Lower Costs for Biosimilar Development Will Yield Myriad Benefits: Part 2

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.

Who Are the Key Lucentis Biosimilar Players to Watch?

Note: This is an update to a January 2020 post to include Lupin’s investigational agent in phase 3 trials.

Roche’s reference product Lucentis^® (ranibizumab) seems to be the next likely target for biosimilar competition. Sales of the drug in the US were last reported to be $1.5 billion in 2017, but Roche’s revenues from Lucentis are expected to slip, owing to competition from Eylea^® (aflibercept) primarily and some newer agents. And new Lucentis biosimilars will hasten that decline.

Ranibizumab is approved for use for several ophthalmologic indications, including wet age-related macular degeneration, diabetic retinopathy and diabetic macular edema, myopic choroidal neovascularization, and macular edema following retinal vein occlusion.

According to reporting by the UK-based Generics and Biosimilar Initiative (GaBI), the patents on Lucentis expired in the US in June 2020 and will expire in Europe in 2022. GaBI had found some 10 organizations or partnerships working on investigational ranibizumab biosimilars, but little updated information (some were reported as early as 2015).

Today, our research into the Lucentis biosimilar space revealed just a couple of active players, but with rapidly advancing plans. Here are the three initiatives reported publicly:

1. Coherus-Bioeq

This one is a little complex—stick with it, as it could be the first to obtain FDA approval, as early as later this year.

Formycon AG, a German manufacturer, gave Bioeq IP AG exclusive global commercialization rights to FYB201, Formycon’s ranibizumab biosimilar. In November 2019, with Formycon’s assent, Bioeq signed an agreement with Coherus Biosciences to commercialize the biosimilar in the US.

At the recent JP Morgan investor conference, Coherus President Denny Lanfear disclosed that Bioeq filed for FDA approval in December 2019. Coherus is expecting FDA acceptance of the application shortly, and a fourth quarter 2020 decision. This could set up a product launch, according to Coherus, in 2021.

Interestingly, Coherus originally had a different biosimilar ranibizumab in its own pipeline. This agent, CHS-3351, fell by the wayside a couple of years ago. The deal with Bioeq seems to have created a new ranibizumab opportunity for Coherus.

2. Xbrane-Stada Arzneimittel

Sweden-based Xbrane signed an agreement with the German generics manufacturer Stada Arzneimittel to co-develop Xbrane’s Lucentis biosimilar. This agent, currently dubbed Xlucane™, is being tested in a phase 3 trial involving 580 patients with age-related macular degeneration, which is slated for completion in February 2021 (interim results available in May 2020).

3. Biogen-Samsung Bioepis

Samsung Bioepis completed its phase 3 trial of SB11 in December 2019 (primary completion date of May 2019). This trial comprised 705 patients with neovascular age-related macular degeneration. SB11 seems poised to be submitted for approval via the 351(k) biosimilar pathway, and Samsung’s deal with Biogen (already a part owner of the joint venture with Samsung Biologics) for commercialization. Therefore, Biogen will take the marketing reins once an FDA decision has been given. If Samsung submits its filing in Q2 2020, a launch could be possible in Q2 2021, assuming a positive decision.

4. Lupin

In September 2020, the India-based manufacturer Lupin began a phase 3 trial of its investigational ranibizumab biosimilar LUBT010. This trial will include 600 participants in total, who will receive either LUBT010 or Lucentis for 12 months. The study is scheduled for completion in October 2022. However, it is not confirmed that Lupin will seek to market this agent in the US. The study population is unclear, as only one eye clinic located in India is listed as recruiting patients, in an ClinicalTrials.gov update posted December 30, 2020. Assuming the patient population represents multiple countries, it may be possible for Lupin to submit an FDA application as early as Q1 2023, with a potential launch of Q1 2024.

Are There Any Other Active Players Out There?

The development of PF582 by Pfenex has been on hold since 2018, after the company was handed back the full rights to the agent by former partner Hospira. Pfenex no longer lists this product (or any other biosimilar for that matter) on its pipeline. The drug had progressed through phase 1/2 studies, but has not advanced.

None of the other significant players in the biosimilar industry (including Pfizer, Sandoz, Mylan, Amgen, Celltrion, or Biocon) have publicly announced a ranibizumab biosimilar program at present.

A Profile on Lesser-Known Player in the Biosimilar Space: Formycon AG

On occasion, we profile some biosimilar manufacturers about whom our readers may not be as familiar as the large players like Sandoz, Amgen, and Pfizer. This generally refers to companies that have products that are in earlier-stage research or those who simply have not been in the news as often as their colleagues. In this updated post, we highlight a German company, Formycon AG, which has eyes on the US marketplace.

Formycon acquired Scil Technology GmbH in 2012, and hired a new CEO the following year. Carsten Brockmeyer, PhD, has extensive experience in the biosimilar field, previously helping Hexal Biotech to develop EPO and filgrastim biosimilars for the European market.

Why you may be hearing more about this company: Formycon has two principal biosimilar targets, ranibizumab and ustekinumab. The company disclosed that “it successfully completed a Type IV pre-submission meeting with the US Food and Drug Administration (FDA) in December 2018 and clarified other pivotal issues. The filing with the FDA for the approval of FYB201 is expected at the beginning of the fourth quarter of this year.” A filing for the European Medicines Agency is planned for 2020. A phase 3 clinical trial of this agent was completed in June 2018. In the development of this agent, Formycon partnered with Bioeq GmbH, but it is unclear whether a marketing partner exists for a possible US launch.

The patent for ustekinumab (Stelara^®) expires in 2023 (US) and 2024 (Europe). It is partnered with Aristo Pharma GmbH on the manufacture and testing of this interleukin 12/23 inhibitor (also known as FYB 202).

Formycon is in the early stages of developing a phase 3 trial for its biosimilar version of Eylea^® (aflibercept or FYB 203), the next generation of macular degeneration treatment. It is partnered with Santo Holding GmbH on the development of aflibercept.

In other biosimilar news… Amgen decided to pull its EMA application for its infliximab biosimilar, likely due to market competition. The company has not taken similar action with regard to an FDA application for the same product, ABP 710. Considering that neither Samsung Bioepis or Pfizer failed to gain traction in the US marketplace for infliximab, Amgen must think that some biosimilar infliximab marketshare growth in the US is still possible.