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Biosimilars Shake Off Doubters, Go on a Roll

Seven biosimilars have crossed the FDA-approval finish line. An abbreviated approval pathway has helped, but some believe the FDA should place more emphasis on relevant phase 3 trials.

Thomas Reinke
Contributing Editor

It seems the FDA’s approval of biosimilars is almost becoming routine. In August it approved Cyltezo (adalimumab-adbm) as a biosimilar to Humira (adalimumab). Then in September it approved Mvasi (bevacizumab-­awwb) from Amgen and Allergan as a biosimilar to one of the top cancer drugs, Avastin (bevaci­zumab). Avastin is one of the top-selling drugs for Roche with worldwide sales in 2016 of almost $7 billion.

Mvasi is approved for Avastin’s indications for colorectal, non–small-cell lung, kidney, cervical, and brain cancer. The newcomer stands out among biosimilars because it is the first oncologic biosimilar in the United States. Amgen has also filed for approval in Europe. Although there are many more biosimilars on the market in Europe, Mvasi would be the first oncologic biosimilar there as well.

Biosimilar friendly

In a little over two years, the U.S. landscape for biosimilar approvals has changed dramatically. Originally, the biosimilar approval pathway was characterized by high anxiety among biosimilar sponsors who were nervous about the criteria and standards the FDA would apply. Health professionals also had trepidations: Would biosimilars be truly comparable to the brand-name biologic? The FDA only requires biosimilars to be “highly similar” and not identical in the way that generic versions of small-molecule drugs must be with their brand-name counterparts.

FDA-approved biosimilars
Approval date Biosimilar Original product
March 6, 2015 Zarxio
(filgrastim-sndz)
Neupogen
(filgrastim)
April 5, 2016 Inflectra
(infliximab-dyyb)
Remicade
(infliximab)
Aug. 30, 2016 Erelzi
(etanercept-szzs)
Enbrel
(etanercept)
Sept. 23, 2016 Amjevita
(adalimumab-atto)
Humira
(adalimumab)
April 21, 2017 Renflexis
(infliximab-abda)
Remicade
(infliximab)
Aug. 25, 2017 Cyltezo
(adalimumab-adbm)
Humira
(adalimumab)
Sept. 14, 2017 Mvasi
(bevacizumab-awwb)
Avastin
(bevacizumab)

The FDA’s approval of Mvasi was based on a recommendation of the agency’s Oncologic Drug Advisory Committee (ODAC), which voted 17–0 to recommend approval. That committee has a diverse membership, including some people representing patients.

The resounding endorsement is another indication that the biosimilar development and approval process is becoming, if not exactly routine, fairly normal. Concerns about products that are only almost identical to the original biologic may be fading, although the approved biosimilars still face a briar patch of patent litigation that complicates their sales and marketing.

On the same day the ODAC recommended a go-ahead for Mvasi, it also unanimously recommended approval of a second anti­cancer biosimilar, MYL-14010, for Herceptin (trastuzumab). MYL-14010 is a product of Mylan in partnership with Biocon, an Indian generic drugmaker. Herceptin treats breast cancer and has sales that exceed $6 billion worldwide. Like Avastin, Herceptin belongs to Roche, so the company is facing a real challenge to its future revenues. Meanwhile, Mylan is supping on success. Early last month, it won approval to make a generic version of Copaxone, the best-selling drug for multiple sclerosis.

Shorter pathway

Robert Rifkin, MD

FDA approvals are based on the totality of evidence, analytic similarity, and clinical performance, says Robert Rifkin, MD, of US Oncology. Much less emphasis is placed on phase 3 trials.

Biosimilar developers appear to have mastered the abbreviated pathway intended to facilitate the development of biosimilars. The FDA has largely held to the abbreviated pathway it laid out originally. The big change is that the rest of the world is starting to understand it. Approvals are based upon “the totality of evidence,” “analytic similarity,” and clinical performance with much less emphasis placed on phase 3 trials, says Robert Rifkin, MD, US Oncology’s expert on biosimilars.

The objective of Mvasi’s phase 3 clinical trial was to follow the FDA’s guidance and show there is no meaningful clinical difference between it and Avastin. The trial was not intended to meet the goal of phase 3 trials of new drugs, which is to establish the safety and efficacy of the product. The primary endpoint in Mvasi’s phase 3 trial was simply to show equivalence between it and Avastin on overall response rate.

While a routine approval process can streamline approvals, it also can have a downside— complacency. Biosimilars and the FDA approval process are still very new; only seven products have crossed the finish line in the United States. Any new process needs to be fine-tuned and further developed. The approval of Mvasi and the recommended approval of MYL-14010 highlight a concern that may warrant further attention by the FDA. Rifkin points out that Avastin is most commonly used to treat colorectal cancer, yet Mvasi’s phase 3 trial was in non–small cell lung cancer. That may cause oncologists to have some reluctance about using Mvasi to treat colorectal cancer.

Rifkin added that Mvasi’s phase 3 trial was a comparison with Avastin in which both were used in combination with carboplatin and paclitaxel. Rifkin says that combination regimen is now being replaced by others.

The possibility that the FDA needs to devote more attention to phase 3 trials was actually raised in the review of MYL-14010. The summary minutes for the review meeting include a recommendation from a panelist that careful consideration needs to be given to trial design and endpoint selection. A second comment highlighted that Herceptin is often given in conjunction with Perjeta (pertuzumab), and that the MYL-14010 phase 3 trial used taxane chemotherapy as the combination agent.

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