Teva Pharmaceuticals Co. Ltd. is facing investor doubts about regulatory prospects for its oral multiple sclerosis drug laquinimod after the drug missed the primary endpoint in a second Phase III trial, called BRAVO.

The immunomodulator failed to show a statistically significant reduction in the annualized relapse rate, a standard measure in MS trials, compared to placebo after 24 months of treatment in BRAVO, the company announced Aug. 1.

However, baseline status between placebo and treatment groups differed in terms of the presence of enhanced lesions on T1-weighted MRI images and the volume of lesions on T2-weighted MRI images at baseline. Those on treatment had more severe disease based on these two parameters. And once figures were adjusted according to a pre-specified sensitivity analysis, the drug did meet the primary endpoint of a statistically significant reduction in annualized relapse rate (21.3%). No immunosuppressive effects were demonstrated nor new safety signals reported.

Teva is set to file laquinimod - which it hopes will be the successor to its blockbuster MS drug Copaxone (glatiramer) - with FDA in early 2012. The highly competitive oral MS space opened up with the approval of Novartis' Gilenya (fingolimod) in October 2010, and other drugs, notably Biogen Idec's BG-12 (dimethyl fumarate), are in late stage development (Also see "Novartis' Gilenya: Efficacy, Patient Assistance Lie At Heart Of Marketing Push" - Pink Sheet, 11 October, 2010.).

During a call on the study results Aug. 1, Teva execs faced numerous questions from skeptical analysts about laquinimod's prospects for approval, with some noting that FDA requires two placebo-controlled studies that meet statistical significance with relapse rate reduction in MS.

Execs acknowledged this requirement for FDA approval, but maintained that though the endpoint was missed, the results from a pre-specified sensitivity analysis and marked improvements on secondary disease progression endpoints, along with results from the positive Phase III ALLEGO trial, should suffice. In ALLEGRO, laquinimod did show a statistically significant effect on ARR, though the efficacy was viewed as modest (Also see "No Homerun, But A Base Hit For Teva's Laquinimod" - Pink Sheet, 12 April, 2011.).

The BRAVO design has been discussed with FDA, Rivka Kreitman, senior VP for global innovative R&D, said in response to questions during the call, and the company believes that the sensitivity analysis will be accepted. She also pointed out that BRAVO is not a stand-alone study, as the company previously had reported ALLEGRO.

John Congleton, VP and general manager in neuroscience, brushed off inquiries about whether Teva had a back-up plan for a third study: "BRAVO is supported by the ALLEGRO data so I think we feel fairly comfortable with the clinical development program we have right now to go in front of the agencies."

The BRAVO study included 1,331 patients with relapsing-remitting MS and compared laquinimod to placebo; Biogen Idec's Avonex (interferon beta-1a) was included as a reference arm. Compared to placebo, laquinimod was shown to bring about a 17.6% reduction in ARR, which was not statistically significant. The reduction was a statistically significant 21.3%, however, following the sensitivity analysis.

Laquinimod also demonstrated marked improvements on secondary endpoints, with a 33.5% reduced risk of disease progression, as measured by the expanded disability status scale (EDSS), and a 27.5% lower risk of losing brain tissue.

Inclusion of Avonex was intended to show a comparative risk/benefit assessment of the drugs, but the study was not powered to show statistically significant differences in efficacy. Compared to placebo, Avonex demonstrated a statistically significant reduction in ARR prior to the sensitivity analysis and afterward. But it did not demonstrate a statistically significant improvement when it came to EDSS and brain tissue loss.

Putting The Best Face On BRAVO

Asked how the company would position laquinimod relative to other oral drugs and established injectables, Congleton noted that the effects on relapse as well as the effects on disease progression are achieved in a "very safe manner" with a drug that is convenient to take.

Teva did not present safety data from BRAVO, but reported that the findings were "benign" and consistent with ALLEGRO.

Safety has emerged as a major issue for other oral MS drugs. During FDA review, efficacy was pretty much a non-issue for Gilenya, but there were important safety concerns. The drug was approved with a Risk Evaluation and Mitigation Strategy that includes an educational program about warnings and precautions in the label. Prescribing information advises monitoring patients for six hours after the first dose and performing a number of other tests.

Safety was also a major factor in the review of Merck KgaA's oral agent cladribine, which recently received a "complete response" letter (Also see "Merck KGaA Pins Cladribine Hopes On Ongoing Studies After Complete Response Letter" - Pink Sheet, 2 March, 2011.).

Genzyme/Sanofi-Aventis' once-yearly injectable Lemtrada (alemtuzumab), now in Phase III, could be competitive to oral therapies, but that drug has been associated with immune thrombocytopenic purpura, hyperthyroidism and hypothyroisism ([A#1216099165884]).

A Sliding Scale Of Skepticism

In an Aug. 1 note on Biogen Idec stock, Baird analyst Christopher Raymond maintained that there is "no regulatory precedent in MS" for the correction Teva used in BRAVO. However, like other analysts, Raymond also cautioned that MS trials are variable. Results from Biogen's DEFINE trial of BG-12 were positive but data from a second study called CONFIRM are still pending.

"While downside to this competitive agent is clearly bullish for BIIB, we think it also underscores variability of MS trials," Raymond wrote.

Many analysts called attention to the lack of treatment-naïve patients in MS trials, which results in lower event rates in placebo arms.

CrossCurrent Research's Alex To also pointed that studies are done in different geographic areas and relapse rates differ: "Placebo rates are heterogeneous, contributing to the phenomenon of drugs looking promising in one trial but failing other trials."

Secondary endpoints like reduction in brain atrophy and improvements in EDSS are not well-accepted measures and may not predictive of ARR, he wrote. For example, brain atrophy on MRI is only "weakly linked" to reduction of relapse, he noted.

However, as there are few regulatory precedents it is difficult to gauge the regulatory outcome, To says. The rejection of cladribine over safety could be interpreted as a good for laquinimod, in his view. Laquinimod could also wind up emerging as a good add-on therapy.

In contrast, Jefferies analyst Corey Davis concluded boldly that investors should "assume laquinimod is not approvable."

"In a different era when only the interferons and Copaxone were available, FDA might be more willing to bend the rules on this one. But with all the progress on new MS drugs, we think the agency is more likely to stick to the rules requiring new drugs to have two positive Phase III studies," Davis said.

- Emily Hayes (e.hayes@elsevier.com)

Disappointing BRAVO Data Raise Doubts About Laquinimod's Chances With FDA

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