BioCryst's Antiviral Drug Peramivir Aims to Keep Swine-Flu Body Count Low

BioCryst Pharmaceuticals‘ experimental drug peramivir is now available for treatment of hospitalized patients with suspected or confirmed 2009 H1N1 influenza under emergency use authorization (EUA) by the FDA. The resultant recommendation, however, may have sprung from the need for political expediency to showcase that swine flu will not become President Barack Obama’s Hurricane Katrina  — as opposed to actual, proven efficacy of this intravenous antiviral agent.

Peramivir is an antiviral drug that inhibits the enzyme neuraminidase, which is critical to the spread of influenza infection within the host. Specifically, intravenous (IV) peramivir has been authorized for (a) hospitalized and pediatric patients not responding to the two approved neuraminidase (the N part of H1N1) inhibitors, Roche’s oral therapy, Tamiflu (oseltamivir), and the inhaled antiviral Relenza (zanamivir), made by GlaxoSmithKline; and (b) where an intravenous drug delivery route is preferential, such as in patients who can’t physically swallow pills, those with chronic respiratory problems, and for those with co-morbid malabsorption disorders.

Influenza activity is now widespread in 48 states. The declaration by federal regulators to allow emergency use of peramivir in a hospital setting hews to a strategy of muting criticism that the Obama administration mishandled the swine-flu vaccination campaign, as chronic shortages of vaccine continue to be reported throughout the U.S. Epidimiologists report the highest hospitalization rate is in children (0-4 years old), according to a Centers for Disease Control and Prevention (CDC) update. Since April 2009, the CDC has also received reports of 114 laboratory-confirmed pediatric 2009 H1N1 deaths. Hence, the urgency to act.

Does the totality of scientific evidence on peramivir support the intravenous administration of the drug in aforementioned patients with suspected 2009 H1N1 influenza — and outweigh the known and potential risks? FDA Commissioner Margaret Hamburg opines that the answer is “yes” in her Letter of Authorization granting EUA to peramivir, despite knowing the following facts:

• Dosing in pediatric patients is based on modeling of pharmacokinetic data from adult healthy volunteers and adult patients with influenza. No children (under the age of 18) have received peramivir in clinical trials.
• Elderly patients would seem likely candidates for use of peramivir, given the higher incidence of concomitant diseases, including cardiac, renal, and lung problems. The FDA admits that it cannot make any conclusions about the overall safety profile in this at-risk group, as there is scarce information on those over 65 years of age who have even received the drug.
• The FDA admits that the efficacy to support the use of peramivir in a hospital setting is inconclusive — as only one of the four completed trials was with hospitalized patients (total number was 42).
• Preliminary results out of the one pivotal, late-stage (Phase 3 study) conducted by Japanese-based partner Shionogi in the 2008 - 2009 flu season were inconclusive. Researchers randomized 1,099 patients from out-patient clinics in Japan, South Korea, and Taiwan to get one of two doses of peramivir IV (300 or 600 milligrams) or five days of oseltamivir taken twice a day at 75 milligrams. BioCryst brags that both doses of its drug demonstrated non-inferiority for the primary endpoint — the time-to-alleviation of a composite of symptoms (temperature, oxygen saturation, respiration rate, heart rate, and systolic blood pressure)  — compared to the oseltamivir group. Peramivir IV 300 and 600 mg demonstrated a clinically insignificant 3.8 and 0.8 hours improvement over oseltamivir. Peramivir IV was no better — but no worse — than oral therapy with oseltamivir. As comedian Bill Cosby said, “Is the glass half full or half empty? It depends on whether you’re pouring or drinking.”

Proponents argue the rationale behind a non-inferiority trial design is that demonstrated superiority in placebo-controlled trials is irrelevant — and unethical — as there are enough placebo-controlled trials out there already documenting the efficacy of Tamiflu. Unethical in that it would be unfair to withhold treatment from any patient given knowledge of proven benefits of antiviral therapies to patients suffering from the ill-effects of the flu. In my opinion, the non-inferiority approach should be debunked for what it really is — an R&D cost saving initiative.

Designing non-inferiority trials with the appropriate active control is difficult. Consequently, the FDA prefers placebo-controlled studies when evaluating treatment of uncomplicated, acute influenza because the risks of receiving placebo are low and the efficacy of available treatment is modest (at best, a one-day difference in time-to-evaluation of symptoms), variable, and cannot be predicted well-enough to support a non-inferiority margin (usually picked by investigators and subject to bias).

BioCryst is working with the FDA on two peramivir late-stage studies to support U.S. registration: one will focus on the antiviral activity of its drug in hospitalized patients and the second will examine the effectiveness of peramivir IV in [addition to] hospitalized patients compared to patients receiving standard of care plus placebo [in time to resolution of symptoms]. Cubist painter Georges Braque said, “Truth exists, only falsehood has to be invented.” As results will not trickle out until first-quarter 2011, real proof of efficacy for peramivir IV will likely be defined for all of us this winter by the count: will hospitalized children and the elderly too sick to swallow Tamiflu capsules — the two clusters most likely to receive the experimental drug — leave the hospital in horizontal or vertical positions?