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.