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.

Alnylam’s RSV Program Causes Excitement Among Lung Transplant Surgeons- An Example for a Shrewd RNAi Therapeutics Development Strategy?

“Yes, it’s interesting how what we think about most often begins to surround us” replied Chris, a friend from down the hall with whom I share an addiction of going to Stanford biomedical seminars, to an email of mine where I noted that RNAi Therapeutics is honestly popping up almost everywhere now. It happened this week Monday in a chemical engineering seminar on the delivery of crystal-like drug particles (think small 20-30nm, stable needle-like siRNA particles) or during a lung transplant talk on Friday.

Despite close to half a century of lung transplantation, with more than 2000 procedures performed annually world-wide, there has been very little progress in the 2-5 year morbidity and mortality, meaning that less than half of transplant recipients survive beyond 5 years. Community-acquired viral infections in the immuno-suppressed patients are responsible for roughly a third of such chronic rejection and declining lung function cases, with the respiratory syncytial virus (RSV) clearly topping the list.

Stanford is a fairly large lung transplant center, and the situation is not much different here. The seminar I attended concerned a review of the history of 25 lung transplant patients that had acquired either RSV or paraflu viral infections (23 of which with RSV) and were treated with the broad-spectrum antiviral ribavirin either alone or in addition to pavlizumab, a neutralizing antibody that is normally used for and really only effective in the prophylaxis of RSV.

Without going into the details, at the end of the presentation it was clear that, in the absence of any effective treatment, ribavirin and pavlizumab are given as a last resort and desperate effort (yes, despite of what you read in the press these days, these people really seem to care about improving the health of their patients) to make a dent against RSV, but that nobody was really convinced that this would more good than harm. Actually, inhaled ribavirin is even considered a safety hazard to attending nurses and docs.

Then suddenly, there was a commotion in the room as somebody mentioned the word “s-i-r-n-a”. Wasn’t there something in clinical trials right now that would attack the virus directly, a treatment that would even work in immuno-compromised patients? And yes, hadn’t it shown already some kind of antiviral activity in the clinic? Wow, maybe we should give it a try- anything that had been shown anywhere to inhibit RSV in man… There was a lot of excitement and confusion, for example about the mechanism of action, and "some commercial company” was mentioned. Probably worth revisiting.

This experience told me that, no, I am not living in an RNAi Therapeutics bubble, but that RNAi Therapeutics slowly, but surely is making its way into mainstream medicine. Given that there was confusion about what exactly RNAi was even among Stanford lung transplant surgeons, maybe some education would help. A better understanding should also help in recruiting the best centers for clinical trials and consequently facilitate drug development, and maybe if Alnylam reads this, they may want to approach them and spend a couple of minutes educating them what ALN-RSV01 is about. I'm confident they would find receptive ears.

It also changed my view about the prospect for ALN-RSV01 and the development path Alnylam has taken. It is clear that the experimental infection model studies were not, as sometimes criticized, an advertisement ploy irrelevant to the development path and future use of ALN-RSV01. With no alternatives, it appears that having shown some type of antiviral activity, ALN-RSV01, similar to ribavirin, could be widely applied for the treatment of RSV infection even if only approved for a small sub-population of RSV patients.

Testing ALN-RSV01 in the lung transplant setting therefore makes a lot of sense, as this may turn out to be the setting where ALN-RSV01 could be approved first. Lung transplant patients have the highest medical need for such a treatment, even more so than other immuno-suppressed transplant patients as the infection affects the graft itself and may lead to graft failure. Moreover, any type of therapy that depends on the immune system is unlikely to work in this setting due to the immuno-suppression therefore increasing the competitiveness of an RNAi Therapeutics. As the early detection of RSV should be critical for the success of ALN-RSV01, the fact that lung transplant patients are regularly monitored for and highly sensitized to the possibility of RSV infections is highly advantageous. And finally, as I learned this Friday, the viral shedding of RSV is prolonged in immuno-suppressed patients, meaning that instead of the typical 5 day RSV infection window, ALN-RSV01 gets more time to attack RSV. An interesting aside to the immuno-suppression theme here is that any efficacy of ALN-RSV01 would be much less likely due to non-specific immune responses elicited by the unmodified siRNA.

When the RNAi Therapeutics story has have been written and taught in business schools, one of the main lessons for which ALN-RSV01 could be a prime example should be that by applying innovation to areas of large medical unmet need, a sweet spot can easily develop into a large market opportunity. Due to its unique mechanism of action, RNAi Therapeutics is ideally positioned to repeatedly take advantage of that strategy.