Alnylam Pharmaceuticals Inc. and Medtronic Inc. are moving forward with a collaboration inked in 2005 to develop drug-device combination products utilizing RNAi to treat central nervous system (CNS) diseases.

The initial focus of the collaboration is on a Huntington's disease treatment consisting of an RNAi therapeutic delivered using Medtronic's implantable infusion pump. Medtronic currently uses the pump technology to deliver pain medications directly into the spine. A Medtronic spokesperson said the companies have not disclosed details regarding where the pump would be implanted in the Huntington's disease program, although an Alnylam spokesperson said via email that the approach would involve direct rather than systemic delivery.

Thus far, most RNAi treatments in development have utilized a direct delivery approach rather than systemic administration, in which the RNAi must be protected from degradation. Some of the most advanced RNAi products include Opko Health Inc.'s Phase III siRNA drug bevasiranib and Allergan Inc.'s Phase II siRNA drug AGN211745 (previously known as Sirna-027). Both involve direct injections into the eye to treat wet age-related macular degeneration. Also in Phase II is Alnylam's ALN-RSV01, which is delivered directly to the lungs to treat Respiratory Syncytial Virus (RSV).

Several companies are pursuing RNAi approaches to the treatment of neurodegenerative diseases: Sirna Therapeutics Inc. had an early stage research program in Huntington's disease prior to its acquisition by Merck & Co. Inc., and CytRx Corp. subsidiary RXi Pharmaceuticals Corp. has a program targeting the mutant SOD1 gene in familial amyotrophic lateral sclerosis (ALS). RXi's program involves direct injection into the spinal cord.

The original Alnylam-Medtronic collaboration called for Alnylam to handle discovery and early development work while Medtronic would manage late-stage trials and commercialization. Medtronic also would make an equity investment in Alnylam and pay potential milestones and royalties. (See BioWorld Today, Feb. 10, 2005.)

As part of the decision to continue the collaboration, the two companies restructured the deal into a 50/50 co-development and profit sharing arrangement in the U.S. Medtronic will still handle U.S. commercialization, although Alnylam now has the opportunity to invest in clinical development. In Europe, Medtronic will handle development and commercialization and pay Alnylam royalties. Specific financial terms were not disclosed.

The companies' decision to advance the program follows positive preclinical data in Huntington's disease. Specifically, in vivo data demonstrated that an siRNA targeting the huntingtin gene inhibited huntingtin protein levels and disease progression in a mouse model of Huntington's disease. The approach also decreased neuronal pathological protein aggregates by 70 percent and reduced abnormal behaviors including clasping and footslips by 50 percent and 70 percent, respectively.

Huntington's disease is an inherited degenerative brain disorder caused by the huntingtin gene. Current treatments address symptoms rather than the underlying disease itself, which affects an estimated one in 10,000 Americans.

Earlier this year, one of the most advanced Huntington's disease treatments in development, Amarin Corp. plc's Miraxion, failed two Phase III clinical trials. Still moving forward are Avicena Group Inc.'s creatine formulation HD-02, which is slated to begin Phase III trials early next year, and Medivation Inc.'s Dimebon, which is in a Phase I/IIa trial. (See BioWorld Today, April 25, 2007.)

If Alnylam and Medtronic's approach to Huntington's disease proves successful, the companies also may collaborate on drug-device combination products for other neurodegenerative diseases, such as Parkinson's disease.

Shares of Cambridge, Mass.-based Alnylam (NASDAQ:ALNY) rose 33 cents to close at $24.74 on Monday, while shares of Minneapolis-based Medtronic (NYSE:MDT) rose 32 cents to close at $51.13.