On November 13, Pfizer began marketing its biosimilar version of epoetin alfa. Pfizer launches Retacrit® at a 33.5% discount to Amgen’s reference product Epogen®.
Retacrit was originally developed by Hospira, which Pfizer acquired in 2015. Retacrit was one of the first biosimilars approved in the EU. It had a long journey to reaching the market in the US, however, including rejections by the FDA for manufacturing plant problems. It was finally approved by the FDA on May 15, 2018. The Retacrit launch comes 180 days after the approval.
The wholesale acquisition cost (WAC) of this biosimilar will be $11.03 per 1,000 units/mL, which represents an even steeper discount (57%) to Epogen’s sister product, Procrit® by Johnson & Johnson.
When the Food and Drug Administration (FDA) approved the first biosimilar pegfilgrastim (Mylan’s Fulphila™), it broke precedent in more ways than one. Not only was this the first biosimilar member of the pegfilgrastim class to be approved, but its approval did not require an FDA Advisory Committee recommendation.
The FDA has been a bit fuzzy with respect to when an FDA Advisory Committee will be necessary. In the past, however, these AdComms had been required for all first biosimilar approvals to a new reference product. This was the case for filgrastim, infliximab, etanercept, trastuzumab, bevacizumab, adalimumab, and epoetin. Second biosimilars did not always require an AdComm, most recently last September with Boehringer Ingelheim’s Cyltezo®, the second adalimumab approved by FDA.
Various problems with the 4 pegfilgrastim biologic license applications and resubmissions have provided the FDA ample time to review data and mull the consequences of approval or rejection. This case could be an exception. A greater challenge may be upcoming though.
Not that a great deal was achieved with the biosimilar AdComms. In general, votes for recommended approvals have been unanimous or lopsided. A recommendation for approval does not always result in approval—sticky manufacturing issues have gotten in the way (e.g., for Pfizer’s Retacrit). The FDA Advisory Committee meetings does give the public and other stakeholders a chance to air their views. Generally, this has been not for or against the biosimilar being reviewed but for or against biosimilars as a whole.
In March, I raised the case of Adello Biologics, which is attempting to gain approval of its filgrastim biosimilar without any phase 2 or phase 3 clinical data. This may be the second filgrastim biosimilar approved, so the FDA can avoid an AdComm on this basis. More importantly though, this agent could be the first biosimilar approved without any patient-based clinical testing (phase 1 is usually conducted in healthy volunteers). The next FDA Blood Products AdComm is not scheduled until November 29, 2018, and we do not know if Adello’s product will be part of that discussion. With a submission date of September 2017, one would expect a decision from FDA in the third quarter of this year.
An unusual market situation awaits Pfizer’s new biosimilar epoetin, one that few approved medications has to face. Not only does Retacrit® need to pass muster with payers like health plans and insurers, which we assume it will, but Retacrit will need to be accepted by the two 800-pound gorillas of the kidney dialysis field as well.
Retacrit and Dialysis Centers
The different part of this discussion is that providers are not usually so concentrated except in the treatment of the rarest diseases. Cancer medications are utilized by independent treatment centers throughout the country. Biosimilar agents like infliximab are also used throughout the nation by hospitals, large medical groups, and solo practices. In the case of epoetin, its primary use is in anemia related to kidney dialysis. The vast majority (85%) of kidney dialysis centers are owned by one of two networks, Fresenius Medical Care North America and DaVita Kidney Care. According to a report by Healio, Fresenius accounted for 42.6% of the total patient market in 2017, and DaVita is just behind, with 42.0% of the 453,000 patients receiving dialysis services. In other words, get buy-in from these companies and the payers, and Pfizer would have a chance to gain significant share of the epoetin market.
Nephrologists seem to be onboard, in general. The results of national survey of nephrologists conducted in March 2018 confirm this. According to the research, only one in five respondents would be averse to switching to the biosimilar. One barrier to use may exist, however, on the provider side. The long-acting agents may be preferred by some. These include Amgen’s darbepoetin alfa (Aranesp®) and Roche’s Mircera® (methoxy polyethylene glycol-epoetin beta). To the extent that nephrologists may be less willing to use short-acting biosimilar instead of the more expensive long-acting brand may define Pfizer’s success with Retacrit. This is somewhat similar to the situation brewing with the use of injectable biosimilar pegfilgrastim (once approved and available) and the Neulasta® Onpro® delivery system. The share of use of the long-acting erythrocyte-stimulating agents has been increasing.
On May 15, 2018, Pfizer’s epoetin biosimilar Retacrit was approved by the Food and Drug Administration (FDA), the first biosimilar competitor to Epogen® and Procrit®. Retacrit is not officially available yet.
In other related biosimilar news…Pfizer announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended marketing approval for its biosimilar version of trastuzumab.
Apotex and its Apobiologix division has claimed a significant prize—the first pegfilgrastim biosimilar approval in Western markets. None have been approved in the US or EU to date. Health Canada granted marketing authorization to the company on June 1. The new drug will be called Lapelga™.
It has taken a long time, but Pfizer finally earned approval from the U.S. Food and Drug Administration (FDA) on the first biosimilar version of Epogen®. The drug, Retacrit® (epoetin alfa-epbx), had originally been submitted for approval in December 2014. Its much stalled road to approval is finally at an end.
After an initial rejection, the FDA’s Advisory Committee voted overwhelmingly (14–1) in May 2017 to give the product a green light. However, the FDA changed the traffic light to red, issued a second complete response letter in June 2017, citing issues with its manufacturing plant in McPherson, Kansas (a plant Pfizer inherited with its acquisition of Hospira).
Retacrit is approved for the treatment of anemia caused by chemotherapy or chronic kidney disease, for use in patients taking zidovudine for the treatment of HIV infection, and to reduce the need for red-cell blood transfusions before, during, or after surgery.
In other biosimilar news… Mylan’s earnings call on May 9 produced little clarity on the fate of its upcoming FDA decision on its pegfilgrastim biosimilar. Although CEO Heather Bresch believes that its product will represent one of its most important launches of the year, she could not shed any light on partner Biocon’s response to the FDA’s critical review of its manufacturing facility. The PDUFA date is June 4; a positive decision means that Mylan/Biocon will have beaten the competition to the market for this important biosimilar product.
Following a 14-1 vote by its Oncology Drug Advisory Committee last month to recommend approval for Pfizer’s biosimilar version of Epogen®, the Food and Drug Administration (FDA) on June 22 sent the drug maker a complete response letter outlining its decision to reject the product.
It is unusual for the FDA to decide against a clear majority recommendation by its Advisory Committee, but the agency pointed to potential manufacturing issues at one of Pfizer’s facilities. Pfizer stated, “This [complete response letter] relates to matters noted in a Warning Letter issued on February 14, 2017 following a routine [FDA] inspection of the company’s facility in McPherson, Kansas in 2016. This facility was listed as the potential manufacturing site in the BLA for the proposed epoetin alfa biosimilar. The issues noted in the Warning Letter do not relate specifically to the manufacture of epoetin alfa.” Although Pfizer responded to that notification by submitting a corrective and preventative action plan the following month, apparently, the FDA is not yet confident in the drug maker’s plan. According to Pfizer’s statement, the agency did not request that additional clinical data be submitted.
The FDA had cited this particular plant for several issues regarding the presence of foreign matter in medications being produced there. In its Warning Letter, the agency suggested there was “a significant loss of control in your manufacturing process” that represents a “severe risk of harm to patients.” The plant was one that Pfizer acquired in its purchase of Hospira in 2015.
This is Pfizer’s second rejection for Retacrit™, a product that was developed and brought to market in Europe by Hospira. Pfizer had resubmitted the 351(k) application in 2016.
The manufacturer stated that it is seeking to clear up any remaining issues at the plant cited by FDA. However, it is not clear whether Pfizer will have to resubmit its application entirely, as the rejection does not seem to be related to safety or efficacy issues involving the agent.
Pfizer purchased Hospira in 2015, and one of its prizes was a biosimilar version of Epogen® and Procrit® that was already being reviewed by the Food and Drug Administration (FDA). The FDA rejected that 351(k) application and issued a complete response letter. Pfizer’s Hospira unit resubmitted its application for its Retacrit™ version of epoetin alpha in 2016. They received good news this week from the agency.
According to the FDA’s staffers’ summary released ahead of the May 25th Oncology Advisory Committee review, Retacrit fulfilled the requirements for biosimilarity. Today, the Advisory Committee added further support to this conclusion by voting 14-1 to recommend approval for all extrapolated indications, despite some safety concerns expressed by committee members.
According to the staff review, “The totality of analytical data support the determination that ‘Epoetin Hospira’ is highly similar to US-licensed Epogen/Procrit notwithstanding minor differences in clinically inactive components.” Nor were any clinically meaningful differences in immunogenicity risk found. The FDA staff review documents also concluded that Retacrit’s biosimilarity evidence supports extrapolation across its intended indications.
Last month, the Food and Drug Administration removed the Risk Evaluation and Mitigation Strategy (REMS) on the originator product, indicating that it is no longer necessary to “ensure that the benefits of Epogen/Procrit and Aranesp® outweigh the risks of shortened overall survival and/or increased risk of tumor progression or recurrence, for the treatment of anemia associated with myelosuppressive chemotherapy.” The originator agent has been linked with cardiovascular safety concerns, which has affected utilization of epoetin alpha over the years.
The first epoetin biosimilars were approved for use in Europe in 2007; a tremendous amount of real-world data have accumulated on their use. However, the FDA Oncology Advisory Committee cannot consider this in their decision.
Members of the FDA Committee expressed “residual concerns with immunogenicity and safety.” For example, patients with chronic kidney disease who require hemodialysis may have a reduced response to Retacrit.
The rather unique “dual” originator products (Epogen/Procrit) resulted from a duel in the 1990s between Amgen and Johnson & Johnson. Amgen originally manufactured the product in the late 1980s and licensed it to J&J’s Ortho Biotech unit. A stormy relationship developed, with lawsuits passed back and forth. The result was a licensing agreement that the drug would be manufactured under license (sounds a bit like a biosimilar, doesn’t it?) by each company for different indications.