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.