Although it provides somewhat of a dampener to the start of American MS Awareness Month, the FDA’s complete response to Merck KGaA’s MS pill Movectro (cladribine) was widely expected. The company is re-analysing existing data on the drug to see if it can address the regulator's concerns over potentially severe side effects, or if new trials are required (Event - Hopes fading for Merck KGaA's Movectro, February 3, 2011).
The expected nature of the rejection showed in Merck's share price today, which was largely unmoved at €65 following an initial dip. Merck pulled its application for Movectro from Europe last month after receiving a second negative opinion, although the drug was launched in Russia and Australia at the end of last year. Further applications are pending in over 40 countries, but with many of these likely to take their cues from the US and Europe, the bigger issue now is how much longer Merck will pursue and support the drug.
Once a leader
An unfortunate fall from grace, Movectro once led the race to put an MS pill in a major market, demonstrating similar efficacy in relapse-remitting MS but with much less frequent dosing than its once-daily rival, Novartis’ Gilenya (Novartis wins strong label for first oral MS pill, September 22, 2010).
The drug's side effects have prevented regulatory progression, most notably five cancer-related deaths and incidences of lymphopaenia during the pivotal Clarity trial, thought to have been caused by Movectro’s powerful immunosuppressive and cytotoxic activity.
The FDA initially issued a refuse-to-file letter before granting priority review, which consequently was extended in November last year.
Meanwhile Europe rejected the candidate twice – once last year, then Merck's appeal was given the thumbs-down a month ago (Negative EU vote on cladribine leaves Gilenya strolling to the finish line, September 24, 2010). Interestingly, the committee's outlook was not unanimous, some recommending conditional approval as an alternative treatment option for relapsing patients. Nevertheless, Merck has withdrawn its European application.
Pivotal trials continue
Analysts at UBS wrote today they are uncertain whether existing phase III data will be enough to address the FDA’s concerns. Separate pivotal trials are ongoing.
Clarity Extension, a follow-on trial to Clarity, and Oracle MS, in early disease patients, are due to read out by year-end. Despite this it is hard to imagine a drug with such marked safety signals in later-stage disease getting approval for early-stage patients.
Results of Onward, a study of Movectro as an adjunctive therapy to standard interferon-beta, are expected in the first half of next year. Merck markets the two top-selling versions of interferon-beta for MS – Avonex, which sold $2.5bn last year, and Rebif, selling $2.2bn. As they start to feel Gilenya’s presence, and with both due to lose patent protection in 2013, there may yet be an opportunity for lower dosage combinations with Movectro.
Lastly the eight-year Premiere study is also ongoing, hoping to show the frequency of serious adverse events is not clinically significant in the long term, a factor which Merck contested when Movectro was rejected in Europe. Unfortunately when this trial reads out, in 2018, the competitive landscape is likely to be significantly more challenging.
That landscape is already taking form, with some alternative MS pills already at pivotal stages. Teva and Active Biotech’s laquinimod for example has already reported strong preliminary phase III safety and efficacy data (Dark horse laquinimod reveals potential as MS pill, December 9, 2010).
The safety signals also appear encouraging for Biogen Idec’s BG-12, which will report phase III data in coming months (Event – Biogen’s MS pill has high bar to cross, February 18, 2011).
Consensus continues down
Consensus estimates still see global sales of $777m in 2016. Banks such as Bernstein and Nomura had already removed Movectro sales from their forecast models prior to the FDA’s decision, while others reduced estimates substantially. That consensus will likely come down a whole lot harder after today.
Movectro was launched in Russia and Australia in late 2010, and as such is not likely to report sales for some time. While the regulators in these countries may have looked favourably on Movectro, initial sales figures could be quite telling of the ‘real world’ view and potential adoption of the drug, as Russian and Australian physicians evaluate the risks of prescribing to their patients.
Movectro’s chance of major success seem all but dashed in its two most lucrative markets. Indeed, even if the FDA does eventually approve the candidate, holding its own against Gilenya and other promising candidates will be extremely tough. It could yet be adopted for combination therapy, or in smaller global regions, but with such limited opportunity Merck could well be considering whether to cut its losses.