Managing Editor

Optimism could be building for Sanofi SA's Lemtrada (alemtuzumab), the drug at the center of negotiations surrounding the big pharma's acquisition of Genzyme Corp. earlier this year, following the release of detailed data from the first pivotal trial in relapsing-remitting multiple sclerosis (MS) patients that boosts positive top-line results reported in July.

Also at this year's Joint Triannial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS) conference in Amsterdam, the Netherlands, oral MS therapies duked it out, with Biogen Idec Inc.'s BG-12 scoring a big win among investors.

Lemtrada, a CD52-targeting antibody already marketed as Campath for leukemia, met its endpoint in the CARE-MS I trial, demonstrating a 55 percent reduction in relapse rate compared to Rebif (interferon beta-1a, Merck Serono SA) over two years (p < 0.0001). But those fell short of analyst expectations. That, plus a missed secondary endpoint – Lemtrada failed to show statistically significant improvement in Expanded Disability Status Scale score vs. Rebif – left some analysts dubious that the drug could gain sufficient enough market share to translate into the full contingent value rights attached to the Genzyme/Sanofi acquisition. (See BioWorld Today, July 12, 2011.)

Further data presented over the weekend at ECTRIMS/ACTRIMS, however, yielded some promising news for the drug. Investigators reported that Lemtrada hit statistical significance for several secondary endpoints, including demonstrating that 78 percent of patients remained relapse-free for two years compared to 59 percent in the Rebif arm.

Investigator Alasdair Coles, of the University of Cambridge, UK, noted that one of the most exciting findings was Lemtrada's effect on brain volume in MS patients. Data showed statistically significant less change in brain parenchymal fracture compared to Rebif (0.87 vs. -1.49 median percent change from baseline, p < 0.0001), as measured using MRI.

Brain volume as a measure of long-term disability in MS patients was a hot topic this year.

Even in healthy adults, brain volume decreases each year; but MS patients show a higher rate of brain atrophy, Coles told BioWorld Today. Data from CARE-MS I showed that Lemtrada "reduces the rate of brain atrophy to something you would see in a normal, healthy adult."

Statistically significant improvement also was seen for Lemtrada over Rebif in the percentage of patients with new and enlarging T2-hyperintense lesions (49 vs. 58, p = 0.035), with new gadolinium-enhancing lesions (15 vs. 27, p = 0.0006); and with new T1-hyperintense lesions (24 vs. 31 , p = 0.05). And other secondary findings suggested positive outcomes, with improvements over the Rebif group in Multiple Sclerosis Functional Composite scores that measure physical and cognitive function.

CARE-MS I was designed to target a very specific patient population, Coles said. The 581 patients enrolled had not had any prior treatment for MS, had the disease for less than two years and had above average rates of relapse.

He also pointed out that the study tested Lemtrada against an active comparator.

That makes its 55 percent reduction in relapse rate difficult to compare data with existing MS treatments. Biogen's Tysabri (natalizumab), for instance, demonstrated a 67 percent reduction in relapse rate in its Phase III AFFIRM study, but that trial only evaluated Tysabri against placebo. (See BioWorld Today, April 14, 2005.)

Lemtrada's safety data have been consistent, as well. "There were no safety signals," Coles said of the CARE-MS I trial. Common adverse events, including infusion-associated reactions, generally were mild, and the incidence of serious adverse events was similar between the Lemtrada and Rebif groups.

Sanofi anticipates data from a second Phase III study, dubbed CARE-MS II, later this year. That trial is testing Lemtrada against Rebif in relapsed-remitting MS patients who have relapsed while on disease-modifying therapy. Pending a positive outcome, the Paris-based pharma firm anticipates filing for approval of the fast-tracked program early next year.

Upon approval, holders of Genzyme's contingent value rights (CVR) would win another $1 per share, according to the acquisition deal, which valued the Cambridge, Mass.-based biotech at about $74-per-share, or $20.1 billion, up front, with up to another $13-per-share in CVRs tied to Lemtrada. Skepticism, however, has reigned from the get-go that the CVRs would end up paying out the $12 connected to sales milestones, given the increasing competition in the MS space, and CVRs (NASDAQ:GCVRZ) were trading Friday at a mere 99 cents apiece. (See BioWorld Today, Feb. 17, 2011.)

But, as a physician, Coles said he believes Lemtrada would make a promising addition to the MS treatment options.

"Crowded markets are the pharmaceutical firms' problems," he said. "When you've got a patient sitting in front of you, they want choices, and the more, the better."

Biogen Jumps on BG-12 Data

Also coming up behind the current MS blockbusters – Avonex (interferon beta-1a, Biogen Idec Inc.), Betaseron (beta interferon 1b, Bayer AG), Copaxone (glatiramer acetate, Teva Pharmaceuticals Inc.), Rebif and Tysabri – are a handful of oral MS drugs. Novartis AG's Gilenya (fingolimod) was the first to hit the market, gaining FDA approval last fall, but Biogen's BG-12 is closely following, with some stellar efficacy data to boot.

In April, the immune modulator yielded better-than-expected top-line data, and detailed results from the DEFINE study presented at ECTRIMS/ACTRIM showed that 240 mg of BG-12, administered either twice daily or three times daily reduced the proportion of patients who relapsed by 49 percent and 50 percent, respectively, at two years compared to placebo (p < 0.0001). It also reduced the annual relapse rate by 53 percent and 48 percent, respectively, (p < 0.0001), and reduced the risk of disability progression by 38 percent in the twice daily group (p = 0.005) and 34 percent in the three times daily group (p=0.0128). (See BioWorld Today, April 12, 2011.)

MRI scans showed that BG-12 patients experienced significant reductions in the number of brain lesions compared to the placebo group.

The news sent shares of Weston, Mass.-based Biogen (NASDAQ:BIIB) up $5.96 Friday to close at $107.63.

Laquinimod, from Active Biotech AB, of Lund, Sweden, and Teva Pharmaceutical Industries Ltd., of Jerusalem, has not fared quite as well. Despite hitting its endpoints in the first Phase III trial, a second study fell short. During the ECTRIMS/ACTRIMS meeting, investigators reported that, when imbalances in baseline characteristics were corrected, the study showed that laquinimod significantly reduced annualized relapse rates by 21.3 percent (p = 0.026). Whether the FDA will accept that adjustment or request an additional study remains to be seen. (See BioWorld Today, Aug. 2, 2011.)

Also in the oral MS pipeline is Sanofi's Aubagio (teriflunomide), which is under FDA review for use in patients with relapsing disease. The company reported data at ECTRIMS/ACTRIMS showing that the once-daily drug significantly cut annualized relapse rates.