|Systematic (IUPAC) name|
|5'-Inosinic acid, homopolymer, complex with 5'-cytidylic acid polymer with 5'-uridylic acid (1:1)|
|(what is this?)|
Rintatolimod (tradename Ampligen, also known as poly I:poly C12U), is an experimental immunomodulatory double stranded RNA drug developed by Hemispherx Biopharma of Philadelphia, Pennsylvania. Rintatolimod was first synthesized in the 1970s and has been proposed and tested as a treatment for illnesses including chronic fatigue syndrome (CFS) and acquired immunodeficiency syndrome (AIDS).
Hemispherx reports that it completed a Phase III clinical trial for CFS in 2004. In 2007 it filed a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) to market and sell rintatolimod for the treatment of CFS, but this was rejected in December 2009 because the FDA concluded that the two RCTs "did not provide credible evidence of efficacy" and "because of clinical, statistical, clinical pharmacology, nonclinical, product quality, and facilities inspection deficiencies." The FDA requested Hemispherx conduct at least one additional controlled trial to demonstrate efficacy in treating CFS. In August 2012 Hemispherx submitted further analyses of the original clinical trial data, although did not submit additional trials for review. Four months later a committee of the FDA voted 8-5 against approval for Ampligen, again citing "insufficient safety and efficacy data."
Rintatolimod was developed in the 1960s after Merck & Co. synthesized a double-stranded RNA compound composed of inosinic and cytidylic acid residues (poly I:poly C or poly I:C). Poly I:C inhibited tumor growth by inducing interferon production. In the mid-1970s, William A. Carter, a post-doctoral researcher at Johns Hopkins University, modified the dsRNA molecule by adding uridylic acid molecules at specific interval along the RNA chain. The new compound, called Ampligen (for AMPLIfied GENetic activity) stimulated interferon production like poly I:C, but was less toxic.
Carter founded a company based upon the compound and licensed it from Johns Hopkins. By the late 1980s, Carter and his company, HEM Research, Inc., were pursuing human therapeutic uses for rintatolimod, as well as non-therapeutic uses, such as diagnostic testing for HIV and protecting plants from pathogens.
Rintatolimod was tested in clinical trials in America beginning in 1988, after DuPont invested $30 million in Hemispherx. Initial success in a small trial for AIDS treatment was followed by difficulties in persuading the FDA to permit large scale trials. By 1991, it was thought that the chance of approval for a large trial being conducted in the USA had gone. Hemispherx then began to move clinical trials to Canada and Belgium.
In Belgium, rintatolimod has been available for use since the drug's trial beginning in May 1996. It has also been available under Canada's Emergency Drug Release Program for both chronic fatigue syndrome (CFS) and HIV treatment since 1996, with marketing rights controlled by Biovail Corporation International. An agreement between the Spanish company Esteve and Hemispherx in 2002 gave Esteve the rights to perform clinical trials at their own cost in Spain, Portugal, and Andorra. Bioclones (PTY) Ltd, a UK based company, was granted the exclusive marketing rights to rintatolimod in the United Kingdom, Ireland, and several countries in the Southern Hemisphere. The marketing agreement with Bioclones was terminated in 2005. Over its developmental history, rintatolimod has received various designations, including “orphan drug product” and “emergency compassionate cost recovery sales authorization” both from the FDA and "promising" clinical outcome recognition based on the evaluation of certain summary clinical reports (AHRQ, Agency Health Research Quality).
On December 3, 2007, the FDA deemed the NDA submitted by the company on October 10, 2007 to be incomplete. Specifically, eleven deficiencies were noted in the Clinical Section and three in the Pre-Clinical Section.
The FDA postponed an announcement about rintatolimod scheduled for May 25, 2009 for "one to two weeks."  Critics said that Hemispherx is regularly using "an eight year old government report to assure investors the company's chronic fatigue syndrome drug will be approved soon."
The company received a Complete Response Letter from the FDA on Ampligen's NDA in December 2009.
Hypothesized mechanism of action
The manufacturer says rintatolimod acts by stimulating the innate immune system. According to a study published in the Journal of Immunology and a press release by Hemispherx, rintatolimod binds to the Toll-like receptor 3 (TRL-3). TLR-3 is a receptor on the cell surface which is a part of an evolutionarily conserved family of “pattern recognition” receptors that detect pathogens immediately, even those the body has not yet encountered, long before adaptive immunity can intervene against foreign invaders. These receptors are critical to the first line of immunological defense against a broad range of pathogens and normally double-stranded RNA molecules from an infection with RNA viruses would bind to the TLR 3 receptors.
The mechanism of rintatolimod in relation to CFS is not known but it is thought to involve the RNase L enzyme. When TLR3 senses a dsRNA, it is thought to relay a message to the cell to produce interferons (IFNs). IFNs are a group of signaling molecules released by cells in response to the presence of pathogens such as viruses or bacteria. These signaling molecules activate (among others) the protective defenses of the immune system that eradicate pathogens. One such defense mechanism which is thought to be activated by Rintalolimod is the production of RNase L. This enzyme degrades all RNA in a cell (both cellular and viral). Degradation of all RNA within the cell is the cell's last stand against a virus before it attempts apoptosis. Accumulation of an inactive form of RNase L may be associated with CFS.
Clinical trials and approval status
A randomized study of rintatolimod (AMP 516 Phase III clinical trial for treatment of CFS) in the USA was completed in 2004. The AMP 511 open-label study of rintatolimod in CFS is still recruiting participants. Open-label studies are typically used when the controlled trial has ended and treatment is continued so that the subjects and the controls may continue to receive the benefits of the investigational drug until marketing approval is obtained. Hemispherx management had missed several target deadlines for new drug application (NDA) filing in the past, including the end of 2005, the third quarter of 2006, and the first quarter of the year 2007. In October 2007, the US Food and Drug Administration (FDA) Ampligen NDA was filed. In December 2009 the FDA issued a CRL refusing Hemisherx's new drug application for rintatolimod's treatment of CFS. The FDA concluded that the two RCTs "did not provide credible evidence of efficacy." The agency recommends a minimum of one additional six month 300 patient study, and rodent carcinogenicity studies.
Rintatolimod is received intravenously. It is generally administered twice weekly for periods of one year or greater. Two toxicology studies were recently completed that establish the safety of intranasal and intramucosal methods of rintatolimod administration. Hemispherx states it is currently researching an oral drug that uses nucleic acid technology related to rintatolimod.
Approximately 760 patients have received rintatolimod as part of clinical trials in the US, representing about 75,000 doses. Some chronic fatigue syndrome patients have reported a complete recovery, with others reporting clear and measurable improvements, although success has not been universal. More common benefits include improved cognitive skills, an increase in energy and greater oxygen uptake. These improvements can be measured on the Karnofsky scale.
Side effects and safety
Hemispherx consider that rintatolimod has been "generally well tolerated", with a "low incidence of clinical toxicity", particularly when compared to the toxicity of the diseases it is used to treat. "No serious safety issues have resulted from the administration of ~75,000 doses IV (most commonly 400 mg) twice weekly for up to one year periods or greater. Animal toxicity studies support this observation in humans with primates demonstrating the greatest margin of safety." A mild flushing reaction has occurred in about 15% of patients, and other reported side effects include chills, fever, malaise, leukopenia, neutropenia and leukocytosis. A full list is available on the Hemispherx website. The extent of these side-effects is unknown. According to Hemispherx, side-effects usually subside within "several months".
Hemispherx has on two occasions received warning letters from the FDA for its promotion of rintatolimod as safe and effective before approval from the FDA, in violation of the Federal Food, Drug, and Cosmetic Act.
Manuel Asensio, an investment adviser who reports on companies he considers to be overvalued, has criticized Hemispherx and its rintatolimod results, alleging a variety of misdemeanors including accusations of refusing to supply rintatolimod after clinical trials have ended, and issuing misleading results to widen markets for rintatolimod.
In 1998, Hemispherx Biopharma filed a complaint against Asensio and his company, alleging defamation, conspiracy and interference with its business relations through a short selling plot. After a jury rejected the defamation claims against Asensio, a mistrial was declared.
On November 2, 1999, Mary Schweitzer, a chronic fatigue syndrome patient who had been treated with rintatolimod, raised the question of why rintatolimod had never been fast-tracked by the US public health authorities at the Chronic Fatigue Syndrome Co-ordinating Committee of the U.S. Department of Health and Human Services.
In June 2009, The Street alleged Hemispherx was "seeking to divert investors' attention away from the delayed approval of rintatolimod as a treatment for chronic fatigue syndrome" by issuing three press releases in seven days about research from 2007 into possible applications for rintatolimod as a flu vaccine booster. Hemispherx stated that rintatolimod could be used against the H1N1 swine flu. The Street also alleged the Hemispherx press releases were misleading because they imply the research had been done in 2009. Hemispherx's attempts to put rintatolimod in the H1N1 market were unsuccessful. The company stated they were "shut out of the U.S. government's efforts to stockpile vaccine against the H1N1 flu."
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