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Rintatolimod, sold under the tradename Ampligen, is a medication intended for treatment of
chronic fatigue syndrome Chronic fatigue syndrome (CFS), also called myalgic encephalomyelitis (ME) or ME/CFS, is a complex, debilitating, long-term medical condition. The Pathophysiology, causes and mechanisms of the disease are not fully understood. Distinguishing c ...
(CFS). There is some evidence it may improve some CFS symptoms. It is an
immunomodulator Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunother ...
y
double-stranded RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohyd ...
drug similar to the prototypical RNA poly I:C, first synthesized in the 1970s and manufactured by Hemispherx Biopharma, which was later renamed AIM ImmunoTech. Although Ampligen was initially cleared for use in Canada in 1997, and obtained
orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment o ...
status for treatment of 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 as it's still classified by the
U.S. Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...
(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 trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical te ...
s "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, 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, however, and as of May 2021 is involved in phase 3 and phase 2 trials for 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 to be 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 potentially act synergistically with other antiviral drugs in preventing human infections from
avian influenza Avian influenza, known informally as avian flu or bird flu, is a variety of influenza caused by viruses adapted to birds.


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 In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
include
chills Chills is a feeling of coldness occurring during a high fever, but sometimes is also a common symptom which occurs alone in specific people. It occurs during fever due to the release of cytokines and prostaglandins as part of the inflammatory r ...
,
fever Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...
,
malaise As a medical term, malaise is a feeling of general discomfort, uneasiness or lack of wellbeing and often the first sign of an infection or other disease. The word has existed in French since at least the 12th century. The term is often used ...
,
leukopenia Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of inf ...
,
neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteri ...
, and
leukocytosis Leukocytosis is a condition in which the white cell (leukocyte count) is above the normal range in the blood. It is frequently a sign of an inflammatory response, most commonly the result of infection, but may also occur following certain parasit ...
. 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 protect and stimulate the
innate immune system The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...
, 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 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 The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system ...
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. 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 In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...
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.


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 Johns Hopkins University (Johns Hopkins, Hopkins, or JHU) is a private university, private research university in Baltimore, Maryland. Founded in 1876, Johns Hopkins is the oldest research university in the United States and in the western hem ...
, modified the
dsRNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carb ...
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. 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.Business Description: HEM Research, Inc.
1986. Retrieved on February 25, 2007.
Rintatolimod was tested in clinical trials in the United States beginning in 1988, after
DuPont DuPont de Nemours, Inc., commonly shortened to DuPont, is an American multinational chemical company first formed in 1802 by French-American chemist and industrialist Éleuthère Irénée du Pont de Nemours. The company played a major role in ...
invested $30 million in Hemispherx. Initial success in a small trial for
AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ...
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 Canada is a country in North America. Its Provinces and territories of Canada, ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, covering over , making it the world ...
and
Belgium Belgium, ; french: Belgique ; german: Belgien officially the Kingdom of Belgium, is a country in Northwestern Europe. The country is bordered by the Netherlands to the north, Germany to the east, Luxembourg to the southeast, France to the ...
. 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.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.
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 , image_flag = Bandera de España.svg , image_coat = Escudo de España (mazonado).svg , national_motto = '' Plus ultra'' (Latin)(English: "Further Beyond") , national_anthem = (English: "Royal March") , ...
,
Portugal Portugal, officially the Portuguese Republic ( pt, República Portuguesa, links=yes ), is a country whose mainland is located on the Iberian Peninsula of Southwestern Europe, and whose territory also includes the Atlantic archipelagos of the ...
, and
Andorra , image_flag = Flag of Andorra.svg , image_coat = Coat of arms of Andorra.svg , symbol_type = Coat of arms , national_motto = la, Virtus Unita Fortior, label=none (Latin)"United virtue is stro ...
.SEC Filing (Form S-3): Hemispherx Biopharma, Inc.
" January 14, 2003. Retrieved on February 25, 2007.
Bioclones (PTY) Ltd, a UK based company, was granted the exclusive marketing rights to rintatolimod in the
United Kingdom The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Europe, off the north-western coast of the continental mainland. It comprises England, Scotland, Wales and No ...
,
Ireland Ireland ( ; ga, Éire ; Ulster-Scots: ) is an island in the North Atlantic Ocean, in north-western Europe. It is separated from Great Britain to its east by the North Channel, the Irish Sea, and St George's Channel. Ireland is the s ...
, and several countries in the Southern Hemisphere. Mismatched Double-Stranded RNA: Ampligen, Oragen, Polyi:Polyc12u
" ''Drugs in R&D.'' February 1, 2002. Retrieved on February 26, 2007.
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).
/ref> 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." 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
carcinogen A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substa ...
icity data. 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. The company received a Complete Response Letter from the agency on rintatolimod's NDA in December 2009, requesting further data. In 2007, and again during the
2009 swine flu pandemic The 2009 swine flu pandemic, caused by the H1N1 influenza virus and declared by the World Health Organization (WHO) from June 2009 to August 2010, is the third recent flu pandemic involving the H1N1 virus (the first being the 1918–1920 Sp ...
, Carter said that rintatolimod could also be used as an
H1N1 In virology, influenza A virus subtype H1N1 (A/H1N1) is a subtype of influenza A virus. Major outbreaks of H1N1 strains in humans include the Spanish flu, the 1977 Russian flu pandemic and the 2009 swine flu pandemic. It is an orthomyxovirus ...
flu vaccine booster, citing ''in vitro'' studies with Ampligen and neuraminidase inhibitors oseltamivir and zanamivir (brand names Tamiflu and Relenza). 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). The Complete Response Letter asked for more study data prior to rintatolimod approval. 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."Hemispherx Press Release" (February 23, 2015)
/ref> 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.


Status around the world as of 2022

Although Ampligen was initially cleared for use in Canada in 1997, and obtained
orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment o ...
status for treatment of 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 Access Program, via the My Tomorrows program set up in Amsterdam. It is so far without FDA approval, and is classed as experimental in the United States. It was approved for use in Argentina and will soon be ready for commercial sales. Interest rise in that country after increases in the number of ME/CFS cases after its SARS epidemic in 2002–2003, and it anticipates a similar rise in ME/CFS cases from SARS-CoV-2. In 2007, Hemispherx filed a new drug application with the
U.S. Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...
(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 trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical te ...
s "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 to FDA, 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. Work continues on the drug, and there has been no approval by the US FDA, as of May 2021. There is open-label use in the US, under Dr. Dan Peterson in Nevada. As of 2022, rintatolimod was approved in Argentina and is ready to "Launch pending FDA export authorization"


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 The United States Federal Food, Drug, and Cosmetic Act (abbreviated as FFDCA, FDCA, or FD&C) is a set of laws passed by the United States Congress in 1938 giving authority to the U.S. Food and Drug Administration (FDA) to oversee the safety of f ...
. Also in the late 1990s, Manuel Asensio reported on Hemispherx, saying the company was overvalued. He criticized Hemispherx and its rintatolimod results,Asensio & Company: Hemispherx Analyst Makes False Ampligen HIV Efficacy Claims Despite Failed Test and FDA Violation Notice
alleging a variety of
misdemeanors A misdemeanor (American English, spelled misdemeanour elsewhere) is any "lesser" criminal act in some common law legal systems. Misdemeanors are generally punished less severely than more serious felonies, but theoretically more so than admi ...
, 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 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 The United States Department of Health and Human Services (HHS) is a cabinet-level executive branch department of the U.S. federal government created to protect the health of all Americans and providing essential human services. Its motto is ...
. Grassroots activism for FDA approval of Ampligen grew and continues. Efforts in 2015 to spur FDA approval of Ampligen include petitions, appeal for congressional hearing, and popular social media group organizing. Adam Feuerstein, a journalist for ''The Street'', 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. 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."


Research

Rintatolimod has been studied in humans since 1994. In early 2015, the AMP 511 open-label study of rintatolimod in CFS was 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 investigational drug until marketing approval is obtained. 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. In October 2007, the US FDA Ampligen NDA was filed. 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 Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
. 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. Hemispherx has conducted research on a by mouth versions of rintatolimod using nucleic acid technology related to rintatolimod.


References

{{reflist


External links


Hemispherx Ampligen Page



Main Hemispherx Ampligen Page with updated status: as of 2022, now approved, "Launch pending FDA export authorization"
Immunostimulants Anti–RNA virus drugs Orphan drugs