Article reprinted from "The Pink Sheet" February 17, 2009
With nearly a dozen new multiple sclerosis drugs in some phase of mid- to late-stage development - from the first oral options to infrequently administered biologics - the treatment paradigm for the debilitating disease appears on the cusp of significant change. Read more now...
With nearly a dozen new multiple sclerosis drugs in some phase of mid- to late-stage development - from the first oral options to infrequently administered biologics - the treatment paradigm for the debilitating disease appears on the cusp of significant change.
The idea that patients and physicians will jump at the chance to try or prescribe new disease-modifying agents seems obvious, given that existing drugs require injection dosing and have moderate long-term efficacy. In MS drug development, the hope of an oral treatment is often held out as the "holy grail."
But given the generally long-term progression of relapsing remitting MS, the young age at which many patients are diagnosed and the relative safety of existing medicines, drug switches might take longer than some expect.
While there is certainly a race among drug makers to be first-to-market with a breakthrough MS treatment, there's no guarantee that the stampede to try them will be as aggressive, at least initially. Pending final efficacy and safety data, it's quite possible that even a convenient oral option could be relegated to the second-line setting.
Neurologists Skittish On Side Effects
Neurologists specializing in MS, speaking during a panel discussion at the BIO CEO & Investor conference Feb. 10, appeared eager to add to their treatment arsenal. But at the same time, enthusiasm for the late-stage drugs in development was subdued given the potential for risky adverse events.
"One can imagine that if the first available oral drug were to have roughly similar efficacy and tolerability and safety measures [to current options] that probably that drug would steal the market," said John Richert, Exec VP for Research & Clinical Programs for the National Multiple Sclerosis Society
However, he added, "if the first or any of the oral drugs turned out to have the same or better efficacy data but turned out to have safety issues, then we've got the issue of will they be first-line drugs or second-line drugs, and I think there is not enough information to sort that out."
Unfortunately, what seemed a stellar field of potential MS candidates in early development has lost some luster in larger later-stage trials on the long and winding road toward regulatory approval (1Pharmaceutical Approvals Monthly June 2006, p. 3). Serious side effects, including malignancies and autoimmune disorders, have emerged with some of the highest profile late-stage candidates.
Serious side effects may be problematic to neurologists, who are comfortable with the safety profile of existing first-line treatments for MS, mainly Biogen Idec's Avonex (interferon beta-1a), Merck Serono's Rebif (interferon beta-1a) and Teva's Copaxone (glatiramer). Avonex and Rebif carry warnings for depression and suicide, anaphylaxis and hepatic injury. Labeling for Copaxone doesn't include any warnings.
"You're thinking about this young, otherwise healthy woman who might want to have children in the next year or two and that plays a role," said Mark Tullman, Director of the Multiple Sclerosis Clinical Care and Research Center at Columbia University, referring to neurologists' treatment decisions and traditional newly diagnosed patients, frequently women in their 30s.
"The first generation of therapies has just been so remarkably safe, and that's a little bit of a problem I think for us and our colleagues," he said.
Tysabri Provides Exposure To Risk/Benefit Scale
The MS community is just now getting its first serious taste of negative drug side effects, and the balance of weighing benefit and risk, with Biogen Idec/Elan's Tysabri (natalizumab), which is linked to the potentially deadly brain infection progressive multifocal leukoencephalopathy. The drug is marketed under a restrictive risk management program, TOUCH, to ensure that cases of PML are detected and reported. Several such cases have occurred in recent months (2"The Pink Sheet" DAILY, Feb. 9, 2009).
TOUCH is providing MS patients and prescribers with their first exposure to a restrictive access program, but it could be the first of several such programs to come down the road if certain drugs reach the market.
The risk of PML with Tysabri is thought to be about one in 1,000, but use of the biologic has been primarily relegated to the second or third-line setting, despite its apparent efficacy benefit over the traditional first-line drugs. "You are only talking about 4 or 5 percent of patients who are receiving that drug as their initial MS modifying therapy," Tullman said of Tysabri.
Physicians in areas like rheumatology and oncology have had more experience balancing the benefit/risk scale for drugs with serious side effects. "Neurologists are pretty new to this game," Richert said. "I think over the next five years or so neurologists might become more like rheumatologists when it comes to their ease at prescribing drugs that carry a small percentage of very risky side effects."
With Efficacy Comes Opportunity
What does bode positively for potential new drugs, however, is the modest efficacy of the interferons and Copaxone, and the clear unmet medical need that remains for patients. Drugs that show a clear efficacy benefit on disability outcomes - oral or injectable - will have a much clearer market opportunity.
"Disability by and large is really the gold standard," Richert said. "There are studies in Phase II trials that look at relapse rate and MRI findings, [but] personally, if it is not disability data, I tend not to pay much attention to it."
That said, patients are clearly unsatisfied with existing medications due to the injection schedule and breakthrough disease, Richert added. He pointed to data showing that about 12 percent to 15 percent of patients who start on the first-line drugs stop treatment permanently; another 25 percent who continue the drugs are not satisfied with treatment.
Fingolimod, Cladribine Targeted For 2009 Filing
Among some of the late-stage candidates in development are two oral immunosuppressants, Novartis' fingolimod (FTY720) and Merck Serono's cladribine, and two oral immunomodulators, Biogen Idec's BG-12 (dimethyl fumarate) and Teva/Active Biotech's laquinimod.
Novartis' fingolimod is being studied in two ongoing Phase III studies and is targeted for regulatory filing in the second half of the year. Preliminary data from a one-year Phase III trial released in December showed patients treated with fingolimod experienced significantly fewer relapses than those treated with Avonex. However, seven cases of localized skin cancer were seen in the fingolimod arm, and two patients taking the higher 1.25 mg dose died (one from disseminated varicella infection and another from herpes encephalitis) (3"The Pink Sheet" DAILY, Dec. 23, 2008).
"The FTY side effect profile in Phase III ... is going to temper my use," cautioned Jeffrey Bennett, associate professor of neurology at the University of Colorado.
Given the early data, safety results to come out of Novartis' two ongoing two-year placebo-controlled trials (evaluating frequency of relapses and slowing of the progression of disability) will be critical.
With Merck Serono's cladribine, a two-year, placebo-controlled trial met its primary endpoint of clinical relapse rate reduction in patients with RRMS. Regulatory filing based on the single Phase III trial is targeted for mid-2009. A second Phase III trial evaluating cladribine in patients who have experienced a first clinical event suggestive of MS was also initiated last year.
Merck Serono reported increased cases of lymphopenia with cladribine, but provided little other safety data. However, rumors about malignancies in the treatment arm have circulated in the MS community.
"We know almost nothing about safety, and I think in terms of approval by the FDA and utilization, it is all going to come down to what the safety data look like," Tullman said of the prospects for cladribine.
Bennett noted, "If the top-line data hold up, it would certainly be something I would add to the armamentarium."
BG-12 Data "Underwhelming," Neurologists Say
Biogen's BG-12 is currently being studied in two Phase III trials, but a Phase IIb study showed the drug reduced the number of new gadolinium-enhancing lesions in patients with a tolerable safety profile.
Neurologists on the BIO panel, however, noted that the early data for BG-12 is "underwhelming," especially given that the trial evaluated dosing three times a day. "I don't think TID is a deal breaker, but it certainly doesn't make it attractive," Bennett said, citing patient compliance issues.
But Tullman pointed out that safety will trump dosing frequency. "If you are the only oral in town, we can deal with it," he said. A modestly effective oral therapy with a strong safety profile could become a first-line treatment option, with riskier, more efficacious drugs relegated to the second-line position, he added.
Teva is also studying an oral option, laquinimod, in two placebo-controlled Phase III trials. The company announced that FDA granted fast track designation to laquinimod Feb. 12. Phase IIb study results showed oral laquinimod administered daily reduced MRI disease activity in RRMS patients and showed a favorable trend toward reducing relapse rate compared to placebo. Teva is eyeing a potential launch in 2011.
Alemtuzumab Safety Also In Question
Another drug in development is Genzyme/Bayer's marketed oncologic Campath (alemtuzumab).
Early efficacy data on alemtuzumab has excited neurologists. Phase II data, released in October, showed patients with early RRMS taking once-yearly cycles of alemtuzumab reduced their risk of relapse by 74 percent and reduced risk of sustained accumulation of disability by 71 percent compared to the active comparator, Rebif. And treatment benefits were sustained for at least three years.
Nonetheless, side effects were concerning, with more alemtuzumab-treated patients experiencing life-threatening infections and autoimmune thyroid disease. Three percent of alemtuzumab-treated patients developed the potentially serious autoimmune disease idiopathic thrombocytopenic purpura, which can lead to uncontrolled bleeding, including one fatal case. The study enrolled 334 patients.
Evaluation of the drug is continuing in two Phase III trials under a robust monitoring program to manage safety. Campath, marketed for the treatment of B-cell chronic lymphocytic leukemia, carries a "black box" warning for cytopenias, infusion reactions and infections for that indication.
The disability results are "interesting," particularly given the active comparator arm, Bennett said, but the side effect profile, pending the Phase III results, could be a downside in terms of quick adoption.
Genentech is also studying a second generation anti-CD20 molecule, ocrelizumab, in RRMS. The company expects to complete enrollment in a 200-patient, Phase IIb trial evaluating ocrelizumab in the first half of the year. The firm has no further plans to develop Rituxan (rituximab), its first-generation anti-CD20 molecule, for MS, however, after it failed in a Phase II/III trial in primary progressive MS, a harder to treat patient population (4"The Pink Sheet" DAILY, April 14, 2008).
- Jessica Merrill
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