogenic avian influenza virus (H5N1)  . In September 2014, company released positive data on Alferon® LDO in prevention of viral infection caused by H5N1 in non-human primate model  .
A preclinical programme to investigate interferon-α-n3 for oseltamivir (Tamiflu®)-resistant influenza A H7N9 virus strains in Switzerland was announced in May 2014 [see Adis Insight Drug profile 800007569]  .
Hemispherx Biopharma stated that preclinical studies of Alferon N Injection®/Alferon LDO® were underway in the US and Canada for avian influenza. Company researchers have indicated that these products may be promising in the treatment of oseltamivir-resistant influenza A virus H7N9 infections in both animals and humans   . Phase II trials of Alferon LDO® for the prevention and treatment of influenza are in the preparation stage (Hemispherx's pipeline, March 2015). The US FDA authorised the protocol for a randomised, double-blind, placebo-controlled, dose-ranging phase II trial of Alferon® LDO for the prophylaxis and treatment of seasonal influenza in more than 200 subjects.
In April 2010, Hemispherx Biopharma and the Indian clinical research organisation (CRO) Max Neeman International announced a collaborative research effort for interferon-α-n3 for influenza virus infections. The partnership aimed to improve the treatment of seriously ill patients hospitalised with either seasonal influenza or pandemic influenza (influenza A virus infections). Approval from the Indian Drugs Controller General for this phase II trial (CTRI/2010/091/001115; study ALFN 101) was granted on 13 July 2010, with enrolment commencing immediately, intending to coincide with the Indian monsoon season (July to mid-October; peak in August)    . Only 25 out of 60 patients completed the study across eight investigative sites. Hence, in June 2012, the trial was suspended due to slow enrolment and interim analysis of results on 30 out of 60 planned patients was pending (Hemispherx Form 10-K, March 2012). Subsequently, due to delayed interim analysis and reduced resources, the trial was discontinued (Hemispherx Form 10-K, March 2014). Furthermore, no recent reports on development for this indication in India identified.
Hemispherx Biopharma was planning trials of Alferon N Injection® in seriously ill, hospitalised patients with influenza in Argentina (Hemispherx Biopharma annual report, February 2011).
In January 2011, the FDA lifted the clinical hold on Hemispherx's planned phase II clinical trial in the US investigating SC interferon α n3 in patients with influenza. The hold was lifted following review of a complete response to the agency submitted in November 2010. The proposed randomised trial will involve approximately 200 subjects and will evaluate the prophylaxis and treatment of seasonal and pandemic influenza. The study has been delayed as the company intended to conduct a confirmatory study using gene expression methods to identify the systemic gene activation effects in peripheral blood leukocytes following treatment with interferon α n3 (Hemispherx Form 10-K, March 2012).
Hemispherx Biopharma has received FDA-approval to conduct a well-controlled phase II trial investigating the efficacy and tolerability of low-dose oral interferon α-n3 (Alferon® LDO) for the prevention and treatment of influenza in a family setting   .
Early-stage clinical trials of Alferon® LDO were conducted by Hemispherx Biopharma in the influenza indication. A clinical trial in healthy volunteers to investigate whether the agent could resuscitate broad-spectrum antiviral and immunostimulatory genes was delayed because of funding issues. However, the study has recommenced (Hemispherx Biopharma Form 10-K, March 2010).
In November 2005, Hemispherx Biopharma entered into an agreement with Defence R&D Canada, an agency of the Canadian Department of National Defence, to investigate the antiviral efficacy of interferon-α-n3 in human respiratory influenza virus infections in validated animal models  .
Preclinical studies, conducted in collaboration with ViroClinics, have indicated that Alferon LDO® may have potential in the treatment of seasonal influenza pandemics. Hemispherx was planning to conduct clinical trials in this indication  .
Alferon® LDO has been shown to reduce the severity of pathology resulting from infection of macaques by a highly pathogenic strain of avian influenza. Hemispherx has been hoping that Alferon® LDO can receive expedited review and emergency-based approval as an anti-HPAI (highly pathogenic avian influenza) agent, solely relying on the 'animal rule' for demonstration of efficacy. This is where marketing approval can be granted based on efficacy in relevant animal models with only phase I safety trials required in humans  .
Middle East Respiratory syndrome (MERS)
In January 2016, Hemispherx reported that the European Medicines Agency has granted orphan drug designation to Alferon N Injection® for the treatment of MERS. The EMA's decision was based on the positive opinion given by the Committee for Orphan Medicinal Products (COMP)   . Research conducted using human cells in culture suggested that the agent may be effective either as a preventative and/or treatment of early MERS infection  .
In June 2004, Hemispherx commenced a multiple sclerosis salvage programme. As part of the programme, the company was to conduct a multicentre, open-label, phase IIb trial evaluating the safety and efficacy of injectable interferon-α-n3 in patients with multiple sclerosis who have discontinued current treatments (Avonex®, Rebif® or Betaseron®) because of clinical progression, intolerance or formation of neutralising antibodies. The primary endpoints included the annual clinical relapse rate at baseline compared with week 48. Hemispherx received FDA approval for this trial in July 2004, but the trial had not been initiated by late 2012. However, according to the Hemispherx pipeline, the company is still intending to conduct a phase II trial in this indication in the US   .
Severe Acute Respiratory Syndrome (SARS)
Multiple collaborations with non-commercial organisations have been conducted in this indication. However, while the therapy may have potential in this indication it appears that commercial development is not underway.
In May 2003, Hemispherx announced that, in response to an urgent request from the Singapore government, it was initiating a collaboration with the Genome Institute of Singapore (GIS), to evaluate Alferon® N and Ampligen® [see Adis Insight Drug profile 800001203] for the potential treatment of SARS  . Results of an independent study conducted at the GIS and published in April 2004, showed that Alferon® N has superior antiviral activity in an in vitro model of SARS-CoV, when tested among 19 other clinically approved compounds from several major antiviral pharmacological classes  .
In June 2003, at the Anti-SARS Forum, held at the University of Pennsylvania, Hemispherx presented data from a comparative safety study of Alferon® N and Intron® A [see Adis Insight Drug profile 800009995], conducted in healthy volunteers  . Based on promising new results obtained from NIH sponsored independent laboratory research on human and related coronaviruses, Hemispherx will stockpile injectable and/or oral formats of Alferon® N and Ampligen®  .
In December 2003, Hemispherx initiated a strategic programme with Aplicare to package more than 100 000 sachets of Alferon LDO® (Low Dose Oral Interferon), as a topically applied experimental broad-spectrum immunotherapeutic/antiviral for SARS. This is designed to prevent the spread of SARS once the first cases are identified   .
Hemispherx announced the initiation of a new joint multi-part clinical programme for the treatment of SARS in collaboration with Vanderbilt University in January 2004. As part of the programme, Alferon N Injection® will be used in a placebo-controlled, double-blind clinical trial to evaluate its efficacy in the treatment of SARS. In a parallel second trial Alfredo LDO® will be evaluated versus placebo for efficacy in prophylaxis of infection by SARS  . A further collaboration with the Princess Margaret Hospital in Hong Kong, announced in November 2004, involves a randomised dose-ranging study of Alferon® LDO in normal volunteers and or asymptomatic subjects with exposure to a person known to have SARS or possible SARS  .
Small cell lung cancer
Phase II development of interferon-α-n3 injection was underway in patients with small cell lung cancer in the US. However, no development was reported and development in this indication is presumed discontinued.
West Nile Virus programme
Clinical development of Alferon N Injection® was continuing for the treatment of West Nile virus infection. However, the company stated that its ability to continue the study was hampered by a significant reduction in the number of confirmed cases of the disease. An investigator sponsored US-based phase II/III trial is also being planned (Hemispherx Biopharma Form 10-K, March 2010).
Hemispherx has initiated a joint clinical programme with New York Hospital for the treatment of West Nile Virus (WNV) infection with Alferon N Injection®. The phase IIb placebo-controlled, double-blinded study is designed to evaluate the efficacy of Alferon® N when administered to patients with, or at high risk of, acute meningoencephalitis caused by WNV infection. In view of the spread of WNV infections into twelve states in the US, Hemispherx announced in July 2004 that it would be accelerating the clinical activities for Alferon®N. As of August 2007, enrolment in the phase IIb trial had reached approximately the 50% mark     .
Zika virus infection
In February 2016, Hemispherx announced its intention to explore the oral use of Alferon® LDO in non-pregnant patients with Zika virus infection. The study aims to establish whether or not Alferon® 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  .
Kaposi's sarcoma (AIDS-related)
Phase II trials were underway in Mexico in patients with AIDS-related Kaposi's sarcoma. However, development appears to have been discontinued.
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 interferon-α-n3 as a preventative for seasonal and pandemic influenza  .