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Randi Hernandez was science editor at BioPharm International from September 2014 to May 2017.
On Feb. 9, 2016, an FDA Arthritis Advisory Committee will meet to discuss a biologics license application (BLA) for CT-P13 (Remsima), a proposed biosimilar to Janssen Biotech's Remicade (infliximab), by South Korea’s Celltrion in partnership with Pfizer. The BLA was submitted via the abbreviated 351(k) pathway and seeks to cover all of the eight indications that are approved for Remicade.
On Feb. 9, 2016, an FDA Arthritis Advisory Committee will meet to discuss a biologics license application (BLA) for CT-P13 (Remsima), a proposed biosimilar to Janssen Biotech's Remicade (infliximab), by South Korea’s Celltrion in partnership with Pfizer. The BLA was submitted via the abbreviated 351(k) pathway and seeks to cover all of the eight indications that are approved for Remicade. A biosimilar version of Remicade-under the names Inflectra and Remisima, depending on location-has already been approved in various regions, including parts of Europe, Canada, South Korea, Japan, and India.
Although Remsima is already available in Canada, it is only approved for some of Remicade’s indications. Health Canada gave the drug the green light for rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), and plaque psoriasis, but not for Crohn’s disease (CD) or ulcerative colitis (UC). Health Canada did not approve these indications based on the uncertainty surrounding the small differences in antibody-dependent cellular cytotoxicity (ADCC) for patients with inflammatory bowel disease (IBD). Although the European Medicines Agency (EMA) allowed for the extrapolation of all indications for CT-P13, the agency also asked Celltrion to conduct an additional trial comparing CT-P13 to Remicade for the treatment of CD. Importantly, Celltrion is also seeking approval for the pediatric forms of UC and CD, which may be a point of concern at the meeting. An FDA briefing released prior to the meeting indicates that FDA will allow for full extrapolation of all indications for Celltrion’s product, saying extrapolation is “scientifically justified.”
Remicade is a monoclonal antibody (mAb) that binds to human tumor necrosis factor alpha (TNFα). Current anti-TNF therapies on the market that serve as competitors to infliximab include adalimumab, certolizumab pegol, and golimumab. This class of medication is typically administered in a hospital or a physician’s office.
In briefing documents released in advance of the meeting, Celltrion wrote that from a structural and functional standpoint, CT-P13 was highly similar to the reference product and “residual uncertainties arising from physicochemical and structural studies had little or no impact on biological activities.” Celltrion says that no clinically meaningful differences were observed in pharmacokinetics, pharmacodynamics, efficacy, safety, or immunogenicity in AS and RA patients. More than 30 distinct orthogonal methods were used to evaluate the analytical similarity of CT-P13 to Remicade, including testing of quality attributes such as primary structure, protein content, higher-order structure, aggregates, charge, glycosylation profiles, mechanism of action exploration through multiple bioassays, and binding assays of TNF and the Fc receptors.
FcγRIII binding and glycosylation differences
The “Chemistry, Manufacturing and Controls (CMC)” section of the briefing did note some differences in product glycosylation between Celltrion's candidate and Remicade. FDA wrote, "the binding affinity of CT-P13 to the NK [natural killer] expressed FcγRIIIa and b was shifted lower compared to US-licensed Remicade . . . this was associated with subtle shifts in glycosylation at Asn297 on the heavy chain of the two antibody products detected in the analysis using a HPAEC-PAD [high performance anion-exchange chromatography with pulsed amperometric detection] chromatography method (e.g., CT-P13 on average had <39% G0F, the predominant form, while US-licensed Remicade & EU-approved Remicade had 41–46% G0F).” Although the briefing articulates that glycosylation of antibodies is typically heterogeneous, and up to 20 different detectable N-linked glycan forms can exist in an antibody preparation, "the relative levels of minor species like G0 (no terminal galactoses, but no fucose), which were different between CT-P13 (0.7%) and US-licensed Remicade (1.4%), can have an impact on binding to FcγRIII and are important to measure and control in antibody-based biopharmaceuticals."
So, why does glycosylation matter in the context of the discussion of the approval of CT-P13? FDA writes in its briefing, "ADCC activity may vary with the strength of the FcγR:Fc bridging, which in turn may be dependent on the glycan composition on the antibody." Thus, glycan composition could play a part in ADCC activity, which could influence how effectively a drug works within the body. For emphasis, FDA pointed out that TNF inhibitor Enbrel (etanercept), which has low ADCC activity, is not approved for treatment of CD or UC. Despite these differences in glycosylation and binding, FDA concluded that when CT-P13 is compared with the reference product, “the biological functions that these subtle differences might impact (ADCC) are nevertheless within the quality range of the reference product.” FDA also admitted that it is difficult to pinpoint the exact mechanism of action of TNF inhibitors in IBD, and ADCC is only one of the many mechanisms of action (MoA) that could be at play: "It is noteworthy that products without any ADCC capability have been approved for the treatment of patients with Crohn’s Disease (i.e., certolizumab)." Celltrion further justified this position: “Indeed, Cimzia (certolizumab pegol) lacks the Fc region required for ADCC and CDC activities yet is licensed in the US in RA, AS, PsA, and for reducing signs and symptoms of CD and maintaining clinical response in CD (Cimzia USPI, 2015), implying that CDC and ADCC activities do not play a critical role in the therapeutic MoA.”
As Stacie Ropka, an IP attorney from Axinn Veltrop & Harkrider who holds a PhD in microbiology and immunology told BioPharm International, glycosylation differences can affect ADCC. "If ADCC is an important mechanism regarding efficacy of the antibody and changes to the glycosylation pattern either reduce or block ADCC, there is potential for reduced efficacy. If there are changes in the glycosylation pattern that interfere with the interaction between the Fc portion of the antibody and the receptors on the natural killer cells (cell B), you might not get ADCC or the ADCC might be less robust," Ropka said. "But I emphasize, this will depend on how important ADCC is to the overall efficacy in the first place and how much ADCC is diminished (if at all) by a different glycosylation pattern."
Interchangeability on the horizon?
RAPS’ Zachary Brennan reported that at a House committee on Feb. 4, 2016 FDA’s Center for Drug Evaluation and Research (CDER) Director Janet Woodcock hinted that the agency “may approve a biosimilar as interchangeable.” However, interchangeability is not proposed nor requested in Celltrion’s BLA. The company writes in a briefing prior to the meeting, "CELLTRION is not seeking an interchangeability designation between CT-P13 and US Remicade with this BLA at this time."
Even though the company is clear that it does not seek this designation, it is still possible the company could request an interchangeability status if the product is approved by FDA. Evercore ISI’s Mark Shoenebaum told BioPharm International that Celltrion will apply for this designation, but will likely be required to conduct further clinical trials, which may take a few years. In the meantime, Celltrion may already have some preliminary data to support switching-FDA wrote in its briefing, “the single transition from EU-approved Remicade to CT-P13 during the long-term extension studies in RA and AS did not result in worse safety or immunogenicity profile. This would support the safety of a clinical scenario where non-treatment naïve patients undergo a single transition to CT-P13.”
Remicade generates $6.5 billion in annual sales for J&J-most of that revenue in the US-and analysts predict a biosimilar version would slash the price of Remicade by 25%. Overseas, Merck markets Remicade. Merck executives recently said on a fourth quarter earnings call that it expects biosimilars to continue to have a negative impact on earnings; sales of the drug fell 29% in the final quarter of 2015. Merck said, however, that is expects many new users to be attracted to biosimilars, and said that it has not yet seen significant switching in overseas markets.
Disease organization concerns linger
The Crohn's & Colitis Foundation of America weighed in about its major concerns about the safety of biosimilars in a press release. The organization insisted that all biosimilars should undergo human testing to reduce immunogenicity risk, and reasonable proof must be provided before a patient switched from the reference product to the biosimilar version, writing, “We are opposed to indiscriminant switching of therapies by pharmacies or payers.” The consortium also stressed the importance of transparency in prescribing.
Sources: FDA, RAPS, Celltrion, The Crohn's & Colitis Foundation of America