Biosimilar to Enbrel Unanimously Recommended by FDA Panel

Troy Brown, RN

July 14, 2016

The US Food and Drug Administration's (FDA's) Arthritis Advisory Committee voted unanimously (20 yes, 0 no, 0 abstain) to recommend licensure for GP2015 (Sandoz, Inc), a biosimilar product to Enbrel (etanercept; Amgen, Inc). GP2015 is proposed as a treatment for rheumatoid arthritis, polyarticular juvenile idiopathic arthritis in patients aged 2 years and older, psoriatic arthritis, ankylosing spondylitis, and adults with plaque psoriasis.

GP2015 is a tumor necrosis factor alpha (TNFα) inhibitor that is administered subcutaneously. It is available as an injectable solution in a prefilled syringe or autoinjector with strengths, dosage forms, and administration routes (25 mg/0.5 mL or 50 mg/1.0 mL) previously approved for US-licensed etanercept for the treatment of the same indications.

TNFα inhibitors are effective for these disorders, but many patients are unable to benefit from them because of their high cost. Biosimilar drugs make TNFα inhibitors accessible to more patients because they are less expensive.

"I thought it was a very well-presented, clearly presented case, both by the sponsor and the FDA, and I hope the marketplace will validate the hope of the sponsor that this will increase access and decrease price," said temporary voting committee member Richard Siegel, MD, PhD, senior investigator and chief, Autoimmunity Branch, and clinical director, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland.

The committee's vote follows their recommendation of approval for another biosimilar (Amgen's version of AbbVie's TNF inhibitor Humira [adalimumab]) the day before. Both biosimilar products may take years to reach the market, however, because the makers of the original drugs are trying to block marketing of the biosimilar versions, according to multiple media sources. Amgen has filed a lawsuit against Sandoz, claiming the company is wrongly profiting from its research on etanercept. AbbVie claims its patents protect adalimumab from competition from biosimilar products until 2022.

"Paradigm Shift"

Mark McCamish, MD, PhD, global head of development, Sandoz Biopharmaceuticals, attempted to clarify issues of concern voiced at the previous day's meeting regarding the data required for evaluation of biosimilars vs reference products. He said that consideration of research conducted during a biosimilar development program differs from that of research conducted during the development of the reference, or stand-alone, product. Both types of development programs include similar types of data, but necessarily have different emphases and goals.

Stand-alone development programs emphasize clinical data, he said, whereas because that has already been done for the reference product, biosimilar development programs focus on analytical data and on demonstrating that the biosimilar meets the requirements set by the FDA. Specifically, the FDA writes in its brief, a biosimilar must be "highly similar to the reference product notwithstanding minor differences in clinically inactive components," and "there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product."

Dr McCamish said the European Medicines Agency uses a slightly different definition of biosimilar product, calling it a product that is "essentially the same" as the reference drug.

"The development of a biosimilar, as you have learned, requires a paradigm shift. This paradigm shift will need to happen in the community of all clinicians as well," Dr McCamish said.

"Sandoz did an excellent job of educating us about how to think about these issues.... I do think that we need to be very careful, going forward, in how we look at these drugs and also how we assess how they do in the market after the approval process," said voting committee member Beth L. Jonas, MD, director, Rheumatology Fellowship Training Program, University of North Carolina School of Medicine, Chapel Hill.

Pharmacokinetic, Clinical Research

The committee voted after reviewing data from three single-dose pharmacokinetic (PK) studies and one comparative clinical study.

PK studies 101, 102, and 104 and cross-study comparison report 105 compared GP2015, US-licensed etanercept, and European Union (EU)-approved etanercept in a total of 216 healthy volunteers. The studies were designed to support the PK similarity of GP2015 and US-licensed etanercept and to demonstrate that PK comparative data generated using EU-approved etanercept could be used to demonstrate the biosimilarity of GP2015 to US-licensed etanercept.

"[T]he three products met the pre-specified criteria for analytical similarity," the FDA writes in its brief. "Further, an adequate analytical bridge between EU-approved etanercept, US-licensed etanercept, and GP2015 was established as part of the scientific bridge to justify the relevance of the comparative data generated using EU-approved etanercept to support a demonstration of the biosimilarity of GP2015 to US-licensed Etanercept."

Study 302 was a 52-week, randomized, double-blind, multicenter study conducted outside the United States. The study included 531 patients with moderate to severe chronic plaque psoriasis, who were randomly assigned in a 1:1 ratio to receive 50 mg GP2015 or EU-approved etanercept subcutaneously twice weekly for 12 weeks (treatment period 1), followed by 50 mg weekly thereafter. Those who completed the week 12 visit and achieved an improvement in the Psoriasis Area Severity Index (PASI) of 50% or higher were rerandomized to either continue on their initial treatment or undergo predefined switches between the two products at 6-week intervals during week 12 to week 30 (treatment period 2). Patients continued with the last assigned treatment from week 30 to week 52. The researchers assessed safety and immunogenicity in patients who completed treatment period 2.

The study's primary outcome was PASI 75 at week 12, defined as a reduction in the PASI score of at least 75% from baseline. At week 12, 73.4% (n = 239) of patients in the GP2015 group and 75.7% (n = 241) of patients in the etanercept group met the primary outcome (difference, −2.3%; 95% confidence interval, −9.85% to 5.3%).

In the GP2015 group, 35 (13.3%) patients experienced one or more treatment-related treatment-emergent adverse event (TEAE) compared with 37 (13.9%) patients in the etanercept group. In the GP2015 group, no patients experienced one or more treatment-related serious adverse events compared with one (0.4%) patient in the etanercept group.

The most common TEAE was nasopharyngitis, which occurred in 17 (6.4%) patients in the GP2015 group and 13 (4.9%) patients in the etanercept group. Other TEAEs, which occurred in less than 3% of patients, were upper respiratory tract infection, increased alanine aminotransferase, headache, viral respiratory tract infection, back pain, pharyngitis, viral upper respiratory tract infection, weight gain, hypertension, and arthralgia.

Predose PK samples were collected for determination of trough serum concentrations from 147 patients at day 1 and weeks 2, 4, 8, and 12 during treatment period 1. Mean trough serum concentrations were comparable at each point between the biosimilar and EU-approved etanercept at steady state, and steady state was reached from week 2 for both drugs.

"In considering the totality of the evidence, the data submitted by Sandoz show that GP2015 is highly similar to US-licensed etanercept, notwithstanding minor differences in clinically inactive components, and that there are no clinically meaningful differences between GP2015 and US-licensed etanercept in terms of the safety, purity, and potency of the product to support the demonstration that GP2015 is biosimilar to the US-licensed etanercept in the studied indication of [plaque psoriasis]," the FDA writes in its brief.

Patients Concerned About Nonmedical Switching, Interchangeability

During the open public hearing, 14 people talked about the importance of TNF inhibitors, and several expressed concern that they might be switched to a biosimilar for nonmedical reasons. More than one speaker talked about the potential for an adverse response to even the smallest change in their medications.

"I thought that it was convincingly shown that GP2015 is a biosimilar for etanercept. I think that the label, going along with the 'interchangeable' issue...should clearly state that this is a biosimilar, not an interchangeable drug," said voting committee member Andreas M. Reimold, MD, chief of rheumatology, Dallas VA Medical Center, Rheumatology Section, Medical Service, Texas.

One speaker said that FDA advisory committees should vote on each indication separately. The committee widely agreed on the need for postmarketing data, particularly in patients with conditions in which those data had been extrapolated from other conditions.

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