[Update following this morning’s conference call: 1) Importantly, statistical analysis showed that the reduced infection rate following ALN-RSV01 administration was independent of the level of pro-inflammatory cytokines, and therefore further indicates an RNAi-based mechanism of action, instead of an siRNA-triggered non-specific cytokine response; 2) The dosages were at the upper end based on previous phase I nasal administration safety studies. There were two dosages used, a 75mg group (8/88 subjects) and a 150mg group (80/88). This number was too small, and probably too close together, to determine dose-response. 3) while I labeled the virus in my summary as a “laboratory strain”, it was stressed that the virus was a relatively fresh clinical, wild-type isolate from an RSV patient and therefore not attenuated; 4) the slides from John De Vincenzo’s presentation in Singapore will be available on the company’s website this weekend.]
Concurrent with a presentation at the respiratory disease conference in Singapore, Alnylam has just released more detailed data from the phase II experimental infection study of ALN-RSV01, an unmodified siRNA for the treatment of RSV infection via RNAi. The study, termed GEMINI, was designed to demonstrate the safety and antiviral activity of intranasally administered ALN-RSV01 in adult volunteers artificially infected with a laboratory strain of RSV virus. As such, it could therefore represent statistically validated proof-of-concept for RNAi activity in humans.
According to the press release, there were no obvious adverse effects attributable to ALN-RSV01. Although this may have been expected based on the previous phase I intranasal safety study results, considering the inflammatory potential of some siRNAs (which were apparently excluded during the pre-clinical siRNA screening process) , an siRNA in the context of a viral infection could have conceivably triggered unforeseen safety issues, even worsening rather than treating the viral infection.
On the efficacy side, ALN-RSV01 statistically reduced the infection rate across a range of laboratory parameters. When given 5 times daily, 2 days before and 3 days after viral administration, the number of volunteers remaining infection free almost doubled, from 12/42 to 24/43 treated with placebo and ALN-RSV01, respectively. Measures of viral dynamics in those patients in which viral infection took hold showed a trend towards improvement with ALN-RSV01, although they did not reach statistical significance. Similarly, symptom scores were not much different between ALN-RSV01 and placebo (at least they were not worse as may have been expected for a siRNA-triggered inflammatory response!).
It therefore appears that at least in this setting efficacy was largely an all-or-none and once viral infection took hold there was little stopping it. For a drug candidate that is designed to treat, but not prevent RSV infection (note that there are very effective preventive neutralizing antibodies for RSV on the market), this may appear disappointing at first glance.
However, there are a number of factors that complicate how predictive these results are for naturally infected patients. One unknown to me is the dose used in the study and whether they were on the conservative or aggressive side, which could have made a big difference in antiviral efficacy (but also safety, of course). Another factor is that in order to achieve reliable experimental infection, the nasal epithelium was probably overwhelmed with viral loads that would not be encountered at early stages of a natural infection. Moreover, although the experimental infection should have initially been largely restricted to the nasal epithelium, the odd survivors may be able to establish reservoirs in areas of the respiratory tract not reached by the nasal administration of the drug, at which point the route of administration became limiting in the ability of ALN-RSV01 to stop RSV replication. This may be addressed with the use of aerosolized versions of ALN-RSV01, or even in conjunction with nasal administration, in future studies.
It will also be interesting to find out whether the all-or-none response was due to viral escape mutants that have changed their sequence at the siRNA target site, as had been observed in a number of pre-clinical antiviral RNAi studies before. In that case, co-administering two different siRNAs, similar to Benitec’s HIV and HCV RNAi strategies, should considerably lower the likelihood of such an event.
Today’s results are probably almost all one could have hoped for. They are the culmination of a very well-planned and executed scientific program involving challenges such as the not-so-trivial task of establishing the experimental infection model itself. But there will be little time to rest on their laurels. The eyes are now on the design of the phase II natural infection study slated to start in the first half of this year. The all-or-none response seen here strengthens pre-clinical results suggesting that early detection and treatment will be important for the success of ALN-RSV01 of such studies, and ultimately in the clinic. With increasingly rapid nucleic acid-based diagnostics coming online, hospital-acquired cases of RSV may be the low-hanging fruit. Tomorrow’s conference call may give many of the answers, possibly linked to the enigmatic post-hoc naming of the trial as “GEMINI”.
In the larger scheme of things, the results may also have implications for the treatment and prevention of other respiratory viral infections. In terms of human proof-of-concept, with RNAi and viral infections one always has to take into account the possibility that stimulation of innate immune responses rather than specific gene silencing may have caused the antiviral effect. However, based on the preclinical studies and the fact that the drug was apparently well tolerated, one would probably have to give human proof-of-concept a pass.
Sunday, March 2: The Singapore presentation is now available on the company’s website.
Disclosure: I hold stock in Alnylam Pharmaceuticals.
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