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April 27, 2009 1:59 pm

Merck-Serono’s cladribine could face regulatory hurdles

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This article is provided to readers by Pharmawire—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market.

Merck-Serono’s cladribine could face regulatory hurdles regarding the risk of malignancy seen in clinical trials to date, as well as overall market limitations due to a current pregnancy category D label that the drug carries in hairy cell leukemia, physicians told Pharmawire.

A pregnancy category D label means the drug has some significant risks, and should be used during pregnancy only when the alternatives are worse.

Cladribine would likely be used as a second or even third-line agent, depending on the upcoming final study results, they said.

Results from the pivotal Phase III study CLARITY, are scheduled to be presented as a late-breaking oral presentation at the American Academy of Neurology Conference in Seattle on 29 April. Other oral agents in late-stage development include Novartis’ (NYSE:NVS) FTY720, Teva’s (TLV:TEVA) laquinimod, Biogen’s BG-12 (NASDAQ:BIIB) and Sanofi-aventis’ (NYSE:SNY) teriflunomide.

Cladribine (2-chlorodeoxyadenosine) is currently marketed as an intravenous infusion to treat hairy cell leukemia, an uncommon chronic B-cell lymphoproliferative disorder. The drug is marketed as Leustatin by Ortho Biotech, a division of Johnson and Johnson (NYSE:JNJ).

Dr Samuel Hunter, an investigator for a number of MS drugs in development and a neurologist at the Advanced Neurosciences Institute in Franklin, Tennessee, said cladribine causes immunosuppression, and it is unlikely to be used in patients with better prognoses. It will not be used in pregnant women, due to the drug’s associated risks with serious infection.

Merck-Serono is only conducting one pivotal registrational trial testing its new oral MS agent cladribine. Other companies such as Novartis, are conducting multiple trials for submission for approval.

The FDA usually requires two studies, unless there are extenuating circumstances, noted Dr Jack Burks, a consultant for Merck-Serono and an investigator on a number of MS trials. ”We’d all like to see two studies. We’re in the position of getting fragments of data with one trial. We need more info, before we’re 100% clear,” he said. Bayer’s Betaseron was approved with one trial, but that was 15 years ago, he added.

Although cladribine is currently approved as an oncologic agent, the patient population in MS is different, since they are much younger and healthier, Burks noted. ”We already have drugs approved that are safe and effective, and the question is whether you want to give an oncologic drug to a 22-year old treatment naïve-patient who wants to have children one day,” he said. These are issues that neurologists will have to face once they receive the specifics of the cladribine data, Burks added.

One industry executive involved in the development of novel MS agents agreed that there is definitely an ”overhang” with cladribine’s cancer risk, adding that there was no question about that risk in the JNJ trials with the drug. ”I would be shocked if the FDA doesn’t take that into account; that’s a very significant finding,” the industry executive noted.

Merck-Serono could not be reached for comment.

One study by Saven et al. in the journal Blood 92: 1918-1926, titled ”Long-Term Follow-Up of Patients With Hairy Cell Leukemia After Cladribine Treatment,” found that in 349 evaluable patients, dermatomal herpes zoster was the most frequent late infection, and is likely related to the potent immunosuppressive properties of cladribine.

An industry investor who read the study in Blood noted that while most of the patients were in their 60-70s when diagnosed and most cancer cases were prostate adenocarcinomas, which are not ”too scary,” there is still a safety signal. ”I do not see how the FDA would not want more long term safety data for use in a younger and healthier MS population,” he added.

When asked about the incidence of cancer seen thus far with cladribine, Dr David Brandes, medical director of the Northridge Multiple Sclerosis Center and assistant clinical professor of neurology at UCLA, said that the rate is higher than one would expect in this age group, but it remains to be seen if it’s a concern. There may be some other risk factors in these patients that are not related to the agent, he noted.

Due to cladribine’s pregnancy risk, it will not be given to women of childbearing age, said Dr Michael Racke, an investigator on general MS trials and the Helen C. Kurtz chair of neurology at Ohio State University Medical Center.

Brandes similarly noted that teratogenicity with this agent is a reasonable concern, and has to be explained to patients. Novantrone, an MS drug marketed by EMD Serono, caused women to be permanently infertile, he added. MS is not a fatal disease, and physicians have to worry about the potential risks in women with childbearing age, Burks added.

Some literature has also suggested that the drug causes variable absorption leading to excessive toxicity (Langtry et al, 1998).

Dr Clyde Markowitz, the local principal investigator for several national and international clinical trials of new and combination MS therapies and assistant professor at the department of neurology at the University of Pennsylvania, said the absorption rate and pharmacokinetic data for cladribine is still unknown, but variable absorption might be an additional issue.

When asked whether the drug’s association with renal toxicity and myelotoxicity are a cause for concern, Markowitz said that this is really a concern with all the new compounds in MS at this point. ”We don’t know how significant this is, or what the risks are,” he added.

Markowitz was hesitant to say whether the drug would receive approval based on one study, since MS patients are younger than the patient population with hairy cell leukemia.


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