In Argentina, Ampligen has just been commercially approved for severe ME/CFS

PHILADELPHIA, Aug. 23, 2016 (GLOBE NEWSWIRE)

  "“In Argentina, rintatolimod (Ampligen) has just been commercially approved for the severe disabling form of ME/CFS.  The number of patients with ME/CFS is estimated to be over three million worldwide, however, only a portion of these have the severe and disabling form of the disease which we are targeting with this drug,” stated Tom Equels."

  "Several post-approval activities are required to be completed before product launch, including manufacturing site inspections and reimbursement evaluation by the Health Services Authority (SSS), the central health authority in Argentina."

 

Characteristics of ME/CFS Responders to Rintatolimod (Ampligen)

@sciforschenonline:


Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME): Characteristics of Responders to Rintatolimod

David R Strayer1
Bruce C Stouch2
Staci R Stevens3
Lucinda Bateman4
Charles W Lapp5
Daniel L Peterson6
William A Carter1
William M Mitchell7*

1Hemispherx Biopharma, Inc., Philadelphia, Pennsylvania, United States of America
2BCS Statistical Solutions LLC, Philadelphia, Pennsylvania, United States of America
3Workwell Foundation, Ripon, California, United States of America
4Fatigue Consultation Clinic, Salt Lake City, Utah, United States of America
5Hunter-Hopkins Center, Charlotte, North Carolina, United States of America
6Sierra Internal Medicine Associates, Incline Village, Nevada, United States of America
7Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America


*Corresponding author: William M. Mitchell, Department of Pathology, Microbiology & Immunology, Vanderbilt University, Nashville, TN 37205, USA, Tel: 615-322-3238;
E-mail: bill.mitchell@vanderbilt.edu

Abstract

Background: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a debilitating disease of unknown pathogenesis consisting of a variety of flu-like symptoms including severe fatigue. Initial analysis of the use of rintatolimod (Poly I: Poly C₁₂U), a selective TLR3 agonist, in a Phase III, double-blind, randomized, placebo-controlled trial of CFS/ME demonstrated statistical significance (p<0.05) in the reduction of fatigue as measured by exercise tolerance (ET) as the primary endpoint using a modified Bruce protocol with reduced physical exertion in patients with severe CFS/ME as defined by a Karnofsky performance score (KPS) of 40-60.

Methods and Findings: In order to better identify responders to rintatolimod, primary and secondary endpoints have been reexamined post hoc as a function of a pre-specified study baseline ET duration >9 minutes. Analysis of improvement in exercise performance at the ≥ 25% and ≥ 50% levels using ET at 40 weeks compared to baseline was performed for the intent-to-treat (ITT) population (n=208) using the pre-specified baseline exercise stratum (baseline ET duration >9 minutes). For this subset of patients (n=126), 33% (n=20), and 12% (n=8) of rintatolimod vs. placebo patients, respectively, improved ET duration by ≥ 25% (p=0.004) while 23% (n=14) compared to 4.5% (n=3) of rintatolimod vs. placebo patients, respectively improved ET duration by ≥ 50% (p=0.003). This corresponds to increases of ≥ 186 and ≥ 373 seconds for patients receiving rintatolimod, respectively, at ≥ 25% and ≥ 50% improvement responses. A frequency distribution analysis of ≥ 25% improvement, <25% change, and ≥ 25% deterioration in ET from baseline at 40 weeks for the baseline >9 minutes cohort showed net improvement to be 18.3% for the rintatolimod cohort vs. 4.6% deterioration for placebo (p=0.015). A continuous responder analysis using 5% increments from ≥ 25% to ≥ 50% provided a robust clinical enhancement in ET effect in the rintatolimod cohorts as compared to placebo. The KPS and Vitality (SF-36 subscale) quality of life secondary endpoints demonstrated similar clinically significant improvements for the rintatolimod cohort as a function of the same ET dichotomization. Rintatolimod was generally well-tolerated in this CFS/ME population.

Conclusions: Using a modified Bruce ET protocol with reduced physical exertion allowed clear identification of patient responders to rintatolimod with severe CFS/ME syndrome. Rintatolimod produced significant enhancement in ET and quality of life indicators in patients able to complete >9 minutes in a modified Bruce ET test. Rintatolimod also reduced deterioration in ET compared to placebo in patients with the poorest initial ET. Exercise endurance >9 minutes in a Bruce protocol modified for patients with CFS/ME provides a method to identify patients most likely to respond to rintatolimod.

Ampligen improves Low Natural Killer (NK) Activity across the Chronic Fatigue Syndrome (CFS) disease spectrum

P HILADELPHIA, Jan. 12, 2015 (GLOBE NEWSWIRE) :: -- Hemispherx Biopharma, Inc. (NYSE MKT:HEB) (the "Company" or "Hemispherx"), reported today that it has conducted new "in vitro" studies of natural killer (NK) cells obtained from CFS patients in conjunction with a comprehensive review of the medical literature to determine the relative incidence of NK cell functional deficiencies in CFS disease. This review indicates that low NK cell cytotoxicity (NKCC) has been consistently reported in CFS patients compared to normal controls. In the new laboratory studies, Ampligen® (rintatoliod), an experimental therapeutic, was found to increase "in vitro" NK activity utilizing cells from CFS patient donors. The authors of the new report are all affiliated with Hemispherx.

NK cells are an important component of the innate immune response and may play an important role as a surveillance mechanism against viruses, other microbial pathogens, and tumor cells (Herberman", et al". Science 1981; 214:24-30). CFS is a debilitating disorder, characterized by disabling fatigue, flu-like symptoms, recurrent infections, and an apparent increased incidence of certain cancers, including lymphomas and brain tumors (Levine, "et al". Ann Epidemiol 1998;8:245-249). The vast majority (88%) of published studies (15 of 17) evaluating NKCC in patients meeting Centers for Disease Control (CDC) disease criteria for CFS concluded that CFS is associated with a reduction in NKCC compared to healthy controls. Two of the studies that did not find a difference in NKCC between CFS patients and normal controls appear to contain design flaws, which may have influenced results, for example, including the exclusion of CFS patients sick for 10 years or longer. Notably, studies at the University of Miami (176 CFS patients) found a range of 2 to 25 years from onset of CFS symptoms with an average of 10 years (Fletcher, "et al". PLoS One 2010; 5(5):e10817).

The medical literature indicates that the mean percent decrease in NKCC for the CFS population as defined using the CDC 1988 diagnostic criteria is significantly greater than that for the CFS patients defined by the CDC 1994 diagnostic criteria (the CDC 1988 criteria require more symptomatology to meet the requirements for a CFS diagnosis). Multiple published studies presented data, which support a relationship between a lower NKCC and a higher level of CFS symptom severity.

Ampligen® (rintatolimod), an experimental therapeutic, increased mean NK cell activity "in vitro" over 100% in the fifteen (15) CFS patients who donated NK cells. The mean age of the subject population was 48 years and two-thirds of the subjects were female. The observed NKCC increase was achieved with concentrations of Ampligen® achievable with a standard clinical treatment regimen of 400 mg given twice weekly. More than 100,000 doses have been given clinically, principally to CFS patients.

Historically, Hemispherx's double-blind, placebo-controlled and open-label clinical trials in CFS have emphasized quantitative measures of increased physical performance. For example, in a Phase III trial comparing twice weekly IV Ampligen® vs. placebo conducted in 234 subjects with long-standing debilitating CFS, the primary endpoint was intra-patient change from baseline at week 40 in exercise tolerance (ET). Subjects receiving Ampligen® for 40 weeks improved intra-patient placebo adjusted ET 21.3% from baseline in an intent-to-treat analysis. Correction for subjects with reduced dosing compliance increased placebo adjusted improvement to 28% (p=0.022) (Strayer, "et al". PLoS ONE 7(3):e31334. doi:10.1371/journal.pone.0031334).

The improvement observed represented approximately twice the minimum considered medically significant by regulatory agencies. An FDA Advisory Committee, convened in December 2012, when asked "Is the safety profile of Ampligen® adequate for approval for the treatment of CFS?", the "Yes" vote was 8, and the "No" vote was 5. When asked has the application "provided sufficient efficacy and safety data to support marketing of Ampligen® for the treatment of chronic fatigue syndrome?", the "Yes" vote was 5 and the "No" vote was 8. Thereafter, the Agency declined to approve the marketing application. Subsequently, the Company has been in dialogue with the Agency as well as selected regulatory authorities worldwide regarding potential paths forward to advance the experimental product for potential treatment of severe CFS. The evidence that severity of CFS is associated with progressive derangement of immune surveillance mediated by NK cells may afford a new path to identify opportunities for CFS therapeutic intervention. While NK studies were not systematically performed in the earlier well-controlled clinical study cited in the PLoS One peer-reviewed publication, improvements in vitality score, Activities of Daily Living score, and reduction in concomitant medications usage were observed. Quality-of-life improvements may be sequelae of improved immunosurveillance.

- See more at: http://globenewswire.com/news-release/2015/01/12/696686/10115028/en/Low-Natural-Killer-NK-Activity-Observed-Across-the-Chronic-Fatigue-Syndrome-CFS-Disease-Spectrum.html#sthash.6L3eBJ2q.dpuf