Ampligen

Rintatolimod (tradename Ampligen) is a mismatched, double-stranded RNA molecule with immunomodulatory and antiviral properties. The drug acts as a TLR3 agonist which stimulates the production of interferons and tumor necrosis factors. It is manufactured by Hemispherx Biopharma.

It has been shown to raise natural killer cell function.

History
Ampligen was based on a double-stranded RNA (dsRNA) compound developed by the pharmaceutical company, Merck, in the 1960s, as a potential cancer drug. Though effective in the petri dish, the original compound proved to be too toxic for human use.

William A. Carter, MD, a researcher at John Hopkins University, was able to modify the compound in the 1970s to reduce its toxicity (see section below on "Mechanism of action"). The new compound was named Ampligen, short for “AMPLIfied GENetic activity.” Dr. Carter obtained the license for the compound from John Hopkins University and started Hemispherx Biopharma to develop it.

In the late 1980s, Hemispherx Biopharma partnered with Dupont to start clinical trials for Ampligen. After a couple years, Dupont severed its business relationship with Hemispherx Biopharma.

Through the years, Dr. Carter's confidence in Ampligen's ability to stimulate the body's immune system lead to him offering the drug as a treatment for a variety of diseases including cancer, AIDS, chronic fatigue syndrome, hepatitis C, Gulf War Illness, swine flu, and ebola. Hemispherx Biopharma stated: "...we believe that Ampligen® may have broad-spectrum anti-viral and anti-cancer properties."

This over-confidence resulted in a case action suit by stockholders in 2013.

Testing for efficacy in ME/CFS started in 1990 and continues to the present (see section below on "Drug approval status"). Testing for other conditions has been sporadic. At present the University of Pittsburgh is sponsoring Phase I/II studies using Ampligen as an adjunct treatment in ovarian, peritoneal, and colorectal cancer.

In 2015, Hemispherx Biopharma partnered with a European company, myTomorrows, to bring Ampligen to the EU and Turkey through an Early Access Program for experimental drugs.

In late fall 2015, Dr. Francis Collins announced that the NIH was considering the possibility of sponsoring a clinical trial for Ampligen, as well as Rituximab and other treatments.

Mechanism of action


The chemical formation of Ampligen begins with the known immunostimulant called Polyinosinic:polycytidylic acid (usually abbreviated Poly I:C). Poly I:C is a mismatched double-stranded RNA (dsRNA) with one strand being a polymer of inosinic acid and the other strand a polymer of cytidylic acid.

Poly I:C is structurally similar to the type of dsRNA present in some viruses. When introduced into the body it stimulants the immune system because the body thinks a virus is present.

Ampligen is formed when uridine (one of the five standard nucleosides which form the building blocks of RNA) is introduced into this Poly I:C strand, altering the strand to Poly I:C12U.

As a result, one strand of the dsRNA is a homopolymer, poly rI and annealed to this strand is a heteropolymer, polyC12U.

This alteration increases the compound's instability and shortens the half life to less than 40 minutes after IV administration. Plasma RNase (an enzyme naturally present in blood) degrades the Ampligen compound into separate ribonucleotides which are completely natural degradation products the body can easily handle, thus lessening its toxicity.

Ampligen is a TLR3 agonist. It stimulates the production of toll-like receptor 3 (TLR3), which is a naturally occurring protein. TLR3 recognizes the dsRNA present in some viruses, such as retroviruses, and stimulates a series of biochemical reactions that result is an increase in the production of interferon. Interferon, an important player in the body's immune system, protects against viral infections and activates immune cells, such as natural killer cells (NK cells).

Evidence in ME/CFS
In 2016, William M. Mitchell published a review in the journal, Expert Review of Clinical Pharmacology that stated: "Rintatolimod has achieved statistically significant improvements in primary endpoints in Phase II and Phase III double-blind, randomized, placebo-controlled clinical trials with a generally well tolerated safety profile and supported by open-label trials in the United States and Europe." Mitchell is the Chairman of the Board for Hemispherx Biopharma and a Professor of Pathology, Microbiology and Immunology at Vanderbilt University School of Medicine, Nashville, Tennessee.

In 1994, a study done by the Department of Biochemistry, Temple University School of Medicine, Philadelphia, using IV therapy of Ampligen "resulted in a significant decrease in HHV-6 activity (P < .01) and in downregulation of the 2-5A synthetase/RNase L pathway in temporal association with clinical and neuropsychological improvement."

Drug approval status


Ampligen has been passed through five different FDA review divisions since 1990. Hemispherx Biopharma, Inc, wrote in a presentation to the FDA on Dec 20, 2012: "Most products have [the] same review Division during their entire development. Guidance from five (5) different Divisions [has provided] diverged/conflicting advice on major points, such as: interpreting primary endpoints (method of analysis), its collection and analysis, and different thresholds for determining toxicity and safety. In contrast, Hemispherx has had the same medical monitor for more than 20 years (Dr. David Strayer)."

Notable studies

 * 2016, Efficacy of rintatolimod in the treatment of chronic fatigue syndrome/ myalgic encephalomyelitis (cfs/me)
 * 2015, Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop
 * 2012, A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome

Learn more

 * Wikipedia - Rintatolimod
 * 2016, Making the Case for Ampligen in Chronic Fatigue Syndrome (ME/CFS)
 * 2016, Ampligen and CFS
 * 2016, Hemispherx Biopharma (HEB) Comments on Recent Meeting with NIH for ME/CFS Research Advancement (see also NIH Post-Infectious ME/CFS Study)
 * 2016, Ampligen Co-Inventor / Head of Hemispherx Biopharma Fired: Implications for ME/CFS Drug Unclear
 * 2015, FDA Response Letter Regarding Approval of Ampligen for ME/CFS
 * 2015, Ampligen price more than doubles - Available soon in Europe
 * 2015, FDA Approval of MS Drug Puts Ampligen Back In Play
 * 2013, Ampligen and biomarkers: my testimony to FDA Dec 2012
 * 2013, Hemispherx Biopharma,Inc sued in a class action brought by stock holders claiming the company misrepresented whether Ampligen would be FDA approved. The stockholders prevailed.
 * 2012, Ampligen I: Effectiveness
 * 2012, Slide presentation to FDA Arthritis Advisory Committee by Hemispherx
 * 1994, The Aids Drug No One Can Have Mindy Kitei (see also Mindy Kitei)
 * 1990, Chronic Fatigue Syndrome