Update on Biosimilar Approvals and Pending Applications in Europe and the U.S.
Approvals of biosimilar products in Europe continue to outpace those in the United States. 28 biosimilars are currently approved in Europe and five in the U.S. In 2017, the European Medical Agency has approved six biosimilar applications, including applications for biosimilars to two of the best-selling complex biologics, Humira (adalimumab) and MabThera (rituximab). EMA is likely to approve seven more biosimilar applications in the coming months. The Food and Drug Administration in turn has approved one biosimilar this year, and has scheduled an advisory committee meeting for later this month for Pfizer’s proposed biosimilar of Amgen’s EPO (epoetin alfa), which the agency previously rejected. Proposed biosimilars of complex biologics in a number of new classes are pending before both agencies at the same time.
2017 Biosimilar Approvals in Europe
The EMA has approved six biosimilar applications so far this year, in four classes. In January, EMA approved STADA Arzneimittel’s and Gedeon Richter’s biosimilars of the Eli Lilly osteoporosis drug Forsteo (teriparatide, sold under the trade name Forteo in the U.S.), a recombinant 1-34 N-terminal fragment of human parathyroid hormone. These approvals were followed in February by approval of Celltrion’s Truxima, a biosimilar of Roche’s monoclonal antibody MabThera (rituximab), which is marketed as Rituxan in the U.S. In March, EMA approved Amgen’s applications for its biosimilar of AbbVie’s Humira (adalimumab). Finally, in April, EMA approved Merck’s biosimilar of Sanofi’s Lantus (insulin glargine), the second such biosimilar to receive approval in the EU. Other than for Merck’s biosimilar of insulin glargine, all the other products approved this year fall into new categories of biosimilars for the European market. There are now 28 approved biosimilar medicines in Europe.
Biosimilars Approved in Europe as of May 2017 (1)
|Biosimilar Trade Name||Marketer||Active Substance||Reference Drug||Year of Approval|
|Epoetin Alfa Hexal||Hexal||epoetin alfa||Eprex/Erypo||2007|
|Retacrit (2)||Hospira||epoetin zeta||Eprex/Erypo||2007|
|Abasaglar (7)||Eli Lilly||insulin glargine||Lantus||2014|
|Low-Molecular Weight Heparins|
|Inhixa||Techdow Europe AB||enoxaparin sodium||Clexane||2016|
|Thorinane||Pharmathen S.A.||enoxaparin sodium||Clexane||2016|
|Flixabi (9)||Samsung Bioepis||infliximab||Remicade||2016|
|Parathyroid Hormone Fragment|
|Benepali (12)||Samsung Bioepis||etanercept||Enbrel||2016|
(1) Three additional biosimilars were approved by the EMA but subsequently had their authorizations withdrawn.
(2) An FDA advisory committee meeting is scheduled for May 25, 2017 for Hospira’s U.S. biosimilar application.
(3) Biosimilar application to market in the United States was accepted for review by FDA but has not been approved.
(4) Approved in the United States as a biosimilar under the Biosimilar Price Competition and Innovation Act of 2009 (BPCIA) with the trade name Zarxio.
(5) Approved in the United States under the 505(b)(2) pathway.
(6) Sanofi’s application for a biosimilar of Eli Lilly’s Humalog (insulin lispro) received a favorable opinion from EMA’s Committee for Medicinal Products for Human Use (CHMP) in May 2017 and may soon be approved in Europe.
(7) Original EU trade name was Abasria; it was approved in the United States under the 505(b)(2) pathway with the trade name Basaglar and launched in the United States in December 2016.
(8) Approved in the United States in September 2016 with trade name Amjevita. Amgevita and Solymbic are different trade names for the same monoclonal antibody.
(9) Approved in the United States in April 2017 under trade name Renflexis.
(10) Inflectra has been approved in the United States as a biosimilar under the BPCIA. Inflectra and Remsima are different trade names for the same monoclonal antibody.
(11) Other applications for biosimilars of MabThera/Rituxan, Sandoz’s Rixathon/Riximyo and Celltrion's Blitzima/Tuxella/Ritemvia received favorable opinions from CHMP in April and May 2017 and may soon be approved in Europe.
(12) A different biosimilar of Amgen’s Enbrel, Sandoz’s Erelzi, has been approved in the United States as a biosimilar under the BPCIA. Erelzi received a favorable opinion from CHMP in April 2017 and may soon be approved in Europe.
CHMP Issues Positive Opinions for Seven More Applications
In April and May 2017, EMA’s Committee for Medicinal Products for Human Use (CHMP) issued seven positive opinions on biosimilar applications. In April, CHMP recommended approval of Sandoz’s Erelzi (etanercept), a biosimilar of Amgen’s Enbrel that is already approved in the United States, as well as Sandoz’s Rixathon and Riximyo, a biosimilar of Roche’s MabThera/Rituxan (rituximab). On May 18, 2017, CHMP recommended approval of Celltrion’s Blitzima/Tuxella/Ritemvia rituximab biosimilar applications and Sanofi’s application for a biosimilar of Eli Lilly’s Humalog (insulin lispro). The positive opinions from CHMP mean that EMA is likely to approve these additional applications in the coming months.
Pending Biosimilar Applications in Europe and a Recent Withdrawal
Eleven additional biosimilar applications are under evaluation by the EMA as of May 2017: two applications for biosimilars of AbbVie’s (adalimumab), one application for a biosimilar of Sanofi’s Lantus (insulin glargine), two applications for biosimilars of Amgen’s Neulasta (pegfilgrastim), four applications for biosimilars of Genentech’s Herceptin (trastuzumab), and two applications for biosimilars of Genentech’s Avastin (bevacizumab). Eight of the pending applications seek to introduce biosimilars for products without biosimilars on the European market, i.e., biosimilars of pegfilgrastim, trastuzumab, and bevacizumab.
One application was recently withdrawn. Sandoz withdrew its proposed biosimilar of Amgen’s Neulasta (pegfilgrastim) after the EMA required additional data on a timetable that Sandoz could not meet. Sandoz’s application is the third application for a biosimilar of pegfilgrastim that has been recently withdrawn. The two pegfilgrastim biosimilar applications currently under review by EMA are from Coherus and Mylan/Biocon.
Five Biosimilars Approved In the U.S.
FDA has approved another biosimilar this year, Samsung Bioepis’ Renflexis (infliximab-abda), for a total of five approved biosimilar medicines. Renflexis, the second biosimilar of infliximab, was the first biosimilar to be approved in the U.S. without a public advisory committee meeting. FDA has said that it does not plan to hold public advisory committee meetings after the first biosimilar of a product is approved.
US Approved Biosimilars as of May 2017
|Marketer||Reference Drug||Approval Date|
|Zarxio (filgrastim-sndz)||Sandoz||Neupogen||March 6, 2015|
|Inflectra (infliximab-dyyb)||Celltrion||Remicade||April 5, 2016|
|Erelzi (etanercept-szzs)||Sandoz||Enbrel||August 30, 2016|
|Amjevita (adalimumab-atto)||Amgen||Humira||September 23, 2016|
|Renflexis (infliximab-abda)||Samsung Bioepis||Remicade||April 21, 2017|
Although the U.S. was first to approve a biosimilar of AbbVie’s Humira (adalimumab), with the EMA’s March 2017 approval of Amgen’s Amgevita (Amjevita in the U.S.), every reference product with an approved biosimilar in the U.S. also has an approved biosimilar in Europe. If EMA approves Sandoz’s application for its biosimilar of Amgen’s Enbrel, as expected from the favorable CHMP recommendation, each of the biosimilars approved in the U.S. will also be approved for marketing in Europe.
Pending Biosimilar Applications in the U.S.
Many of the biosimilar applications that are currently pending before the EMA are also under review by FDA. Just as in Europe, Coherus and Mylan/Biocon have pending applications for a biosimilar of Amgen’s Neulasta (pegfilgrastim). No biosimilars of pegfilgrastim have been approved in the U.S. or Europe. Apotex was the first to file a proposed biosimilar application for pegfilgrastim. It did so in 2014 but Apotex experienced hurdles with its proposed biosimilar. With applications now pending before FDA from two competitors, in a recent citizen petition Apotex has asked FDA to require biosimilar applicants that are trying to obtain approval of a pegfilgastim biosimilar to conduct appropriate clinical studies for this complex biologic. Apotex also noted that Coherus apparently has not conducted the necessary studies. Although the status of Apotex’s own proposed pegfilgrastim biosimilar is unclear, Apotex still hopes to be the first pegfilgastim biosimilar on the U.S. market.
In addition to the applications for a biosimilar pegfilgrastim, a number of other applications are being reviewed by both FDA and EMA. Mylan and Biocon have an application for a biosimilar of Genentech’s Herceptin (trastuzumab) under review by FDA and EMA. Amgen and Allergan have a proposed biosimilar of Genentech’s Avastin (bevacizumab) under review by FDA and EMA. Boehringer Ingelheim has a pending application for a proposed biosimilar of AbbVie’s Humira before the FDA and EMA.
FDA appears to have completed its review of a biosimilar of Amgen’s EPO (epoetin alfa). Although biosimilars of EPO have been on the European market for many years, there is no biosimilar EPO on the U.S. market. Pfizer (Hospira) encountered difficulties in obtaining approval of an EPO biosimilar in the U.S. FDA has now scheduled a May 25, 2017 meeting of the Oncological Drugs Advisory Committee to consider Hospira’s application for its biosimilar of Amgen’s EPO. If the Advisory Committee issues a favorable recommendation, FDA will most likely approve Hospira’s application this summer.
Although the European biosimilars market continues to outpace the U.S., FDA and EMA are currently reviewing the same applications for complex biologics. Biosimilar products that would be new to both markets are under review. 2017 is likely to see an expansion of product classes of biosimilars in both markets with guidance from both sets of regulatory agencies as to what is needed to obtain approval of biosimilars in these classes.