On July 20, the US Food and Drug Administration (FDA) approved the second biosimilar version of filgrastim. Pfizer’s filgrastim biosimilar is named Nivestym™ (filgrastim-aafi).
The originator product, Amgen’s Neupogen®, has steep competition from two other products (Sandoz’s Zarxio® [filgrastim-sndz] and Teva’s Granix® (tbo-filgrastim]). Granix was approved as a follow-on biologic, before the biosimilar pathway was implemented.
The FDA granted Nivestym the following indications:
To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever.
For reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML).
To reduce the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation (BMT).
For the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.
For chronic administration to reduce the incidence and duration of sequelae of severe neutropenia (e.g., fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.
Although a launch date was not announced for Pfizer’s filgrastim biosimilar, the company’s press release stated that “Nivestym is expected to be available in the US at a significant discount to the current wholesale acquisition cost (WAC) of Neupogen.”
Rather than competing aggressively for the filgrastim market, Amgen seems to be focusing its efforts on its pegfilgrastim brand, a longer-lasting version. Specifically, it is seeking to move its utilization to the Onpro formulation of Neulasta®. The first biosimilar to pegfilgrastim was approved in June (Mylan and Biocon’s Fulphila™).
In Europe, several manufacturers are marketing approved biosimilars to the same originator product. In fact, 7 manufacturers compete for the biosimilar filgrastim market, 5 biosimilar versions of epoetin are sold, and 3 biosimilars of infliximab seek marketshare from Remicade®. In the US, this situation is not a reality yet. It will be one day, however, and it raises a couple of important questions.
We know that the biosimilars are not exactly the same structurally as the originator products, but how similar may they be to each other? In other words, at some point, payers will prefer one biosimilar version of filgrastim over another one, as some do currently with Zarxio® versus Neupogen®. We can assume that with 3 filgrastim biosimilars sold in the US, payers will seek to leverage 1 against the others and make it their preferred or only available form of filgrastim available. However, is another manufacturer’s version of filgrastim biosimilar to Zarxio? We can also assume that the new manufacturer’s product has received US Food and Drug Administration approval through testing for comparability only with the originator product—not against Zarxio. How about compared with Teva’s product tbo-filgrastim (a follow-on biologic, not a biosimilar according to the regulatory and statutory rules)?
What does this mean for switching products, much less interchangeability? Is one biosimilar interchangeable with another? Based on what we know about the FDA, the answer is likely no, as the agency seems to be having difficulty devising interchangeability guidelines for a biosimilar and its originator product.
Why is this important? Consider the patient with Crohn’s disease in 2019 who changes health plans. The patient was receiving biosimilar A, and the new plan covers only biosimilar B. Maybe he or she needs to enroll in a new plan in 2020, and the reverse is true. Regardless of whether we like it, that patient may be unintentionally providing real-world evidence of interchangeability.
For conventional drug manufacturers, standard lifecycle management considerations include extending patent life through development of new dosage forms, formulations of extended- or sustained-release versions, or even the “next-generation” molecule (e.g., Prilosec® vs. Nexium®).
For manufacturers of biologics, the tools at their disposal for extending patent life are a bit more limited. A change in dosage forms is likely, as are extended-release versions. They can still attempt to develop next-generation versions that are more effective or safer than the parent molecule, which would offer at least some protection against biosimilar competition. These offspring are considered “biobetters.” Unlike the term, this concept is not really new. In the past, agents like colony-stimulating factors have been “pegylated” to produce enhanced effects.
Let’s consider one example. Roche’s (Genentech’s) product obinutuzumab (Gazya®) was approved by the FDA. This agent is a CD20-receptor antibody that is similar to the original CD20 product rituximab (Rituxan®). There are differences, however. The molecular structures differ slightly. Roche believes that Gazya has more antibody-dependent cell-mediated cytoxicity than Rituxan. This may translate into improved progression-free survival. Gazya has only one of Rituxan’s 7 indications (chronic lymphocytic leukemia), so it will not be a strict replacement for Rituxan. Rituxan may be facing biosimilar competition by 2018, and it will indeed be interesting to see how payers will utilize another version of rituximab. This may also be dependent on the extrapolation of indications for the original product.
Roche made the decision to seek approval for Gazya through the supplemental biologics license application (BLA) pathway, and it will be able to take advantage of full exclusivity periods, and possibly premium pricing (at least until biosimilars arrive). That may well justify the cost of conducting the full clinical trial program required for BLA approval.
Others took the “follow-on biologic” route—in this case, the molecule is not considered substantially different. Teva filed for approval of Granix® (tbo-filgrastim) as a BLA, because at that time, the 351(k) pathway did not yet exist. As a result of its approval, Teva received the full market exclusivity benefits of an originator biologic even though it is truly a biosimilar version of filgrastim. Entering a competitive marketplace, Granix has eroded Neupogen®’s marketshare, but it is subject to biosimilar competition to Zarxio®, in addition to whatever future filgrastim agents are approved. That might make a follow-on biologic little more than a “me-too,” with limited lifecycle prospects.