ProNeuron Alleges Unfair Co-Licensing Behavior by Teva

Teva Pharmaceuticals, the maker of Copaxone (glatiramer acetate) and an aggressive peddler of generic drugs, is being investigated by Israel's Minister of Health for the company's study of Copaxone in patients with amytrophic lateral sclerosis (ALS). The investigation stems from claims made by Teva's co-licensing partner, ProNeuron, which alleges that Teva deliberately sabotaged the clinical study of Copaxone in neurodegenerative diseases to protect its exclusive interest in the drug.

Copaxone is currently approved by the US FDA for reducing relapses in relapsing-remitting multiple sclerosis (MS). North American and European sales of the drug during the first quarter of this year approached $2 billion, according to news sources.

The co-licensing back story is gleaned largely from a December 2007 story in Haaretz and a recent report in the Globes. (However, the linear story of the 2 companies, especially beginning around 2006, is not as transparent as it could be.)

1986: Yeda, which commercializes intellectual property from Israel's Weizmann Institute, and Teva enter into a licensing agreement, which allows Teva to develop glatiramer acetate (copolymer-1) for the treatment of MS.

1996: On the basis of preclinical glaucoma studies, Yeda gives biotech startup ProNeuron a license to develop glatiramer acetate for the treatment of neurodegenerative diseases.

December 1996: The US FDA approves Copaxone 20 mg SQ daily for the reduction of relapses in relapsing-remitting MS.

1996 and later: ProNeuron conducts preclinical trials, which show that "vaccination" with glatiramer acetate is effective in certain neurodegenerative conditions, like a Huntington's disease model or in cases of optic nerve degeneration due to glaucoma (eg, Kipnis J et al. Proc Natl Acad Sci U S A. 2000;97:7446-7451). However, glatiramer acetate is not effective and, in fact, shows adverse effects in an animal model of ALS. On the basis of the collective preclinical results, Teva shows interest in ProNeuron.

2003: Teva, ProNeuron, and Yeda sign agreements, giving Teva a secondary license to develop and commercialize glatiramer acetate for the treatment of neurodegenerative diseases. Teva and ProNeuron set up a joint venture, in which Teva comes to own approximately 13% of the company. Drug-development milestones and ProNeuron's royalties are established.

2005: A secondary co-licensing agreement between Teva and ProNeuron (according to ProNeuron) ensures that clinical trials with glatiramer acetate in neurodegenerative diseases will begin no later than October 2006. The agreement stipulates that Teva can delay clinical development by 1 year, if it pays ProNeuron $5 million. The agreement also stipulates that, after clinical development begins, ProNeuron loses the right to terminate the agreement, if the agreement is breached by Teva. [Blogger's note: Not sure why ProNeuron would agree to this last condition.]

February 2006: According to ProNeuron, Teva negotiates to delay clinical study by a year, owing to the mixed results of the preclinical trials. However, a few days later, Teva indicates that it will begin clinical development of daily glatiramer acetate in ALS, despite the negative preclinical trial results and the fact that the glatiramer dose used in the preclinical model was not comparable to daily administration of the drug.

April 2006: Investigators at Columbia University report the results from a 6-month, prospective, randomized phase 2 study, partially funded by Teva, in which patients with ALS received randomly assigned glatiramer acetate 20 mg SQ daily or biweekly. According to the article, 30 patients were enrolled between June and September 2004 (which would predate the secondary licensing agreement between Teva and ProNeuron). The authors conclude that the tolerability of the drug and the "sufficiently meaningful" immune responses support ongoing study, despite the fact that one patient showed unusual neurodegenerative changes at autopsy.

June 2006: An international, 1-year phase 2 study of glatiramer acetate 40 mg SQ daily is begun. The study is sponsored by Teva and is to be conducted in Belgium, France, Germany, Israel, Italy, and the United Kingdom.

December 2006: An e-pub study from Johns Hopkins shows that vaccination with Teva's investigational compound, TV-5010 (which is a high-molecular-weight version of glatiramer acetate) does not alter disease onset or survival in 3 different rodent models of ALS.

December 2007: Final data are to be collected from Teva's phase 2 study of high-dose glatiramer acetate in ALS. ProNeuron asks the Tel Aviv District Court to terminate its 2003 and 2005 agreements with Teva and requests to retain its exclusive rights to develop glatiramer acetate in neurodegerative diseases. ProNeuron claims that Teva hastily conducted its ALS clinical study, knowing that the investigation was likely to fail on the basis of the negative preclinical results.

Early 2008. The Israeli Ministry of Health begins investigating the conduct of the Health Ministry, which approved Teva's ALS trial, and the Tel Aviv Sourasky Medical Center (Ichilov Hospital), where part of the trial was conducted. The investigation reveals that the Ministry of Health did not receive all of the necessary information before approving the trial—specifically the negative preclinical trial results in the ALS animal model.

March 2008: Teva announces negative results from the phase 2 trial of high-dose glatiramer acetate in ALS.

July 2008: The Israeli Ministry of Health appoints a special committee to study Teva's conduct in the clinical investigation of glatiramer acetate in ALS. On a somewhat related note, Teva reports that it will file a lawsuit against Momenta/Sandoz for patent infringement, given the filing by Momenta/Sandoz of an abbreviated NDA that requests certification of generic Copaxone.

HT: Pharmalot