By Doug Macron
Quark Pharmaceuticals said last week that its partnership with Pfizer for the siRNA-based ocular disease treatment PFE-655 has been amended, shifting to Quark the responsibility for conducting a planned phase IIb study of the drug and giving Pfizer the opportunity to pull out of the arrangement, depending on the trial's outcome.
The decision stems from data from a halted phase II trial of PFE-655 in patients with diabetic macular edema, which showed that although the agent was well-tolerated, it was unlikely to produce a therapeutic effect at the dose levels tested that was superior to the current standard of care, Roche/Novartis' Lucentis.
By stepping back, but not entirely away, from PFE-655, Pfizer is apparently making good on its previously disclosed plan to look for ways to maintain promising nucleic acid-based drug programs after having shuttered its in-house oligonucleotide therapeutics unit earlier this year (GSN 2/3/2001).
PFE-655, formerly called RTP801i-14, is an siRNA targeting the proprietary human gene RTP-801. In 2006, Quark licensed to Pfizer both the gene target and the drug for certain diseases including DME and wet age-related macular degeneration (GSN 9/28/2006).
Since then, the drug has been tested in humans for both indications. A Pfizer-run phase II trial in AMD is ongoing, with full data expected to be available in the second half of this year. The phase II trial in DME, however, was terminated halfway into its planned 24-month run, Quark said.
In that scuttled study, 184 patients were randomized to receive treatment with either one of three doses of PFE-655 — 0.4 mg, 1 mg, or 3 mg — or laser photocoagulation therapy. After 12 months, researchers observed a dose-dependent improvement in visual acuity in PFE-655-treated patients, with the best results achieved with the 3 mg dose. PFE-655 also demonstrated a statistically significant benefit over laser treatment.
Yet the improvements weren't on par with those achieved with Lucentis. As such, “it was decided to conduct a further phase IIb study in order to test higher doses of PF-655 and to determine the optimal dose to be included in the pivotal phase III studies,” Quark said in a filing with the US Securities and Exchange Commission.
However, it appears that Pfizer is hedging its bets with PFE-655 in case the higher doses aren't sufficient to best Lucentis.
Quark said that the companies agreed that they should amend their original deal for the drug so that Quark will be responsible for running the phase IIb at higher doses. The companies have also agreed to jointly develop the trial's protocol.
When the trial ends, data will be delivered to Pfizer, at which point the big pharma will decided to either make a milestone payment that “exceeds the anticipated cost of the trial” and resume responsibility for PFE-655's development at its own expense, or terminate its license to the drug and return its rights to Quark, according to the SEC filing.
“In consideration of us conducting the phase IIb trial, Pfizer agreed to increase the overall development and product approval milestone payments associated with the first ophthalmic use of PF-655 and to increase the royalty rates under the agreement,” Quark added.
Additional terms of the new arrangement were not disclosed. Quark officials were unavailable because the firm is observing an SEC-mandated quiet period related to a planned initial public offering (GSN 1/27/2011). Pfizer did not return a request for comment.
Not Entirely Unexpected
Pfizer's decision to amend the Quark deal was not entirely unexpected in the industry given the company's recent decision to end its in-house nucleic acid drug development amid a broader cost-cutting initiative.
In February, the company said it was closing its oligo therapeutics unit, but in an e-mail to colleagues, Art Krieg, head of the unit, said that Pfizer had not made “a blanket decision to abandon any RNAi or other oligo development.”
He said that there “continues to be strong internal interest in oligos as a therapeutic modality,” and that “decisions to pursue future RNAi, antisense, or other preclinical or clinical programs will be made on a case-by-case basis.”
A Pfizer spokesperson told Gene Silencing News at the time that the company was specifically considering transferring promising programs to other areas of the company. Should the phase IIb data on PFE-655 be positive, it now seems that this is how the drug will be handled.
Questions about PFE-655 have also been lingering given the success Lucentis has had in DME and AMD, which raised the bar for other potential treatments. In fact, Lucentis directly contributed to Alnylam Pharmaceuticals' pulling out of the AMD field in 2005 (GSN 9/23/2005) and Allergan's decision to return the siRNA-based AMD drug AGN-745 to Merck (GSN 8/28/2009). AGN-745 was originally licensed from Sirna Therapeutics, which was later acquired by Merck.
“Given the reported efficacy in phase III studies from competing drugs targeting vascular endothelial growth factor for the treatment of age-related macular degeneration, [Alnylam] has made the strategic business decision to suspend further development of [its AMD drug] … in order to allocate resources to other product opportunities,” the company said at the time, which was just before Lucentis received approval from US regulators.
Allergan's phase II trial of AGN-745 was specifically designed to compare the drug with Lucentis, and found that the siRNA agent “did not meet its efficacy hurdle,” a company spokesperson said in 2009. As such, the drug went back to Merck, which said it had no plans to resume its development.
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