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Alnylam Blindsided

Alnylam, the big name in RNAi therapeutics, had an awful day of it yesterday, and is having another one today. More may be on the way. Rivusiran, their Phase III candidate for transthyretin amyloidosis (ATTR), has been abruptly pulled from trials. This is particularly out of the blue, since the company had just completed enrollment this summer.

The reason was rather memorably given in the press release last night as an “imbalance of mortality”, which is exactly what you think it is: more people were dying in the treatment group than in the controls. The company appears to have no theories yet as to what led to this – the patients that have died during the trial have had their deaths ascribed largely to cardiac-related issues, but that’s not really unexpected, given that cardiac pathology is a distinguishing feature in ATTR itself (the patients in this trial were specifically selected with this pathology). The company had asked the data monitoring committee to look into the ongoing trial numbers because of some reports of worsening neuropathy (also a common problem in the disease). They reported back, after examining unblinded data, saying that the neuropathy issue was not the real problem, but that the trial still needed to be halted because of what was happening in the treatment arm.

This puts a major dent in Alnylam’s pipeline, and the big question is how it affects their other candidate in this area, patisiran, which is being studied in ATTR patients with polyneuropathy and other projects the company has coming up behind these. The uncertainty, for now, is hard to overstate: without any idea of why rivusiran failed, or even if it failed because of anything to do with rivusiran at all, there’s just no way of saying what might happen to patisiran. It might be a completely different story or it might run into the exact same problem, if there is a problem. Or it could be that rivusiran just wasn’t helping much at all, and these patient deaths were the normal course of events in these patients.  Any of these are plausible, and that’s not what investors really want to hear: ALNY is down 47% as I write. Clarity, in the form of a good explanation for the rivusiran problems or solid clean data from the patisiran trial, is the only thing that’s going to resolve this, and that’s not going to be coming any time soon.

22 comments on “Alnylam Blindsided”

  1. Anon says:

    I don’t know what there is to clarify. The drug failed safety big time, so they need to a) drop it fast; and b) review the other drug program very closely. But finding out *why* the drug failed won’t change the fact that it did.

    1. Hap says:

      No, but if it’s based on the mechanism then they can’t do anything and can expect the other drug to fail (and can kill it early, probably), If it’s based on the structure (something inherent with the linkages), then they might be hosed, too, but they might be able to fix other stuff (find another sequence, for example). Like the Merck drug, though, it’s unlikely they’ll want to spend enough to find out for sure, because it may not be able to help them.

      1. Anon says:

        Agreed, but the best/only way to find out whether the other drug faces the same issues is to test it anyway – cautiously! That would be much easier, faster, cheaper and more reliable than finding out why the first drug failed, and inferring whether the second drug might or might not fail for the same reason.

        1. Anon_III says:

          While it might be cheaper, faster and easier, testing the next drug in humans may not be safer than figuring out why this one failed.

          1. Anon says:

            Hence the need to monitor very closely for signs developing through the trial

    2. Just a thought says:

      If they find out the “why” and it is something related to a specific patient group, not all patients, they can rescue the drug by removing that patient population.

  2. Barry says:

    What’s the record to-date of RNAi in the clinic? There was a time when it was billed as the (latest) revolution that was going to replace med. chem.

    1. Rule (of 5) Breaker says:

      Agreed. One of the most over-hyped approaches in recent memory.

      1. tangent says:

        It does *sound* pretty good though, doesn’t it? Like a lot of things. DNA vaccines. Tokamak fusion. Peroxynitrites in Alzheimer’s.

        1. anonymous says:

          @ tangent-Remember that most startups and others are flaunting to get more money into their coffers! General rule of thumb is higher the volume of sales pitch (PR, raising funds etc.) the outcome is poor for the said drug!
          @ Barry-No drug has come out of RNAi based technology (for selective gene suppression). Cellular delivery of these molecules are still huge hurdle! At best it compliments gene KO and nothing more. My previous company left this area after buying SiRNA/RNAi for a billion dollars and that was almost 12+ years back. People are moving into miRNA area, but rest assured it is another boondoggle waiting to happen!

  3. Calvin says:

    I always thought it a bit curious that Alnylam was valued at several billion dollars (until yesterday) despite the fact that they had no products, and no RNAi product had ever made it to the market (well I do understand it but always thought the markets were crazy). I have a feeling that it will still be a long time until one makes it. In our industry there is too much of a tendency to focus on the technology rather than what it does clinically. Patients and clinicians really don’t care all that much about the technology, only that the drug works. Nor do they care about novel targets, first in class or anything like that. Companies that get hooked on the technology rather than the application are always playing a dangerous game. I see other RNAi companies are being hammered now; action and reaction are equal and opposite……..

  4. Andy II says:

    I thought Ionis Pharma has one. KYNAMRO® (mipomersen sodium) Injection is used along with other lipid-lowering medications and diet in people with homozygous familial hypercholesterolemia (HoFH) to reduce LDL.

    1. steve says:

      That’s antisense, not siRNA; different technologies though both suppress gene expression.

      1. NJBiologist says:

        –although the early antisense hype was pretty similar to the later siRNA hype. If the timeline from discovery to drug for mipomersen holds, we might get an siRNA approval in, what, another ten years?

  5. steve says:

    The big issues with siRNA have been delivery and off-target effects. Off-target effects you generally can engineer out. Delivery is a bigger problem. Rivusiran used GalNAc conjugated to siRNA to deliver it to scavenger receptors (ASGPR). The question is whether the tox is due to the siRNA or the delivery mechanism. If the former then possibly other products won’t have the same problem; if the latter then the company is pretty well hosed.

  6. Me says:

    Dealt with some tox data on an antisense product once: there’s definitely a class effect from high levels of circulating nucleotide.

    1. steve says:

      If that’s the case, then loading cells up with siRNA through a scavenger receptor may not be the way to go. What’s puzzling is that the patients experienced a lot of neuropathy in the study. Not sure what would have caused that.

      1. Me says:

        Yeah that sounds scary – the effect I’ve seen is inflammatory, and I don’t think any CNS effect was seen.

  7. anon says:

    KYNAMRO was approved (01/2013) and rights for marketing got bounced around but has never been marketed yet, I think

    1. Andy II says:

      Anon, you are almost right.

      From their 10K filing, (,
      “During 2015 and 2014, we did not earn any revenue from our relationship with Genzyme. During 2013, we earned revenue of $32.5 million from our relationship with Genzyme, which represented 22 percent of our total revenue for that year.”

      Not sure what is wrong for its low sales number. It was projected as a blockbuster potential and Genzyme licensed it. It was now licensed to Kastle with $95+M potential payment In May this year.

  8. watcher says:

    This company is another Christoph Westphal (eg Sirtrus) midnight special.

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