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Background Analysis: US FDA Advisory Committee to Review Amgen’s Proposed Biosimilar to Humira – JUL 12, 2016 (AAC)

Announcement

The US FDA has scheduled an Arthritis Advisory Committee (AAC) meeting for Tuesday, July 12, 2016, to discuss biologics license application 761024, for ABP 501, a proposed biosimilar to AbbVie Inc.'s Humira (adalimumab), submitted by Amgen, Inc. (Amgen).

Indication Background

Description of Indication

Humira is a “blockbuster drug”; it routinely appears on Top 10 pharmaceutical sales lists. Amgen is seeking approval for all but one of the indications included in the label of the reference product, Humira, with their proposed biosimilar, ABP 501. The only indication it does not propose is for pediatric Crohn’s disease.

The complete wording of the proposed indications is as follows:

1.     reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis (alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs));

2.      reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 4 years of age and older (alone or in combination with methotrexate);

3.     reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis (alone or in combination with non-biologic DMARDs);

4.     reducing signs and symptoms in adult patients with active ankylosing spondylitis;

5.     reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy (ABP 501 would be indicated for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab);

6.      inducing and sustaining clinical remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine or 6- mercaptopurine (6-MP) (the effectiveness of ABP 501 would not be established in patients who have lost response to or were intolerant to TNF blockers); and

7.     treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate (only to be administered to patients who will be closely monitored and have regular follow-up visits with a physician).

Product Background

Description of Product

Adalimumab is a recombinant human IgG1 specific for tumor necrosis factor (TNF). It acts by interfering with TNF by acting as a TNF inhibitor. TNF is a key inflammatory cytokine involved in the pathogenesis of a variety of inflammatory diseases. ABP 501 is a proposed biosimilar to adalimumab. It is administered as a solution for subcutaneous injection in a pre-filled syringe. In a pivotal clinical trial in patients with moderate to severe plaque psoriasis, the drug was administered at a dose of 80 mg for the first week and 40 mg at week two and every 2 weeks thereafter, until week 52. In another pivotal clinical trial in a different patient population, namely patients with moderate to severe rheumatoid arthritis, the drug was administered at a dose of 40 mg every 2 weeks for 22 weeks.

Note that Amgen and AbbVie have been involved in ongoing litigation in regard to Humira’s patent protection.

Clinical Trials

Amgen believes that the analytical, pharmacokinetic, and clinical data (consisting of two confirmatory safety and efficacy studies, one in patients with moderate to severe plaque psoriasis and another in patients with moderate to severe rheumatoid arthritis) provide confirmation of similarity to the reference product.

The Phase 3 trial in patients with moderate to severe plaque psoriasis (ClinicalTrials.gov ID: NCT01970488) was a randomized, double-blind, multicenter study to demonstrate equivalent efficacy and to compare safety and immunogenicity of ABP 501 and Humira. The primary endpoint was the Psoriasis Area and Severity Index (PASI) 75 response rate (the proportion of patients showing at least a 75% improvement in PASI) after the first 16 weeks of treatment). Amgen has reported that the primary endpoint was met, and safety and immunogenicity between the biosimilar candidate and Humira were comparable.

The Phase 3 trial in patients with moderate to severe rheumatoid arthritis (ClinicalTrials.gov ID: NCT01970475) was a randomized, double-blind, multicenter study to demonstrate equivalent efficacy and to compare safety and immunogenicity of ABP 501 and Humira. The primary endpoint was the American College of Rheumatology (ACR) 20 response rate (the proportion of patients showing at least a 20% improvement in ACR core set measurements) after the first 24 weeks of treatment). Amgen has reported that the primary endpoint was met, and safety and immunogenicity between the biosimilar candidate and Humira were comparable.

Amgen says it also has provided data to support the transition of Humira patients to ABP 501.

Regulatory Background

U.S. Regulatory Background

BsUFA date – September 25, 2016

February 2, 2016 – Amgen announced that FDA had accepted its BLA under the 351(k) pathway.

November 25, 2015 – Amgen submitted the BLA under the 351(k) pathway.

Ex-U.S. Regulatory Background

December 4, 2015 –Amgen announced it submitted a Marketing Authorization Application (MAA) for a biosimilar to Humira to the EMA.

Extrapolation

Extrapolation in the US

Only since 2010 has the pharmaceutical industry had an abbreviated approval pathway for interchangeable or highly similar biologics in the US, called the 351(k) pathway, in reference to the Public Health Service Act 42. U.S.C. 262, Section 351(k). The US is behind other countries globally in the regulation of biosimilars.

The ABP 501 BLA was submitted via this abbreviated 351(k) pathway. Amgen is proposing in this BLA that the data collected for the plaque psoriasis and rheumatoid arthritis may be used to support approval for other indications. This is called extrapolation. With regard to extrapolation, the FDA says that if a proposed product meets the statutory requirements for licensure as a biosimilar product under section 351(k), among other things, data derived from a clinical study sufficient to demonstrate safety, purity, and potency in an appropriate condition of use, the potential exists for the biosimilar product to be licensed for one or more additional conditions of use for which the reference product is licensed. However, the FDA says the applicant would need to provide sufficient scientific justification for extrapolating clinical data to support a determination of biosimilarity for each condition of use for which licensure is sought.

Such scientific justification for extrapolation should address, for example, the following issues for the tested and extrapolated conditions of use:

 the mechanism(s) of action in each condition of use for which licensure is sought; this may include:

 the target/receptor(s) for each relevant activity/function of the product;

 the binding, dose/concentration response and pattern of molecular signaling upon engagement of target/receptors;

 the relationships between product structure and target/receptor interactions;

 the location and expression of the target/receptor(s);

 the PK and bio-distribution of the product in different patient populations (relevant PD measures also may provide important information on the mechanism of action);

 differences in expected toxicities in each condition of use and patient population (including whether expected toxicities are related to the pharmacological activity of the product or to “off-target” activities); and

 any other factor that may affect the safety or efficacy of the product in each condition of use and patient population for which licensure is sought.

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: Amgen, Inc. Drug Name: ABP 501, adalimumab Drug Class: recombinant TNF inhibitor Indication: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, Crohn’s disease Other: biosimilar


DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.