Is everybody tired of hearing about Tysabri yet?
The much-touted multiple sclerosis drug from Biogen Idec Inc., which pumped investors' hopes and then bombed, continues to grab headlines, albeit smaller ones. The drug was pulled from the market in February after it was linked to patient deaths from progressive multifocal leukoencephalopathy.
Partnered with Elan Corp. plc, Tysabri (natalizumab) might have caused rare deaths in MS patients, but it's apparently working against Crohn's disease. Late last month, Biogen Idec and Elan said the second Phase III induction trial with the alpha-4 antagonist in Crohn's patients met its primary endpoint of clinical response as defined by a 70-point decrease, as measured at weeks eight and 12 using the Crohn's Disease Activity Index. Tested in moderately to severely active cases, Tysabri met all secondary endpoints in the ENCORE trial, without notable differences in the rates of adverse events between the Tysabri and placebo treatment groups.
But ENCORE patients finished dosing before the firms withdrew Tysabri from the market in February, and by June Biogen Idec sold to Genentech Inc. for $408 million the plant at which it had intended to make the drug.
These days, hardly anyone is talking with enthusiasm about Tysabri's market potential - or even the drug's potential to simply reach the market again, though Andrea Witt, analyst with Decision Resources, thinks the drug still has a chance.
"Its efficacy has been so promising that I think it will be kept as third-line therapy for severe or aggressive forms of relapsing or remitting MS, or those who have not responded" to other therapies, she told BioWorld Financial Watch. "There will be patients desperate enough to take a chance."
Meanwhile, MS as an indication is still hot. Drawing particular attention is FTY720, Novartis Pharmaceuticals Inc.'s oral, once-daily suppressor of the immune system that works by reducing the number of lymphocytes in the blood by redirecting them to the lymph nodes.
In a recently reported 281-patient Phase II trial in relapsing MS patients, FTY720 at doses of 1.25 mg per day or 5 mg per day for six months showed significant reductions in total number of gadolinium-enhancing lesions, which was the study's primary endpoint.
Both doses also reaped significantly improved relapse rate vs. placebo. At six months, 86 percent of drug-treated patients were relapse-free, as compared to 70 percent of placebo subjects, and the drug proved well tolerated, with 91 percent of patients completing the six-month trial, and 89 percent continuing in an extension study.
The Novartis drug is a synthetic analogue of myriocin, derived from culture filtrates of the fungus Isaria sinclairii, and apparently undergoes phosphorylation and interacts with specific G protein-linked receptors to do its beneficial work.
Data with FTY720, which has been explored for use in kidney transplant patients by other researchers, were disclosed at the European Neurological Society meeting in Vienna, Austria, in June - where Biogen Idec offered results from a global study with its approved Avonex (interferon beta-1a) for MS, the compound that could face a challenge from Novartis. That could be serious, since analysts model more than half of Biogen Idec's revenue to come from Avonex. True, the FDA is likely to scrutinize carefully any MS therapies in the wake of the snafu with Tysabri (given accelerated approval on a single year of data). But Novartis is expected to launch a Phase III trial with its compound this year.
Christopher Raymond, analyst with Robert Baird & Co., said the Novartis drug has a good shot, though Witt is skeptical.
"When you come right down to it, the end mechanism of action [of FTY720] is to keep the lymphocytes out of certain organs, which is very similar to that of Tysabri," she said. "I think the FDA may be a little worried that PML might surface" with the Novartis compound as well, pointing to the agency's request that Novartis delay Phase III studies until data are analyzed from trials testing FTY720 in kidney transplants. The compound should entail less risk in the renal patients because "you're not talking [doses given over] long periods of time, like you would be for MS."
Results from that study are expected at the end of this year, and Novartis had predicted a 2006 filing for the drug in that indication.
Others in the MS space are the beta interferon Rebif - already regarded by many physicians as an acceptable alternative to Avonex - from Serono SA, Copaxone (glatiramer acetate); from Teva Pharmaceutical Industries Ltd.; and Betaseron, sold by Berlex Laboratories Inc.
Among the up and comers is Fampridine-SR, from Acorda Therapeutics Inc., which started a Phase III trial last month. The 240-patient study, based on a special protocol assessment issued by the FDA in May, will evaluate whether the drug significantly improves walking ability, with secondary outcomes to include measurements of leg strength and muscle spasticity. The drug is a sustained-release tablet formulation of fampridine.
"With the pall now cast over [Biogen Idec's] growth prospects," Raymond wrote in a research note, his firm has chosen to stay neutral on the stock.
Biogen Idec's other hopes - the once-ballyhooed Amevive and Zevalin - "have largely been disappointments," Raymond wrote. Amevive (alefacept) is approved for psoriasis, and Zevalin (ibritumomab tiuxetan) for relapsed or refractory low-grade, follicular or transformed B-cell non-Hodgkin's lymphoma. Both will have to be "revived, repositioned or replaced," Raymond wrote.
The merger in 2003 of Biogen Inc. and IDEC Pharmaceuticals Inc. created a biotechnology behemoth with a market cap of about $22 billion, a firm that boasts not only the blockbuster Avonex but Rituxan (rituximab) for non-Hodgkin's lymphoma.
But the Tysabri blow has hobbled the company. A research report co-authored last fall by Witt predicted the MS market would more than double by 2013 as compared to a decade earlier, growing at a compounded annual growth rate of 8 percent. At the time, though, Tysabri still shone brightly, and was expected to grab a third of the market by the end of the forecast period, thanks to the compound's novel mechanism of action.
Witt had predicted the MS market would grow to $6.3 billion by 2013, but she has reduced that guess to $5 billion since the Tysabri trouble.
Could Novartis' drug be Tysabri's replacement?
"I'm not bowled over by it," Witt said, noting that FTY720 "has a few additional issues, like the thickening of the lung membranes. What is very exciting is the oral formulation," but other firms, including Acorda, are working toward MS drugs dosed by that route.
Teva has an oral formulation of Copaxone in Phase II trials, though "I think they've had some issues with bioavailability," she said. Also in Phase II is BX-471, the chemokine receptor antagonist from Berlex and parent company Schering AG, though that drug would "work only in patients with a certain genetic makeup," Witt said.
More promising than those might be cladribine, from Serono and IVAX Corp., an oral purine analogue designed to disrupt the proliferation of white blood cells involved in MS. Already approved for use in cancer patients, the drug has reached Phase III trials in the new indication, Witt said.
"Novartis is competing with Serono, as to who will launch that first oral formulation," she said, adding that - because of FTY720's similarity to Tysabri - "Novartis may be thinking, Is it worth pursuing Phase III trials?'"
More MS drugs are certain to appear. "I think drug developers are going to see how much opportunity is there, now that Tysabri is out of the way," at least as a heavyweight contender, Witt said.