Neurological/Neurodegenerative Diseases

Pipeline Table

Project / Compound	Potential Indication	Clinical Phase
Laquinimod	Multiple sclerosis	III
Talampanel	Amyotrophic lateral sclerosis (ALS)	II
TV-1390	Multiple sclerosis	I

Laquinimod for MS

Laquinimod is a novel once-daily, orally administered immunomodulatory compound that is being developed as a disease-modifying treatment for relapsing-remitting multiple sclerosis. In June 2004, Teva acquired from Active Biotech the exclusive rights to develop, register, manufacture and commercialize laquinimod worldwide.

A Phase IIb study in 306 patients was published in The Lancet and demonstrated that an oral 0.6 mg dose of laquinimod, administered daily, significantly reduced MRI disease activity by a median of 60 percent versus placebo in RRMS patients. In addition, the study showed a favorable trend toward reducing annual relapse rates and the number of relapse-free patients compared with placebo. Treatment was well tolerated, with only some transient and dose-dependent increases in liver enzymes reported. Over 1,000 MS patients have received laquinimod in various clinical trials.

Following encouraging results of this Phase II study and after discussions with the FDA and the European Medicines Agency, Teva initiated the phase III clinical program. Laquinimod received Fast Track designation from the U.S. Food and Drug Administration (FDA) in February 2009. Two global Phase III clinical trials, BRAVO and ALLEGRO, have completed enrollment and are currently ongoing.

Selected publications:

Brunmark C. et al (2002); J Neuroimmunology ; 130 : 163-172
Polman C. et al (2005); Neurology ; 64: 987-91
Comi G. et al (2008) Lancet; 371: 2085-2092

Talampanel for Amyotrophic Lateral Sclerosis and other neurodegenerative disease

Teva has exclusive worldwide rights to develop and market talampanel for the treatment of neurological disorders. Talampanel is an orally active antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) neuronal excitatory glutamate receptor. Based on talampanel',s anti-glutamate excitatory activity, Teva believes that talampanel can significantly delay the functional deterioration of ALS patients. Based on the scientific, mechanistic rationale and a positive signal from a small Phase II study in ALS, Teva is proceeding with the development of talampanel for the latter indication, and a Phase II study has been initiated in centers in the U.S., Canada, Europe, and Israel. to evaluate the efficacy, tolerability and safety of an oral administration of 75mg and 150mg daily doses of talampanel for 52 weeks.The recruitment of 559 ALS patients has been completed and the study is scheduled to end by the second quarter of 2010.

Selected publications:

Chappell AS., Sander JW., Brodie MJ., et. al. A crossover, add-on trial of talampanel in patients with refractory partial seizures. Neurology (2002); 58(11):1680-1682
Ramsay R., Fetell M., Bell C: Efficacy in open extension phase of talampanel in refractory partial epilepsy. Neurology (2006);66, Suppl 2, A37

TV-1390 for MS

TV-1390 is an IFN β and human serum albumin (HSA) fusion protein. TV 1390 was generated by genetically fusing the complete IFN β open reading frame to the 5' end of the HSA coding region. Four IFN β products are currently available for the treatment of MS. These products differ somewhat in chemical structure as well as in route and frequency of administration (Once weekly up to 3 times a week). TV 1390 is being developed as a new treatment for MS with the potential for less frequent administration than other marketed IFN β analogs. The molecule has the biological activities associated with IFN β, but with a longer t1/2 and duration of action than currently approved IFN β products which may allow for less frequent s.c. dosing.

Albumin fusion technology has been applied to a number of molecules and has been utilized in the clinic to improve pharmacokinetics (PK) and efficacy of existing therapeutic proteins.

During 2010, Teva is planning to initiate the clinical development plan for TV-1390.