Quark RNAi Therapeutics Drug Candidate for Diabetic Macular Edema Effective, but Changing Competitive Landscape Weighs

A lot has changed in the treatment of diabetic macular edema (DME) since Quark sub-licensed its AtuRNAi compound to Pfizer in 2006. Most notably, the monoclonal antibodies against VEGF, Lucentis and the cheaper derivative Avastin, are replacing laser photocoagulation as the standard of care in this condition that adversely impacts the vision of up to 10% of those living with diabetes.

Quark last week reported 12-month data from the phase II study of PF-04523655 run by Pfizer (DEGAS) enrolling 184 patients with DME. The data suggest that the drug was on track of meeting its primary end-point which would have been superior improvements in mean visual acuity at 24 months compared to laser treatment: a 5.8 letter improvement for ‘655 at the highest dose (3mg) compared to 2.4 for laser (p= 0.08). Pfizer, the company that ran the trial, however, decided to terminate the study at this midway point as it deemed that the study objectives could no longer be met.

This is likely at least partly due to the new competition from the Roche/Novartis drug Lucentis that showed 24-month improvements of 12.5 letters versus 2.6 letters for sham control in a pivotal phase III study (RISE). Nevertheless, the efficacy of ‘655 looks much better if one considers that taking into account the 12 month completers only, the improvement was a very promising 9.1 letters for ‘655 versus 3.2 letters for laser. Moreover, the ‘655 data were reported to be dose responsive whereas the Lucentis data were not. Importantly, no serious adverse events were reported, although additional details remain to be reported at an upcoming conference.

Based on this dataset, it seems to me that ‘655 was efficacious, but unlikely to match the Lucentis data with the doses studied even when allowing for more patients to complete the study. Given the encouraging data, Quark decided to run a phase IIb study on its own dime, hoping that with higher doses the efficacy of Lucentis can be matched or even surpassed. This would confirm that the safety profile in DEGAS was satisfactory. In return, Quark would receive increased milestones and royalties should the drug eventually be approved.

Overall, the data are good news for RNAi Therapeutics in ocular indications in general. 3mg siRNA translate into almost a whopping 100mg per kilogram of human eye that were apparently well tolerated in this study (note, however, that the cost of goods for monoclonal antibodies would still be higher even at the current 0.3-0.5mg/injection). This paves the way for improved RNAi Therapeutics candidates with larger therapeutic indexes due to enhanced uptake and at the minimum the same frequency of administration as Lucentis (monthly). Some RNAi approaches, such as attempted by RXi Pharmaceuticals and Eyegate, may even dispense of the need for needle injections altogether. This would be a major differentiating factor.

Moreover, even with comparable single-drug efficacy, safety, and route of administration, ‘655 may be a viable alternative or complement to Lucentis as its mechanism of action is anticipated to be anti-apoptotic (stabilizing the blood-retina-barrier) instead of anti-angiogenic (preventing abnormal blood vessel formation). However, as indicated in my somewhat less optimistic blog entry last week, this is yet to be convincingly proven given the possibility that ‘655 may have at least partly worked through a non-RNAi mechanism. Demonstrating synergistic action in some animal models would go a long way in showing this.

For investors of Silence Therapeutics, I consider this better-than-expected data as they keep the drug alive and demonstrate the safety of the AtuRNAi design. How the new terms between Quark and Pfizer will affect Silence’s financial stake in the program and whether the present result will trigger any immediate payments, remains to be seen.

Update from March 18 Quark registration statement: In the parallel study of '655 in wet AMD, an interim analysis has shown improvements in mean visual acuity over 3 month period, but at 4 months, the primary endpoint, no numerical benefit over Lucentis was seen in any of the doses. The trial will be continued with full data expected in the second half of 2011.

While Alnylam Focuses Suit on Whitehead and UMass, a New Tuschl Loophole Approach Gains Traction

Not a day goes by in RNAi Therapeutics land without hearing the sounds from the RNAi trigger IP battle grounds. Today is no exception…

Wading through the court documents from the Alnylam-Max Planck suit on how the Whitehead prosecuted the Tuschl I (T-I) patent application (aka the 'Tuschl Tussle'), it struck me that while it was Whitehead, their hired patent counsel, and UMass that apparently conceived of the strategy of how to incorporate data from the T-II patent into T-I against the interests of Alnylam and Max Planck, the MIT seemed to merely go along unwittingly. As a result, MIT not only became a victim in that they were deprived of the benefits from the therapeutic agreement they were part of with Max Planck and the Whitehead, which to my knowledge anticipated equal sharing of the profits from therapeutic licenses derived from the combined T-I and T-II estate, but also because they ended up as defendants in the suit.

Perhaps realizing this, Alnylam announced today that it will leave the MIT off the hook in return that they will be bound by any ruling in favor of Alnylam/Max Planck. It could also help drive a wedge between the former co-defendants as the MIT will now feel less fearful about telling their side of the story which could turn out to be quite revelatory. The MIT should have every reason to be unhappy with the Whitehead and the way T-I was handled. The argument that Whitehead, and implicitly, the MIT, aided UMass for political reasons, thereby leaving therapeutic licensing money on the table, never really flew with me since a) institutions just don’t give away money like this, and b) I could never imagine a research institution of the stature of Whitehead as being nationalistic and therefore anti-Max Planck.

While the Tuschl Tussle is going on, there is another Tuschl loophole movement in the field that appears to be gaining some traction. It initially started with mdRNA’s claims that the mere inclusion of a single ‘funny-looking’ nucleotide into an siRNA, unlocked nucleic acids (UNAs), would help it get around the Tuschls. It long cited evidence by outside patent counsel that supposedly supported their belief that they had freedom-to-operate in the RNAi trigger space. The news that Quark Pharmaceuticals had just initiated dosing for their 5^th (!) clinical RNAi program for a neuroprotective agent of the eye, it reminded me of their similar claims about ‘proprietary siRNAs’. To find out about the nature of these claims, I looked up what potentially applicable patent applications they had filed, and came up with the following main claim:

"1. A compound having structure (IX) set forth below:

(IX) 5' (N)x - Z 3' (antisense strand)

3' Z'-(N')y- z" 5' (sense strand) wherein each of N and N' is a ribonucleotide which may be unmodified or modified, or an unconventional moiety; wherein each of (N)x and (N')y is an oligonucleotide in which each consecutive N or N' is joined to the next N or N' by a covalent bond; wherein Z and Z' may be present or absent, but if present is independently 1-5 consecutive nucleotides covalently attached at the 3' terminus of the strand in which it is present; wherein z" may be present or absent, but if present is a capping moiety covalently attached at the 5' terminus of (N')y; wherein x =18 to 27; wherein y =18 to 27; wherein (N)x comprises modified and unmodified ribonucleotides, each modified ribonucleotide having a 2'-O-methyl on its sugar, wherein N at the 3' terminus of (N)x is a modified ribonucleotide, (N)x comprises at least five alternating modified ribonucleotides beginning at the 3' end and at least nine modified ribonucleotides in total and each remaining N is an unmodified ribonucleotide; wherein in (N')y at least one unconventional moiety is present, which unconventional moiety may be an abasic ribose moiety, an abasic deoxyribose moiety, a modified or unmodified deoxyribonucleotide, a mirror nucleotide, and a nucleotide joined to an adjacent nucleotide by a 2 '-5' internucleotide phosphate bond; and wherein the sequence of (N)x is substantially complementary to the sequence of (N')y; and the sequence of (N')y is substantially identical to the sequence of an mRNA encoded by a target gene."

As the red highlight shows, the ‘proprietary’ claim of the Quark siRNAs rests on the sense/passenger strand similarly containing at least one ‘funny-looking’ nucleotide. I was disappointed, however, that the specifications did not explain why this should have any unique advantages. Since in addition to novelty (that's where they will likely try to focus their arguments on), a patent has to also fulfill the demands of non-obviousness and utility, I have my serious doubts that this and the usiRNA patent applications will stand up to closer scrutiny, and if they did get by any patent offices, Alnylam would ultimately challenge them. It suggests, however, that while patent protection for these RNAi triggers is unlikely, a number of players increasingly view this strategy as a way to at least gain independence from the Tuschls. The exact reasoning behind this is mysterious to me, since these modifications should already be explicitly covered by the Tuschls when they refer to 'nucleoside analogues' which usiRNAs are. And even if the Tuschls did not explicitly mention them, it would appear obvious that an siRNA is an siRNA whether it contains a limited number of ‘funny’ nucleotides or not.

As I said, I have yet to hear a convincing argument by the companies what their belief is based on. Just stating that they believe so is not enough to convince investors and potential partners. I am always willing to listen to such arguments.