ALN-RSV01 Data Put Regulators in a Bind

ALN-RSV01 has been a controversial drug candidate in the field of RNAi Therapeutics not because of doubts that it has antiviral activity, but strong suspicion that it may reduce RSV levels by a non-RNAi mechanism of action, likely related to the activation of innate immunity.  The latest topline data from a phase IIb study in adult lung transplant patients are consistent with Alnylam's most advanced clinical candidate having such antiviral efficacy*.  The data show that inhalation of ALN-RSV01 in RSV-infected lung transplant patients results in improvement in a key important outcomes measure in this underserved orphan patient population: the incidence of new or progressive bronchiolitis obliterans syndrome (BOS) for which RSV infection is a major risk factor and which is associated with transplant rejection and death.

* antiviral efficacy, a secondary outcomes goal is yet to be reported

Despite of what appear to be clinically significant data- ALN-RSV01 treatment was associated with more than 50% relative risk reductions in new or progressive BOS in all reported patient groups (intent-to-treat or not)- critics will point out that, strictly speaking, ALN-RSV01 has barely missed its pre-specified primary endpoint in terms of statistical significance: p-values of slightly below 0.06 in the intent-to-treat populations (note: p-values in the arguably more relevant last-observation-carried-forward population was below the magic 0.05 mark).  This result in probably the largest clinical study of its kind (87 patients enrolled) is consistent with an earlier phase IIa study which was also strongly in favor of ALN-RSV01, but which had suffered particularly from imbalances in patient baseline characteristics which might have skewed results in favor of ALN-RSV01.

Despite the encouraging data, Alnylam made it abundantly clear that it is far from certain that it will further develop ALN-RSV01 for this patient population: having poured what must have been tens of millions into this clinical candidate which has been abandoned for development in the commercially much more attractive infant population due to the aforementioned mechanistic and resulting safety concerns, investing more in an orphan indication with maybe 500 to 1000 annual cases after running the probably largest study of its kind in this patient population would be difficult to justify in economic terms.

As a result, the company more or less said that the ball is now in the court of regulators in the US and Europe to make a tough public health decision: approve ALN-RSV01 with the present data and/or provide us with a path forward towards expanding the patient population without too much added effort (e.g. bone marrow transplant patients), or we will abandon this program and have lung transplant patients continue to be treated for RSV infection with highly questionable agents for which there is no clinical evidence of benefit (inhaled ribavirin is particularly notorious in that regard). Judging from the body language, another pivotal large or even larger phase III study certainly is not in the cards and religious adherence to p= 0.05 won't be taken lightly. 

In my opinion, the secondary outcomes from this trial, including lung function, transplant rejection, and overall survival, all of which were not disclosed yesterday, will tip the scales.  Full results are to be presented at the European Respiratory Society meeting in September of this year.  Mark your calendars.