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Biogen Idec’s (NASDAQ:BIIB) Tysabri will play a significant role in the second line setting for the treatment of remitting multiple sclerosis (MS), despite looming competition from new oral agents in development, neurologists told Pharmawire.
The current standard of care in this setting includes Teva’s (NASDAQ:TEVA) Copaxone and the interferon drugs Avonex, Betaseron, and Rebif. Tysabri is also used in more advanced patients, who have failed on alternative therapies. Novantrone is a chemotherapy drug, which is also FDA approved to treat worsening relapsing MS or secondary progressive MS.
Although patients may prefer these new oral pills over the current injectables, the leading orals in development - Novartis’ (NYSE:NVS) FTY720 and Merck-Serono’s cladribine - will likely face a risk management procedure (REMS) if approved, and may see slower than expected adoption in the real-world setting, specialists noted.
Both cladribine and FTY720 were associated with significant toxicities over the current standard of care, and would likely only see approval with a risk management procedure, similar to what is currently being utilized with a currently marketed drug, Elan’s Tysabri, neurologists noted.
Some of these new oral agents will fail to gain approval and for those that do make it, there will be rigorous pharmacovigilence programs requested by the both the FDA and EMEA, according to Dr Hans Peter Hartung, professor and chairman of the department of neurology at University Hospital Dusseldorf, Germany. These agents will see slow uptake by the majority of neurologists because they will want to see how safety evolves in post-marketing studies, he explained. ”Enthusiasm for these agents has been dampened,” Hartung said.
Tysabri, developed by Biogen and Elan, was withdrawn from the market in 2005, after patient reports of a rare, and potentially lethal brain inflammation known as PML, or progressive multifocal leukoencephalopathy. The drug was reintroduced to the market in 2006 under a REMS, the TOUCH program, in which patients are continuously monitored for PML. Recently, a sixth patient was diagnosed with PML.
In Novartis’ Phase III TRANSFORMS study, the lower 0.5 mg dose with FTY720 demonstrated a 52% lower relapse rate at one year for patients, compared to Biogen’s (NASDAQ:BIIB) Avonex. The higher 1.25 mg dose showed a 38 percent greater reduction in risk for the same endpoint for the 1.25-mg dose. Other oral drugs in development include Biogen’s BG-12, Teva’s laquinomod and Sanofi’s teriflunomide.
Merck-Serono’s pivotal Phase III CLARITY trial, reported a 58% relative reduction in annualized relapse rates with respect to placebo on the low-dose regimen.
Overall, there were 47 patients in the CLARITY study that accessed rescue medication with Rebif, according to a spokesperson for Merck-Serono. Nine patients in the higher 5.25 mg/kg treatment group, 11 patients in the 3.5 mg/kg cladribine tablets treatment group, and 27 patients in the placebo treatment groups received rescue medication.
There have also been concerns with cladribine’s unknown effects on long-term immunosuppression, which may be irreversible, some neurologists speculated. Lymphopenia and leukopenia occurred more frequently in patients on cladribine - six patients in total died, two from each of the cladribine groups.
Dr Daniel Kantor, an investigator on Novartis’ (NYSE:NVS) FTY720 and Genzyme’s (NASDAQ:GENZ) Campath trials, said there were four malignancies, from patients on cladribine, which were all in different organ systems. Although there is no evidence to suggest the risk of brain tumours yet, the appearance of one case would hurt this drug in clinical trials. Kantor is also medical director of the Neurologique Foundation in Florida.
Dr Douglas Jeffrey, an investigator on Teva’s laquinimod trials and associate professor in Wake Forest University’s department of neurology and MS specialty care, speculated that due to cladribine’s effects on long-term immunosupression, patients who fail treatment cannot go on rescue therapy such as Tysabri, because they will be at an increased risk of developing PML. Cladribine also has safety risks on long-term immune function, and is a dangerous drug, he added. Patients taking Novartis’ FTY720 also saw a number of cases of skin cancer, he added.
Tysabri’s place in the new market to some extent depends on the incidence of PML, Hartung said. If the incidence stays similar to what it was when it was approved, it will continue to play an important role in treatment, he said. Tysabri has played a significant role in the second line setting in relapse-remitting MS (RRMS) and in patients who don’t respond to interferon and Teva’s Copaxone, added Dr AM Rostami, chair of the department of neurology at Thomas Jefferson University.
While Tysabri have been effective in decreasing relapses and MRI lesions, PML is a concern, Rostami agreed. Out of 38,000 patients, there have only been a few cases and the hope is that there will not be more. If incidence remains low, Tysabri has a chance in the market alongside the new agents, he agreed.
PML has been carefully monitored via the company’s TOUCH program. ”I suspect that more potent drugs may also be associated with risks that mandate a cautious approach,” Hartung said. Neurologists will follow the new agents to see how things develop since side effects are not always revealed in Phase III studies, he said. If the risk-benefit ratio stays the same for Tysabri, it will maintain or increase its position in the market in the next four to five years, he said.
Dr John Richert, executive vice president of research and clinical programs at the National Multiple Sclerosis Society, said where Tysabri sits in the market two to three years from now will largely depend on the incidence of PML, and whether it stays within the 1:1000 ratio as stated on the label. The issue will be whether that risk stays at the estimated 1:1000, increases or decreases, he added. There are 40,000 to 45,000 patients on Tysabri, he added.
”I think in the short term, it’s hard to predict if anything will be pushed out,” said Timothy Coetzee, Ph.D., executive director of Fast Forward, a venture philanthropy unit of the National Multiple Sclerosis Society, in response to whether new oral MS drugs would end up replacing Tysabri in the future. Coetzee said the medical community’s understanding of the disease is improving significantly, and it is hard to predict what the safety profiles of these new oral agents will be.
But according to Dr Emmanuel Bartholome, a neurologist at the Tivoli Hospital in Brussels, PML will be also eventually be associated with these newer agents. These agents are more potent, he explained, and it is not possible to induce further immunosuppression. ”We have hit the roof,” he added. Ultimately, all MS patients will have to go to MS centers for treatment and neurologists will have to see patients more frequently to monitor for these effects, he said.
In terms of relapse rate, cladribine, FTY720 and Tysabri have all reported a similar figure between 50-70%, Bartholome said. There will be some competition in the second line setting, he added.
”I think in five years, we’ll know the real risk of PML with Tysabri,” said Dr Jack Burks, clinical professor of neurology at the University of Nevada.
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