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.

ALN-RSV01 Update: The Drug is Safe- and Efficacious?

Alnylam provided this Monday an update on their phase II study results of ALN-RSV01 in lung transplant patients naturally infected with respiratory syncytial virus (RSV). RSV infection in lung transplant patients is linked to irreversible damage of the lung, decrease in quality of life, and sometimes even death. With no proven drug for the treatment of RSV, this remains an area of high unmet clinical need.

The 90 day data follow results announced in June that showed the drug to be well tolerated and adds to the growing evidence of safety obtained with this drug in various phase I and II studies. While safety was the primary objective, based on the initial 30 day data report no conclusions could be drawn on the efficacy of the drug as measured by either reduction of RSV titers or symptom scores due to differences in baseline characteristics between the drug-treated (N=16) and placebo control-treated populations (N=8).

The 90 day data confirmed the safety of the drug that was administered 3 times daily via inhalation. The longer time period also allowed for monitoring lung function. Remarkably, while lung function was significantly impaired in about one third of both the drug and control populations at the start of the study, most likely as a result of the RSV infection, at 90 days after drug treatment only 14% of the ALN-RSV01 patients experienced an FEV1 value 20% below baseline compared to 38% in the placebo group. While this did not reach statistical significance in this small study, when another related measure of lung health was considered, namely the incidence of new or progressive BOS (bronchiolitis obliterans syndrome), ALN-RSV01 did significantly better than control (1 in 15 patients for ALN-RSV01 versus 4 in 8 patients of placebo).

Taken together, the drug was shown to do no harm and there is intriguing evidence for clinically relevant efficacy of the drug in a randomized, double-blind trial, albeit somewhat tainted by the baseline differences. The difficulty of running such a trial is illustrated by the fact that 13 institutions around the world were involved and I cannot see a regulatory body requiring a 200 person lung transplant trial when there are only about 2000 lung transplants a year and only a fraction of those actually becomes infected with RSV. The results are certainly better than the standard of care today, ribavirin, which has unproven efficacy at least in this setting and is well known to be toxic. Transplant surgeons certainly would love to have another treatment option, even if only supported by such data. Therefore, is there a case for Alnylam and their co-development partners to talk to the FDA about approving ALN-RSV01 in this orphan patient population (compassionate use argument), maybe after further follow-up confirm the positive trend in improving lung function which has to be the ultimate measure of treatment success?

It would be ironic for the FDA e.g. to deny such a request due to the difficulty in interpreting the RSV biomarker results while the medically relevant outcome, lung function, showed positive results. Normally, the agency rejects drugs that although the biomarkers were positive (e.g. blood sugar and cholesterol), more direct clinical outcomes were not.

Needless to say, such an outcome would be unexpected, but it does not cost much to ask. In any case, for the wider application of RNAi Therapeutics in lung disease it is comforting to see that the inhalation of unmodified siRNAs even in this fragile population was so well tolerated and it will be interesting to see how the RSV program, sometimes criticized for its seemingly labyrinthine course, will unfold.