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An independent data monitoring committee is on the lookout for skin malignancies with Novartis’s FTY720 (fingolimod) - a side effect that would be a significant derailment for the promising oral multiple sclerosis drug, investigators told Pharmawire.

Dr Giancarlo Comi, lead investigator, and neurologist at Vita-Salute San Raffaele, reported seven cases of melanoma, basal cell carcinoma or squamous cell carcinoma in studies of fingolimod. ”This is a problem that may limit the administration of the drug,” he said. ”This is something you have to think about.”

Yet Comi cautioned that it’s still unclear whether FTY720 is responsible for the reports of skin cancer or whether the cases were found because of active patient screening. All patients are enrolled in three-year extension study and are taking an active form of the drug; there is no placebo group for comparative purposes, he noted. ”We are still questioning ... whether there is real excess.”

Dr Shreeram Aradhye, VP and Senior Global Brand Medical Director for FTY720, said there were seven patients with skin cancer in the Phase II extension study, however, the drug is an immunomodulatory agent. Although there may be long-term risks, the FTY720 extension trial is an open-label trial, and he agreed that it is premature to conclude whether it is drug-related.

”Skin cancer is something we have seen, and we have implemented dermatology tests,” said Aradhye.

The risks and benefits will only be known after Phase III data is out, on the localized skin cancer issue. It is unclear whether the lesions were pre-existing in patients, but investigators made an effort to include annual skin check-up.

When asked whether these additional skin tests will affect the labeling of the drug, Aradhye said ”it depends on what we find.” Although it remains premature to comment on labeling, he said the company is monitoring this situation carefully. ”At this point, we will continue as planned,” he added.

However, only 70% of the patients actually finished the Phase II study, Aradhye said. Out of the 280 patients that started on the trial, 250 patients entered the extension study, and 170 patients still remained on FTY720 after 3-years.

”The bottom line is, each Phase III study will have a thousand patients. We will look to file before the end of 2009,” said Aradhye.

About 3,000 patients were recruited into the study; patients received either a 1.25mg dose, a 5mg dose, or placebo for 18 months and were then assigned to a common 1.25mg group for the duration of the study period. (Novartis is also exploring a 0.5mg dose, according to Comi.)

However, a criticism of the drug is the fact that there is comparable efficacy between the 5mg dose and 1.5mg dose. As there were more ”dose events” in the 5mg arm, every patient was then converted to the 1.5mg trial, said Aradhye.

The Phase III trial will test the 0.5mg dose versus 1.25mg dose, he added.

More than 70% of patients completed the entire trial, and 89% were free of inflammatory activity on MRI, Comi reported. The annual relapse rate was 0.2%. ”It’s clear the effect is persistent,” he said, adding that if the drug is successful, it could be a first line MS treatment.

Other adverse events - mainly nasopharyngitis - declined in frequency the longer patients stayed on fingolimod, he noted.

Dr Paul Friedemann, a neurologist at Charite, Humboldt University in Berlin, who has also studied the drug, noted that he has not seen any cases of skin malignancy in his trials. He called the oral formulation ”an attractive option” but agreed that skin cancer would be a significant side effect that could derail a regulatory application.

The first-in-class drug has been hailed for its potential to reverse the course of MS. A poster presented at the American Academy of Neurology suggested, for instance, that the drug positively influences regenerative genes and could reverse neurological deficits associated with the disorder.

Carmen Barske, a researcher at the Novartis Institutes for Biomedical Research, told this news service that the drug works in two ways. It affects the immune system by binding to the S1P receptor - trapping lymphocytes before they can damage the brain. It also has a direct effect on the cells that form the myelin, which are destroyed in MS.

She noted that the company hopes the drug will repair damaged oligodendroglial cells and induce remyelination.

Fingolimod can also cross the blood-brain barrier, contributing to its effect, she added. She too had not seen any off-target effects, but noted that more research is needed.

There are currently three ongoing clinical trials, two placebo-controlled and one active-controlled trial, according to Comi. He described trial recruitment as ”quite easy” - despite the placebo-controlled set-up - because of the number of needle-phobic patients who have avoided therapy. ”They’re quite happy to have the alternative,” he said.

However, Aradhye said patient enrollment for all companies enrolling MS patients is ”going to get complicated as we go along,” as there are several trials that are enrolling patients. Biogen-Idec is currently enrolling patients for BG-12, Teva’s oral MS drug Laquinimod and Sanofi’s Teriflunomide are also running Phase III trials.

But the core submission package, with over 600 patients is completed. The Tysabri-issue has made companies shy from the add-on trial design, he said, but Novartis is confident it is doing what it takes regarding patient enrollment.

The company will not lower its patient enrollment standards, however, and will enroll mild-MS patients as that will decrease the power of the study. Aradhye remained confident that MS patients will choose FTY720 trial as this drug has shown the best Phase II data, and is on track for 2009 filing.

When asked whether PML is an issue with FTY720, as there have also been concerns regarding encephalopathy, Aradhye said the vascular spasm seen in some patients has not occurred in higher dose patients on the Phase II trial.

But the ”PML experience” with Tysabri has caused the investigators to be alert, and there is a low threshold for imaging for PML, he explained.

”We will conduct a comprehensive study to prove certain things don’t happen,” said Aradhye.

Novartis has a market cap of USD 105.68bn.

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