BBIO - Alnylam: Why The FDA Rejection Of Onpattro Is A Minor Setback

2023-10-10 14:48:17 ET

Summary

• Alnylam's stock declined after the FDA issued a complete response letter citing inadequate evidence to support the efficacy of Onpattro in treating ATTR amyloidosis patients with cardiomyopathy.
• This is a minor setback because the HELIOS-B trial of Amvuttra holds the key to Alnylam's TTR franchise in this patient population.
• The HELIOS-B trial will be critical for the stock's medium-term performance.

Shares of Alnylam ( ALNY ) have been in a downtrend ever since the AdCom vote on Onpattro to assess whether it is a good option for patients with ATTR amyloidosis patients with cardiomyopathy, and despite the vote being positive. The stock declined some more today after the FDA issued a complete response letter citing inadequate evidence to support the efficacy of Onpattro in this population.

I disagree with the FDA's conclusion and believe Onpattro should have been approved, but this rejection does not impact Onpattro's existing indication - treatment of ATTR amyloidosis patients with polyneuropathy, and I believe it has no real impact on Alnylam's long-term growth prospects because I did not see Onpattro as a relevant treatment option for this patient population in the absence of hard outcome data (see last year's article ) and in the presence of Pfizer's ( PFE ) tafamidis (Vyndaqel) which does have evidence of a positive impact on cardiovascular mortality in cardiomyopathy patients.

HELIOS-B trial of Amvuttra (vutrisiran) holds the key for the further and significant growth of Alnylam's TTR franchise anyway. This is a proper outcomes trial that should provide us with a definitive conclusion - whether subcutaneously administered TTR silencers have the potential to compete with oral stabilizers such as Pfizer's tafamidis and potentially BridgeBio's ( BBIO ) acoramidis which recently reported positive data from an outcomes trial.

I expect the HELIOS-B trial to generate positive data but do not have a very high conviction to hold Alnylam into this readout, at least not if it stays at current levels. I am also not sure of the magnitude of benefit Amvuttra will produce if the outcome is positive. That said, I will share the reasons why I believe the HELIOS-B trial will report positive results next year.

The only data in cardiomyopathy patients we have from TTR silencers (such as Onpattro and Amvuttra) are from the APOLLO-B trial of Onpattro. However, that trial was not powered for outcomes and follow-up was too short to provide strong confidence in a positive outcome and the primary endpoint was the six-minute walk test. What I do find encouraging is the early trends of mortality benefit of Onpattro that was not seen in trials of tafamidis and acoramidis.

In the ATTRACT trial, tafamidis was at times trending worse than placebo in the first 18 months of the trial and the curves then started to separate, and the difference became strongly visible after approximately 24 months.

The Kaplan-Meier curve in the acoramidis trial looks similar to the one of tafamidis (it is just inverted compared to the tafamidis picture above). Acoramidis was trending worse than placebo during certain periods in the first 18 months, and it took about the same to see separation as it did for tafamidis as the curves started to clearly separate after 24 months. I should note that acoramidis did not achieve statistical significance on all-cause mortality, but it was really close with a p-value of 0.057.

On the other hand, Onpattro began to separate early in the APOLLO-B trial and both the composite endpoint and all-cause mortality showed favorable trends after approximately 13-14 months and 10-12 months, respectively. Of course, the APOLLO-B trial was not large enough or long enough for these results to be statistically significant.

There are also additional post-hoc cardiovascular safety data from trials of Onpattro in polyneuropathy patients that also have cardiomyopathy and these data add to the evidence of the potential benefits of TTR silencing.

And finally, the clinical and cardiac endpoints in trials of Amvuttra and Onpattro favor the treatment arms. Some clearly while others are trending in the right direction and I believe this too bodes well for the HELIOS-B trial.

I believe that positive results in the HELIOS-B trial would speed up the uptake of Amvuttra in polyneuropathy patients (the currently approved indication), specifically mixed phenotype patients that have both polyneuropathy and cardiomyopathy. This suggests a near-instant benefit for Amvuttra if HELIOS-B trial results are positive, but it will take time to prepare the sNDA submission and get Amvuttra approved for use in cardiomyopathy patients.

It will also be interesting and important to see the effect of Amvuttra in combination with tafamidis. If the results of the combination subgroup in the HELIOS-B trial are more impressive than either drug as monotherapy, it should add to the attractiveness of the combination, and, potentially make the situation worse for BridgeBio's acoramidis later this decade when tafamidis goes generic.

The stakes are high for Alnylam as HELIOS-B could add billions to Amvuttra's annual peak sales since the cardiomyopathy population is much larger than the polyneuropathy population where Alnylam's TTR franchise generated $223 million in net sales in Q2 or nearly $900 million annualized. And there are still years of growth in this population.

Conclusion

I believe the FDA rejection of Onpattro will have little to no long-term impact on Alnylam. Amvuttra's HELIOS-B trial is far more important and will determine the fate of the TTR franchise in the cardiomyopathy population.

The HELIOS-B trial will also be critical for the stock's medium-term performance and I can see the stock languishing until 2025 if the trial fails, but I still see Alnylam as well-positioned for long-term value creation regardless of this trial's outcome due to the other potentially very valuable shots on goal.

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