Biogen/Elan Seek First-Line Claim For Tysabri In JCV-Negative MS Patients

Given the risks of progressive multifocal leukoencephalopathy, a proposed restriction appears aimed at blunting the potentially unfavorable impact that longer duration of use in the first-line setting would have on natalizumab’s risk/benefit profile.

Biogen Inc./Elan Corp. PLC’s strategy for a first-line indication for the multiple sclerosis agent Tysabri (natalizumab) includes limiting use to only those patients who have tested negative for antibodies to the JC virus, which is a risk factor for developing progressive multifocal leukoencephalopathy.

This proposed restriction, which is not part of labeling for its current indication for use after failure or intolerance to other therapies, can be seen as an attempt to blunt the potentially less favorable risk/benefit profile given the longer duration of use that a first-line setting would likely entail.

U.S. labeling currently recommends Tysabri for patients who have had an inadequate response to, or are unable to tolerate, an alternate MS therapy.

The companies announced on Jan. 16 that they have submitted applications to the FDA and European Medicines Agency requesting an expanded indication that would include first-line use in people with certain relapsing forms of MS who have tested negative for JCV antibodies. “If approved, a first-line label will allow all appropriate anti-JCV antibody negative patients to consider Tysabri early in the course of treatment, regardless of the level of disease activity or prior treatment history,” the companies said in a joint press release.

Turning To Tysabri Earlier In Disease Course

In the U.S., Tysabri is indicated as monotherapy treatment of patients with relapsing forms of multiple sclerosis to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations.

“Tysabri is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate MS therapy,” labeling states.

In the EU, the integrin receptor antagonist is approved for highly active relapsing-remitting MS in adults who have failed to respond to beta interferons or have rapidly evolving, severe relapsing-remitting disease.

Although there is some first-line use of Tysabri in the U.S., garnering FDA’s blessing for an expanded indication would be expected to increase the compound’s commercial opportunity.

However, FDA may view the risk/benefit profile in the first-line setting less favorably than for use when other MS therapies have failed due to the risk of PML, an opportunistic viral infection of the brain which usually leads to death or severe disability.

Tysabri was approved in November 2004 for treatment of patients with relapsing forms of MS to reduce the frequency of clinical exacerbations. However, it was withdrawn from the market within months following reports of PML. It re-entered the market following FDA approval in June 2006 of a more limited indication recommending second-line use, a boxed warning on PML risk and a risk management program (Also see "FDA Re-Approves Tysabri, Recommends Second-Line Use" - Pink Sheet, 5 Jun, 2006.).

In January 2012, the label was updated with information quantifying the risks of developing PML according to anti-JCV antibody status, duration of exposure and prior immunosuppressant use (Also see "Tysabri’s PML Risk Quantified In Revised Label; Can Added Certainty Add Scripts?" - Pink Sheet, 23 Jan, 2012.). The label’s Warnings and Precautions section lists three factors known to increase the risk of PML in patients treated with Tysabri: longer duration of treatment, especially beyond two years; prior treatment with an immunosuppressant; and the presence of anti-JCV antibodies.

“The risks and benefits of continuing treatment with Tysabri should be carefully considered in patients who are found to be anti-JCV antibody positive and have one or more additional risk factors. Patients with all three known risk factors have an estimated risk of PML of 11/1,000,” labeling states.

For a first-line indication, duration of use would appear to be the most problematic factor from the risk/benefit perspective. Labeling states that there is limited experience in patients who have received more than four years of Tysabri treatment.

Restriction By JCV Antibody Status

Although current labeling does not restrict treatment to only those individuals who test negative for JCV antibodies, such a limitation is being proposed in the first-line setting and would be aided by the availability of Quest Diagnostics Inc.’s Stratify JCV test, which was approved concurrent with the January 2012 Tysabri labeling change.

“Our anti-JCV antibody test, Stratify JCV, helps to determine the most appropriate patients for Tysabri and the data collected to date supports our recent filing for first-line use,” Biogen Senior-VP Development Sciences and Chief Medical Officer Alfred Sandrock said in the press release.

Biogen said the submission was based upon multiple studies, including data from the ongoing STRATIFY-2 longitudinal study of more than 10,000 Tysabri patients “that helped establish the low risk of PML in the anti-JCV antibody negative population.”

The company said the filing did not include data from the Tysabri Observational Program (TOP), an ongoing post-marketing study aimed at evaluating long-term safety, efficacy, associations between baseline treatment history and post-baseline annualized relapse rate, and overall two-year clinical disease-activity-free status.

A poster from the TOP study presented at the European Committee for Treatment and Research in Multiple Sclerosis meeting in Lyon, France in October 2012 showed that natalizumab has a robust and pronounced effect on annual relapse rate, with patients’ Expanded Disability Status Scale (EDSS) scores remaining stable. “Annualized relapse rates were lower in treatment-naive patients than in previously treated patients, and lower in patients with EDSS score <3.0 at baseline, suggesting a potentially greater benefit of natalizumab treatment earlier in the disease course,” the poster states.

Potential Impact Of BG-12 Looms Large

Although analysts were generally positive on the first-line filing, it’s clear that they are awaiting bigger news in the form of FDA approval of Biogen’s investigational MS drug BG-12 (dimethyl fumarate), an oral immune modulator.

In October, Biogen announced that FDA had extended the user fee date for the BG-12 submission by three months (Also see "Biogen Reports Progress In Late-Stage Programs, Plus Some Bumps In The Road" - Pink Sheet, 25 Oct, 2012.). At the recent JP Morgan Global Health Care Conference, the company indicated it expects to launch BG-12 in the second quarter of 2013, according to slides from that presentation.

In a Jan. 16 note, Guggenheim Securities analyst Bret Holley said Tysabri is among the most efficacious of all approved MS therapies and interest in earlier use of the drug in JCV-negative patients is increasing. “Consistent with this, BIIB recently reported that off-label, first-line Tysabri use is increasing somewhat in the U.S. Notably, however, we believe earlier use of Tysabri in the EU is more limited, given restrictions on off-label prescribing, and the label expansion would increase a physician's flexibility.”

Nevertheless, Holley said BG-12 is expected to dominate the front-line treatment both in JCV-positive and -negative patients, with Tysabri likely to remain a principal treatment option in later stage JCV-negative disease.

In a Jan. 16 note, analysts at UBS Investment Research said gaining a label for first-line use in JCV-negative patients “would be an incremental positive as a ‘blessing’ of its use upfront by the FDA and EMA could enable the Tysabri market share to grow beyond the mid-single digit share we believe it has today. We currently model 6% use in front line in the U.S. in 2014 and see upside with formal label expansion.”

Biogen reported $404 million in Tysabri sales for the third quarter of 2012, with Biogen’s share of that revenue totaling $274.8 million.