Pharma majors’ multiple sclerosis drugs safe from EU competition for several years

This article is provided to FT.com readers by BioPharm Insight—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.biopharminsight.com

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Complex clinical trial designs and manufacturing steps required for biosimilars treating multiple sclerosis (MS) in Europe will likely stave off market entry for at least several years, drug consultants told Biopharm Insight.

The European Medicines Agency (EMA) recently issued draft non-clinical and clinical requirements for the development of biosimilar interferon-beta products.

The three, first-line, interferon-beta treatments approved in the EU for MS are Biogen Idec’s (NASDAQ: BIIB) Avonex, Merck Serono’s Rebif and Bayer’s (ETR: BAYN) Betaseron; they differ with respect to their molecular structures, injection routes, dose recommendations and MS indications.

EMA requires a single, one-year trial with an MRI primary endpoint in relapsing-remitting MS (RRMS) patients as the basis for biosimilar approval. The agency further allows the results to be extrapolated to similar conditions such as clinically isolated syndrome.

The requirement is less than the required trial designs for new drugs approval (two trials, two years with clinical efficacy as outcome measure), but is not meant to be taken lightly, said Dr Daniel Kantor, president of the Florida Society of Neurology and medical director of Neurologique, an organization focused on patient-centered care, research and education.

Kantor noted that the most accepted clinical outcome in MS trials is annualized relapse rate reduction, but MRI studies can be shorter than the larger Phase III trials required. Still, while MRI results are aligned with clinical efficacy, the potential for variability between study arms can lead to significant individual patient variability, he added.

“Recent trials, such as Teva’s (NASDAQ: TEVA) BRAVO study of oral Laquinimod for RRMS, have highlighted potential barriers in matching for baseline MRI characteristics,” Kantor noted. “Differences in the baseline characteristics may lead to unexpected disappointing outcomes,” he said.

Thus, in the equivalence study the EMA requires, the biosimilar may potentially appear to have worse outcomes than the reference interferon and if, by chance, the biosimilar is superior, the equivalence study may be considered negative, Kantor said. Considering the legwork involved, it will take at a minimum three years from the time the trial is designed to enter the EU market, he added.

The challenge is conducting an equivalence trial, agreed Dr Robert Spiegel, president, Spiegel Consulting, New Jersey, noting that trial design and statistics depend on the equivalence margin. He said it will probably be at least two years before any drug developers are able to introduce biosimilar interferon-beta drugs.

A 400-to-500-patient study with two arms may be sufficient, Spiegel said, but biosimilar developers may choose to “be on the safe side” and power these trials to 800-to-1,000 patients. An issue in trial recruitment will also be finding previously untreated patients, he noted.

The key issue that drives trial size is the acceptable equivalence margin, said Cecil Nick, vice president, biotechnology, Parexel Consulting, UK. That number in turn relates to assay sensitivity, or the ability to demonstrate if there are any meaningful differences that would have meaningful clinical impact. European bodies favor an equivalence trial where the trial population and study conditions mirror the reference study and there is at least 50% efficacy when compared to the reference trial.

“If one applies these principles, trial sizes are likely to approach 1,000 patients or perhaps more for MS studies,” Nick said.

The guidance is consistent with other EMA guidelines in terms of its rigor, noted a scientist and biosimilars developer. He noted that it is a positive that in vivo studies can be omitted and that equivalence studies are limited to 12 months, but the emphasis on analytics and pharmokinetics requirements make it “extremely difficult” to make a sufficiently sensitive assay. In addition, the mandates for neutralizing antibodies are “complex and strict,” he noted.

If a company was to start development now based on this guidance, it would likely take at least four-to-five years before a interferon-beta drug reaches the market, the developer noted.

Kantor added that the intricacies inherent in an equivalency study make it difficult to design well, especially in the MS field where there is not an established way to do such a study.

To date, Biopartners is the only company to develop an interferon-beta biosimilar (Biferonex IF-beta) and it failed to gain EMA approval in 2009.

Steep manufacturing and patient adoption challenges

Making interferon-beta drugs is labor intensive, Kantor said, noting that it is not an undertaking for many companies. They must obtain an interferon-beta gene by extracting the gene coding for interferon-beta from human fibroblast cells; modify the gene, making a recombinant DNA molecule; and add it to a bacterium; produce interferon-beta-1b by bacterial fermentation; extract interferon-beta-1b from the ferment and add inactive ingredients.

A dedicated cell line has to be available to manufacture such technology, said Dr Samuel Hunter, head of the Advanced Neurosciences Institute, Tennessee, who noted that E. coli-derived biosimilars, as an example, must run on a different line than eukaryotic systems. This manufacturing requires a long-term commitment to staff and quality control, he added.

A biosimiliar company will need to court key opinion leaders to become users and explain the product to prescribers to overcome bias and to counter the messaging that will be coming from the brand legacy sponsors, Spiegel said. There may be specific ‘disincentives’ in that the legacy manufacturers have built strong relationships with current prescribers.

Physicians have used reference interferons for almost two decades, Kantor noted, and any biosimilar interferons on the market may not be well recognized or understood by many prescribers. While convincing physicians to switch patients poses a challenge for any biosimilar developer, the issue is acute in MS, Kantor said, when it is difficult to determine disease progression on many medicines.

Neurologists are generally rather conservative, and are much less keen than oncologists to use aggressive or new therapies, the scientist and biosimilars developer noted.

Because of the unpredictable nature of MS, clinicians are unable to easily judge the treatment effect on an individual patient and therefore are more reliant on trial data, Nick noted. They are therefore likely to be reluctant to switch or start a patient on a new product unless they can be convinced that there will be no loss of efficacy, he added.

“Unless the prescriber was forced by the insurance carrier to choose the biosimilar over the reference interferon, it is unclear why a prescriber would want to take the chance that the two are not really exactly the same,” Kantor noted.

Considering there are already three MS products on the market, and others being developed which could be significantly more effective, biosimilar interferon-beta drugs have a tough market, the scientist said.

Draft comments are due 31 May.

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