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Parkinson's Disease
Brief Marketplace Overview

1Q, 2007

Medtronic’s Activa implantable deep brain stimulation device is marketed by a sales force of more than 100 representatives, providing specific guidance regarding surgical implantation.  The implant procedure is regarded as more invasive than that required for Spheramine or CERE-120, and therefore remains as a non-first line therapy.

Ceregene is presently conducting a Phase III trial evaluating CERE-120 vs. sham surgical implantation.  Enrollment is slow, as the prospect of sham surgery, warnings including carcinogenesis, and the permanent instillation of the viral linked cells is formidable for some patients.  Two sites have recently been added to assure enrollment fulfillment,

Avicena in collaboration with NINDS, will advance PD-02 into Phase III trials following initiation of a dose escalation chronic toxicology study.  Phase II results supported greater than placebo efficacy in slowing Parkinson’s Disease progression.

Teva’s Azilect, marketed as monotherapy and for adjunct usage with levodopa, is under evaluation as part of the 1200 patient Phase III ADAGIO trial.  This 36 week trial administering 1mg, 2mg, or placebo QD, is analyzing the compound’s effect upon disease progression, is expected to close 3Q, 2008, with result available shortly thereafter.

Amarin is developing Miraxion as well as oral apomorphine for disease treatment.  Boston Life Sciences is developing a DAT blocker, while Neurocrine is working on an adenosine A2A receptor antagonist.

Various companies have received grants from the Michael J. Fox Foundation for the treatment of Parkinson’s Disease, including Amicus, Allon Therapeutics, Sangamo, CellCure, ReNeuron, Intra-Cellular Therapies, Wyeth, and ProNeuron, among others.  Intrexon is working with gene-regulation technology,

Sangamo is working to develop ZFP TFs (zinc finger binding protein transcription factors) in activating GDNF (glial cell-derived neurotrophic factor).

Schwarz Pharma has published data supporting transdermal rotigotine usage as a QD intervention in early disease.  It is marketed in the EU as monotherapy.

Several companies are developing stem cell interventional technologies, including Neuroprogen, Neuralstem, and others.

Duodopa, an intraduodenal dosing formulation of Levodopa/Carbidopa, presently in Phase III US trials, overcomes the disadvantages of oral drug delivery. Use of the drug requires a minor surgical procedure for placement of a delivery tube directly into the duodenum. The drug is available for sale throughout the European Union, and for compassionate use in the USA. NeoPharma, seeks a US partner to continue development of the drug. Until such time as they find a partner, development is stalled.

Generic sales of Seligiline have decreased by almost 11% from 4thQ05 to 3rd Q06, but new formulations of the drug are being developed.

Emsam, a transdermal Selegiline formulation is in Phase III trials in the USA. A new formulation of Selegiline, utilizes the Zydis oral delivery system to aid in the rapid dissolution of drug product in the mouth, is available in the USA, United Kingdom, and Germany.  The drug is licensed to Elan Corporation and Valeant Pharmaceuticals International.

The transdermal Rotigotine formulation is now being coupled with the nasal spray formulation of the drug in long-term therapy supplementation. Clinical development strategy for the nasal formulation is under evaluation by Schwarz Pharma, the originator company.  The transdermal patch is in Preregistration, the nasal spray in Phase II.  The patch can be used alone and has recently been approved by the EMEA for use in combination with levodopa.  

Combined Entacapone/levadopa/carbidopa is available to the US market as Stavelo.  The resultant smaller doses of required Levodopa, and simplified dosing resulted in significantly improved quality of life. The market for this drug is positive and could improve by 10%. From 3rdQ05 to 4thQ06, sales increased by almost 10%.  Entacapone alone, for patients with early stage disease, is available in the United Kingdom and is in the pre-registration phase in Japan.  

Generic Levodopa/Carbidopa combined formulations (Sinemet) have shown a slight downward (< 5%) sales trend during 2006.  Vadova, marketed by Impax Laboratories, is a Levodopa/Carbidopa combined dosage form that is currently under review by the US FDA. Impax specializes in the marketing of drugs to treat disorders of the CNS, and has established a 66-person sales force to market a slow-release version of the drug for another indication.  Sirio, licensed to both Chiesi and Vernalis, is a combined Melevodopa/Carbidopa formulation that is available in Italy, with clinical plans to obtain approval in Europe and North America.

A multi-mechanistic product being developed by Newron Pharmaceuticals and Merck Serono has demonstrated success as an add-on to mono-dopamine agonist therapy.  The product, Safinamide, is now in a phase III pivotal clinical trial as an adjunctive therapy to established stable dosing regimens. Filings for regulatory approval in Europe and the USA are expected by 3rd Q 2009.  The drug is not expected to have a large impact on the market. Expected sales for Parkinson’s are $322 million by 2015.  

Twelve patients have been treated in a dose-escalating Phase 1 clinical trial with gene therapy. Using its NLX-P101 technology, Neurologix has conducted the first study to use a viral vector, adeno-associated virus (AAV), for treatment of an adult neurological disease. One year following injection of the gene for glutamic acid decarbosylase (GAD), safety and tolerability were confirmed and all patients demonstrated clinical improvement. This technology is likely to present a simpler competitive alternative to deep brain stimulation.
Pramipexole, is available in the US as monotherapy and combined with Levodopa. It is also available in Japan, the United Kingdom, and Italy. Boehringer Ingelheim is supporting a global study (PROUD) to determine if the drug slows disease progression when prescribed shortly after diagnosis, and to assess the drugs affect on the development of expected motor complications. Sales have increased by almost 11% from 4thQ05 to 3rd Q 06.

SLV 308, a Dopamine D2 receptor antagonist is in Phase III clinical trials in the USA. Solvay’s Japanese partner, Meiji-Seika has discontinued development due to redefined priorities

Sales of GlaxoSmithKline’s Ropinirole have grown by almost 40% from 4thQ05 to 3rd Q06.  Development is ongoing and, SkyePharma will conduct clinical trials with GlaxoSmithKline’s once-daily, controlled-release formulation of Ropinirole. The two companies will submit a regulatory submission for approval

Pfizer’s Cabergoline, licensed to Kissie Pharmaceuticals and Paladin Labs, is registered in Germany, but has been discontinued in the USA.  Generic sales of Pergolide slid almost 19% from 4th Q 05 to 3rd Q 06. Pergolide is marketed by Athena Neurosciences (Elan Corporation) in the USA. Amarin has purchased the license and will continue to pay royalties. Eli Lilly maintains international marketing rights.  Although not definitively defined, there is information suggesting the occurrence of cardiac valvular disease with use of this product.

Aplindore, a small molecule, partial dopamine receptor agonist has been acquired by Neurogen from Wyeth.  Phase II clinical trials are expected to commence during 2007. Compared to full-agonist agents, the Company believes Aplindore may provide an improved side-effect profile and shorter dosing titration period. Penetration of the MS treatment market is expected to increase from around 2% in 2013 to 5% in 2015.

An NDA for Istradefylline, an orally- available selective adenosine A2A receptor antagonist, being developed by Kyowa Hakko was planned for the end of 2006. In several clinical trials, mixed efficacy results were realized. The product is now being studied in Phase II trials in Japan and Canada.

Pharmacopeia is also developing adenosine A2A agonists for potential treatment of Parkinson’s. Compounds are being investigated with the goal of initiating preclinical studies.

The restrictions for the use of  Valeant’s Tolcapone, an orally active inhibitor of catechol-O-methyl transferase (COMT), have recently been softened.  In February 2006, the US FDA approved less restrictive labeling with less frequent monitoring of liver functioning. In addition, higher elevations of a liver enzyme are allowed for patients to remain on the drug. However, warnings requiring patient informed consent of the risks associated with the product remain. Also, the product is recommended only in patients for whom other products have “worn off” or who are not appropriate candidates for other therapies.  The ban on use of the product in Europe was also lifted in March 2005.

Azilect (Rasagiline), a once-daily, potent, selective, irreversible monoamine oxidase-type B (MOA-B) inhibitor is being marketed in the USA by Teva.  The drug exhibits good efficacy and tolerability. It is approved for the early treatment of Parkinson’s and as an adjunct to Levodopa therapy in patients with a more advanced state of disease. In collaboration with Lundbeck, the drug is marketed in 13 EU countries. Once-daily dosing provides an attractive incentive for use of this drug.  In clinical trials the drug has been associated with delays in disease progression, and presently, the drug is being tested to assess potential neuroprotective properties. Success in this arena would be a unique breakthrough for the treatment of Parkinson’s.

Dainippon has filed an NDA for Zonisamide, a 1,2-benzisoxazole derivative, also in pre-registration for Japan.  Eisai expects to file US and European regulatory submissions in 2007 for E2007, an AMPA receptor antagonist.

Another compound demonstrating risk for cardiovascular disease is Budipine, a compound with NMDA agonist properties. This product requires specific physician monitoring procedures.  The drug is in the pre-registration phase in Germany, and Lundbeck has no intention of expanding the market.

Apokyn (apomorphine), the only drug available in the US to treat immobilizing “off” episodes of advanced Parkinson’s had been granted Orphan Drug Status with FDA approval in 2004. The drug is marketed to key neurologists in US metropolitan areas by the Vernalis’ specialty sales force. The drug does have potential serious side effects and contraindications. To date, sales have been disappointing, but the company has addressed several issues and is confident of reaching the lower range of its original estimates ($6 million).

Vectura’s VR040 is a proprietary formulation for inhalation delivery of apomorphine. The drug is also approved in Europe. VR040 is used with Vectura’s Aspirair device. The benefits of VR040 by inhalation include rapid onset of action, predictable therapeutic response, more acceptable and safer route of administration, and possibly the attainment of clinical effect at a lower dose. VR040 has Orphan Drug status in Europe, with an ongoing review by the US FDA. A Phase II study is in progress.
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