Rintatolimod, sold under the tradename Ampligen, is a medication intended for treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). There is some evidence it may improve some ME/CFS symptoms. It is an immunomodulatory double-stranded RNA drug similar to the prototypical RNA poly I:C. It was first synthesized in the 1970s and is manufactured by AIM ImmunoTech (formerly known as Hemispherx Biopharma). Although Ampligen was initially cleared for use in Canada in 1997, and obtained orphan drug status for treatment of ME/CFS in the European Union in 2000, it is approved for use only in Argentina. Its status in Canada, per later information, is as a Special Use Program. Rintatolimod has not yet been approved as a legally prescriptible medication to treat any formally defined health conditions, diseases, or symptoms in the United States of America; it is still classified by the U.S. Food and Drug Administration (FDA) as an experimental drug. 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, but this was rejected in December 2009, because the FDA concluded that the two randomized controlled trials "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 ME/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. There are two open-label uses in the US, under Dr. Dan Peterson in Nevada and Dr. Charles Lapp in North Carolina. Ampligen continues to be evaluated, and as of May 2021 is the subject of phase 2 and phase 3 trials to potentially treat myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and several cancers.
Medical uses As of 2021, there is limited scientific evidence supporting the therapeutic efficacy of rintatolimod in treating CFS. The number of double-blinded, placebo-controlled human trial studies published in well-regarded peer-reviewed journals is very sparse. However, there is a small amount of evidence from preliminary clinical studies of limited scope indicating that administration of rintatolimod may improve the daily quality of life of people diagnosed with CFS. Rintatolimod was designed with the therapeutic intention of preserving the healthy functioning of human cells by enhancing each cell's immunoresistance to actively-invasive viruses and uncontrollably-proliferating tumorous human cells, e.g. cancerous growths. Therefore, if rintatolimod is proven effective in its originally intended role as a compound to enhance human cells' resistance to viruses and tumors, it is hypothesized by some medical professionals that it could act synergistically with other antiviral drugs in preventing human infections from avian influenza if coadministered with them.
Side effects An independent review of rintatolimod trials in CFS was published in the December 2006 issue of the Journal of Clinical Virology. 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." 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.
Mechanism of action One mode of action of this drug is to 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 and reflected in a press release by Hemispherx, rintatolimod 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, long before the slower 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 viruses and cancer. The mechanism of rintatolimod in relation to CFS is not certain, but is thought to include the RNase L enzyme. Rintatolimod is a dsRNA, and when TLR-3 senses a dsRNA, it is thought to relay a message to cells to produce interferons (IFNs). 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 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.
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