[Stitcher]

Treating Parkinson's Disease - Investment Opportunities and Challenges

By Michael D. Becker, Jeffrey Martini, Ph.D., and Janet L. Dally, Monday, August 3, 2009
http://nasdaq-amgn.blogspot.com/2009...nvestment.html

Excerpts from the Amgen Blog post:

"To date, the major difficulties encountered in the use of neurotrophic factors for the treatment of PD may relate to drug delivery issues. For example, neurotrophic factors do not cross the blood-brain barrier and cannot be taken orally. In addition, there are side-effects associated with systemic administration resulting from binding to extra-target receptors. Local administration of neurotrophic growth factors is therefore required to achieve therapeutic concentrations in the tissue, although the site of administration and method of delivery have represented significant barriers to date.

"For example, Amgen, Inc. (AMGN) discontinued its randomized, double blind placebo controlled Phase 2 study of recombinant GDNF for the treatment of advanced PD in 2004. By way of background, Amgen acquired GDNF and several other product candidates through the 1994 acquisition of Synergen, Inc. for approximately $240 million [although Synergen had about $125 million in cash at the time – resulting in an enterprise value closer to $115 million]. The clinical trial of GDNF did not meet its primary endpoint of symptom improvement after six months of treatment as defined by the Unified Parkinson’s Disease Rating Scale [UPDRS]. The company also later identified potential safety issues, as high doses of the drug damaged some monkey brains and a few patients developed antibodies against the drug.

"The failure of Amgen’s Phase 2 GDNF trial may have been related to the site and method of delivery, which included monthly injections of GDNF into the lateral ventricle. In other words, sufficient concentrations of GDNF may not have diffused through the ventricular wall and brain parenchyma to the putamen. This is supported by the success of chronically infusing a low dose of GDNF into the dorsal putamen using an implantable pump [SynchroMed™ by Medtronic, Inc. (MDT)]. Although primarily a safety study in only five patients, chronic GDNF infusion resulted in improved motor function in all patients, reduction in off-time duration and severity, reduction in dyskinesia duration and severity, and a corresponding increase in on-time duration. After 12-months, there was a 39% improvement in the off-medication motor sub-score of the UPDRS and 61% improvement in the activities of daily living sub-score.

"In addition to implantable pump delivery technology, gene therapy is considered one of the most promising approaches to developing a novel effective treatment for PD. In this regard, Amsterdam Molecular Therapeutics [Euronext: AMT] obtained a license from Amgen to use their GDNF gene for the development of a treatment for PD in September 2008. Amsterdam Molecular Therapeutics intends to combine the GDNF gene with their proprietary adeno-associated virus [AAV] gene therapy platform, which the company believes may provide a solution for delivering GDNF to the brain to protect and enhance the function of nerve cells that produce dopamine.

"While gene therapy offers hope, a Phase 2 trial of CERE-120 in advanced PD patients conducted by privately-held Ceregene, Inc. still underscores the importance of drug delivery to the appropriate portion of the brain. CERE-120 is an AAV vector carrying the gene for NRTN, a naturally occurring protein which repairs damaged and dying dopamine-secreting neurons. In November 2008, the company announced that the Phase 2 clinical trial did not meet the primary endpoint of improvement in the UPDRS motor off score at 12-months of follow-up, although several secondary endpoints suggested a modest clinical benefit. In May 2009, Ceregene announced that at the 18-month additional protocol described analyses of the Phase 2 clinical trial; CERE-120 demonstrated a clinically modest improvement and statistically significant treatment effect in the primary efficacy endpoint.

"Ceregene, which expects to conduct a follow-on Phase 2 trial later this year, suggests that the deficient axonal transport of the degenerating nigrostriatal neurons in advanced PD impaired transport of CERE-120 from the putaminal terminals in the putamen region of the brain where the therapy was delivered to the nigral cell bodies. The company believes that it can overcome the transport problems associated with degenerating neurons by modifying the dosing paradigm of CERE-120 to also directly target the cell bodies in the SN. Genzyme Corporation (GENZ) has licensed ex-North American rights for the development and commercialization of CERE-120 from Ceregene.

"Several additional gene therapy programs are currently in clinical development for the treatment of PD:"