Opko Health Announces Initiation of First Phase III Trial of an RNAi Therapeutic

Less than a week after the signing of two significant alliances between RNAi Therapeutics companies with Big Pharma, it is today up to Opko Health to announce the initiation of the first phase III clinical trial for an RNAi Therapeutic. Opko Health is an ophthalmic focused company that was recently formed through a string of mergers and acquisitions with one of the companies involved being Acuity Pharmaceuticals. It is from Acuity that Opko inherited two advanced clinical RNAi Therapeutics programs, one of which is the subject of today’s announcement.

In the proposed COBALT study, Cand5 (bevasiranib), an unmodified siRNA against VEGF, will be given once every 8 or 12 weeks in patients with wet age-related degeneration (AMD). The goal is to assess its safety and, more importantly, whether it has equivalent efficacy compared to a the currently leading wet AMD drug Lucentis, which is another VEGF inhibitor that is given once every 4 weeks by needle injection.

Although the sweet spot for RNAi Therapeutics are targets that are otherwise undruggable by small molecules and monoclonal antibodies, Opko is one of a handful of companies targeting the VEGF pathway for AMD and diabetic retinopathy (see “RNAi and the Eye” post on May 1, 2007). This is in spite of the fact that other widely prescribed drugs, namely the monoclonal antibody Lucentis and the RNA aptamer by OSI Pharmaceuticals already serve this market. While this may reduce development risk and function as a proof-of-concept, RNAi Therapeutics for these applications will have to compete directly with such therapies in terms of safety and tolerability, potency, and duration of efficacy.

The reason why Opko wants to challenge Lucentis on duration is because each needle injection carries a risk of damaging the eye and causing discomfort to the mostly elderly patients. This becomes a particularly pressing issue for a repeat-administered therapy such as for wet AMD. Therefore, being able to reduce the frequency of injections by half or even more without a loss in efficacy would make an RNAi Therapeutics a very attractive treatment option. Indeed, pre-clinical studies published last year on the silencing of liver-expressed ApoB100 by systemic administration (Zimmermann et al. (2006) Nature 441: 111-4) support the notion that RNAi Therapeutics may have comparable or even better pharmacokinetics compared to what is usually observed for therapies such as monoclonal antibodies

While a positive outcome would certainly help the field of RNAi Therapeutics, there is cause to be skeptical. In particular, bevasiranib is an unmodified siRNA that is given without a particular performance enhancing formulation. This may result in suboptimal gene silencing due to RNA instability issues and inferior cell delivery and ultimately exhibit poor pharmacokinetics. Indeed, results from the C.A.R.E. phase II studies in 129 wet AMD patients were mixed and did not show statistically significant evidence for improvement of acuity. Opko clearly sees the need for optimizing RNAi delivery and have two years ago formed an alliance with the RNAi nano-delivery company Intradig to develop topical and other formulations for Cand5. Whether this will directly impact the current studies is unclear.

I am therefore more optimistic about the approach taken by Merck (formerly Sirna Therapeutics) and their partner Allergan to develop a slow-release formula of a modified siRNAs against the VEGF-receptor that when combined may significantly reduce the need for frequent needle injections. Phase II studies for that trial have started earlier this year.