Alnylam’s Next Move: Testing RSV Candidate In Naturally-Infected Adults, Pediatric Patients

RNAi-focused biotech also says it anticipates IND filings this year for hypercholesterolemia and liver cancer candidates.

Having obtained positive proof-of-concept data from a Phase II trial for its lead compound, ALN-RSV01, an anti-viral for respiratory syncytial virus, Alnylam now plans further Phase II trials to test the RNA interference drug in both adult and pediatric patients naturally infected with RSV, the company said during a March 6 R&D presentation.

In the 88-patient, Phase II GEMINI trial, the Cambridge, Mass., biotech tested RSV01 by placing 10,000 particles of the virus directly into subjects' nasal epithelium (¹ (Also see "Alnylam’s Anti-Viral RNAi Drug Shown Effective In Humans" - Pink Sheet, 29 Feb, 2008.)).

The study showed that treatment with ALN-RSV01 resulted in a 38 percent reduction in infections and a 95 percent increase in uninfected adults, the company reported. Alnylam presented results of the trial March 2 at the International Symposium on Respiratory Viral Infections in Singapore.

Alnylam next will test the drug for safety and tolerability, as well as antiviral activity, in 21 adult infected lung-transplant patients, VP-Clinical Research Ashkay Vaishnaw said. Subjects will receive either current standard of care alone or standard of care plus RSV01 at a dose of 0.6mg/kg once daily for three days.

That study will be followed by a Phase II pediatric trial, he said.

RSV01 works by targeting and ostensibly turning off RSV's nucleocapsid, or N, gene. "This is just one of many examples in the pipeline of our ability to target molecules that are otherwise undruggable by current modalities," Vaishnaw said. "And by targeting the N gene, we hope to reduce virus replication and convert that to clinical benefit."

RSV poses a major unmet medical need - there is no treatment for the virus, althoughMedImmune's Synagis (palivizumab) is used to prevent it - leading to more than 125,000 pediatric hospitalizations and 170,000 adult hospitalizations annually in the U.S. The condition results in an annual aggregate cost of greater than $750 million, Vaishnaw said.

Following the adult and pediatric Phase II studies, Alnylam plans to initiate Phase III trials to assess clinical endpoints including decreased lower respiratory tract infection and/or reduced duration of hospitalization and/or reduced incidence of hospitalization, he added.

Some on Wall Street are skeptical about the potential success for the Phase II program. According to Bear Stearns analyst Ahktar Samad, the experimental infection design of the GEMINI trial produced mixed results and the outcome of the planned Phase II trials in naturally infected patients is uncertain.

"Given the experimental infection design and mixed results, extrapolating to upcoming Ph2 trials in naturally infected lung transplant patients and pediatric patients is unclear," he wrote.

Alnylam may choose to partner to commercialize the compound eventually, but such a deal would be "more strategic in nature" for the company given its strong cash position - reportedly more than $450 million - Samad wrote in a March 7 note.

"A partner could help realize the full value of RSV01, but we believe potential partners may await results from a naturally infected study," he added.

Alnylam recently unveiled its new growth strategy, "RNAi 2010," under which it plans to sign four new business deals and bring four new RNAi compounds into the clinic by the end of 2010 (² (Also see "Alnylam RNAi 2010 Program Calls For Four New Business Partnerships" - Pink Sheet, 7 Jan, 2008.)). The firm's current partners include Roche and Medtronic.

Michael G. King, senior biotechnology analyst for Rodman & Renshaw, was more bullish on RSV01's prospects. The 38 percent reduction of infection in GEMINI appears significant enough to prove the drug concept, he wrote, adding he is confident the subsequent Phase II trials will produce strong results.

"The greatest risks are the small planned patient size (21 patients) and use of a single dose, in our view," King said.

Vaishnaw also outlined the status of two other candidates - ALN-PCS to treat hypercholesterolemia and ALN-VSP for liver cancer - in the pipeline. The firm is planning IND filings for both later this year.

ALN-PCS would address the expression of PCSK9, a serine protease excreted by the liver that regulates levels of LDL cholesterol. Preclinical studies in transgenic mice, rats and non-human primates have shown promising results from a single dose, Vaishnaw noted.

ALN-PCS potentially could serve a population of 50 million patients, including those who are statin-resistant, as well as roughly 879,000 patients with acute coronary syndrome and about 500,000 people diagnosed with genetic familial hypercholesterolemia, he added.

ALN-VSP also is showing promise in preclinical study, Vaishnaw noted, adding the drug could be used to treat both metastatic liver cancer and patients with primary hepatic cell carcinoma.

The drug targets tumors via two different pathways - vascular endothelial growth and kinesin spindle protein, which is overexpressed in tumors compared with normal tissue.

Development of the KSP approach has been limited, Vaishnaw said, because the compound can lead to myelosuppression problems in the bone marrow due to broad biodistribution.

One other Alnylam candidate has moved from discovery to development, Vaishnaw reported - ALN-HTT, a treatment for Huntington's disease, on which it is partnered with Medtronic. The 50/50 agreement, announced last year, aims to pair a biologic with a delivery device (³ (Also see "Medtronic Continues To Run (RNA) Interference With Alnylam" - Pink Sheet, 31 Jul, 2007.)

-Joseph Haas ([email protected])