Are Quark Pharmaceuticals’ Ocular Programs About to Meet Expected Fate?

Recent entries to the ocular clinical trials by Pfizer listed in ClinicalTrials.gov (see here and here) suggest that its first-generation RNAi Therapeutics candidate for wet age-related macular degeneration and diabetic macular edema, PF-04523655, is about to meet the same fate as did those for similar indications by Opko and Sirna Therapeutics (Merck)/Allergan before. The phase II study in diabetic macular edema (DEGAS) has already been terminated in December 2010 as ‘the objectives of the study could no longer be achieved’; a study run in parallel with the same candidate for wet AMD (MONET) meanwhile is still ongoing, but without recruiting new patients and after having been intermittently terminated in January as a result of the DEGAS trial.

Although making no mention of the clinical trials interruptions, Quark revealed in its Preliminary Prospectus filed this February that results from the DEGAS study are about to be unveiled this month. Quark is the company from which Pfizer had sub-licensed the AtuRNAi trigger candidate developed originally by Silence Therapeutics and is now making renewed attempts to go public. The Company would likely need such capital quite urgently in case those programs were indeed terminated as most of the recent funding had come from the Pfizer partnership in the form of $52.5M in milestones and cost reimbursements according to the registration statement; about $6M of which went to Silence Therapeutics.

The recent revelations also make it apparent just how much Pfizer had already invested in RNAi Therapeutics. Given that Pfizer announced plans to close its in-house RNAi Therapeutics effort in February, it is no stretch to imagine that the ocular program troubles were the final trigger for Pfizer's decision.

Approach not on sound scientific footing

Just like the previous discontinuations of the ocular RNAi programs by Opko and Allergan/Merck (Sirna Therapeutics), Pfizer’s approach involved the intravitreal needle injection of naked siRNA oligonucleotides and yielded phase I/II results suggestive of efficacy. I was personally never able to make sense of those candidates as they lacked a sound scientific basis for how they would enter target cells in the back of the eye. A study in 2008 by Ambati from the University of Kentucky likely shed light on these results by showing that TLR3 responses triggered by some siRNA structures may ultimately cause the inhibition of blood vessel growth that is a critical factor in those diseases. With the Quark/Pfizer drug likely to meet its unavoidable fate, the door is open for second-generation ocular RNAi Therapeutics approaches that get around TLR3 and into the cytosol of cells. Such efforts include those by RXi Pharmaceuticals and Korean company BioMolecular Therapeutics.

Shares of Silence Therapeutics trade at historic lows following revelations

At this point, it is important to emphasize that the ‘study was not terminated for safety’ according to the clinicaltrials.gov site and have little to no direct bearing on the other clinical and pre-clinical AtuRNAi programs.

Nevertheless, the stock of Silence Therapeutics traded down quite sharply as the revelations made the rounds among Silence investors, giving that company a ridiculous market cap of down to 10M UK pounds. What likely triggered the meltdown is investor worry that Silence had unduly relied on milestone payments from Quark’s programs in their financial planning. I therefore contacted the company on this topic and was informed that the Company does in fact not rely on such milestones in its cash guidance as these are out of their control. The Company added that data from the DEGAS study are yet to be unveiled and that it is not aware of any discontinuation of these programs.

Fair enough, and maybe, amid the confusion and insanely low valuations of some RNAi Therapeutics companies, a buyer will see an opportunity in acquiring a promising cancer candidate and some equally promising delivery technologies to endothelial cells and the lung for…maybe $30M?

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.