Genzyme Corp. will tap its global expertise in patient-focused specialty medicines to help parent company Sanofi grab a significant share of the burgeoning multiple sclerosis market, Genzyme MS Head Bill Sibold told investors during a call April 25 from the American Academy of Neurology annual meeting in New Orleans.

In addition to Sanofi’s current portfolio, which “positions us to compete very effectively,” the company is looking internally at further programs to bring forward, as well as externally “to see what really makes the most sense to round out and build a long-term, leading MS franchise,” Sibold said in an interview the day before.

“We have a very clear goal: we’re committed to becoming true leaders in MS,” said Sibold.

Sanofi’s current MS portfolio consists of alemtuzumab, for which investigators presented what Sibold called “unprecedented” results at the meeting April 24, and teriflunomide, a once-daily pill currently under FDA review that Sanofi feels will compete well against the current line-up of injectable “platform therapies.” Genzyme plans to file a marketing application with FDA for alemtuzumab this quarter.

Calling On Genzyme’s Expertise In Chronic Disease

During the call, Sibold predicted the current $12.5 billion MS market would grow to nearly $18 billion by 2016, driven by unmet need and the number of new therapies entering a market now dominated by injectable interferons and Copaxone (Teva Pharmaceutical Industries Ltd.’s glatiramer acetate).

As more new products enter, “the market will fragment some,” and Sanofi will be there with its portfolio “to capture some of that significant opportunity,” Sibold asserted.

Leading the endeavor will be Genzyme, with its experience in developing treatments for chronic rare diseases. “We have extensive global relationships with physicians, payers and patient advocacy groups,” and the company is assembling an experienced MS team with significant relationships that will allow us to build on that culture and apply those lessons to MS, he said.

Specialty biotech Genzyme will call on its patient-centered experience in rare diseases to make parent Sanofi a leader in the MS space.

Alemtuzumab, which Sanofi proposes to sell as Lemtrada, is a formulation of Genzyme’s Campath, already marketed to treat B-cell chronic lymphocytic leukemia. Results from a second Phase III trial of alemtuzumab in MS presented at AAN demonstrated its success at both slowing disease progression and reversing disability compared to Roche’s Rebif (interferon beta-1a) Also see "Sanofi/Genzyme MS Drug Lemtrada Scores High Against Rebif" - Pink Sheet, 24 April, 2012..

The company released top-line data in November showing the trial had met both of its co-primary endpoints of relapse rate and sustained accumulation (worsening) of disability with high statistical significance. Over the two-year study, patients taking alemtuzumab had a 49% reduction in relapse rate compared to the comparator group, which took Rebif, as well as a 42% reduction in the risk of sustained accumulation (worsening) of disability, as measured by the Expanded Disability Status Scale (EDSS), a scale of 0-10 in which high numbers mean more disability.

New results presented April 24 show the mean EDSS score for patients who took alemtuzumab decreased during the two-year period, while the mean score for patients given Rebif increased (-0.17 versus 0.24). In the end, 29% of patients treated with alemtuzumab had a six-month sustained reduction in disability compared to 13% with Rebif. That is, their EDSS score dropped one point or more and stayed low for at least six months.

But while the CARE-MS II trial in treatment-experienced patients showed a clear benefit in reduction of disability, the earlier CARE-MS I, in treatment-naïve patients, did not. Genzyme attributes this disappointment to unanticipated successes in the Rebif arm. It remains to be seen how regulators will look at the data, though, and that will make a difference in how the disability results are handled in labeling – and ultimately whether Sanofi will be able to differentiate Lemtrada with a disability reduction claim.

The Benefit/Risk Equation

A sign of the unmet need in the space is that two of the newest therapies and their associated side effects have “really forced a discussion in the MS community about benefit-risk,” Sibold pointed out to investors.

Despite the well-characterized risk of progressive multifocal leukoencephalopathy, Biogen Inc./Elan Corp. PLC’s breakthrough therapy Tysabri (natalizumab) is a substantial product, with around 12% of the market at $1.5 billion in sales in 2011, he pointed out. Tysabri, approved to treat relapsing forms of MS in patients unable to tolerate other treatments, is gaining sales as patients avail themselves of a new predictive test for PML Also see "As Majority Of U.S. Patients Tested For JCV, Tysabri Sales Rise, Elan Says" - Pink Sheet, 8 February, 2012.. And Novartis AG’s once-daily oral therapy Gilenya (fingolimod), which launched last year and managed to take a 4% market share with $494 million in sales, has been associated with cardiovascular side effects Also see "EU And U.S. Regulators Toughen CV Monitoring Requirements For Novartis's Gilenya" - Pink Sheet, 20 April, 2012..

But while the MS community may be inured to discussions of benefit versus risk, Lemtrada also has baggage that must be discussed, and Genzyme has its talking points ready.

In the 480-patient CARE-II trial, 15.9% of alemtuzumab-treated patients developed an autoimmune thyroid-related adverse event compared to 5% with Rebif, and 0.9% of alemtuzumab-treated patients developed immune thrombocytopenia during the two-year study period. Genzyme has a management program in place to detect and treat both events.

The autoimmune effects have been described from the early days of alemtuzumab in MS, Michael Panzara, Genzyme therapeutic head of MS, said in the interview. In previous studies it has gone as high as 30%, but over 90% of cases are mild to moderate in severity, and those cases are treated with standard therapies. “What is interesting and very telling about how this is viewed by patients and physicians is we don’t have people dropping out of the study because of [a thyroid condition]. They continue on the study; they actually get their treatment again, even if they develop it before their second infusion. It’s not a barrier to them receiving it because they are experiencing efficacy.”

Regarding ITP, which is much more uncommon and caused a death in Phase II before it was identified as a risk with alemtuzumab, the management program caught all cases in the Phase III program and they were treated successfully, he said.

While regulators may ask for a new plan, during the clinical trials the monitoring program largely comprised monthly blood tests. Also very important was education of patients and clinicians to the potential symptoms of both conditions, Jeffrey Cohen, Cleveland Clinic, and a member of the CARE-MS steering committee, said on the call.

Indeed, said Cohen, four of the seven cases of ITP in CARE-II were picked up on routine blood tests even before the patient had symptoms, and the other three were reported by patients who noticed symptoms. One patient improved spontaneously without treatment, and six improved with standard therapies, one of whom relapsed and underwent splenectomy as second-line treatment.

These cases of “induced” ITP are regarded as very treatable compared to “wild type,” possibly because they are detected earlier and they respond well to the standard regimens, added Alasdair Coles, University of Cambridge, U.K., who also is on the CARE-MS steering committee.

Alemtuzumab may be having an immune-modulating effect, explained Coles. The biologic selectively targets CD52, a protein that appears on the surface of B and T lymphocytes. When those cells repopulate, within weeks after treatment, the new cells appear to secrete neurotropic factors that actually promote neural repair.

Teriflunomide And Biogen’s BG-12 Pending At FDA

Sanofi filed an NDA in August 2011 for Aubagio (teriflunomide), an oral pyrimidine synthesis inhibitor, putting the anticipated action date sometime in June Also see "Sanofi's Oral Aubagio Jostles For Position In Multiple Sclerosis Market" - Pink Sheet, 21 October, 2011..

Oral teriflunomide, “which appears to have interferon-like efficacy,” will compete well in the injectable market, Panzara said during the interview. With teriflunomide and alemtuzumab, “we really have a spectrum of products that cover the whole MS landscape with some overlap,” he said.

The NDA is supported by the Phase III TMESO trial, which compared two doses of the drug to placebo in 1,088 patients. In the study, both teriflunomide doses met the primary endpoint of reducing annual relapse rate by 31% compared to placebo, about the same as would be expected with traditional beta interferon products. Further results from the TENERE trial, comparing Aubagio to Rebif, and top-line data from the TOWER trial, which is structurally similar to TMESO but twice as long, are due during the year.

With the Lemtrada submission, FDA will be looking at three new drugs to treat MS, two of them owned by Sanofi.

Also pending is Biogen’s much-anticipated BG-12 (dimethyl fumarate), which the big biotech filed with FDA Feb. 28, giving it a possible action date in December. If FDA is going to award BG-12 a six-month priority view, the decision could come any day now, UBS analyst Matthew Roden reminded in a note on BG-12 data reported at AAN.

Results shared at the meeting confirm the drug’s favorable safety and tolerability profile, he said. Rates of flushing and GI-related events, high in treatment arms of CONFIRM, the second Phase III trial for BG-12, decreased meaningfully after the first month. Results from the first pivotal trial, DEFINE, produced better-than-anticipated results Also see "Biogen Idec's BG-12 Results Up The Ante In The Oral MS Market" - Pink Sheet, 21 April, 2011..

As well, in a note on alemtuzumab and BG-12, ISI analyst Mark Schoenebaum called the CARE-MS II data impressive, but probably not a threat to Biogen. In a best-case model, Schoenebaum estimates alemtuzumab might gain 8% market share at peak, while “we continue to think BG-12 will dominate front-line market as a safe and efficacious oral with around 25% or more overall share.”

Sanofi Sets Sights On Multiple Sclerosis Leadership

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