Monday, March 21, 2011

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.

4 comments:

Anonymous said...

This is the key challenge for RNAi. How will RNAi differentiate itself in the marketplace? If not on efficacy, then on cost, safety, other?

If pharma can now drug the undruggable targets, then what is the primary driver for alternate technologies? Perhaps it might be genetically enabled enhancements, or multidrug treatments of cancer?

There has to be some new goal that is met via an RNAi-based drug that isn't met by other approaches.

Genetic medicine will have a role to play, it's not a question of if, but rather of when.

bio7mm said...

What do you think of the Rimonim Pharmaceutical Consortium that includes an Israeli subsidiary of Quark Pharma and Rosetta Genomics among others? They are charged with developing novel microRNA mimic and siRNA technologies.

Anonymous said...

Honestly, who really cares about treating eye diseases with siRNA? In the world of antisese, Isis tried with Vitravine and was beaten out by a small molecule (or monoclonal, I can't remember). Then there was the aptamer Macugen. A heavily chemically modified oligonucleotide that was sure to be toxic if given IV/SC or orally (if an oligo could even survive oral, IV/SC for more than 4 h for that matter) that was later beaten out by a small molecule or monoclonal. Pfizer is smart to drop this garbage all together. RNAi therapeutics, antisense, microRNAs, aptamers ect. ONLY have a chance in the liver or maybe the kidney, and a bleak one at that.

Dude, your blog is way too positive. These things are huge negatively charged biopolymers that are difficult to make synthetically regardless of what you may think. Only a handful of company's can make grams to multi-grams let alone kilos or tons.
RNAi is FAR away from ever becoming useful as a therapeutic strategy if ever.

Marion said...

Hey anonymous,
whoever you are, your comments are not what I would call constructive. Why so negative? If small companies like Isis, NeXstar or Archemix wouldn´t have put so much effort in their pioneering work in this field, you probably even wouldn´t have a job, would you? I for myself strongly believe the (off) target specific approach nucleic acid therapeutics address will have success, somehow. Maybe not in the next few years, but it will.
By the way, you forgot the spleen ...

By Dirk Haussecker. All rights reserved.

Disclaimer: This blog is not intended for distribution to or use by any person or entity who is a citizen or resident of, or located in any locality, state, country or other jurisdiction where such distribution, publication, availability or use would be contrary to law or regulation or which would subject the author or any of his collaborators and contributors to any registration or licensing requirement within such jurisdiction. This blog expresses only my opinions, they may be flawed and are for entertainment purposes only. Opinions expressed are a direct result of information which may or may not be accurate, and I do not assume any responsibility for material errors or to provide updates should circumstances change. Opinions expressed in this blog may have been disseminated before to others. This blog should not be taken as investment, legal or tax advice. The investments referred to herein may not be suitable for you. Investments particularly in the field of RNAi Therapeutics and biotechnology carry a high risk of total loss. You, the reader must make your own investment decisions in consultation with your professional advisors in light of your specific circumstances. I reserve the right to buy, sell, or short any security including those that may or may not be discussed on my blog.