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Systematic (IUPAC) name
5'-Inosinic acid, homopolymer, complex with 5'-cytidylic acid polymer with 5'-uridylic acid (1:1)
Clinical data
Trade names Ampligen
Legal status
Routes IV
CAS number 38640-92-5
ATC code None
ChemSpider 34908 YesY
UNII 94325AJ25N
NIAID ChemDB 000136
Synonyms PolyI:PolyC12U
Chemical data
Formula ?
 YesY (what is this?)  (verify)

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.[citation needed] 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,[1] but this was rejected in December 2009 because the FDA concluded that the two RCTs "did not provide credible evidence of efficacy"[2][3] and "because of clinical, statistical, clinical pharmacology, nonclinical, product quality, and facilities inspection deficiencies."[4] 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."[4]


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.[5]

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.[6]

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.[7]

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.[8] 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.[9] 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.[10] The marketing agreement with Bioclones was terminated in 2005.[11] 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).[12]

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.

In 2009, William Carter said that rintatolimod could be a booster for a flu vaccine to the H1N1 flu and fight the 2009 swine flu outbreak.[13]

The FDA postponed an announcement about rintatolimod scheduled for May 25, 2009 for "one to two weeks." [14] 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."[15]

The company received a Complete Response Letter from the FDA on Ampligen's NDA in December 2009.[16]

Hypothesized mechanism of action[edit]

The manufacturer says rintatolimod acts by stimulating the innate immune system. According to a study published in the Journal of Immunology[17] and a press release by Hemispherx,[1] 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.[18] When TLR3 senses a dsRNA, it is thought to relay a message to the cell to produce interferons (IFNs).[citation needed] 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.[19]

Clinical trials and approval status[edit]

A randomized study of rintatolimod (AMP 516 Phase III clinical trial for treatment of CFS) in the USA was completed in 2004.[20] The AMP 511 open-label study of rintatolimod in CFS is still recruiting participants.[21] 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.[22] 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.[23] In October 2007, the US Food and Drug Administration (FDA) Ampligen NDA was filed.[1][24] 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.[25] Hemispherx states it is currently researching an oral drug that uses nucleic acid technology related to rintatolimod.[26]


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,[27] 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.[28][29]

Side effects and safety[edit]

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."[30] 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.[31] The extent of these side-effects is unknown. According to Hemispherx, side-effects usually subside within "several months".[citation needed]


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.[32][33]

Manuel Asensio, an investment adviser who reports on companies he considers to be overvalued, has criticized Hemispherx and its rintatolimod results,[34] alleging a variety of misdemeanors including accusations of refusing to supply rintatolimod after clinical trials have ended,[35] and issuing misleading results to widen markets for rintatolimod.[34]

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.[36]

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.[37]

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.[13] 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."[38]

Other uses[edit]

The manufacturer says rintatolimod can be used for Avian Flu[39][40][41] and AIDS,[42][43] although studies have been limited.[44] Other suggested uses include Ebola and Smallpox.[45]

See also[edit]


  1. ^ a b c Hemispherx Biopharma Files New Drug Application for Ampligen as Treatment of Chronic Fatigue Syndrome NDA of investigational drug includes four well-controlled trials, more than 1,200 trial subjects and 90,000 doses
  2. ^ George, John (Modified: Thursday, December 3, 2009). "FDA rejects Hemispherx's chronic fatigue drug Ampligen". Philadelphia Business Journal. Retrieved 2010-02-12.  Check date values in: |date= (help)
  3. ^ http://www.thestreet.com/_yahoo/story/10636318/1/hemispherxs-ampligen-dealt-fda-blow.html
  4. ^ a b Drug Development for Myalgic Encephalomyelitis and Chronic Fatigue Syndrome (ME and CFS): Questions and Answers - Food and Drug Administration, 5 February 2013
  5. ^ Kitei, Mindy. A History of Ampligen: The AIDS Drug No One Can Have." Philadelphia Magazine. October 1994. Retrieved on February 25, 2007.
  6. ^ "Business Description: HEM Research, Inc." 1986. Retrieved on February 25, 2007.
  7. ^ Johnson, H (1996). Osler's Web: Inside the Labyrinth of the Chronic Fatigue Syndrome Epidemic. Crown Publishing Group. pp. 647–9. ISBN 051770353X. 
  8. ^ Melnyk, Eugene; Howling, Kenneth G. "Biovail Acquires Ampligen Marketing Rights for Canada; New Treatment for Chronic Fatigue Syndrome." Biovail. February 11, 2000. Retrieved on February 25, 2007.
  9. ^ "SEC Filing (Form S-3): Hemispherx Biopharma, Inc.." January 14, 2003. Retrieved on February 25, 2007.
  10. ^ "Mismatched Double-Stranded RNA: Ampligen, Oragen, Polyi:Polyc12u." Drugs in R&D. February 1, 2002. Retrieved on February 26, 2007.
  11. ^ "p. 35
  12. ^ "Securities and Exchange Commission
  13. ^ a b "Hemispherx builds false hope on old data," Adam Feuerstein, The Street, June 5, 2009
  14. ^ "Hemispherx says FDA decision on Ampligen months away" John George, Philadelphia Business Journal, July 22, 2009
  15. ^ "Hemispherx Biopharma,HEB - Losing Ground" June 5, 2009
  16. ^ "Hemispherx gets FDA Complete Response Letter on Ampligen NDA" Dec 1, 2009
  17. ^ Gowen BB, Wong MH, Jung KH, et al. (April 2007). "TLR3 is essential for the induction of protective immunity against Punta Toro Virus infection by the double-stranded RNA (dsRNA), poly(I:C12U), but not Poly(I:C): differential recognition of synthetic dsRNA molecules". J. Immunol. 178 (8): 5200–8. doi:10.4049/jimmunol.178.8.5200. PMID 17404303. 
  18. ^ Suhadolnik RJ, Reichenbach NL, Hitzges P, Adelson ME, Peterson DL, Cheney P, Salvato P, Thompson C, Loveless M, Müller WE (1994). "Changes in the 2-5A synthetase/RNase L antiviral pathway in a controlled clinical trial with poly(I)-poly(C12U) in chronic fatigue syndrome". In Vivo (Athens, Greece) 8 (4): 599–604. PMID 7893988. 
  19. ^ Nijs J, De Meirleir K (2005). "Impairments of the 2-5A synthetase/RNase L pathway in chronic fatigue syndrome". In Vivo 19 (6): 1013–21. PMID 16277015. 
  20. ^ Edgar pro
  21. ^ ClinicalTrials.gov: Study of Ampligen in Chronic Fatigue Syndrome
  22. ^ fda.gov: Guidance for Institutional Review Boards and Clinical Investigators
  23. ^ Edgar pro
  24. ^ "Ampligen". Hemispherx Biopharma. Retrieved 2008-04-26. 
  25. ^ http://sec.gov/Archives/edgar/data/946644/000114420407023929/v074337_10q.htm, p. 20
  26. ^ http://www.hemispherx.net/content/rnd/drug_candidates.htm
  27. ^ Abstracts of Papers Presented at The Bi-Annual Research Conference of the American Association for Chronic Fatigue Syndrome (AACFS)
  28. ^ Suhadolnik RJ, Reichenbach NL, Hitzges P, et al. (1994). "Changes in the 2-5A synthetase/RNase L antiviral pathway in a controlled clinical trial with poly(I)-poly(C12U) in chronic fatigue syndrome". In Vivo 8 (4): 599–604. PMID 7893988. 
  29. ^ Strayer DR, Carter WA, Brodsky I, et al. (January 1994). "A controlled clinical trial with a specifically configured RNA drug, poly(I).poly(C12U), in chronic fatigue syndrome". Clin. Infect. Dis. 18 Suppl 1: S88–95. doi:10.1093/clinids/18.supplement_1.s88. PMID 8148460. 
  30. ^ Mitchell, W. (December 2006). "Review of Ampligen clinical trials in Chronic Fatigue Syndrome". Journal of Clinical Virology. 37, supp. 1: S113. doi:10.1016/S1386-6532(06)70079-8. Retrieved 2007-02-26. 
  31. ^ Ampligen - official Hemispherx site
  32. ^ Notice of Violation - FDA, 7 July 2000,
  33. ^ Notice of Violation - FDA, 15 Oct 1998
  34. ^ a b Asensio & Company: Hemispherx Analyst Makes False Ampligen HIV Efficacy Claims Despite Failed Test and FDA Violation Notice
  35. ^ Ampligen: Excerpts from Osler's Web
  36. ^ Securities and Exchange Commission
  37. ^ U.S. Department of Health and Human Services: Chronic Fatigue Syndrome Advisory Committee (CFSAC)
  38. ^ "Hemispherx Not Among 4 to Get H1N1 Flu Contracts" Adam Feuerstein, The Street, July 14, 2009
  39. ^ "Hemispherx Presents Evidence of Ampligen Synergies with Existing Antivirals at International Avian Influenza Conference". BUSINESS WIRE. 2007-06-04. Retrieved 2008-04-26. 
  40. ^ Alibek K, Liu G. (May 2006). "Biodefense shield and avian influenza". Letter. Emerg Infect Dis. Retrieved 2007-12-14. 
  41. ^ Hemispherix: The TLR3 Agonist, Poly I: Poly C12U, Provides Nasal Adjuvant Activity to a Vaccine Directed Against Highly Pathogenic H5N1 Avian Influenza Virus
  42. ^ ClinicalTrials.gov: The Role of Ampligen in Strategic Therapeutic Intervention (STI) of HAART
  43. ^ ClinicalTrials.gov: Safety and Efficacy of Ampligen in the Treatment of HIV Patients Failing HAART
  44. ^ Hemispherix: Product Candidates Under Development
  45. ^ wired.com: Smallpox Treatment or Snake Oil?

External links[edit]