Alnylam Pharmaceuticals last week announced that partner Cubist Pharmaceuticals has dropped out of its deal to develop Alnylam's investigational respiratory syncytial virus drug ALN-RSV01 following a failed phase IIb trial last year.
Alnylam said that it will now put its efforts with ALN-RSV01 on hold until it can find another partner as it focuses on newer research and development initiatives. These include ALN-TTR02, an intravenous TTR-mediated amyloidosis treatment poised to enter phase III later this year, and ALN-TTRsc, a subcutaneous version of the drug that will begin phase I testing in the coming weeks and which, importantly, is expected to help validate Alnylam's new conjugate delivery approach.
Once Alnylam's lead drug program, ALN-RSV01 hit a major snag last spring when it did not meet the primary endpoint of a phase IIb study in lung transplant patients (GSN 5/31/2012). That trial was designed to extend the results of a smaller phase II study that indicated the drug could decrease the incidence of new or progressive bronchiolitis obliterans syndrome, a non-reversible obstructive lung disease.
It did not do so, and Alnylam said at the time that it would meet with US and European regulators to discuss next steps for the program.
According to Alnylam President and COO Barry Greene, those talks provided the company with “preliminary guidance [on] the design of a phase III study that we believe can lead to approval of ALN-RSV01.” Still, Cubist declined to exercise its option to pick up development of the drug, effectively ending the firms' alliance, he said during a conference call held last week to discuss Alnylam's fourth-quarter 2012 financial results.
Cubist had once been a 50/50 partner on ALN-RSV01, but backed out of that arrangement in exchange for an option to the drug, which Alnylam continued to work on, and access to a next-generation version called ALN-RSV02 ( 11/12/2009). Less than two years later, Cubist ended its involvement with ALN-RSV02, as well.
Greene said last week that Alnylam does not intend to continue working on ALN-RSV01 unless it is able to find a new partner interested in advancing it into phase III testing. The drug remains partnered with Kyowa Hakko Kirin in Asia.
Instead, the company will keep its focus on its pipeline of new candidates, led by ALN-TTR02, which comprises siRNAs that inhibit expression of the protein transthyretin that is mutated in ATTR. This summer, Alnylam reported positive data from a phase I trial showing that the drug triggered up to 94 percent reductions in levels of transthyretin after a single dose — a key milestone given the close link between the disease and levels of the protein (GSN 7/19/2012).
Enrollment in a phase II multi-dose, dose-escalation study of ALN-TTR02 continues, and Alnylam expects data to be available by the middle of the year. Assuming a positive outcome, a phase III trial is slated to begin by the end of 2013 in patients with familial amyloidotic polyneuropathy, a clinical manifestation of ATTR.
Notably, ALN-TTR02 is based on a lipid nanoparticle technology that was at the center of a legal dispute between Alnylam and one-time partner Tekmira Pharmaceuticals. As part of the settlement that ended that row, Alnylam assigned the intellectual property on the lipid nanoparticles to Tekmira, but retained the right to use it with the ATTR drug (GSN 11/15/2012).
Although Alnylam intends to move ahead with ALN-TTR02 in the polyneuropathy patient population, it has been increasingly looking to its proprietary GalNAc conjugate technology for its other drug candidates, and during the call CEO John Maraganore said that the data from the phase I trial of ALN-TTRsc will represent a “validating event for [the] broader pipeline activities” underway at the firm.
That study is expected to enroll 40 patients and examine single and multiple ascending doses of the drug, with results available by the summer. A phase II trial in patients with familial amyloidotic cardiomyopathy, another manifestation of ATTR, is slated for the end of 2013 with phase III testing potentially beginning in 2014.
Meantime, Alnylam said that it remains on track with its other GalNAc-enabled programs including ALN-AT3, which targets antithrombin for hemophilia and is slated to enter phase I testing by year-end; and ALN-AS1, which is designed to silence the enzyme ALAS-1 to treat the rare genetic disease acute intermittent porphyria and expected to move into phase I in 2014.
The hemoglobinopathy treatment ALN-TMP and the AAT deficiency-associated liver disease drug ALN-AAT, which are both in preclinical development, remain on hold until they are partnered. As reported by Gene Silencing News, Alnylam recently partnered its hypercholesterolemia program, which includes the phase I lipid nanoparticle-enabled ALN-PCS02 and the preclinical GalNAc-enabled ALN-PCSsc, with The Medicines Company (GSN/em> 2/7/2013).
The Fourth Quarter
For the three-month period ended Dec. 31, 2012, Alnylam's net loss jumped to $62.2 million, or $1.20 a share, versus a year-ago loss of $14.3 million, or $0.33 per share. Contributing to the loss was a one-time charge of $65 million, which reflects the payment Alnylam made to Tekmira to end their legal dispute.
Revenues in the fourth quarter dropped to $8.5 million from $20.5 million in the same period the year before, a decline due to the completion of the amortization of revenues received from Alnylam's former partner Roche in the third quarter of 2012.
R&D spending slipped to $21.7 million from $23.4 million in the fourth quarter of 2011, which in part reflects the effect of a corporate restructuring in January 2012. General and administrative costs, meanwhile, dipped to $10.2 million from $10.7 million.
At the end of 2012, Alnylam had cash, cash equivalents, and marketable securities totaling $260.8 million. It expects to end 2013 with more than $320 million in cash.