Genzyme Must Give NICE More Data To Avoid New European Problem For Aubagio

Britain’s NICE wants more data to address uncertainties about the clinical and cost-effectiveness of Genzyme’s oral MS drug Aubagio.

Just months after Genzyme Corp.’s Aubagio (teriflunomide) was extricated from a tricky regulatory situation in Europe, the Sanofi biotech subsidiary has found its multiple sclerosis product facing another problem on the reimbursement front: Britain’s National Institute for Health and Care Excellence is on the verge of panning the drug unless the French drug maker can provide further data, remodeled analyses and more accurate evidence of clinical- and cost-effectiveness for Aubagio.

Potentially Well-Placed

NICE likes the novel nature of the drug, saying that as an oral treatment, Aubagio offers a step change for treating relapsing-remitting multiple sclerosis which could have a substantial impact on the quality of life for patients with this condition.

Novartis AG’s Gilenya (fingolimod) is also an oral composition but has only been granted an indication by NICE for highly-active relapsing-remitting MS.

Current standard treatments in the U.K. for relapsing-remitting MS all have to be injected and can be associated with unpleasant side effects. Most patients who have had two relapses in the past two years would be offered a disease-modifying therapy, either one of the beta interferons – Biogen Inc.’s Avonex (interferon beta-1a), Merck KGAA’s Rebif (interferon beta-1a), Bayer AG’s Betaferon (interferon beta-1b),Novartis’ Extavia (interferon beta-1b) – or glatiramer acetate, in accordance with guidelines from the Association for British Neurologists.

Neither beta interferons nor glatiramer acetate are recommended by NICE itself. But the country’s Department of Health has agreed a risk-sharing scheme with manufacturers through which disease-modifying treatments for multiple sclerosis can be provided to patients so long as the department considers them cost effective. They have therefore become firmly established practice in the NHS.

Thus, if Genzyme can address NICE’s doubts about Aubagio – while maintaining a competitive price – it would be well placed to capture a large part of the British market for relapsing–remitting multiple sclerosis. The U.S.-based biotech unit must act fast, because it has just over one month - until Oct. 22 - to provide the additional data to the reimbursement watchdog on Aubagio’s clinical- as well as cost-effectiveness in order to avoid a second problem in Europe.

Genzyme was exasperated when the European Medicines Agency in March this year handed down a positive recommendation for authorizing the drug, but at the same time refused to grant it new active substance status. A product without this status is not eligible for up to 11 years of data and market protection. Thankfully for the Cambridge, Massachusetts-based manufacturer, the CHMP reversed this decision in June, by a majority decision (Also see "CHMP Thinking On Aubagio NAS Status Offers Useful Insights" - Pink Sheet, 10 Sep, 2013.).

Still, at this stage in the NICE evaluation process, Genzyme appears unfazed.

“It is quite usual for NICE to seek further clarification and additional analyses as part of their assessment of how new medicines and treatments should be used in the NHS,” a spokesperson for the company said.

Clinical-Effectiveness Unconvincing

To resolve its issues with NICE, Genzyme will have to add to the evidence it submitted from 3 Phase III randomized controlled clinical trials – TEMSO, TENERE and TOWER – a Phase II trial –Study 2001 – and two extension studies – to Study 2001, and to TEMSO.

TOWER, TEMSO and Study 2001 compared the effectiveness of Aubagio with placebo and, according to NICE, “were well conducted”.

But the reimbursement watchdog was unimpressed with TENERE, which compared the effectiveness of Aubagio with Rebif-44 and was not powered to detect statistically significant differences in all the outcomes. It therefore concluded that the effectiveness of Aubagio compared with Rebif-44 was still uncertain. NICE’s expert review group noted that there were also differences in baseline characteristics that make the results of the trial difficult to interpret.

Genzyme had also carried out a mixed treatment comparison (MTC) that compared Aubagio with each of the treatments in the decision problem - beta interferons, glatiramer acetate, natalizumab and fingolimod. Still, NICE said Genzyme’s decision to exclude trials with patient recruitment prior to the year 2000 was inappropriate, and added that an “all years” MTC would be better.

So overall on the clinical effectiveness side, NICE acknowledged that Aubagio was clinically effective in reducing relapse rates compared with placebo, and that it might have a beneficial impact on accumulation of disability. It also conceded that the TENERE trials and the MTC indicated that there was very little difference in effectiveness between Aubagio and the beta interferons or glatiramer acetate.

As such, NICE said that there was insufficient evidence to make recommendations for teriflunomide for people with rapidly evolving severe relapsing–remitting multiple sclerosis or highly active relapsing–remitting multiple sclerosis.

The Genzyme spokesperson said that in the TENERE study, no statistical superiority was observed between the Rebif and teriflunomide arms (7mg and 14mg) on risk of treatment failure, the primary composite endpoint of the study, which was selected because of its relevance to real-world outcomes, as well as on relative risk of relapse. “Aubagio 14 mg is the only oral MS therapy to significantly delay progression of disability in two Phase III studies,” they added.

Confusion Over Cost-Effectiveness

Where no immediate superiority is detected, though, cost-effectiveness is likely to play a large role in the wider NICE decision-making process.

Genzyme’s base-case cost-effectiveness analyses compared Aubagio with a blended comparator of Rebif-22 (interferon beta-1a [22 micrograms]), Rebif-44, Avonex, Betaferon and glatiramer acetate. The analyses concluded that Aubagio dominated the blended comparator in that it was less expensive and more effective. This suggested a 63% probability of Aubagio being cost effective if the maximum acceptable incremental cost-effectiveness ratio was £20,000 ($32,000) per quality-adjusted life-year (QALY) gained.

NICE, however, considered the blended comparator approach to be “inappropriate” because it simply generated too much uncertainty. It concluded that an incremental approach including all comparators individually was more appropriate.

NICE said that the incremental analysis gave an ICER for Aubagio of £107,000 ($170,800) per QALY gained compared with glatiramer acetate. But use of the base-case MTC (post 2000 trials) rather than the ‘all years’ MTC, reduced the ICER compared with glatiramer acetate to £6000 ($9,600) per QALY gained. In both scenarios, Aubagio dominated beta interferons.

NICE therefore concluded that the most plausible ICER was very uncertain, and could be anywhere between £6000 and £107,000 per QALY gained. Until certainty is injected into this formula by Genzyme, NICE is not prepared to say that Aubagio is cost-effective.

“The Appraisal Committee thought that there was uncertainty about the cost effectiveness of Aubagio against one of the five comparators used in the assessment, namely glatiramer acetate. We are providing the additional information requested which will allow the Committee to make a more precise estimate of the cost effectiveness of Aubagio against this single comparator,” the spokesperson said.

Genzyme has already offered a patient access scheme – manufacturer’s discount – but this seems to have disappeared into the background as a result of the uncertainty that NICE said has been generated by existing data. It is difficult to comment on the price of the product in the U.K. – as this data is currently confidential – but if its U.S. pricing is anything to go by, then the product would seem to be eminently competitive (Also see "Discount Price May Position Aubagio For Greater Than Expected Uptake In Multiple Sclerosis" - Pink Sheet, 17 Sep, 2012.).

Genzyme says it is working with NICE throughout the consultation period to address the further clarifications and analyses requested.

The Appraisal Committee will meet again on Oct. 22 to consider this evidence which has been already submitted; the comments from consultees, and the additional analyses provided by Genzyme.

“We are hopeful that the Appraisal Committee will be able to issue its final draft guidance, the Final Appraisal Document, in the last quarter of 2013,” the spokesperson said.