Wednesday, July 22, 2009

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.


pradeepkumar said...

Is the chemical composition of ALN-RSV01 is available in public domain? I am interested to know what are the chemical modifications employed in this siRNA drug.

Dirk Haussecker said...

ALN-RSV01 is described in Alvarez et al. Antimicrob Agents Chemother. 2009 Sep;53(9):3952-62.

It is an unmodified 19bp siRNA duplex with 2nt 3' overhangs. The sequence is as follows (sense strand):

pradeepkumar said...

Dear Dirk, Thanks a lot for this information. I was always thinking ALN-RSV01 is a a chemically modified one since its from Alnylam. By the way do you have info about any chemically modified siRNAs in Phase II or Phase II of clinical trials? Is there any place/article, I can get info on siRNAs which are in mid or advanced clinical trails? doesnt provide all the info which we are interested in. I will appreciate very much if you could give info regarding this.

Dirk Haussecker said...

To my knowledge, there is not any single place where you can find such information. The 'World of RNAi Therapeutics' map may give you a start on compiling such a list. Quark Pharmaceuticals I believe has 3 ongoing phase II trials that involve modified siRNAs (AtuRNAs with 2'-O-methyl at every second base). So yes, there is precedence for this.

pradeepkumar said...

Thanks a lot for fingering the the trials from Quark. The World of RNi therapeutics is really useful. By the way do you have any update on AGN211745 from Allergen, which was in Phase II (Ref: Nature Reviews Drug Discovery 2009, 8, 525-526). The says the trials have been terminated. Is it true?

By Dirk Haussecker. All rights reserved.

Disclaimer: This blog is not intended for distribution to or use by any person or entity who is a citizen or resident of, or located in any locality, state, country or other jurisdiction where such distribution, publication, availability or use would be contrary to law or regulation or which would subject the author or any of his collaborators and contributors to any registration or licensing requirement within such jurisdiction. This blog expresses only my opinions, they may be flawed and are for entertainment purposes only. Opinions expressed are a direct result of information which may or may not be accurate, and I do not assume any responsibility for material errors or to provide updates should circumstances change. Opinions expressed in this blog may have been disseminated before to others. This blog should not be taken as investment, legal or tax advice. The investments referred to herein may not be suitable for you. Investments particularly in the field of RNAi Therapeutics and biotechnology carry a high risk of total loss. You, the reader must make your own investment decisions in consultation with your professional advisors in light of your specific circumstances. I reserve the right to buy, sell, or short any security including those that may or may not be discussed on my blog.