Pharma’s Cutting Edge

Phase 2 Gemini Study Top-line Results Described

This morning Alnylam presented top-line results from its Phase 2 POC study of anti-RSV RNAi therapy, known as ALN-RSV01, demonstrating an effect of the therapy in experimental upper respiratory RSV infection.

The intent of thes study was to determine whether relatively high doses of ALNRSV-01 delivered intranasally to experimentally infected healthy volunteers could reduce local viral load.  The volunteers were given two doses of the drug (one per day) prior to being nasally inoculated with roughly 10,000 viral particles (much higher than the typical natural infection load).  Then they were given further treatments of ALN-RSV01 or a matching placebo for an additional three days after inoculation; all told volunteers were quarantined for 12 days (yikes).  In order to ensure a reasonable rate of infection, potential volunteers were screened for anti-RSV antibodies.  Those with clinically relevant titers of antibodies were excluded from the study, necessitating the screening of 1,000 people to enroll 88 (double yikes). 

The rate of infection (primary endpoint, by plaque assay), viral load measures, and clinical symptoms were assessed.  In a nutshell, the therapy reduced the rate of viral infection by a number of measures and the primary endpoint was met.  Trends were seen in viral load measures but not in symptoms, which were modest in any case. 

This was a robust demonstration that RNAi delivered locally (and prophylactically) can reduce (but not eliminate) viral infection.  In that respect, it is valuable as a proof of concept in humans for topically delivered RNAi acting against viral cells directly at the site of inoculation.  I don’t think it should be construed as a proper POC of systemically delivered RNAi under any circumstances, nor for topically delivered RNAi directed against endogenous gene expression.  So, RNAi is still in its infancy, clinically speaking, but it’s showing signs of life. 

Investors on the conference call were interested in what this study might mean for the future of this particular therapy.  I think Alnylam’s management were appropriately circumspect when addressing the issue.  If I were an investor (I’m not), I’d be relieved that this important first hurdle has been cleared, but I’d also have to admit to myself that this therapy is still a long way from proving itself in naturally infected kids and fragile adults with RSV pneumonia.  Alnylam mentioned that the next Phase 2 will be a study of adults with naturally occurring RSV infection, presumably upper respiratory infection.  In that setting, ALN-RSV01 won’t be given a headstart over the virus–treatment won’t begin until clinical symptoms have appeared–and effects on symptoms would be helpful to guide future studies and gain investor confidence.  So, like any other drug, we’ll have to see.  But at least now there’s a decent reason to watch.

A few years back, as a consultant, I was asked by GTX to take a look at their unreleased Phase 2 ACAPODENE (toremifene citrate 80 mg) data and to make some recommendations and predictions for Phase 3.  I remember being very bullish on the prospects for this therapy and finding very little for the company to worry about.  They seemed appropriately restrained in their own optimism, so I wasn’t too concerned about them under-powering Phase 3 by assuming too much efficacy.  As it turns out, Phase 2 basically told the same story that GTx is now reporting from their top-line Phase 3 results that tested the drug in men with prostate cancer who’d undergone androgen deprivation therapy (ADT). 

Toremifene, you might know, is a SERM, like its kissing chemical cousin tamoxifen.  For years, the drug–marketed by Orion as Fareston–at lower doses has been used to treatment hormone-responsive postmenopausal breast cancer patients, as its antiestrogenic activity inhibits estrogen-driven cancer cell growth. 

Now, toremifene’s estrogen-like effects in bone and on lipid metabolism, which were always suspected of being a bit stronger than those of tamoxifen, are being exploited in men to inhibit excessive bone resorption and correct the dyslipidemia caused by ADT.  The data released by GTx suggest that the drug worked quite well in both respects, with a modest (~2x) early increase in the risk of VTE, a known risk of SERMs in women.  Data on hot flashes are pending, but you can expect to hear of an increased risk of hot flashes as well; I’m guessing 4x over placebo for the first year, with few med discontinuations due to them.  No news on stroke risk, which is good news.

This is potentially a very inspiring story for those of us who still feel positive about the value of this industry.  Were high-dose toremifene repurposed by a large company, we’d soon be reading criticisms about anticonsumer lifecycle management strategies and a persistent lack of innovation alongside the news of its clinical success (you know, to balance out any good feelings industry proponents might be having).  But that’s what is so great about this situation.  We won’t have to hear these criticisms alongside the good news, because GTx is a small company, largely backed by one guy (JR Hyde, of AutoZone notoriety) with deep pockets, who believed in his people (most notably Mitch Steiner and Marc Hanover) and their ability to bring this drug along without the help from big pharma.  That was gutsy, some might say crazy, but I think most Americans will appreciate the story.

That GTx are likely to have found an important new therapy without the need for medicinal chemistry to create something brand new is a beautiful example of how innovations should be judged by the value they offer and not by the mechanisms through which ideas become reality.  Should ACAPODENE make it to the market, it will be a triumph of ingenuity and entrepreneurial spirit.  We need more stories like this.  I’m sure patients with serious illness would agree.

I’ll update this story when we see further data and learn of regulatory progress.  I anticipate priority review at FDA.

Disclosures:  As indicated, I received consulting revenue from GTx several years ago; none since then.  I own no stock in their company.

After I had fnished reading the recent Supreme Court decision in Riegel v. Medtronic and some news reports describing the supposed implications of the decision for pharma, I was confused.  Were the implications for pharma product liability cases broad and profound or narrow and limited?  Certainly, the upcoming Wyeth Supreme Court case will have its own implications for pharma, but, in the meantime, I turned to my colleague Greg Glass, editor/owner of the Paragraph Four Report, to lend his opinion to the Court’s Medtronic decision.  Here’s what he said:

As for the [Medtronic]  case, you have to read it very narrowly. It appears that the gist of the lawsuit was that the plaintiff did not have much to go on in suing Medtronic. The product [apparently] was contraindicated for the use for which it was administered to the poor guy, and the balloon was filled to 10 atmospheres, rather than the maximum [recommended] pressure of 8.  So, it appears that there was not much product liability theory to go on. ([The situation would have been different] if the facts instead were that the product was used for its intended use and the balloon ruptured at 4 atmospheres).

So, the plaintiff, being “creative,” asserted the product failed to meet certain design and manufacturing standards.

The point of the law [MDA], and the FDCA for that matter, was to create a uniform approval and safety standard. For example, what would happen if Texas passed a law that required new drugs to have three controlled studies before the product could be sold in Texas? So, the idea is to have one set of rules — federal law — to control these things.

[Following this ruling], you can still sue under state laws in state courts for product liability cases — but those laws can’t create higher manufacturing and approval standards than what federal law creates. Federal courts are harder to get into and usually don’t hear the standard product liability cases.

That seems pretty clear to me.  If the device doesn’t work as it’s supposed to, according to the FDA, plaintiffs still have the opportunity to sue in state court under product liability laws.  But if the device is pushed beyond its recognized (labeled) limits, as the facts supported in this case, plaintiffs can’t sue in state court using a state law that creates a tougher standard for the product than the FDA recognizes.