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Hemispherx Biopharma's (HEB) rintatolimod (trade name Ampligen) will be reviewed by an FDA Advisory Committee on December 20, 2012 for the treatment of chronic fatigue syndrome (CFS). Because the etiology of CFS is unknown, such a review presents unusual regulatory and scientific challenges, though of course drugs are approved for conditions whose pathophysiology is incompletely understood, such as the common headache.

Rintatolimod/Ampligen

Rintatolimod (poly I:poly C12U),is an experimental immunomodulatory double stranded RNA. Rintatolimod was first synthesized in the 1970s and has been proposed as a treatment for illnesses such as CFS, HIV, hepatitis B, hepatitis C, and cancers, including renal cell cancer and metastatic malignant melanoma. The biological properties of rintatolimod are conveyed by a unique naturally occurring receptor on the cell surface called "TLR-3." Toll-like receptors or "TLRs" such as TLR-3 serve as "pattern recognition" receptors in the early detection of pathogens and the establishment of early defense mechanisms (innate immunity).

Chronic fatigue syndrome

CFS is a condition characterized by serious medically unexplained mental and physical fatigue of at least 6 months duration, accompanied by sleep disturbances, poor concentration and flu-like symptoms. CFS represents a significant problem for contemporary healthcare because of its high prevalence (estimates vary between 0.5 to 2.5% in the general population), but also because of the associated physical and psychosocial disability, leading to high direct as well as indirect medical and societal costs. Moreover, both clinical experience and research indicate that CFS is often difficult to treat. The most commonly accepted definition of CFS is that published in 1994 by the CDC.

Cause of CFS

Although the disease process underlying CFS is not well understood and has been linked over the years to many different etiologic agents, in particular viruses, is it likely that it has more than one cause. One of the most recent hypotheses for a disease etiology was that CFS was linked to the xenotropic murine leukemia related virus (XMRV), which would have provided a rationale for treatment with rintatolimod (see, 10-K). Unfortunately, studies by experts in this field were unable to replicate the original findings.

Standard of treatment for CFS

In the absence of causative therapies, a wide variety of treatment approaches for CFS have been suggested, including pharmacological, nutritional, immunological, exercise and psychosocial treatments. However, recent meta-analyses and reviews have found that only cognitive behavioral therapy (CBT) and graded exercise treatment (GET) can be considered as evidence based treatments. In particular, on average 40 -50% of CFS patients show clinical improvement in fatigue after CBT or GET compared to about 20-30% in usual care. It is interesting to speculate whether improvements in CFS with GET might be related to release of myokines. Myokines have been shown to have anti-inflammatory activity and at least one of them, brain derived neurotrophic factor (BDNF), has effects on the central nervous system, including protective effects on depression.

Effectiveness of rintatolimod

The primary efficacy endpoint of the Phase 3 study, as reported in the literature, was improvement in treadmill exercise tolerance (ET) at week 40. An analysis of the primary endpoint in the intent to treat (ITT) group is shown in Table 1. (click to enlarge)

By week 40, the rintatolimod cohort (n= 100) had a mean change increase in ET of 96 seconds to 672, corresponding to a group mean increase of 16.6% and an intra-patient mean increase of 36.5%. In contrast, the placebo group (n= 108) increased ET by 28 seconds to 616 corresponding to an intra-group mean increase of 4.8% and an intra-patient mean increase of 15.2%.

Rintatolimod safety

Rintatolimod was reported to be generally well-tolerated in patients with CFS. The total number of adverse events (AEs) were statistically equivalent between cohorts, although patients receiving rintatolimod had an increased incidence in four AEs (flu-like syndrome, chills, vasodilatation and dyspnea) of usually mild severity. FDA has also expressed concerns about the possibility of development of antibodies to rintatolimod and to undesirable cytokine release by rintatolimod that the company believes it has addressed in its resubmission.

Uncertainty in near term regulatory outcome

Typically, to approve a drug, the FDA requires that an NDA include two large well designed randomized control trials, each achieving a level of significance of p<0.05 on the primary endpoint (treatment vs. control). There have been exceptions to that rule, particularly in the field of oncology, with very rare diseases or with dramatically effective treatments in areas of therapeutic need. The FDA's preference, if only one study is the basis for an NDA, is that the study be well designed and very compelling (e.g., p<0.01 favoring the treatment arm, to reduce the risk of Type I error, i.e., false positive outcome). In this regard, the p value reported in the Phase 3 publication is only marginally significant at p=0.047. It should be noted that since CFS is relatively common, the only limitation to Hemispherx performing a second larger well-controlled study, which the Agency originally requested, is time and money, not a dearth of patients. Also, from the Agency's perspective, there may be a greater risk of Type I error in the absence of a compelling biologic rationale for a specific treatment. Furthermore, the large size of the addressable population may encourage conservativism in the approval process. Finally, there may also be a question of whether a gain of less than one minute on average in exercise tolerance in the rintatolimod compared to the placebo groups has clinical significance or makes for a meaningful improvement in the quality of life. On the other hand, there are currently no approved treatments for CFS, and patient advocacy groups are understandably desirous to have available to patients safe and effective treatments. FDA's approach to CFS has also undergone some evolution since the previous NDA submission, though how much impact this will have on the approval process remains unknown.

Source: Hemispherx's Ampligen For The Treatment Of Chronic Fatigue Syndrome: A Regulatory Conundrum