Emerging biosimilars market presents opportunities and challenges

A flurry of approvals

The first biosimilar approvals in oncology in the United States came in the supportive care niche (Table 1). Filgrastim-sndz (Zarxio), approved in March 2015, is a biosimilar of the granulocyte-macrophage colony stimulating factor (G-CSF) analog filgrastim (Neupogen). Owing to its mechanism of action in stimulating the production of neutrophils in the bone marrow, filgrastim is used to help reduce the risk or severity of neutropenia in patients undergoing myelosuppressive chemotherapy regimens.

Filgrastim-sndz was approved for use across all 5 indications for which the reference product is approved, based on the totality of evidence, which included results from the key phase 3 PIONEER study.⁹ Market entry was initially delayed by lawsuits filed by Amgen, the maker of the reference product, but the biosimilar was subsequently cleared by the US Court of Appeals for the Federal Circuit. The wholesale acquisition cost (WAC) for a 300µg syringe is $324.30 for filgrastim and $275.66 figrastim-sndz, representing a 15% reduction on the reference product.¹⁰

In 2018, the FDA approved a second filgrastim biosimilar, filgrastim-aafi (Nivestym),¹¹ in addition to 2 biosimilars of the pegylated form of filgrastim, pegfilgrastim-jmdb (Fulphila)¹² and pegfilgrastim-cbqv (Udenyca)¹³ – these forms of filgrastim have been modified by the addition of polyethylene glycol polymer chains that help to increase circulation time.

Approval for the 2 pegfilgrastm biosimilars was originally delayed by complete response letters (CRLs) from the FDA. For pegfilgrastim-jmdb, the CRL was reported to be related to a pending update of the Biologic’s License Application (BLA) to include information regarding facility requalification activities that had been taken after the addition of plant modifications. The CRL for pegfilgrastim-cbqv requested that the company provide additional manufacturing information and reanalyze a subset of samples with a revised immunogenicity assay.

Once the CRL concerns were addressed, regulatory approval was awarded and Mylan recently confirmed that pegfilgrastim-jmdb has been launched in the US marketplace at a WAC that reflects a 33% discount over the reference product.¹⁴

Approval data for filgrastim-aafi and pegfilgrastim-cbqv have not yet been published, however the respective manufacturers reported that approval was based on totality of evidence demonstrating a high degree of similarity to the reference products. Filgrastim-aafi was approved for all of the indications of the reference product and launched in the US on October 1, 2018 at a 30% discounted WAC.¹⁵

Epoetin alfa-epbx (Retacrit), a biosimilar of epoetin alfa, was also approved in 2018. It is a recombinant analog of erythropoietin (EPO), which stimulates the production of blood cells and has proved useful for the treatment of anemia, including in cancer patients receiving myelosuppressive chemotherapy. Approval of the biosimilar followed earlier receipt of a CRL from the FDA citing concerns relating to the manufacturing facility, which the company addressed. Pfizer has said that it expects to launch the biosimilar this year (2018), but a WAC has not been disclosed.¹⁶The FDA also recently approved the first biosimilars for the treatment of cancer. Trastuzumab-dkst (Ogivri) and bevacizumab-awwb (Mvasi) were approved in the second half of 2017 for the same indications as their respective reference products, which are mAbs directed at the human epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor, respectively.^17,18

Approval data for bevacizumab-awwb included a comparative clinical trial in patients with advanced/metastatic non–small-cell lung cancer (NSCLC), which was considered the most sensitive patient population. The BLA for trastuzumab-dkst included data from the phase 3 comparative HERiTAge clinical trial, in which the biosimilar was compared with the reference product, both in combination with docetaxel or paclitaxel, in patients with previously untreated HER2-positive metastatic breast cancer. Neither biosimilar has been launched on the US market yet because the patents for their reference products do not expire until 2019, so it is not clear what the price discount will be for these drugs (Table 2).^9,19-22