Saturday, June 28, 2008

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.


Anonymous said...

Dirk, I was always convinced that ALNY's RSV program represents a significant commercial opportunity, so your account of the lung transplant related seminar does not come as a great surprise (although it is obviously great to hear of this interest from lung transplant surgeons that have no connection to ALNY).

However, it is my view that the breadth of this commercial opportunity, and indeed the value of the program, will depend on how well ALN-RSV01 actually works.

While the lung transplant market may be there for grabs as long as ALN-RSV01 is confirmed to be safe and tolerated and continues to demonstrate at least some level of anti-viral efficacy (simply because, as you write, there are no viable alternatives), the value of the program will likely be driven by the extent to which ALN-RSV01 can be used to effectively treat RSV infection in the pediatric and elderly populations and the related hospitalizations. To unlock this value, ALN-RSV01 program will need to demonstrate more than that which may suffice for its successful application in the lung transplant context. And that remains to be seen, although I do take some comfort from the Kyowa deal as I do not believe (contrary to the many skeptics out there) that Kyowa would simply throw USD 15M ALNY's way without first having done their due diligence on the program - remember that, from Kyowa's perspective, the deal is a single program play, unrelated to how RNAi fares in general.

However, I do not quite understand why is it that ALNY is the only one developing RNAi therapeutic for RSV treatment. If I count correctly, there are now 3 AMD programs in clinical trials, pretty much filling up that space (and even if the programs are successful they will compete against each other), while there is only 1 RSV program. Of course, this is good for ALNY if the program proves itself but why is it that no one else commenced an RSV program. ALNY's blocking target-related IP? Skepticism as to the program's success? Cost of related R&D? Some other reason?

What is your view?


Dirk Haussecker said...

Martin- valid points as always. Yes, the better the actual data, the better the commercial prospects for ALN-RSV01. But one thing is for sure, Alnylam is not the only RNAi player with RSV programs. Sirna Therapeutics/Merck-GSK and AstraZeneca-Silence Therapeutics have noted such development programs before and may be approaching the clinic. So the keen interest of developing RSV RNAi Therapeutics supports the promise of RNAi for that indication.

Anonymous said...

Dirk, it would seem that since the date of your paper on the Business of RNAi Therapeutics paper, the landscape is evolving in that more and more Big Pharma are starting to seriously pursue RNAi Therapeutics (Pfizer, Takeda, Abbott,...) Which of the Big Pharma has NOT declared in one way or another its intent to pursue RNAi Therapeutics? What are the routes they can take if they want to jump on the bandwagon? Internal development? Unlikely at this point as they would likely be too far behind in R&D and unless they believe they can develop a way that gets around the fundamental patents. Acquire or partner with one of the me-too companies with dubious IP positions and try to develop on their platforms and hope to fight their way thru any IP roadblocks? (perhaps cheaper in the short run but risky) Partner with Alnylam or with a company working on the basis of Alnylam IP (or acquire such company) for the freedom to operate? (perhaps more expensive in the short run but no IP risk)
It would be interesting to hear from you on these thoughts or on some of the other topics from your paper that have gone thru development since you wrote it.


Dirk Haussecker said...

Martin- Indeed, in the 6 months that have passed since the review was written, it seems that the Big Pharma RNAi Therapeutics avalanche has only grown in size. And if you are involved in molecular biology research in today’s laboratories there is just no way of ignoring RNAi. I personally cannot imagine how I would conduct my own research without RNAi. Kind of like trying to imagine what it was like before the internet came around.

If you then truly believe in the promise of RNAi Therapeutics and have the cash, and most Big Pharma still do as judged by their still very generous dividends, then why risk being left out by being cheap and saving a few million dollars now by relying on uncertain IP only to pay billions later as AstraZeneca did for MedImmune and Cambridge Antibody Technology for a real piece of monoclonal antibody? Also, time is money and these partnerships also provide for the transfer of technology know-how to speed up development. Acquiring smaller biotechs with nucleic acid know-how like Pfizer with Coley makes sense, but the time has come that if you have not done so already then you better get your internal capabilities going.

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Respiratory Syncytial Virus

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