Oligonucleotides that work via an RNAi mechanism continue to face developmental challenges. Big pharma started pulling back from its RNAi programs; Roche chose to chop RNAi from its budget in announcing plans to shut down its efforts in Kulmbach, Germany, Nutley, NJ, and Madison, WI. Alnylam cut its staff back in September 2010 after Novartis departed without picking up a $100 million option on Alnylam’s targets.
On May 30, Alnylam announced that its most advanced RNAi drug candidate, ALN-RSVO1, failed to meet the primary endpoint of a Phase IIb study. The drug was tested in RSV-infected lung transplant patients to determine whether, at 180 days post infection, it reduced the incidence of progressive brinciolitis obliterans syndrome (BOS).
While the study missed its primary endpoint in an “intent-to-treat” (ITTc) analysis of confirmed RSV infected patients, it achieved statistical significant reductions in two other prospectively defined analyses. In all analyses, ALN-RSV01 treatment was associated with a clinically meaningful treatment effect, with a reduction of over 50% in the incidence of day 180 BOS as compared with placebo.
But what Alnylam will do with the drug remains to be seen. “To be clear, we could decide to continue development of ALN-RSV01 toward regulatory approval or alternatively we could decide to terminate all further development efforts,” CEO John Maraganore said on a conference call following the May announcement. Analyst and blogger commentary suggests that having put “what must have been tens of millions” into the drug candidate and given a limited potential upside for the indication, the company may pass on further development.
But in what may signal a small but meaningful comeback for RNAi drugs, Alnylam reported results of an open-label extension study of its RNAi therapeutic ALN-VSP02 in liver cancer patients who had responded to therapy in a Phase I study on June 4, saying that it was well-tolerated and showed evidence of anti-VEGF pharmacology and antitumor activity. ALN-VSP02, composed of lipid nanoparticle-formulated siRNAs, targets both VEGF-A and kinesin spindle protein (KSP). And although the oligo is an early-stage candidate, it has generated some excitement because it is the most advanced RNAi drug designed to circulate in the blood stream.
Citing the relative advantages of oligonucleotide molecules, Viaud remarked, “Intermediately sized bioactive molecules, peptides, small RNAs, and DNA oligonucleotides may offer the advantages of both small molecule-based drugs and biologicals while avoiding many of their shortcomings.” From the point of view of a drug developer, these molecules have multiple advantages including simplified rational drug design; simple, scalable, and inexpensive synthesis; and the possibility of extensive chemical modifications to enhance their properties, such as pharmacokinetic and clearance profiles, he added.
GEN asked Viaud what challenges remain for oligonucleotide development. “Since not many antisense oligonucleotides have made it to regulatory approval, our biggest challenge has been for our community to recognize the potential of an oligonucleotide.” But given the advantages of oligonucleotide drugs and some recent clinical successes, large pharma companies may reconsider their development pipeline options.