Pfizer Gets FDA’s Green Light on Its Filgrastim Biosimilar

Pfizer's Biosimilar Filgrastim
FILE PHOTO – The Pfizer logo is seen at their world headquarters in Manhattan, New York, U.S., August 1, 2016. REUTERS/Andrew Kelly/File Photo

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™).

Evidence to Support Zarxio Use Presented at AMCP

Two posters presented at the Academy of Managed Care Pharmacy bolstered the case for moving away from the use of the originator filgrastim product Neupogen®.

In a study from Magellan Rx Management, Scottsdale, AZ, the researchers grouped both Zarxio® and Granixzarxio® together as alternatives to the originator filgrastim in the granulocyte-colony-stimulating factor (G-CSF) category as supportive oncological care. They studied the effect of a step edit, requiring the use of either Zarxio or Granix first, and its effect on utilization trends and cost savings among 2.7 million covered lives.

The step edit was implemented in October 2016 and the results for the fourth quarter of 2016 were compared with utilization and cost data from the first three quarters of that year. In terms of utilization, the marketshare of Neupogen dropped from 18% in early 2016 to only 2% by the third quarter of 2017. As expected, the drop in utilization occurred just after the step edit was introduced a year ago. The combined marketshare of Granix and Zarxio jumped from 9% to 21% over that time, but the dominant player in the G-CSF space, Neulasta® (pegfilgrastim), maintained utilization, rising from 73% to 77%. Over the one-year period since the step edit was introduced, the authors calculated a cost savings of $662,278; the cost savings in the quarter after the policy change was $106,980, or approximately 8% of the total spent for the G-CSF category.

The authors noted that the cost savings were calculated using wholesale acquisition cost (WAC) not average sales price (ASP), and manufacturer discounts or rebates were not considered in the estimates.

The second poster, sponsored by Sandoz, was a retrospective claims analysis of the incidence of febrile neutropenia in patients receiving chemotherapy who were treated with Zarxio or Neupogen. This study covered 13 months of claims (from Optum) from 162 patients taking Zarxio compared with 3,297 receiving Neupogen. The groups did not differ significantly in terms of demographics, insurance, or tumor type.

The researchers found that the incidence of neutropenia (in addition to fever and/or infection) was nonsignificantly greater in those receiving the biosimilar compared with the reference product (2.3% vs. 1.7%, respectively).

Coverage Uptake: Zarxio® Covered by 94% of Employer-Sponsored Plans

An analysis released by Avalere on July 11 showed that coverage of biosimilar filgrastim is the rule, not the exception, by employer-sponsored plans.

Avalere surveyed medical or pharmacy executives from 45 health plans and insurers, representing 183 million lives, about coverage for their commercial products. They found that 94% had placed Zarxio (filgrastim-sndz) on formulary. Forty-two percent of the plans responding to this online survey indicated that Zarxio was a preferred brand. This is on par with the competitors (Granix®, Neupogen®, and Neulasta®), one of which is preferred for 45% of the plans surveyed.

In the report, titled “Policy 360: Biosimilars—US Payer Perspective,” Avalere found that coverage in these same employer-sponsored plans for Inflectra® (infliximab-dyyb) was trailing, with 42% covering the biosimilar but only 7% listing it as preferred on their 2017 formularies. Pfizer has only been available for 7 months, so these numbers are expected to rise over time.

Unsurprisingly, health plans ranked relative cost as the number 1 factor in coverage decision making for biosimilars (95%), followed by efficacy (80%), safety (73%), and existing contracts (53%).

In other news: Mylan and its partner Biocon hit a stumbling block to approval of its trastuzumab biosimilar in Europe (application filed in 2016). French inspectors cited Biocon’s manufacturing facility in Bangalore, India, for a number of violations that need to be corrected before the partners can receive authorization to market from the Europeans Medicines Agency. An inspection of the facility, conducted in March, also revealed problems that could affect the production of Mylan and Biocon’s pegfilgrastim biosimilar. The companies had filed for Food and Drug Administration approval of both products, with trastuzumab being reviewed by the Oncology Advisory Committee on July 13. It is not known whether a potential US-licensed version of the drug will be produced at the same Bangalore plant.

Taking the “Biobetter” or “Follow-on” Biologic Route

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.