Industry Trend Analysis - EMA Approval Race Underway For Biosimilar Pegfilgrastim - APR 2018

BMI View: Gedeon Richter is in a regulatory race with Sandoz (Novartis) for the first biosimilar pegfilgrastim product to be approved in the EU. However, both companies have suffered regulatory setbacks with their applications, highlighting the difficulties pegfilgrastim presents for biosimilar manufacturers. Gaining first-to-market status will be important for either firm, but Amgen's branded sales are declining in the EU; this will further diminish the likely returns for any biosimilars.

The EMA has accepted the regulatory resubmission of Gedeon Richter's proposed biosimilar pegfilgrastim product, a potential biosimilar version of Amgen's Neulasta, used in cancer patients to reduce the duration of neutropenia and the occurrence of febrile neutropenia. The product, with a proposed trade name of Cavoley, was originally submitted to the EMA's CHMP in 2015. However, in November 2016, Richter notified the CHMP that it was withdrawing the marketing application. At the time of the withdrawal, Richter had presented results of studies to show that Cavoley was highly similar to Neulasta. The application was withdrawn after the CHMP had evaluated the documentation provided by Richter and formulated lists of questions. After the CHMP addressed Richter's responses to the last round of questions, some issues remained unresolved.

At the time of the withdrawal, the CHMP had some concerns and was of the provisional opinion that Cavoley could not have been approved for reducing neutropenia. The CHMP was concerned that study results had not shown the proposed biosimilar would be handled by the body in the same way as Neulasta and so was not of the opinion that Cavoley had been demonstrated to be highly similar to Neulasta. In its letter to the CHMP notifying it of the withdrawal, Richter stated that having considered the conclusion reached, it had decided to withdraw the application but would continue developing the product and follow the CHMP's advice to eliminate the remaining uncertainty.

The product's resubmission follows the successful completion of an additional clinical study, which provided data demonstrating biosimilarity of both the pharmacokinetics and pharmacodynamics of the proposed biosimilar and Neulasta. The biosimilar pegfilgrastim is currently under review by the EMA for the same indications as the reference product.

In August 2015, Richter signed a licence and distribution agreement with Stada Arzneimittel; under the terms of the agreement, Stada has received non-exclusive distribution rights for Richter's pegfilgrastim biosimilar for Europe, including Russia. Richter retained its rights to distribute and market the biosimilar worldwide. Stada commented at the time that the agreement was part of its continuing strategy of selective in-licensing.

Pegfilgrastim Has Proved Difficult For Biosimilar Manufacturers

Gedeon Richter is not the only company to have found difficulties in developing a biosimilar version of Neulasta. Amgen has previously identified potential competition from Sandoz ( Novartis), Apotex, Coherus BioSciences and Mylan. As yet, no versions have been approved in the US or EU; all of the above companies are looking for US approvals, but Sandoz has also looked to the EU. Sandoz's MAA for its biosimilar pegfilgrastim was accepted for review by the EMA in early 2016. However, in February 2017, the company notified the CHMP that it was withdrawing the MAA for the product, to be marketed as Zioxtenzo. Sandoz had presented the results of studies designed to show that Zioxtenzo is highly similar to Neulasta. In addition, two studies in patients receiving cancer medicines compared the safety and effectiveness of Zioxtenzo and Neulasta. However, based on the review of the data, at the time of the withdrawal, the CHMP had two main concerns and was of the provisional opinion that Zioxtenzo could not be approved as a biosimilar of Neulasta. The CHMP was concerned that study results were not able to show that the concentrations of pegfilgrastim in blood were the same after taking Zioxtenzo and Neulasta. The other concern was the lack of a certificate of GMP for the medicine's manufacturing site. An inspection of the site was therefore necessary before the biosimilar could be approved. At the time of the withdrawal, Sandoz had not demonstrated that Zioxtenzo was highly similar to Neulasta and an inspection to confirm that it was being manufactured according to GMP standards had not yet taken place. In its letter notifying the CHMP of the withdrawal, Sandoz stated that it would not be able to provide the additional data required by the CHMP within the timeframe allowed for the procedure. Sandoz has since resubmitted its MAA with the CHMP; the EMA accepted it for regulatory review in November 2017.

Whilst companies have found difficulties in developing a biosimilar pegfilgrastim, the same is not true of filgrastim, the originator version of which is marketed by Amgen as Neupogen. In the EU, the first biosimilar version of Neupogen to be approved was on September 9 2008, and came from Teva Pharmaceutical Industries' subsidiary, ratiopharm. In total, eight biosimilar versions of filgrastim have been approved in the EU, including two versions from Sandoz.

It would seem that it is only a matter of time before a biosimilar version of Neulasta is approved, especially as it is an ageing drug, but there are clearly difficulties in producing a biosimilar. Neulasta was first approved in the US in early 2002, and although it is still a blockbuster drug, sales have started to tail off. In FY17, Amgen reported total Neulasta sales worth USD4,534mn, down by 2.5% over the USD4,648mn reported in FY16. This in turn was down by 1.4% over the USD4,715mn reported in FY15. Sales have fallen y-o-y only in the last two years, however, but it is likely that the decline will continue to increase in FY18 and beyond.

The majority of Neulasta sales are raised in the US, which will give Amgen some comfort in the event that either Richter or Sandoz's versions are approved by the EMA. In FY17, US sales were worth USD3,391mn, equal to 86.7% of total sales. This was flat against FY17, rising by just 0.2% over the USD3,925mn reported in FY16. By contrast, sales outside of the US have seen something of a collapse, falling by 16.6% in FY17, from USD723mn in FY16 to USD603mn.

Neulasta Sales Are In Decline
Amgen's Annual Neulasta Sales (USDmn)
Source: Amgen, BMI