PharmExec Blog

Running Interference for the RNA Interference Breakthrough

moonwalk.jpgA morning-after assessment of the proof of concept news reveals that while Alnylam CEO John Maraganore (below) thinks he’s on a “moonwalk,” it’s really just cloud nine reached by “nice, small steps.”

Alnylam Pharmaceuticals’ announcement last Friday that it had scored the industry’s first human proof of concept with RNA interference sure sounded like a big deal.

“This is really the first moonwalk for RNAi therapeutics,” said the Cambridge, MA–based biotech’s CEO as he passed around verbal cigars to the press. A venti-size research breakthrough is just the thing to give pharma a much-needed buzz. Mozel tov…clink…and ka-ching!

John Maraganore, Ph.D.But things have been moving awfully fast for RNAi since it first arrived a mere decade ago. The two guys who discovered the gee-whiz gene-silencing technology nabbed Nobles in 2006—while still in their 40s. Since then, Big Pharma has been having bidding wars and placing billion-dollar bets on RNAi real estate, big and small. Alnylam was founded in 2002, went public in 2004, and is already the sole standalone RNAi biotech left. Its treasure-trove of patents, technology, and expertise have enticed partnerships with Roche, Novartis, Biogen Idec, and Medtronic. Pinch yourself.

So how big a deal is this big deal? We asked a friend who is the director of chemistry at a drug-discovery shop up in the Boston biocluster and who follows RNAi as an amateur stock analyst. He has no relationship with Alnylam, competitive, financial, or otherwise, but he asked not to be identified by name.

So how big, bud? “I do think it’s a big deal—and will perhaps be considered bigger than it honestly is,” he said. “The target was a very shrewd selection by Alnylam for proof of concept. But it was certainly not a swing for the fences.”

That’s a polite way of saying that a proof of concept is only as big as its target, and this target was maybe a little modest to make history.

The target was RSV, or respiratory syncytial virus, an infection linked to childhood asthma, potentially life-threatening for infants and the elderly, and a significant (300,000 annual hospitalizations) unmet and neglected medical need. Marketing a novel RSV treatment to showcase RNAi’s medical promise would be a feel-good bonanza.

Alnylam’s first-out-of-its-platform product, ALN-RSV01, was designed to silence a gene in cells in the lining of the lungs that RSV uses to spawn. In a Phase II trial of 88 men—half got a five-day nasal-spray course of the RNAi juice, half got nuttin’, and all got jabbed in the schnoz with the virus. Results: 24 of 43 men on the drug remained uninfected compared with 12 of 42 on placebo.

As a sound bite, that translates nicely as Alnylam’s ALN-RSV01 cut RSV infection rates by 38 percent! Safe and well tolerated, too. What’s not to love?

Our anonymous Mr. Science has the answers:
1. Design of trial Being small, it’s hard to get significance from. Being a safety trial, efficacy was secondary, measured by viral load, but not where it counts: in the lungs. And the ALN-RSV01-treated men didn’t actually feel any better or worse than those on placebo—no clinical difference. “And note that they are looking to prevent infection, not improve condition after infection already exists. Which is the harder endpoint remains to be seen,” says our source.

2. Drug delivery “Note that we are still talking about a non-systemic target,” he adds. Being inhaled into the lungs, ALN-RSV01 completely circumvents the challenge of surviving degradation in the bloodstream. “A more ambitious proof of concept, efficacy, and safety would require drug injection that targets an internal organ or broad cellular function.”

3. Disease target “By focusing on an infectious disease rather than a gene-expression problem (and, in general, for gene expression, the problem is lack of expression, not overabundance),” our source says rather cryptically, Alnylam was effectively scaling down risk and expectation.

4. Market potential FDA approval: “It’s early, but looks good.” Yet whether ALN-RSV01 will be a profitable investment or a loss leader could get tricky. Its potential may, for all practical purposes, be limited to infants and the elderly—especially if the price tag is high. “Third-party payers may balk a bit at reimbursement of a $1,000 treatment when the alternative is simply a harsh cough for a week.”

So that’s why our biochemist–slash–amateur stock analyst downgrades ALN-RSV01 from a “moonwalk” to “nice, small steps.”

“I like the stepwise approach Alnylam is taking regarding RNAi efficacy,” he says. “They are taking nice, small steps toward proof of concept.”

Damning with faint praise? You decide.

“I’m not running out to buy Alnylam stock,” he says, “but I might take a flyer on some ahead of the next Phase II results.” The company’s pipeline is said to include agents for everything from pandemic influenza to high cholesterol to bioterrorism.

And our source will be tuning in—along with all of Boston’s lagging biocluster (and Alnylam’s self-proclaimed new rival, CytRx, a Southern Cali start-up boasting one of RNAi’s discoverers)—to Alnylam’s live webcast of its R&D Day tomorrow from 9:00 a.m. to noon. Check the Web site (visit the Investors section).

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  1. Jeroen
    Posted March 5, 2008 at 9:09 am | Permalink

    Although I agree that based on these results RNAi is not yet ready to replace many small molecule blockbuster drugs, there is nothing wrong with the target disease selection. RSV has been used extensively as a target for antisense drugs (look up some of Paul torrence papers on 2-5A-DNA antisense agents). Also, let’s not forget that it took Isis years and years to successfully get past intra-ocular administration of their antisense drugs, so we cannot realistically expect Alnylam to be able to immediately show proof of concept with systemic administration of their RNAi drug.

    It is very hard to show an effect of any gene silencing drug in a whole animal, so being the first to accomplish that in humans with a novel approach is quite an achievement. I agree it is not a moonwalk, but at least it is starting to look like a spaceship….

  2. Steve
    Posted March 5, 2008 at 9:17 am | Permalink

    Well done and balanced article.

  3. REAL Biochemist
    Posted March 5, 2008 at 2:37 pm | Permalink

    Oh dear, you really should have sought an opinion from someone other than your “friend who is the director of chemistry at a drug-discovery shop up in the Boston biocluster and who follows RNAi as an amateur stock analyst” and whom you later describe as a “biochemist–slash–amateur stock analyst” .

    I am a REAL biochemist PhD with 30 years research experience, now with a large multinational pharmaceutical company, and I can state categorically that Point 3: “Disease target” is actually the other way around. Disease is generally associated with over-expression of genes or expression of a mutant form of the natural gene. These are ideal targets for RNAi treatment and Alnylam, which owns most of the intellectual property in the arena, and has now demonstrated human proof-of-concept, has a very, very, very bright future. So, in my extensive experience, your “friend” misses it on both counts – as a scientist and as an analyst.

    REAL Biochemist

  4. Posted March 5, 2008 at 6:10 pm | Permalink

    loss leader or lost litre?

  5. Kodger
    Posted June 17, 2010 at 4:35 pm | Permalink

    “Loss Leader”, “Lost Litre”, or “Loss Litre” mean essentially the same thing.

    All 3 refer to the marketing practice of selling a product at or less than margin to entice customers into the store so that the consumer may then elect to buy something else, which the store sells at a profit.

    If I recall correctly, the origin of the phrase comes from the marketing concept of selling a litre (liter) of milk below cost to promote traffic into the merchant’s store….since “litre” and “leader” sound similar many use the word “leader” especially in the USA because the metric system is not used there by consumers and so many persons are not familiar with the word.

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