Merck Serono, the pharmaceuticals division of Germany's Merck KGaA, on June 22 announced it was terminating development of oral cladribine tablets for relapsing-remitting multiple sclerosis. The decision comes after FDA in March requested further information on the drug, and follows European regulators' rejection in September 2010.

Merck said that further clinical work required by regulators in order to refile the product would take several years to complete and be prohibitively expensive. Even then, approval would not be guaranteed. Merck also announced it was withdrawing the product from Russia and Australia, where it is sold as Movectro.

Ongoing concerns about the potential association between oral cladribine and lymphopenia (abnormally low lymphocyte counts) and cancer prompted the European Medicines Agency's initial rejection. The CHMP upheld that decision in January 2011, following an appeal by the company. Merck said in February that it would withdraw the application.

FDA's March 2011 complete response letter, issued to U.S. subsidiary, EMD Serono, requested further understanding of cladribine's safety risks, either through additional analyzes or new studies Also see "Merck KGaA Pins Cladribine Hopes On Ongoing Studies After Complete Response Letter" - Pink Sheet, 2 March, 2011.).

Initially, Merck might have thought ongoing clinical studies would be sufficient to address the regulatory concerns. But, following an end-of-review meeting with FDA earlier this spring, the company concluded that the agency's requirements for the product's approval would require a new clinical trial program, which would take several years to complete. Data from ongoing clinical trials were very unlikely to address the FDA's demands, and would not have provided a basis for approval, the company said. The feedback from FDA was consistent with that from the European Medicines Agency.

The company is also withdrawing all remaining marketing applications for oral cladribine in a small number of other countries, and is taking a one-time charge of €20 million ($29 million) in its second quarter to account for the decision. It took an impairment loss of €50 million earlier this year, after US and European regulators rejected the product.

Increasing Competitive Pressures

Besides the regulatory hurdles, the decision to end development of cladribine also took into account the "changing competitive landscape" in MS, said the newly appointed President of Merck Serono, Stefan Oschmann.

Novartis AG's oral MS therapy, Gilenya (fingolimod) became the first oral MS drug to gain approval, winning US support in September 2010, followed by Europe's in March. It is challenging Merck's leading drug, Rebif (interferon beta-1a), as well as several other competing drugs. Rebif sales of €1.67 billion accounted for 29% of the company's pharmaceutical revenues in 2010. In the first quarter, Rebif's sales declined by 4% to €411 million compared with the first quarter of 2010, although Merck said this was mainly due to higher U.S. wholesaling stocking.

Still, if Gilenya doesn't erode Rebif sales significantly, additional potential oral therapies are nearing the market, including Biogen Idec's BG-12 (dimethyl fumarate), Sanofi's teriflunomide and Teva Pharmaceuticals Ltd.'s laquinimod, all in Phase III trials [A#110503]).

Cladribine's demise is likely part of a portfolio review that Oschmann -- previously president of emerging markets at Merck & Co, -- initiated since taking over at Merck Serono from Elmar Schnee in January 2011. Schnee left for ''personal reasons', following a string of development setbacks.

Merck says it will pursue its other R&D programs in MS - mostly line extensions for Rebif (interferon beta-1a). It will need to "actively pursue in-licensing opportunities" to strengthen its MS pipeline, said Oschmann.

Merck Serono said in a statement that it will complete ongoing clinical trials of oral cladribine. The core 96-week treatment period will be completed in the company's current clinical trials - CLARITY, EXTENSION, ORACLE MS and ONWARD - in order to "add knowledge" for the scientific community.

- John Davis (j.davis@elsevier.com)

Germany's Merck Scraps MS Drug Cladribine After Regulators' Rebuff

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