Status: NDA rejected, was reconsidered in late 2012, rejected in Feb. 2013

Organizations involved:

Hemispherx Biopharma Inc. – Manuf.; R&D; Tech.: World mark.

GP Pharm Latinoamerica - Latin Amer. mark. GP Pharm S.A. – Parent

Johns Hopkins University – R&D; Tech.

Description: Ampligen is an aqueous formulation of synthetic mismatched double-stranded RNA - a polynucleotide derivative of poly I-poly C (poly-inosine–poly- cytosine), with occasional uracil residues to provide RNase cleavage sites. Ampligen has immune modulating and stimulating activity.

Note, as a fully synthetic product, Ampligen is not considered to be a mainstream biopharmaceutical product. It may be considered to be an antisense drug by some, although it is not complementary to any known human DNA sequence, does not selectively bind to any DNA sequence in a sequence-specific manner, and does not function through an antisense mechanism. A more complete monograph for this borderline or non-biopharmaceutical product will be provided upon approval.

Nomenclature: Ampligen [TR]; Rintatolimod [USAN; INN]; Poly(I)-Poly(C12U) [SY]

Companies.: Hemispherx Biopharma Inc. is developing and will manufacture and market Ampligen.

In July 2010, Hemispherx granted exclusive sales, marketing and distribution right for Ampligen in Argentina to GP Pharm Latinoamerica, a subsidiary of GP Pharma SA.

Status: On Dec. 29, 2006, the FDA received pre-submission of pre-clinical information and assigned an NDA number. On Oct. 7, 2007, Hemispherx Biopharma filed its New Drug Application (NDA) with FDA for Ampligen to treat Chronic Fatigue Syndrome (CFS). The company also planned filings in countries outside the U.S.

On Dec. 2, 2009, FDA rejected approval of Ampligen and requested a new trial of its therapy for chronic fatigue syndrome before making a final decision on the NDA. Another late-stage trial would easily require hundreds of patients and prove to be very expensive, with its earlier Phase III taking six years to complete.

Over its long development history, Ampligen has received various designations, including Orphan Drug Product Designation (FDA), Emergency (compassionate) Cost Recovery Sales Authorization (FDA) and “promising” designation by the Agency on Health Research Quality (AHRQ).

The NDA was refiled, but a Complete Response Letter (CRL) was issued. The FDA said Hemispherx should “conduct at least 1 additional clinical trial, complete various nonclinical studies and perform a number of data analyses”. The FDA says that the “data does not provide sufficient information to determine whether the product is safe for use in CFS due to the limited size of the safety database and multiple discrepancies within the submitted data”. This is similar to the 8-to-5 decision made by the FDA Arthritis Advisory Committee Meeting (AdComm) in December 2012 – not providing sufficient data. Hemispherx BioPharma plans to ask for an end-of-review conference with the FDA as a step to submitting a formal appeal.

Tech. transfer: Ampligen was originally invented/developed by Johns Hopkins University, which has exclusivley licensed the product to Hemispherx Biopharma.

Trials: The NDA submission includes data from four well controlled, or pivotal, trials are now being reported in more than 1,200 subjects evaluated with ~90,000 dose administrations.

Hemispherx has completed a total of five open-label and three double-blind, placebo controlled trials, including two Phase III trials evaluating Ampligen for the treatment of CFS in 757 subjects. Top-line data from one Phase III trial in patients receiving Ampligen for 40 weeks showed statistical significance on endpoints such as improved exercise, treadmill performance and oxygen utilization. Concomitant use of drugs for pain, sleep and depression was reduced significantly in the Ampligen arm in both Phase II and Phase III trials.

Disease: Centers for Disease Control and Prevention (CDC) estimates that CFS affects more than 1 million Americans, and results in $9.1 billion in lost wages and earnings in the U.S. annually, not including health care costs and disability benefits.

Market: Hemispherx will initially launch Ampligen targeting the approximately 50 CFS centers that have already participated in clinical trials with Ampligen. The initial rollout would include an “untraditional” sales force, including no more than 5-10 specialists who would engage in educational forums. An expanded launch may eventually involve partnering with a specialty pharmaceutical company that focuses in chronic debilitating diseases.

The timing of Ampligen’s approval could be fortuitous, with the Centers for Disease Control and Prevention (CDC) stepping-up efforts regarding CFS, including a national public education and awareness campaign on CFS, including radio, print and TV ads. The campaign, called “Get Informed. Get Diagnosed. Get Help,” is designed to increase awareness of the disease among physicians and the public “because 80 percent of Americans afflicted with CFS illness may not know they have it,” according to CDC.