The removal of the phase 3 trial mandate for biosimilar manufacturers opens the door for lower development costs and for new biosimilar players. At last week’s Festival of Biologics program in Basel, sessions focused on pembrolizumab biosimilar activity driven by these lower costs.
Formycon’s Pembrolizumab Case Study
On October 13, the news had just been announced that the FDA had accepted Formycon AG’s 351(k) application for FYB206, marking the first pembrolizumab biosimilar candidate to reach that milestone. That day, Andreas Seidl, PhD, Chief Scientific Officer, Formycon AG, detailed why the company avoided comparative efficacy trials on FYB206.
This case study spoke to the scientific rationale for a pharmacokinetic (PK)-focused development program. The updated guidance from the FDA, said Dr. Seidl, specified that comparative efficacy studies (CESs) should only be conducted if they will provide meaningful additional information.
In the case of the reference product Keytruda, the molecule has high affinity for the target PD-1 receptor. The biology of pembrolizumab is well characterized, and its mechanism of action is well understood. It is a humanized IgG4 monoclonal antibody, and analytical similarity can be adequately demonstrated. As a result, any CES would not provide added value. Dr. Seidl stated, “At the approved dose, saturated target engagement and a flat exposure-response relationship limit the sensitivity of the comparative efficacy endpoints. A PK-focused program is proportionate when the integrated evidence sufficiently resolves residual uncertainty.”
Formycon’s FYB206 has comparable parameters, including PK and molecular weight, to the reference product, and their glycan profiles are highly similar. This translates into comparable neonatal Fc receptor (FcRn) binding. The company negotiated with FDA that a late-stage CES study was unneeded. Their PK study comprised 96 patients with completely resected stage II/III melanoma. This study also assessed the safety and immunogenicity of FYB206, as well as an exploratory efficacy endpoint.
With Changes to the Phase 3 Trial Mandate, the Race is on for New Biosimilar Manufacturers
Bert Thomas, PhD, Senior Vice President of Business Development, Bio-Thera Solutions, emphasized that removing the late-stage CES requirement has been a priority point of discussion at the Festival of Biologics meetings for years. “Once the dam broke, pretty much everyone else followed, because the science is there.
“The hope is lower prices through lower development costs, faster development timelines, and more competition.” As a result of these efforts, he said it may be possible to start considering biosimilar competition for lower-revenue biologics. “The promised land is filling the biosimilar void,” proclaimed Dr. Thomas.
Based on the high costs of development, Bio-Thera had exited the oncology biosimilar arena. They re-entered the field with a pembrolizumab candidate (BAT3306), only because the phase 3 trial mandate was removed.
“We all go after biosimilars for the same high revenue targets. In reality, after the phase 3 clinical trial mandate was removed, there are many new players,” said Dr. Thomas. He stated there are more than 30 pembrolizumab biosimilars globally, and at least 15 dipliumumab biosimliars in various stages of development. “Most of these players don’t have an existing FDA or EMA approval—there is a learning process there. Do they know how to get a phase 3 waiver? How do they ask questions of the regulator? Do they have the capacity to support global launches? And the intellectual property challenge with originators is not getting easier or cheaper,” he pointed out.
The change to the phase 3 trial mandate has also changed the outlook of major biosimilar players: Samsung Bioepis, Celltrion, and Sandoz all announced significant pipeline expansions in the past year alone. These moves will also carry their commercialization partners (e.g., Teva, Harrow, Hikma, and Accord to name just a few) into more product areas.
This article was written by our Director of Content, Stanton Mehr. Stan has been writing commentary and reporting news about the biosimilar industry since the submission of the first biosimilar 351(k) application to the FDA 13 years ago. Since that time, BR&R has been tracking the US biosimilar marketplace, with the industry’s original, comprehensive and updated database of biosimilar filings with the FDA.
