Biogen Inc. plans to seek labeling for its multiple sclerosis candidate BG-12 that reflects a benefit for reducing disability progression, even though the oral agent missed this endpoint in its second Phase III trial, CONFIRM.

The company plans to submit BG-12 (dimethyl fumarate) in the first half of 2012 and believes it could find a first-line role in MS, based on the strong efficacy and reassuring safety results from CONFIRM and an earlier Phase III trial, DEFINE.

The placebo group in CONFIRM showed progression in disability at half the rate that has been reported in other MS trials, including DEFINE, Biogen Idec said.

Positive top-line results from CONFIRM, which tested two dosing regimens of the drug (240 mg twice or three times daily) against placebo, and also included a reference arm with Teva Pharmaceuticals’ once-daily injectable Copaxone (glatiramer acetate), in 1,430 patients with relapsing-remitting multiple sclerosis, were released on Oct. 26.

The drug met the primary endpoint of the trial, reducing annualized relapse rates at two years by 44% for the BID arm and 51% for TID compared to placebo. Adverse events were said to be consistent with what has previously been reported, but details were not provided.

Copaxone reduced ARR by 29% compared with placebo at two years, in line with what would be expected based on historical trials. The trial was not powered to compare BG-12 to Copaxone, but the result does show how Copaxone would perform in practice today, against a placebo, in the same patient population.

Both dosing regimens of BG-12 met secondary relapse and MRI endpoints for disease burden. But BG-12 missed another important secondary endpoint – reduction of disability based on expanded disability status scale (EDSS) results after 12 weeks. A standard measure in MS trials, EDSS assesses a patient’s mobility.

While BG-12 reduced disability progression numerically (21% for BID and 24% for TID), the results were not statistically significant. Copaxone reduced EDSS by 7% compared to placebo in the CONFIRM study.

In the previously reported pivotal DEFINE study, BG-12 showed a statistically significant effect on EDSS compared to placebo. As for ARR, results were also better in DEFINE but were nevertheless robust and still got a very positive reception Also see "Biogen Idec's BG-12 Results Up The Ante In The Oral MS Market" - Pink Sheet, 21 April, 2011..

Setting aside the usual limitations of comparing across trials, BG-12 appears to have held its own when it comes to ARR in CONFIRM. The ARR is much better than traditional injectables (about 35%) and approaches efficacy of Novartis AG’s Gilenya (fingolimod), the first FDA-approved oral drug, which has been shown to reduce ARR by 54% Also see "Gilenya Off And Running, But Keeping Pace Long-Range Is Key" - Pink Sheet, 8 August, 2011..

Pursuing Disability Claim

But the disappointing EDSS result has the potential to emerge as a competitive issue.

During an investors’ call Oct. 26, Biogen execs explained that the baseline EDSS results were similar in CONFIRM and DEFINE. In the case of CONFIRM, however, progression in disability in the placebo group was half the rate of what has been reported in trials of other approved and experimental therapies, including DEFINE. Further analysis is needed to explain the results in CONFIRM.

Nevertheless, the company will be pursuing a claim for effect on disability progression in product labeling.

“We will certainly look to get labeling for EDSS based on the data we have seen in the DEFINE study and now. Even though we missed on statistical significance, we were moving in the right direction with the CONFIRM study as well,” Douglas Williams, executive VP for research and development, said during the conference call.

Analysts pressed execs on how the EDSS result would affect competitive positioning.

Gilenya, for example, is approved for the indication of reducing clinical exacerbations and reducing disability. Biogen Idec’s Tysabri (natalizumab) is approved for delaying accumulation of disability and reducing exacerbations.

In one pivotal trial against a placebo, Gilenya showed a statistically significant positive effect on EDSS. But in a second study against Biogen Idec’s Avonex, it did not, so there is a precedent for labeling based on one study, Alfred Sandrock, senior VP for neurology research and development, pointed out.

However, the second Gilenya study was against an active comparator, rather than placebo as in the CONFIRM trial.

Tysabri was positive on all endpoints, including EDSS, in two studies.

Considering that the injectables are well-established, safety is an important consideration for new drugs, and both Tysabri and Gilenya are associated with severe side effects ([A##06140020006]).

Pressed during the call to comment on the drug’s competitive positioning in an increasingly competitive landscape for MS drugs, Sandrock said: “I think that the benefit/risk profile of BG-12 looks quite attractive and I would hazard a guess that it looks like a first-line therapy to me.”

Biogen: Twice Daily Will Do

Execs also faced questions about the difference in results between twice daily and three times a day dosing. In DEFINE, the BID result was 53% reduction in ARR and TID 47%, and 44% for BID and 51% for TID in CONFIRM.

“Our conclusion looking across both studies is that both TID and BID provide approximately comparable results,” Williams said. “We don’t see that there is a huge or meaningful difference between either dosing regimen based on the aggregate data we have seen. So we think that BID dosing for this drug will be appropriate.”

In an Oct. 26 note, Bernstein Research analyst Geoff Porges noted that while the CONFIRM data are solid and should enable a good launch if approved, the key weaknesses in the CONFIRM data were the missed EDSS endpoint and the strength of the TID data versus the BID arm.

“Since the BID arm met its primary and most secondary endpoints, we still expect approval for both dose schedules, particularly when data from CONFIRM and DEFINE are combined,” he said.

And while the ARR results in CONFIRM were lower than in DEFINE, they still compare favorably against the traditional ABCRs [Avonex, Betaseron (Bayer), Copaxone and Rebif (Merck)], as well as teriflunomide (Sanofi) and laquinimod (Teva), Porges concluded.

Biogen Idec To Pursue Disability Label Claim For BG-12 Despite Missed Endpoint

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