Ampligen®[polyI:polyC12U] is a mismatched double-stranded RNA that acts by inducing interferon production (immunomodulator) and by activating an intracellular enzyme (RNase-L) against viral RNA transcripts (antiviral). Ampligen®, currently under development by Hemispherx Biopharma in the US, acts on the immunological system through T-lymphocyte stimulation and is indicated for the treatment of chronic fatigue syndrome and acquired immunodeficiency deficiency syndrome (AIDS), as part of the combined therapy.Ampligen®is available for licensing worldwide.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 Ampligen®for the potential treatment of chronic fatigue syndrome in Germany, Switzerland and Austria. An option fee of euro400 000 was paid pursuant to the terms of the option agreement and upon execution of the Distribution Agreement, Fujisawa will pay Hemispherx fees and milestone payments with a potential worth of several millions of dollars.[1]In September 2003, Hemispherx Biopharma Inc. entered into an agreement with Guangdong Medicine Group Corporation to organise clinical trials, marketing, sales and distribution for both of its lead compounds, Ampligen®and Alferon N®in the People's Republic of China. The agreement stipulates that the Guangdong Medicine Group Corporation (GMC) will conduct clinical trials with Ampligen®for the treatment of HIV. All costs related to the trials are to be covered by GMC. Additionally, GMC has to develop and implement marketing and promotional programmes.[2]In May 2003, Hemispherx Biopharma and the Center for Cell and Gene Therapy entered into a research project agreement that will see Ampligen®implemented in a protocol used in patients with relapsed EBV-positive Hodgkin's Lymphoma.[3]In March 2002, Esteve and Hemispherx Biopharma entered into a collaborative agreement under which Esteve will be the sole distributor of Ampligen®in Spain, Portugal and Andorra for the treatment of chronic fatigue syndrome. 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 coinfected with HIV/HCV.In July 2001 Hemispherx Biopharma announced that it had formed a strategic alliance with Empire Health Resources for clinical trials of Ampligen®in the treatment of HIV and hepatitis C virus infections. Empire Health Resources, a healthcare management firm, will be responsible for accrual and retention of patients for HIV trials, and protocols for trials in patients with hepatitis C or both HIV and hepatitis C infections.Hemispherx has entered into a collaboration with RED Laboratories, and RED Laboratories NV expects that this will facilitate the continued development of Ampligen®. Hemispherx has also entered into an agreement with Schering Plough to use a Schering facility as its principal manufacturing platform in the US. This agreement may be expanded to include other territories.Hemispherx and AOP Orphan Pharmaceuticals have signed a marketing agreement for Ampligen®for the treatment of chronic fatigue syndrome for Austria, the Czech Republic, Poland and Hungary.In an arrangement between Hemispherx and Bioclones, Bioclones has certain marketing rights for Ampligen®in the Southern Hemisphere, UK and Ireland.In the US, Ampligen®has been granted orphan drug status for the treatment of AIDS, renal cell carcinoma (phase II, completed), chronic fatigue syndrome (phase III) and invasive/metastatic malignant melanoma (phase II).In August 2004, Hemispherx announced that it intends to use the proceeds from the private placement of company stock to complete the clinical work for its immunotherapeutics/ antivirals Ampligen®and Oragens™.Previously, Hemispherx submitted an application to the EMEA for the approval of Ampligen®for the treatment of chronic fatigue syndrome; the first stage of the regulatory review has been cleared. In 2000, Hemispherx Europe (Hemispherx) obtained orphan drug status for Ampligen®for the treatment of chronic fatigue syndrome in the EU, providing Hemispherx with 10 years of marketing exclusivity following the launch of the drug, as well as potential financial research benefits for the agent.In February 2000, Crystaal Corporation (now Biovail Pharmaceuticals Canada) acquired exclusive marketing rights to Ampligen®in Canada, where it submitted an NDA for the agent for the treatment of chronic fatigue syndrome. In the meantime, Ampligen®has been available since May 1996 under the Canadian Emergency Drug Release Programme for the treatment of chronic fatigue syndrome and immune dysfunction syndrome by Rivex Pharma (Helix BioPharma).Bioclones has initiated clinical studies with Ampligen®for the treatment of chronic fatigue syndrome in Australia. The active substance for Ampligen®is manufactured by F.H. Faulding Ltd. Clinical treatment programmes for chronic fatigue syndrome in other Pacific Rim countries are planned. Ampligen®is available for severe chronic fatigue syndrome on a named patient, cost-recovery basis in South Africa.Hemispherx has developed a ‘ready-to-use’ liquid formulation of the drug and has begun treating patients with chronic fatigue syndrome in ongoing clinical trials. Hemispherx has also developed an oral version of the drug (Oragen®), which is undergoing preclinical evaluation.In February 2001, Hemispherx Biopharma announced that it was initiating phase II/III trials of Ampligen®in the treatment of late-stage, multidrug-resistant strains of HIV in the European Union. Patients treated in these studies will have exhausted all other treatment options.In July 2001, Hemispherx stated that Ampligen®was being evaluated in a phase IIb trial in patients with HIV in the US. The trial, comprising two studies, REARMI and REARMII (Research/Evaluation of Ampligen®for Retroviral Mutations I and II), will evaluate the ability of Ampligen®to prevent the emergence of mutated, drug-resistant strains of the virus. ‘Several hundred’ patients currently on antiretroviral therapy and at risk of viral relapse will be enrolled at centres in Connecticut, New York, Florida and California. A second phase IIb study evaluating the effect of Ampligen®on structured treatment interruptions (STI) is also underway. Final results from this study were reported in December 2002.NIH sponsored studies of potential therapies for SARS have identified Ampligen®as having unusually high and consistent antiviral activity against human coronavirus, the pathogen implicated as the causative agent of the disease. Ampligen®demonstrated very high potency at very low concentrations (0.4 µg/mL) and had a favourable safety profile.[4]In October 2003, Hemispherx announced that, based on these promsing new results, the company will stockpile injectible and/or oral formats of Ampligen®and Alferon N®.[5]Independent researchers have demonstrated the antiviral activity of Ampligen®against flaviviruses (West Nile virus, Equine Encephalitis virus, Dengue fever virus and Japanese Encephalitis virus) as well as virus classes associated with bioterrorism. In an animal study, Ampligen®was shown to prevent destruction of nerve cells, reduce virus concentrations in the brain and blood stream and increase survival rates.[6]Researchers at the Rega Institute in Belgium have published results from an animal study demonstrating that Ampligen®was superior at protecting mice against coxsackie B3 virus-induced myocarditis compared with pegylated interferon.[7]In May 2004 Hemispherx announced that it had filed an expanded US patent application covering the use of Ampligen®for the potential treatment and prevention of severe acute respiratory syndrome (SARS) and dreaded emerging viruses.