Fate of Quark Wet AMD Program in Limbo

PF-4523655 is arguably RNAi's most advanced clinical candidate. A naked, 19bp blunt-ended intravitreally injected AtuRNAi molecule, it had completed a phase II study in diabetic macular edema (DME) for which the results suggested a benefit over laser treatment; there was another phase II study of the same molecule in wet age-related macular degeneration (wet AMD) for which Quark, along with partner Pfizer had yet to report results.

These studies were also important for Silence Therapeutics, as an advance of any of these programs into phase III would have spelled the long-awaited non-dilutive funding (about $4M). Unfortunately, despite the suggestive DME efficacy data, Pfizer was not satisfied with the commercial competitiveness of the results in light of the newer VEGF pathway inhibitors. Therefore, Pfizer and Quark agreed that Quark would run a phase IIb study on its own dime testing higher doses of ‘655 in a head-to-head trial with VEGF MAb Lucentis. Pfizer would retain opt-in rights.

Still, the results from the wet AMD trial were outstanding. Expectations were relatively low though as in March 2011, as Quark attempted (yet again) to go public, the company disclosed that ‘655 was ‘not superior’ compared to Lucentis at the primary endpoint. Still, full results remained to be reported, probably in H2 2011. These results, however, never came. Since clinicaltrials.gov indicated that the study had been completed, it became obvious that there had been no positive surprises.

In its full-year results presentation, Silence Therapeutics today confirmed that while ‘[t]he trial demonstrated a dose-dependent increase in benefit of PF-04523655. Quark is now awaiting results from the Phase IIb trial in diabetic macular oedema before deciding on plans for the drug in age-related macular degeneration.’ In other words, not good for Quark and not good for Silence Therapeutics either: the fate of the wet AMD program now depends on the results from the phase IIb DME trial. It also seems that, like for DME, Pfizer has handed back the compound to Quark for wet AMD based on changes in the clinicaltrials.gov database in November 2011 that show ‘Pfizer’ being changed to ‘Quark’ in a number of entries relating to the sponsor of the trial. The silence (small letter) by Quark can be explained by the fact that it seems to have given up on going public for the time being.

From a medical point of view, the DME and wet AMD developments are a pity. If it is indeed the commercial profile vis-à-vis the protein-based VEGF pathway inhibitors that is keeping ‘655 from going into phase III, and not lack of efficacy, it may indicate some unjustified bias against RNAi Therapeutics. Both classes are intravitreally injected and there are many patients that are dissatisfied with the efficacy of these proteins. As a result, patients seek help from (expensive) treatments (such as acupuncture) that have not passed, or even undertaken formal clinical studies. What would be attractive with a molecule such as ‘655 is that it is not supposed to work as a VEGF pathway inhibitor and would thus offer a complementary mechanism of action (anti-apoptotic). On the other hand, since Quark has been so coy with the data, I suspect that bias alone may not explain Pfizer’s decision. Maybe with a sounder basis of delivery, next-generation RNAi Therapeutics candidates can address that void.

Pfizer and Quark Progress RNAi Therapeutic for Diabetic Macular Edema into Phase II

Quark Pharmaceuticals today announced that development partner Pfizer has initiated dosing of the first patient in a phase II trial of the RNAi Therapeutic candidate PF-4523655/RTP801i-14) for diabetic macular edema (DME). The start of the phase II trials is a vote of confidence in RNAi Therapeutics for eye diseases by a major pharmaceutical company with a considerable eye care franchise and growing ambitions in RNAi Therapeutics.

The 160-person safety and efficacy trial follows phase I/II studies conducted by Quark that showed the drug to be safe and well tolerated in patients with wet age-related macular degeneration (wet AMD). Similar to DME which affects about 10% of type I and II diabetics, wet AMD is caused by the growth of leaky blood vessels in the back of the eye leading to blurred vision, and in some cases blindness. For this reason, it is not uncommon that a given compound is being tested for both indications.

The reason that Pfizer has chosen DME instead of wet AMD as the indication for this trial may be related to the fact that the wet AMD RNAi Therapeutics space has become crowded with Opko Health and Sirna Therapeutics/Merck having wet AMD RNAi Therapeutics in phase III and II studies, respectively. Opko Health also has a phase II study for DME using the same compound. It may also be related to the recent controversy caused by a Nature paper that showed that dsRNA-triggered immune responses alone may be anti-angiogenic in a mouse model for wet AMD and that this may have led to mis-interpretations of data from related pre-clinical RNAi Therapeutics studies.

However, PF-4523655 is unlike Sirna’s and Opko’s compounds in that it is intended to prevent abnormal blood vessel growth and leakage in a VEGF-independent manner. It is also a 19bp blunt-ended compound and therefore unlikely to trigger non-specific TLR3 responses (21bp seems to be the cut-off where you have to take TLR3 signaling into account). I trust that the former Coley Pharmaceutical’s folks with their deep understanding of TLR biology and that are now running the RNAi Therapeutics show at Pfizer will have closely looked at the issue.

Quark received an undisclosed amount for the initiation of the trials, Silence Therapeutics which had originally licensed the AtuRNAi technology to Quark collected $1.9M, and Alnylam from which a technology license was subsequently obtained on Pfizer’s insistence another undisclosed amount. Clearly, with today's allowance of Silence Therapeutics’ 10/633630 patent in the US which specifically claims AtuRNAi molecules of 18 or 19 base-pairs the IP battles are about to begin, and will be addressed in a follow-up blog entry. In any case, it is an interesting coincidence that the initiation of the phase II studies and the patent allowance occurred on the same day.

Independent of all these patent issues, I look forward to the results of this compound which has the makings of a safe and differentiated RNAi Therapeutic for DME.