pharmawire - Novartis' MS oral drug.
17:14 Novartis' oral MS drug FTY720 comes under physician scrutiny; side-effects affecting patient enrollment in US trial - analysis
Story Novartis' oral multiple sclerosis drug FTY720 (fingolimod) is under scrutiny in light of recent adverse events which are affecting ongoing patient enrollment in Phase III US trials, physicians said.
While EU and global trials have finished enrollment, US placebo-controlled trials are still far from meeting that goal, said Dr Daniel Kantor, assistant professor of neurology and director of the Comprehensive Multiple Sclerosis Center at the University of Florida. Kantor said the enrollment process was a year behind what he had expected.
"We were all very excited about FTY720, but the company is having a lot of problems enrolling patients in the trial," he said.
Earlier this year, two patients developed a serious infection, one of whom died from a disseminated varicella infection. The other developed a life-threatening herpes encephalitis infection. "I was astounded when the company told me [the cases] were not related to the drug, and that regular people had this [disease]," said Kantor.
Dr Daniel Wynn, director of clinical research at Consultants in Neurology in Chicago, agreed that the main concerns surrounding FTY720 are safety issues, which have been stalling the trials.
The concerns center around the drug's effect on the lymphoblastic cardiac and pulmonary receptors, as the compound appears to decrease lung functions and slow a patient's heart rate. A couple of patients developed severe opportunistic infections, and the patient with the herpes infection died after developing a disseminated intravascular coagulation, Wynn explained.
Novartis representatives were not available for comment.
Wynn said he did not believe that all the safety issues that the company found have been made public. "There are less patients who want to go into the trial and fewer doctors who are putting people into these trials," he said.
Many hospitals conducting this trial are relatively inexperienced, and many have few patients, Wynn said, adding that data analysis becomes far more complicated - and accuracy decreases - as enrollment declines. Side effects might also go under-reported, he added.
Although oral MS drugs may be easier to take than current injectables and infusion treatment, patient compliance may be worse, said Kantor, who drew a parallel with the current lack of compliance with oral high blood pressure medications. These new oral MS drugs will likely be used in newly diagnosed MS patients who have not been treated with injectables yet, he added. Other patients could include individuals who cannot tolerate the current drugs on the market.
"Most patients do well on standard MS therapies, and I'm not sure patients will be switching straight away to oral medicines," Kantor said.
The new oral MS drugs will most likely be used in conjunction with current therapies, physicians said. Yet some physicians, such as Kantor, noted that in light of the concerns that a combination of Biogen Idec's Tysabri and Avonex could lead to progressive multifocal leukoencephalopathy (PML) - a typically fatal brain infection - neurologists may now be more hesitant to combine MS drugs. "There’s no data looking at FTY720 in combination. After what happened with Tysabri and Avonex, I’m not sure that physicians are going to feel that comfortable," Kantor said.
FTY720 will likely have the highest efficacy among oral therapies, physicians agreed. "But with that strength will come side effects. That is going to be very concerning to physicians and patients," Kantor said.
Dr Patricia O'Looney, director of biomedical research programs at the National Multiple Sclerosis Society, said that many patients will transition to oral therapies once they become available. But she noted that some advanced stage patients can lose their ability to swallow, and there will always be a need for non-oral therapies for this group of patients.
"Whether the oral therapies will be as effective as Tysabri, or other IVs, still remains unknown," she noted.
Dr Keith Edwards, a neurologist and director of Empire Neurology in New York, noted that FTY720 appears to increase the risk of sinus infections, but it is unclear whether the two cases of serious infection - herpes encephalitis and disseminated zoster - were definitely drug related. The drug may be so effective that a lower dose (0.5 mg) may work, without causing the excessive immunosuppressive issues, he suggested.
Kantor noted that FTY720 will carry an absolute contraindication for use with pregnant women. The drug can cause fetal malformation, as a result of the drug's mechanism of action, he added. MS is a disease that affects young women, and data from animal studies suggest that precautions should be made for patients who may be pregnant.
Dr Timothy Vollmer, medical director of the Rocky Mountain MS Center, noted that FTY720 is an immunosuppressant. Although the drug differs from traditional chemotherapy, it could still cause infections. "These are problems with all immunosuppressants, whether they're selective or non-selective," he said.
Unlike Tysabri, FTY720 is more of a general immunosupressant, and can cause not only PML, but acute infections as well, Vollmer noted. Viral infections could be even more of a concern than PML, Wynn noted.
Vollmer added that the tolerability of FTY720 will be negated if patients have to go to a different physician every week to check for its effect and safety on major organs. "It will be a very challenging drug for clinicians and patients to use," Vollmer said.
When asked whether the drug will be rejected at the FDA, Vollmer said 5,000 patients are currently on it. The agency wants to get 3,000 patient exposures with new MS drugs. FTY720 will likely be shown to be substantially more effective than current first-line agents, but the larger issue is how the FDA will view the drug's safety profile in terms of other organ toxicities, he noted.
"That’s a tough call," Vollmer said regarding approval, pointing to skin cancer cases that also arose during studies. Approval will depend on whether Novartis can convince the FDA, based on the natural history of the illness, whether side-effects are coincidental, said Vollmer.
There are at least two other oral drugs in development, including Biogen Idec's BG-12 and Teva's laquinimod.
by Kimberly Ha and James Avallone
AI
