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Rintatolimod

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Rintatolimod
Clinical data
Trade namesAmpligen
Other namesPolyI:PolyC12U
Routes of
administration		IV
ATC code
  • none
Identifiers
  • 5'-Inosinic acid, homopolymer, complex with 5'-cytidylic acid polymer with 5'-uridylic acid (1:1)
CAS Number
UNII
KEGG
NIAID ChemDB
CompTox Dashboard (EPA)
Chemical and physical data
3D model (JSmol)
  • O=P(O)(O)OC[C@H]3O[C@@H](n1c2N\C=N/C(=O)c2nc1)[C@H](O)[C@@H]3O.O=C1/N=C(/N)\C=C/N1[C@@H]2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O.O=C/1NC(=O)N(\C=C\1)[C@@H]2O[C@@H]([C@@H](O)[C@H]2O)COP(=O)(O)O
  • InChI=1S/C10H13N4O8P.C9H14N3O8P.C9H13N2O9P/c15-6-4(1-21-23(18,19)20)22-10(7(6)16)14-3-13-5-8(14)11-2-12-9(5)17;10-5-1-2-12(9(15)11-5)8-7(14)6(13)4(20-8)3-19-21(16,17)18;12-5-1-2-11(9(15)10-5)8-7(14)6(13)4(20-8)3-19-21(16,17)18/h2-4,6-7,10,15-16H,1H2,(H,11,12,17)(H2,18,19,20);1-2,4,6-8,13-14H,3H2,(H2,10,11,15)(H2,16,17,18);1-2,4,6-8,13-14H,3H2,(H,10,12,15)(H2,16,17,18)/t4-,6-,7-,10-;2*4-,6-,7-,8-/m111/s1 checkY
  • Key:KNUXHTWUIVMBBY-JRJYXWDASA-N checkY
  (verify)

Rintatolimod, sold under the tradename Ampligen, is a medication intended for treatment of chronic fatigue syndrome (CFS).[1] Low-strength evidence indicates it can diminish CFS symptoms.[1]

It is an immunomodulatory double-stranded RNA drug similar to the prototypical RNA poly I:C, first synthesized in the 1970s and manufactured by Hemispherx Biopharma.[2]

Although Ampligen was cleared for use in Canada in 1997,[3] and obtained orphan drug status for treatment of CFS in the European Union in 2000,[4] it is so far without FDA approval, so is classed as experimental in the United States. In 2007, Hemispherx filed a new drug application with the U.S. Food and Drug Administration (FDA) to market and sell rintatolimod for the treatment of CFS,[5] but this was rejected in December 2009, because the FDA concluded that the two randomized controlled trials "did not provide credible evidence of efficacy"[6][7] and "because of clinical, statistical, clinical pharmacology, nonclinical, product quality, and facilities inspection deficiencies."[8] 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, but did not submit additional trials for review. Four months later, a committee of the FDA voted 8-5 against approval for rintatolimod, again citing insufficient data.[8]

Medical uses

For people with CFS, low-quality evidence showed that rintatolimod can improve the quality of life.[1] Rintatolimod is designed to boost cellular defenses against viruses and tumors, and could be synergistic with other antivirals used for avian influenza.[9][10]

Side effects

An independent review of rintatolimod trials in CFS was published in the December 2006 issue of the Journal of Clinical Virology.[11] It concluded that Ampligen has been "generally well tolerated", with a "low incidence of clinical toxicity", particularly when compared with the toxicity of the diseases it is used to treat. "No serious safety issues have resulted from the administration of about 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."[12] A mild flushing reaction has occurred in about 15% of patients, and more rarely reported side effects include chills, fever, malaise, leukopenia, neutropenia, and leukocytosis. Some of these side effects may be attributed to a temporary Herxheimer reaction in response to pathogen die-off. According to Hemispherx and patient testimonials, side effects, when they occur, usually subside within 3-4 months or less.[13][14]

Mechanism of action

One mode of action of this drug is to protect and stimulate the innate immune system, also called the nonspecific immune system, and the first line of defense. According to a study published in the Journal of Immunology[15] and reflected in a press release by Hemispherx,[16] Rintatolimod protects and stimulates the innate immune system by binding to toll-like receptors 3 (TLR-3), and activating the TLR-3 receptors for broad-spectrum immune response. TLR-3 receptors are located intracellular at the membranes of endosomes. They are part of a 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, including otherwise lethal viruses and various forms of cancer. When, for example, double-stranded RNA molecules from an RNA viral infection bind to TLR-3 receptors, the virus in this way inactivates the innate immune system, rendering it unable to signal the rest of the body's defenses. When rintatolimod binds to TLR-3 receptors, the virus cannot do so, and the body is able to marshal its defenses and launch an assault on the virus.

The mechanism of rintatolimod in relation to CFS is not certain, but is thought to include the RNase L enzyme.[17] Rintatolimod is a dsRNA, and when TLR-3 senses a dsRNA, it is thought to relay a message to cells to produce interferons (IFNs).[18] IFNs are a group of signaling molecules released by cells in response to the presence of pathogenic viruses or bacteria. These signaling molecules activate (among other things) the protective defenses of the immune system that eradicate pathogens. One such defense mechanism thought to be activated by rintatolimod is the production of the enzyme RNase L. This enzyme degrades pathogenic RNA, both viral and cellular. Degradation of RNA prevents viral and cell replication, and destruction of all RNA within a virus or cell is the last step before apoptosis or death. Accumulation of an inactive form of RNase L may be associated with CFS.[19]

History

Rintatolimod development evolved from a 1960s synthesis by Merck & Co., a double-stranded RNA compound of inosinic and cytidylic acid residues (poly I:poly C or poly I:C). Poly I:C inhibited tumor growth by inducing IFN production, but was too toxic to use. In the mid-1970s, William A. Carter, a postdoctoral researcher at Johns Hopkins University, modified the dsRNA molecule by adding uridylic acid molecules at specific intervals along the RNA chain. The new compound, called Ampligen (for AMPLIfied GENetic activity) stimulated interferon production like poly I:C, but with much lower toxicity.[20] It is also known as "poly I:poly C12U".

Dr. 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 nontherapeutic uses, such as diagnostic testing for HIV and protecting plants from pathogens.[21]

Rintatolimod was tested in clinical trials in the United States 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, the chance of approval for a large trial being conducted in the USA was thought to be gone. Hemispherx then began to move clinical trials to Canada and Belgium.[22]

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 CFS and HIV treatment since 1996, with marketing rights controlled by Biovail Corporation International.[23] 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.[24] 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.[25] The marketing agreement with Bioclones was terminated in 2005.[26] 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).[27]

According to the US National Academy of Sciences Institute of Medicine, "Chronic fatigue syndrome is a disease characterized by profound fatigue, cognitive dysfunction, sleep abnormalities, autonomic manifestations, pain, and other symptoms that are made worse by exertion of any sort. CFS can severely impair patients’ ability to conduct their normal lives."[28] In October 2007, Hemispherx BioPharma submitted their first new drug application (NDA) to the FDA for rintatolimod to treat CFS. In December 2007, the agency deemed the application incomplete, citing deficiencies including lack of dose ranging, statistical analysis plans inconsistent with protocols, database discrepancies, and lack of clinical pharmacology and carcinogenicity data.[29] In early 2009, Hemispherx again submitted rintatolimod for FDA approval for CFS treatment. The FDA scheduled their decision for May 25th of that year and twice postponed.[30][31] The company received a complete response letter from the agency on rintatolimod's NDA in December 2009, requesting further data.[32]

In 2007, and again during the 2009 swine flu pandemic, Carter said that rintatolimod could also be used as an H1N1 flu vaccine booster, citing in vitro studies with Ampligen and neuraminidase inhibitors oseltamivir and zanamivir (brand names Tamiflu and Relenza).[33]

Hemispherx Biopharma continues to work with the FDA on rintatolimod approval for CFS treatment. On December 20, 2012, an FDA Advisory Committee voted in favor of rintatolimod's safety for commercial use (vote 8 to 5), but not in favor of its efficacy (4 to 9).[34] The Complete Response Letter asked for more study data prior to rintatolimod approval.[35] On January 12, 2015, the company released new in vitro study findings showing that low natural killer cell function associates with greater CFS disease symptom severity, and that rintatolimod treatment increases average NK cell activity over 100%. The new study report, "Low Natural Killer (NK) Activity Observed Across the Chronic Fatigue Syndrome (CFS) Disease Spectrum," has been submitted as a scientific paper for peer review and publication. In addition to the new study findings, the paper summarizes six supportive publications of results with more than 150 CFS patients, correlating increased debility of CFS and low NK cell activity.[36] Clinical testing is currently under way to determine whether NK cell activity augmentation by rintatolimod in vivo associates with lessened CFS disease severity and increased physical endurance and performance measures.[36]

Controversy

In 1998 and 2000, Hemispherx received notices of violation from the FDA for promoting rintatolimod as safe and effective before FDA approval, in violation of the Federal Food, Drug, and Cosmetic Act.[37][38]

Also in the late 1990s, Manuel Asensio reported on Hemispherx, saying the company was overvalued. He criticized Hemispherx and its rintatolimod results,[39] alleging a variety of misdemeanors, including accusations of refusing to supply rintatolimod after clinical trials have ended,[40] and issuing misleading results to widen markets for rintatolimod.[39]

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.[26] After a jury rejected the defamation claims against Asensio, a mistrial was declared.[41]

On November 2, 1999, Mary Schweitzer, a CFS patient who had been treated with rintatolimod, raised the question of why Ampligen has 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.[42] Grassroots activism for FDA approval of Ampligen grew and continues. Efforts in 2015 to spur FDA approval of Ampligen include petitions,[43] appeal for congressional hearing,[44] and popular social media group organizing.[45][46][47][48]

Adam Feuerstein, a journalist for The Street,[49] has published several articles harshly critical of Hemispherx BioPharma, Inc. In June 2009, Feuerstein alleged the company was "seeking to divert investors' attention away from the delayed approval of Ampligen as a treatment for chronic fatigue syndrome" by issuing three press releases in seven days about research from 2007 into possible applications for Ampligen as a flu vaccine booster, in which Hemispherx stated that Ampligen could be used against the H1N1 swine flu.[50] This article also alleged the press releases were misleading, because they implied the research had been done in 2009. When Hemispherx offered Ampligen as a potential H1N1 vaccine or vaccine booster, the U.S. government turned them down, and Feuerstein wrote, "Hemispherx Biopharma has been shut out of the U.S. government's efforts to stockpile vaccine against the H1N1 flu."[51]

Research

Rintatolimod has been studied in humans since 1994.[52] In early 2015, the AMP 511 open-label study of rintatolimod in CFS was still recruiting participants.[53] 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 investigational drug until marketing approval is obtained.[54] Hemispherx management had missed several target deadlines for NDA filing in the past, including the end of 2005, the third quarter of 2006, and the first quarter of 2007.[55] In October 2007, the US FDA Ampligen NDA was filed.[5][56] In December 2009, the FDA issued a complete response letter refusing Hemispherx'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 recommended a minimum of one additional six-month, 300-patient study, and rodent carcinogenicity studies.

Rintatolimod is administered intravenously. It is generally administered twice weekly for periods of one year or longer. Two toxicology studies had been completed as of 2007, which established the safety of intranasal and intramucosal methods of Ampligen administration as a vaccine immunostimulant.[57][full citation needed] Hemispherx has conducted research on a by mouth versions of rintatolimod using nucleic acid technology related to rintatolimod.[58][59]

References

  1. ^ a b c Smith, ME; Haney, E; McDonagh, M; Pappas, M; Daeges, M; Wasson, N; Fu, R; Nelson, HD (16 June 2015). "Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop". Annals of Internal Medicine. 162 (12): 841–50. doi:10.7326/M15-0114. PMID 26075755.
  2. ^ Official website
  3. ^ http://wwcoco.com/cfids/ampligen2.html
  4. ^ http://www.cfsfacts.org/2009/12/facts-about-ampligen-research-in-cfs.html
  5. ^ a b 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
  6. ^ George, John (December 3, 2009). "FDA rejects Hemispherx's chronic fatigue drug Ampligen". Philadelphia Business Journal. Retrieved 2010-02-12.
  7. ^ http://www.thestreet.com/_yahoo/story/10636318/1/hemispherxs-ampligen-dealt-fda-blow.html
  8. ^ a b Drug Development for Myalgic Encephalomyelitis and Chronic Fatigue Syndrome (ME and CFS): Questions and Answers - Food and Drug Administration, 5 February 2013
  9. ^ Alibek K, Liu G (May 2006). "Biodefense shield and avian influenza". Letter. Emerg Infect Dis. PMC 3374437. PMID 16710964. Retrieved 2007-12-14. {{cite journal}}: Cite journal requires |journal= (help)
  10. ^ "Hemispherx Presents Evidence of Ampligen Synergies with Existing Antivirals at International Avian Influenza Conference". BUSINESS WIRE. 2007-06-04. Retrieved 2008-04-26.
  11. ^ http://www.journalofclinicalvirology.com/article/S1386-6532(06)70079-8/abstract
  12. ^ 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.
  13. ^ "Ampligen: Adrienne Dellwo (Updated 2014)"
  14. ^ "FDA Letter Section: Abstracts of Patient Session on Ampligen (1998)"
  15. ^ Gowen BB, Wong MH, Jung KH, Sanders AB, Mitchell WM, Alexopoulou L, Flavell RA, Sidwell RW (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.
  16. ^ New Report Illuminates Ampligen’s Unique Mechanism of Action Hemispherx Biopharma’s Proprietary Experimental Therapeutic Activates TLR-3 Receptor to Potentiate Broad-Spectrum Immune Response
  17. ^ 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.
  18. ^ Liang, Shu-Ling (2006). "RNase L: Its biological roles and regulation". IUBMB Life. 58 (9): 508–514. doi:10.1080/15216540600838232. PMID 17002978.
  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. ^ Kitei, Mindy. A History of Ampligen: The AIDS Drug No One Can Have." Philadelphia Magazine. October 1994. Retrieved on February 25, 2007.
  21. ^ "Business Description: HEM Research, Inc." 1986. Retrieved on February 25, 2007.
  22. ^ Johnson, H (1996). Osler's Web: Inside the Labyrinth of the Chronic Fatigue Syndrome Epidemic. Crown Publishing Group. pp. 647–9. ISBN 978-0517703533.
  23. ^ Melnyk, Eugene; Howling, Kenneth G. "Biovail Acquires Ampligen Marketing Rights for Canada; New Treatment for Chronic Fatigue Syndrome." Biovail Corporation International|Biovail. February 11, 2000. Retrieved on February 25, 2007.
  24. ^ "SEC Filing (Form S-3): Hemispherx Biopharma, Inc.." January 14, 2003. Retrieved on February 25, 2007.
  25. ^ "Mismatched Double-Stranded RNA: Ampligen, Oragen, Polyi:Polyc12u." Drugs in R&D. February 1, 2002. Retrieved on February 26, 2007.
  26. ^ a b "HEMISPHERX BIOPHARMA INC, Form 10-K, Annual Report, Filing Date Mar 19, 2007". secdatabase.com. Retrieved May 15, 2018.
  27. ^ "Securities and Exchange Commission
  28. ^ "Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness" February 10, 2015
  29. ^ https://www.fda.gov/Drugs/NewsEvents/ucm337759.htm ["FDA Drugs: News & Events"]Last Updated 02/05/2013: Retrieved February 21, 2015
  30. ^ "Hemispherx Biopharma, HEB - Losing Ground" June 5, 2009
  31. ^ "Hemispherx says FDA decision on Ampligen months away" John George, Philadelphia Business Journal, July 22, 2009
  32. ^ "Hemispherx gets FDA Complete Response Letter on Ampligen NDA" Dec 1, 2009
  33. ^ "Ampligen Synergies with Existing Avian Flu Antivirals" (June 4, 2007) Retrieved February 21, 2015
  34. ^ "US National Academy of Sciences Institute of Medicine Reframes Chronic Fatigue Syndrome (CFS)"
  35. ^ https://www.fda.gov/Drugs/NewsEvents/ucm337759.htm ["FDA Drugs: News & Events"] Last Updated 02/05/2013: Retrieved February 21, 2015]
  36. ^ a b "Hemispherx Press Release" (February 23, 2015)
  37. ^ Notice of Violation - FDA, 7 July 2000,
  38. ^ Notice of Violation - FDA, 15 Oct 1998
  39. ^ a b Asensio & Company: Hemispherx Analyst Makes False Ampligen HIV Efficacy Claims Despite Failed Test and FDA Violation Notice Archived August 28, 2006, at the Wayback Machine
  40. ^ Ampligen: Excerpts from Osler's Web Archived February 4, 2007, at the Wayback Machine
  41. ^ Securities and Exchange Commission
  42. ^ "My History with ME/CFS:Mary M. Schweitzer, Ph.D."
  43. ^ http://wh.gov/iTFRb
  44. ^ "Congressional Hearing:Ampligen FDA Roadblocks"
  45. ^ "Ampligen Facebook Page"
  46. ^ "Hunger Strike for Ampligen"
  47. ^ "Why No Antivirals & Ampligen?" (2011) YouTube Video
  48. ^ "Ampligen patient speaking to an FDA representative" (2013) YouTube Video
  49. ^ "Adam Feuerstein: Profile"
  50. ^ "Hemispherx Builds False Hope on Old Data," Adam Feuerstein, The Street, June 5, 2009
  51. ^ "Hemispherx Not Among 4 to Get H1N1 Flu Contracts" Adam Feuerstein, The Street, July 14, 2009
  52. ^ 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.
  53. ^ ClinicalTrials.gov: Study of Ampligen in Chronic Fatigue Syndrome
  54. ^ fda.gov: Guidance for Institutional Review Boards and Clinical Investigators
  55. ^ "HEMISPHERX BIOPHARMA INC, Form 8-K, Current Report, Filing Date Jan 3, 2006". secdatabase.com. Retrieved May 14, 2018.
  56. ^ "Ampligen". Hemispherx Biopharma. Retrieved 2008-04-26.
  57. ^ , p. 20
  58. ^ "Hemispherx Biopharma Receives New Patents for Oral Broad-Spectrum Immune Activators (2003)" Retrieved February 8, 2015
  59. ^ "Mismatched double-stranded RNA: polyI:polyC12U". Drugs in R&D. 5 (5): 297–304. 2004. doi:10.2165/00126839-200405050-00006. PMC 7100700. PMID 15357629.
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