Biosimilars are a niche sector of the overall pharmaceutical market, but as the regulatory pathway becomes more defined in the US, innovator drug companies and biosimilar developers seek to gain a piece of the market.

Although only two biosimilars have been approved in the US and only one biosimilar commercially launched to date, the market is poised to grow. A recent analysis by Thomson Reuters points to at least 19 different innovator biologics being developed as biosimilars. So where is the potential and what regulatory and market considerations come into play? DCAT Value Chain Insights (VCI) examines the US biosimilars market.

Biosimilar market in the US
In evaluating the market potential of biosimilars, several important issues need to considered according to a recent report by Thomson Reuters, Biosimilars: US Market Opportunities and Critical Strategies 2016. To date, the US Food and Drug Administration (FDA) has approved two biosimilars: Sandoz's Zarxio, referencing Amgen's Neupogen (filgrastim), and Celltrion's Remicade, referencing Johnson & Johnson' Janssen's infliximab, which will be marketed by Pfizer as Inflectra. Inflectra is manufactured by Celltrion, based in Yeonsu-gu, Incheon, Republic of Korea, for Hospira, now part of Pfizer following Pfizer’s $17 billion acquisition of Hospira in 2015.

The FDA approved Inflectra in April 2016 and Zarxio in March 2015, and only Zarxio has made it to the market, launching in September 2015, notes the Thomas Reuters analysis. Because of the 180-day commercial marketing notice required under the Biologic Price Competition and Innovation Act (BPCIA), Inflectra may not launch until October 2016, conditioned upon Cellitron and Pfizer having Janssen's single remaining US patent invalidated. That patent (US Patent 6,284,471) is in under re-examination by the US Patent and Trademark Office, which had previously rejected all claims, points out the Thomson Reuters’ analysis. Janssen also sued Cellitron in federal court for patent infringement. The US District Court for the District of Massachusetts is set to hear the case in February 2017, but Janssen has requested that the trial be moved up to September 2016 given the pending launch of Inflectra.

With only one commercial product now on the market, the biosimilars market in the US has been slow to emerge, but as the Thomson Reuters analysis points out, the biosmilars pipeline is robust. As of September 2015, the FDA had received 22 investigational new drug applications (INDs) in its biosimilars program, and at least six of those INDs have advanced to 351 (K) applications that the FDA has accepted for review, which is the FDA's abbreviated regulatory pathway for biosimilar approval. Industry estimates project that the FDA expects to receive five new 351(K) applications each year, along with two interchangeable applications, once the interchangeability development pathway is developed. Overall, the FDA indicates that there are 60 biosimilar candidates as of April 2016 with the agency fielding requests for 19 different biologics, according to the Thomson Reuters analysis. Roughly half of the referenced biologics facing patent expirations are now top-selling biologics, led most notably by the patent expiration of AbbVie's Humira (adalimumab), one of the industry's top-selling drugs in 2015 with sales of approximately $14 billion. The FDA has accepted one 351 (K) application referencing Humira, and at least seven other companies have adalimumab biosimilar candidates in Phase III trials in the US. Table I outlines the top biosimilar targets in the US.

Key issues
A key issue forthcoming for the US biosimilars market is how the Supreme Court may rule on a provision of the BPCIA, which was enacted in March 2010 as part of the Patient Protection and Affordable Care Act. Sandoz has asked the Court to overturn a federal circuit decision from 2015 that said that a biosimilar maker cannot send the required 180-day notice of commercial marketing until after the FDA has approved the follow-on biologic. That decision forced Sandoz to delay the launch of Zarxio, the first biosimilar approved in the US, as such. In the same case, Amgen has asked the court to rule on the federal court's decision that the patent exchange in the BPCIA is optional. The Supreme Court is expected to decide in June 2016 whether to hear the case, according to the Thomson Reuters report. The patent exchange refers to a schedule whereby the biosimilar applicant and the reference product sponsor exchange information regarding the application for the biosimilar; in particular, the parties exchange information regarding patents that may be the subject of litigation regarding the proposed biosimilar product (1). This information exchange may then culminate in two rounds of litigation: an “immediate patent infringement action” on agreed-upon patents, followed by a second round when the biosimilar applicant gives notice to the reference product producer “not later than 180 days before the date of the first commercial marketing” of its proposed bio-similar. Once the reference product sponsor receives notice of commercial marketing, it may seek a preliminary injunction on any patents that it identified during its information exchanges with the applicant (1).

In putting forth a defense by innovators against biosimilar competition, the Thomson Reuters analysis points to several key strategies. One strategy is to build a comprehensive and deep patent estate to help delay the introduction of biosimilar competition. For example for Humira, AbbVie has more than 60 patents, including two product patents, 11 use patents, 26 formulation patents, nine process patents, and eight patents on delivery devices, according to Thomson Reuters' Cortellis. Although some of these patents expired in February 2016, several of the method and manufacturing patents don't expire until 2033 and at least one extends to 2034, according to the Thomson Reuters analysis.

Another strategy, also pursued by AbbVie for Humira, is to pursue new indications for a biologic. For example, AbbVie is pursuing a pediatric exclusivity provision for Humira for children with moderate-to- severe ulcerative colitis. When the FDA approved Cellitron's biosimilar to Remicade earlier this year, it did so for all indications of the referenced product, but one. The agency said it would not extrapolate Remicade's pediatric ulcerative colitis indication until the biologics' pediatric exclusivity ends in September 2018.

Lifecycle development is also another important strategy as part of a biosimilar defense. The Thomson Reuters analysis points out to Amgen's approach of the epoetin alfa franchise as a good example. Amgen licensed epoetin alfa to Johnson & Johnson, which marketed it as Procrit in the United States and Eprex in Europe while Amgen marketed the drug in the US. In 2001, Amgen launched Aranesp (darbepoetin alfa) as a next-generation version. Later on, the FDA accepted Hospira's (now part of Pfizer) biosimilar application that listed Epogen as the reference product. Amgen then raised the price of Epogen and lowered the price of Aranesp to shift sales to Aranesp. “Once biosimilars enter the market, the innovator's strongest defense will be name recognition and brand loyalty, along with ability to match the follow-on's lower price,” noted the Thomson Reuters report. “That's where payers may have the most influence as they will drive much of the education about biosimilars and push for their use in the market,” notes the report.

Interchangeability, or the automatic substitution of biosimilar for a referenced biologic, is another key issue in consideration of uptake of biosimilars. Although the European Union (EU) has lead the biosimilars market from a regulatory and commercial perspective to date, the EU path as no separate development for interchangeables and leaves biosimilar substitution up to the individual member states. As a result, biosimilars have not eroded the market share of the several referenced biologics as might have been otherwise expected. The US, facing greater pressures of higher drug prices, may become more responsive to biosimilar approval, particularly when the FDA opens up a pathway for interchangeables, according to the Thomson Reuters report.

For a follow-on to be considered interchangeable in the US, it must produce the same clinical results of the referenced product. The risk, in terms of safety and efficacy, of the interchangeable cannot be less than the referenced products. Although the FDA has indicated that switching trials (meaning clinical trials showing that the risk or efficacy was not reduced with the biosimilar) would be necessary to demonstrate interachangeability, it has not mapped out a path for it as the industry continues to wait for guidance on interchangeability from the FDA. Interchangeability would allow a pharmacist to substitute a biosimilar for the original biologic without a physician’s approval would be important to the biosimilars market.

Looking forward
As both innovators and biosimilar developers consider the market, regulatory, and scientific considerations in biosimilar development, the interest in the US market remains strong. Table II highlights key product developments in the US biosimilars pipeline.

Note: Thomson Reuters will host an upcoming webinar, “Driving Biosimilar Success: Insights from the Industry's Leading Experts,” on Wednesday, June 15, 2016 from 11 am ET (8 am PT). Scott Foraker, Vice President & General Manager, Biosimilars of Amgen Inc. and Mari Serebrov, Regulatory Editor – Thomson Reuters BioWorld will discuss the core competencies needed to succeed in today's biosimilars landscape,and best practices. Further information, including how to register, may be found here.

Reference

1. A. Potter, “Interpreting the BPCIA – Is the “Patent Dance” Mandatory?,” The Columbia Science and Technology Law Review, April 2016.