FirstWord List: Five things to watch out for in the biosimilars market in 2014...

2014 is already proving to be an important year in the broader biosimilar calendar, both from a commercial and regulatory perspective. There have been a number of important approvals, including more success for Celltrion’s and Hospira’s Remsima and Inflectra (both biosimilar versions of infliximab), respectively, in Canada in January 2014, and the Russian approval of Biocad’s AcellBia (rituximab) in May 2014. From a regulatory perspective, both the FDA and EMA have been busy either updating or publishing new biosimilar development guidelines, and more regulatory clarity is expected later in the year.

To discuss some of the key findings from two recently published FirstView reports which both analyse the biosimilars market in robust detail, FirstWord's own Duncan Emerton – senior director of syndicated research and renowned biosimilars expert – will be presenting a webinar in association with Bloomberg Industries this Thursday (June 12) discussing the outlook for the global biosimilars market. To register for the Where Next for Biosimilars? webinar for FREE click here. As a primer for the webinar we look below briefly at five key biosimilar market events that are likely to occur in 2014...

Biosimilar antibodies – a commercial reality in Europe

Regular FirstWord readers will know we have been tracking closely the launch of Celltrion and Hospira's biosimilar Remicade product (sold as Remsima and Inflectra) in Norway with help of volume sales data provided by the Norwegian Medicines Agency (NoMA).

Despite biosimilar Remicade only being available in a handful of EU markets at present, due to IP limitations, Norway is proving to be an important test case on a number of counts. Celltrion and Hospira offered a near 40 percent discount for their product to secure a position on the annual public-sector tender, and uptake of the biosimilar in volume terms has been impressive in the first half of 2014. Steinar Madsen, Medical Director for (NoMA), told FirstWord; "The tendering results show both the potential for biosimilars to reduce costs and make it possible to treat more patients. Data to the end of May 2014 show biosimilar infliximab has taken nearly a 20 percent volume share of the Norwegian infliximab market." To drive uptake even further, NoMA will shortly initiate a real-world 'switching' study - called NOR-SWITCH – designed to demonstrate to physicians that patients already receiving branded Remicade (regardless of which of Remicade’s indications they are being treated for) can be safely and effectively switched to the biosimilar and back again if necessary. In combination, Norway's willingness to embrace biosimilar mAbs and its approach to driving future use look set to provide a strong platform for further expansion in 2015 when biosimilar Remicade is approved in larger markets across the EU (which is expected to occur from February 2015 onward).

Jockeying for position in the biosimilar Herceptin race

If 2013 saw something of a shakeout among those players developing biosimilar rituximab (Rituxan; Roche) products, then in more recent months there has been a shift in how the biosimilar community is looking to secure approval for biosimilar trastuzumab (Herceptin; Roche) products. Much has been discussed in relation to why Celltrion has not yet submitted CT-P6 (a proposed biosimilar version of trastuzumab) for EU approval. Based on key decisions by a number of other biosimilar trastuzumab developers, clarity is emerging as to why.

"The constant delay from Celltrion in submitting CT-P6 to EMA on the basis of metastatic HER-2 positive breast cancer [mBC] data raised the spectre of mBC data not being enough to secure approval. With Celltrion now studying CT-P6 in early HER-2 positive breast cancer [eBC], along with Amgen and Samsung Bioepsis, this seems to have been the case.

Out of the leading biosimilar trastuzumab developers, Pfizer is the only company still pushing on with an mBC study. In 2014 it's highly likely that Pfizer will initiate a Phase III study for trastuzumab in eBC patients " says Emerton. Furthermore, Emerton adds "the message from regulators has clearly filtered through that data in mBC is no longer considered sufficient to gain approval". This in itself may provide a key challenge for biosimilar developers who will be required to enrol an increased number of first-line patients into a head-to-head study where Herceptin is such a strongly recognised standard of care.

Reasons other than regulatory approval could also be behind these decisions, so say a number of biosimilar experts interviewed recently for FirstView’s biosimilar report; "Celltrion’s eBC [adjuvant] clinical trial has only been done for commercial reasons, not to support a regulatory submission", said one such expert. Despite this assertion, one can only wonder how much of an influence regulatory advice had on a distinct change of strategy for Celltrion.

Originator's defence strategies coming to the fore

The strategy being pursued by Roche – which markets the branded version of Herceptin – dictates that by the time biosimilar trastuzumab products are commercialised, the standard of care will have been progressed sufficiently to limit their usage to second or even third-line patients (in the developed markets at least).

To this end, publication of data from the MARIANNE study during the second half of 2014 will be pivotal and will largely dictate whether a combination of Roche's newer HER2 breast cancer therapies Perjeta and Kadcyla replace Herceptin in first-line patients.

While Roche is relying on innovation to raise the 'efficacy bar' for future biosimilar competition, other players will be more heavily dependent on pursuing a legal route to defend their branded biologic products from a loss of market share. With biosimilar development now appearing to benefit from a headwind, and with clinical and regulatory issues likely to play an increasingly limited role in slowing progression to market, adds Emerton, expect originator companies to turn to the courts over the next 12 to 18 months. Emerton commented "we’ve seen a number of very high profile legal cases in recent months, the vast majority of which have focused on defending and attacking IP. Odds are that legal activity will increase in the next 12 to 18 months simply because originator companies have been forced to move away from questioning clinical, regulatory and quality issues due to these issues being, for the most part, resolved."

Will the FDA deliver with its interchangeability guidance?

The FDA may be taking its time in developing biosimilar regulatory policy but it is trying to do something different as the only global regulator which is poised to tackle head-on the issue of interchangeability between biosimilar and branded biologics. The administration has committed to publishing its draft guidance on interchangeability later this year, having already recently published draft guidelines on the clinical pharmacology of biosimilars. See Physician Views Poll Results: Rheumatologists cautious towards FDA biosimilar regulatory guidance; oncologists less so

This recently published document has laid out a four point scoring system of comparability , which suggests that a high end score will be necessary to shape interchangeability potential. Clearly this has profound commercial implications and should be watched closely, while on a related note Bernstein analyst Ronny Gal believes that the FDA's recent guidance "stresses the difference of logic between proving a new compound works and proving biosimilarity". If the FDA follows this logic, adds Gal, we could witness some innovative biosimilar trial designs in the US.

Due to the lack of consensus in the US regarding how interchangeable biosimilars will be handled at the pharmacy level, significant uncertainty remains regarding the commercial value of an interchangeability designation. If automatic substitution isn't permitted at the state level, or legislation is in place that slows down the process, the commercial value becomes a moot point. As one European biosimilar market commentator said to FirstView for its recent report "how worthwhile will interchangeability be to a company if a state has specifically blocked it or has not introduced legislation to handle automatic substitution of biosimilars?"

All eyes on the US, but Europe will still remain a leader in terms of approvals

While the FDA may be seeking to deliver something innovative in terms of biosimilar interchangeability, the fact remains, however, that 2014 should see the EMA enhance its position as the most advanced biosimilar regulator in the developed markets. Having approved its first biosimilar monoclonal antibody (mAb) in 2013 (the aforementioned Remsima/Inflectra – a biosimilar Remicade product), and most recently approving Finox Biotech's Bemfola, a biosimilar version of Merck KGaA's Gonal-f (follitropin-afal), the EMA is expected to green light another biosimilar in the fourth quarter of 2014 when it approves Eli Lilly/Boehringer Ingelheim's LY2963016, a proposed biosimilar version of Sanofi's long acting basal insulin, Lantus (insulin glargine).

Approval of this product in the US has been delayed until 2016 at the earliest due to court proceedings initiated by Sanofi. It is telling, however, that having been submitted with the FDA via the 505(b)(2) regulatory pathway, LY2963016 is considered neither a biosimilar or an ANDA in the eyes of the FDA.

Approval in the EU will, therefore, be a notable event not only for Eli Lilly but also for the EMA. Despite several previous attempts, it will be the first biosimilar insulin to be approved in Europe. How physicians utilise the product is another matter, with Eli Lilly on its part indicating to investors that they should perceive the launch as that of a typical branded product. Data from both Phase III trials that were used to support the US and EU filing – ELEMENT 1 (type 1 diabetes) and ELEMENT 2 (type 2 diabetes) – will be presented at this year’s American Diabetes Association (ADA) meeting in San Francisco later this week.

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