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.

Preview: Phase II Study of AtuRNAi PF-04523655 for Wet AMD

PF-04523655, formerly known as RTP-801i, is the clinically most advanced RNAi Therapeutic candidate and has been in two phase II studies for diabetic macular edema (DME) and the exudative form of age-related macular degeneration (wet AMD). ‘655 is a 19bp blunt-end AtuRNAi trigger targeting the RTP801/REDD1 apoptotic stress response gene in the choroid. ‘655 was originally discovered by Silence Therapeutics and Quark Pharmaceuticals, licensed to Quark and eventually partnered by Pfizer which is largely in control of clinical development.

Data from the DME study were reported earlier this year (see related blog entry here). These showed that while ‘655 was well tolerated and efficacy was strongly suggestive of superiority versus laser photocoagulation, the old standard-of-care, Pfizer and Quark agreed to run a phase IIb study using higher dosages to take into account the emerging standard-of-care for DME, Lucentis, a monoclonal antibody against VEGF. Data from the phase II wet AMD study should be imminent.

Unlike the DME study, the ~150 patient wet AMD trial design for the wet AMD study, MONET, already took into account Lucentis as the new standard-of-care in that indication. As you can see from the treatment groups below, the goal is to either show superiority to Lucentis, or at least show a synergistic effect when used in combination with Lucentis (a positive outcome would be to show superiority of Arms 4 or 5 over Arm 1). Unlike many other wet AMD/DME-targeting agents in development, ‘655 should not act via the VEGF pathway and therefore has potential as an add-on to Lucentis.

Treatment arms in phase II wet AMD study:

Arm 1: 0.5 mg intravitreal injection of Lucentis given every 4 weeks from baseline to Week 12 (note: 0.5mg once a month is the recommended standard for Lucentis);

Arm 2: 0.5 mg of Lucentis given by intravitreal injection at baseline followed by 3 mg of PF-04523655 given every 2 weeks from Week 4 to Week 12;

Arm 3: 0.5 mg of Lucentis given by intravitreal injection at baseline followed by 1 mg of PF-04523655 given (weekly) from Week 4 to Week 12;

Arm 4: 0.5 mg of Lucentis given at baseline by intravitreal injection followed by 3 mg of PF-04523655 given every 4 weeks from Week 4 to Week 12;

Arm 5: 0.5 mg of Lucentis given by intravitreal injection at baseline followed by 1 mg of PF-04523655 (30 minutes later) given in combination every 4 weeks from baseline to Week 12.

Dosing had been completed and preliminary data from the study were known already in November 2010. Unfortunately, while ‘655 as single agent or in combination with Lucentis did show improvements in mean visual acuity over the 3 month dosing period, 6 and 9 letters respectively, it failed to show superiority to Lucentis at any of the doses at the important 4 month primary endpoint. No remarkable safety events were seen in MONET (all this can be gleaned from reading Quark Pharmaceutical’s latest prospectus). By comparison, large studies with Lucentis (0.5mg, monthly) have shown 6.6-9.8 letter average improvements from baseline at two years.

Outlook for ‘655 in Wet AMD

Most likely due to missing the primary 4-month endpoint, Quark Pharmaceuticals already indicated that following full data review Pfizer is unlikely to directly enter phase III trials, but would either decide to run a phase IIb study or abandon the program altogether. It is disappointing that ‘655 has apparently not shown synergism when used together with Lucentis as one might have expected from the presumed mechanism of action of ‘655, but possibly not from an immunostimulatory antiangiogenic VEGF-related artefact. A synergistic effect, however, may be masked by the initial Lucentis activity and only emerge over time. What is also often forgotten when it comes to the competitive space for the novel therapeutics in ocular diseases is long-term safety, not just absolute efficacy and dosing frequency, so studies with longer dosing than just the 3 months in MONET may be worth the risk. Maybe such safety and efficacy signals will emerge from the upcoming full data presentation.

Finally, instead of combining '655 with an antibody like Lucentis, combining it with the approved anti-VEGF aptamer Macugen (an oligonucleotide) might have practical advantages. Macugen has been struggling in the marketplace following the introduction of Lucentis due to perceived potency disadvantages. Curiously though, it is Pfizer that holds the commercial rights to Macugen, and combining it with '655 to reinvigorate the competitiveness of Macugen must have crossed their mind.

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?

Is Novartis' Kidney RNAi Drug Deal Part of its Grand RNAi Therapeutics Strategy?

In a reminder that the $100M adoption license option decision is coming close, Quark just announced that it has granted Novartis, for $10M in upfront and another $600M or so in potential milestones, the option to fully license Quark’s drug candidate QPI-1002, an siRNA targeting the famous 'guardian of the genome', p53. Delivered in its naked form intravenously, QPI-1002 is currently in phase I/II studies for the treatment of ischemia-reperfusion-related injuries of the kidney. While the deal is certainly supportive of Novartis’ interest in RNAi Therapeutics, questions remain whether this deal could reflect Novartis’ view of Alnylam’s RNAi trigger IP.

It is possible that this deal has indeed very little to do with Novartis’ general RNAi Therapeutics platform strategy and was largely driven by its therapeutic focus area and commercial groups that simply regarded this candidate as an interesting pipeline addition. As long as the underlying scientific data, market potential, the mechanism of drug action look attractive and the candidate is adequately protected by IP etc, Novartis may not care much about for example whether its core RNAi Therapeutics development group likes the Atu-siRNA structure or not. This would be somewhat reminiscent of the situation at Pfizer where the RNAi drug candidate licensing history does not seem to tell us much about its grand platform strategy.

Nevertheless, given the timing of the license, it is interesting to think that the various departments at Novartis in fact talk to each other occasionally. Such a conversation would probably have been centered around the siRNA structure and IP as well as delivery.

In terms of siRNA structure, QPI-1002 is a 19bp blunt-ended Atu-siRNA that is protected under licenses from both Silence Therapeutics and Alnylam. Since it is an Atu-siRNA structure and patents have actually been issued on this in major markets, there is little question about the need for the license from Silence Therapeutics which it obtained in 2005. In 2006, however, Quark also struck a license with Alnylam for additional patent protection. Because of its size and blunt-endedness, I would agree that such protection may be indeed required due to Kreutzer-Limmer in Europe (15-21bp), although the eventual outcome of the opposition proceedings remains to be seen. Consequently, I expect a decent portion of the Novartis payments to flow to Silence Therapeutics (10%?) and probably also to Alnylam.

In pre-clinical studies reported last year, QPI-1002 demonstrated decent potency with an IC50 of 230pM in tissue culture experiments. Potency has been my biggest concern when it comes to Atu-siRNAs. While I still believe that the rigid Atu-siRNA design makes it quite a bit more difficult to find potent RNAi triggers, at least this study is further support that Atu-siRNAs of clinically relevant potency, let's say an IC50 of less than 50nM, can be found.

The heavily modified Atu-siRNA structure makes QPI-1002 also very stable in biological fluids which is presumably required for the type of naked delivery approach that Quark has taken. Which gets us to the question of delivery.

All of Quark’s RNAi drug candidates are unformulated siRNAs. This raises, of course, a lot of skepticism about their scientific soundness. Quark counters that it just looks at where the naked siRNA goes after various routes of administrations and then select the indication accordingly. Since naked siRNAs following their unformulated administration quickly accumulate in the proximal tubule where the process of the re-uptake of the bulk of the primary urine begins, and since apoptosis in that area is believed by some to be important for the type of kidney injury Quark is targeting, it may explain why the company may have seen success whereas others have apparently failed.

In general, when it comes to target selection, I also like the approach where you carefully match pathophysiology, target, and siRNA pharmacology, instead of having a fixed idea of the target and cell at the start of your project and desperately try and find a suitable delivery technology for it.

Nevertheless, how the siRNA escapes into the cytoplasm of the proximal tubular epithelial cells still remains a mystery although it is always possible that cells in general, especially those with high membrane dynamics, have a general leakiness that allows some siRNA to get through the lipid bilayer when siRNA concentrations are very high. And because siRNAs can be highly potent, this would be sufficient to prompt knockdown.

Similar reasonings may apply to Quark’s eye drugs, one of which, another Atu-siRNA structure, has been licensed to Pfizer and the other one Quark is apparently out to license, too. I guess being too productive in entering the clinic may not be the best way to build value if you are a small and private company.

Overall, this deal is good for the RNAi Therapeutics field as it shows that it is yielding candidates in various therapeutic areas that can attract serious funding by the industry. Not that I need to be convinced of this, but headlines like this should encourage further investments in the space. We shall soon see how this investment will look like in more detail for Novartis. One thing is for sure: delivery has to be a critical part of that equation, and this creates a number of interesting scenarios. I guess I was not the only one wondering about those when I first heard of the news.

Tekmira Awarded Ebola Contract, Continues to Build on Momentum

The mystery surrounding the abrupt halt to the trading of Tekmira shares on July 14 was solved when Tekmira announced that it was awarded a significant US government contract for the development of an Ebola drug worth up to US$140M, $35M of which could be earned over the next 3 years. This essentially provides Tekmira with a free shot on goal for early product revenues, and should also prove beneficial for its overall balance sheet because of the typical fee component of such contracts plus expenses generally applicable to SNALP drug development.

This development nicely builds on the impressive SNALP-Ebola study published in the prestigious journal The Lancet less than 2 months ago where Tekmira scientists along with collaborators from Boston University (Geisbert group) showed for the first time the complete protection of non-human primates in a post-infection model.

While this is not the Big Pharma buy-out deal that I had speculated about yesterday, this endorsement of SNALP technology by the US government only makes one more likely now. It is even more impressive given that Tekmira, based in Canada, obtained this contract on a shoe-string budget without the significant government support that competing groups have enjoyed, and in a much shorter period of time.

The initial funds will be used for IND-enabling pre-clinical development and one phase I human safety study. This should involve more extensive safety and efficacy testing in animals, especially non-human primates, and the development of biomarkers predictive of efficacy in humans where efficacy cannot be tested. Ultimately, the big payout in the form of the first RNAi Therapeutics product revenues may come from government stockpiling contracts after further successful clinical safety and non-human primate efficacy testing.

The contract raises once again questions about Tekmira’s relationship with Alnylam. Alnylam actually have earned from 2007-2009 about $30M in hemorrhagic fever virus R&D government funding and may therefore at one point have competed with Tekmira (then Protiva) for such government contracts. Another interesting issue is whether Tekmira would have to exercise a target pick under the Alnylam RNAi trigger license. It is possible, however, that Tekmira will not have to exercise one because it is likely that the US government, the eventual main customer of any Ebola product, has rights to many of Alnylam’s fundamental RNAi trigger patents. It is also curious that Alnylam appears to have given up their pursuit of Ebola therapeutics, and could possibly reflect the influence that Tekmira enjoys in practical terms in who is able to pursue SNALP products and for which targets (‘Tekmira know-how’).

Overall, this was unexpected news to me. I had mainly considered the value of the Ebola program as being a quite visible proof-of-concept for the wider applicability of SNALP delivery, not expecting any significant funding windfalls. Following the wide publicity that The Lancet paper received, the fact that this study now turns out to have actual positive financial implications for the company could mean a significantly shortened trajectory towards profitability and increased investor interest to coincide with the upcoming Nasdaq listing. If that were not enough, the upcoming filing of the IND for SNALP-PLK1 and the $100M Novartis decision means that the momentum is now decidedly in Tekmira’s favor.

In related RNAi Therapeutics deal news

Quark Pharmaceuticals and Japanese Co. Nitto Denko announced a collaboration whereby Quark will contribute its RNAi triggers, with supposedly structural features that provides them with freedom-to-operate, with Nitto Denko’s siRNA delivery technology to develop an RNAi Therapeutic for cirrhosis of the liver. Financial details were not disclosed, except that it said to be in the double-digit million dollar range. While the exact nature of the delivery technology was not disclosed, the press release referred to a 2008 Nature Biotech paper that successfully employed small molecule-targeted cationic liposomes to knock down a cirrhosis-related gene in specialized cells of the liver. Liver cirrhosis is certainly another disease of the liver of high unmet medical need and attractive for liposomal siRNA delivery. Ligand-targeted liposomes should even further expand the utility of SNALP-siRNA delivery and I look forward to learning more about progress in that area, including the detailed structural and functional characterization of such particles.