Who says that the phenomenal success of blockbuster drugs is mostly eaten away by  ‘look-alikes’ of the same, immediately after respective patent expiry? It doesn’t seem to be so any longer, not anymore! Several examples will vindicate this emerging trend. However, I shall quote just a few of these from the published reports.

In 2016, the patent of AbbVie’s Humira (Adalimumab), indicated in the treatment of autoimmune diseases and moderate to severely active rheumatoid arthritis, expired in the United States (US). It will also expire in Europe by 2018. This event was expected to create significant opportunities for lower priced Adalimumab biosimilars in the US market, increasing the product access to many more patients at affordable prices. Just as it happens with patent expiry of small molecule blockbuster drugs. One of the classic examples of which, is a sharp decline in sales turnover and profit from Pfizer’s Lipitor (Atorvastatin), as its patent expired on November 30, 2011.

However, Humira topped the prescription-drug list of 2016 with an annual growth of 15 percent, accounting for USD 16 billion sales, globally. More interestingly, according to a recent report of EvaluatePharma, AbbVie’s Humira will continue to retain its top most ranking in 2020 with expected sales of USD 13.9 billion. Nevertheless, possible threat from biosimilars has slightly slowed down its growth. Although, there are many other similar examples, I would quote just three more of these to illustrate the point, as follows:

• Rituxan (Rituximab, MabThera) indicated in the treatment of cancer and co-marketed by Biogen and Roche, went off-patent in 2015. However, in 2016, the product held 4^th position in the prescription drug market with a revenue growth of nearly 3 percent. Even five years after its patent expiry, Rituxan is still expected to occupy the 17^th rank with an estimated turnover of over USD 5 billion in 2020, according to the EvaluatePharma report.

• Remicade (Infliximab) indicated for autoimmune diseases and manufactured by J&J and Merck, lost market exclusivity in 2015. But, in 2016 it still held 5^th place in the global ranking. Five years after it goes off patent, Remicade is expected to feature in the 6^th rank in 2020, with an estimated turnover of over USD 6.5 billion, according to the same report as above.

• The US product patent for Lantus – a long-acting human insulin analog manufactured by Sanofi, expired in August 2014. However, in 2016, clocking a global turnover of USD 6.05 billion, Lantus still ranked 10 in the global prescription brand league table. Six years after its patent expiry – in 2020, Lantus will continue to feature in the rank 20, as the same EvaluatePharma report estimates.

These examples give a feel that unlike small molecule blockbuster drugs, patent expiry is still not end of the road to retain this status for most large molecule biologics, across the world. In this article, I shall discuss this point taking Humira as the case study.

What about biosimilar competition?

In any way, this does not mean that related biosimilars are not getting regulatory approval in the global markets, post-patent expiry of original biologic drugs, including the United States. Nonetheless, biosimilar makers are facing new challenges in this endeavor, some of which are highly cost intensive, creating tough hurdles to make such drugs available to more patients at an affordable price, soon enough. It happened for the very first biosimilar to Humira, as well. On September 23, 2016, almost immediately after its patent expiry in 2016, the USFDA by a Press Release announced approval for the first biosimilar to Humira (adalimumab). This was Amgen’s Amjevita (adalimumab-atto), indicated for multiple inflammatory diseases.

The second biosimilar to AbbVie’s Humira – Boehringer Ingelheim’s Cyltezo (adalimumab-adbm), was also approved by the USFDA in August 2017. So far, six biosimilars have been introduced in the United states. But, none of these got approved as an ‘interchangeable’ product. Some of these, such as Cyltezo could not even be launched, as yet. I shall discuss this point later in this article. Thus, Humira is expected to retain its top global prescription brand ranking in 2020 – over 4 years after its patent expiry.

In Europe, two marketing authorizations were reportedly granted by the European Commission (EC) in March 2017 for Amgen’s biosimilars to Humira, named Amgevita (adalimumab) and Solymbic (adalimumab). Later this year, in November 2017 Boehringer Ingelheim’s – Cyltezo also received its European marketing approval.

It is worth noting that in December 2014, the Drug Controller General of India (DCGI) reportedly granted marketing approval for Zydus Cadila’s Adalimumab biosimilar (Exemptia) for treating rheumatoid arthritis and other autoimmune disorders in India. The company claims: “This novel non-infringing process for Adalimumab Biosimilar and a novel non-infringing formulation have been researched, developed and produced by scientists at the Zydus Research Centre. The biosimilar is the first to be launched by any company in the world and is a ‘fingerprint match’ with the originator in terms of safety, purity and potency of the product.”

Several important reasons indicate why a full throttle competition is lacking in the  biosimilar market early enough – immediately after patent expiry of original biologic molecules. I shall cite just a couple of these examples to illustrate the point. One is related to aggressive brand protection, creating a labyrinth of patents having different expiry dates. And the other is a regulatory barrier in the form of drug ‘interchangeability’ condition, between the original biologic and related biosimilars:

In the labyrinth of patents:

The most recent example of innovator companies fiercely protecting their original biologic from the biosimilar competition by creating a labyrinth of patents is Boehringer Ingelheim’s Cyltezo. This is biosimilar to AbbVie’s Humira, approved by the USFDA and EC in August 2017 and November 2017, respectively.

According to reports: “BI does not intend to make the drug commercially available in Europe until the respective SPC (supplementary protection certificate) for adalimumab, which extends the duration of certain rights associated with a patent, expires in October 2018. Cyltezo is also not yet available in the US despite its approval there in August, because of ongoing patent litigation with AbbVie. AbbVie reportedly holds more than 100 patents on Humira, and believes that Boehringer could infringe 74 of these with the launch of its biosimilar. Similarly, the firm has also taken Amgen to court to block the launch of its proposed Humira biosimilar.”

Another interesting example is the epoch-making breast cancer targeted therapy Trastuzumab (Herceptin of Roche/Genentech). The patent on Herceptin reportedly expired in 2014 in Europe and will expire in the United States in 2019. The brand registered a turnover of USD 2.5 billion in 2016. However, a November 21, 2017 report says that creating a series of hurdle in the way of Pfizer’s introduction to Herceptin biosimilar, Roche has sued Pfizer for infringement of 40 patents of its blockbuster breast cancer drug. Pfizer hasn’t yet won approval for its Herceptin biosimilar, though, USFDA accepted its application in August 2017 – the report highlights

‘Interchangeability’ condition for biosimilars:

In the largest global pharma market – the United States, USFDA classifies biosimilars into two very distinct categories:

• Biosimilars that are “expected to produce the same clinical result as the reference product”
• Biosimilars that are “interchangeable,” or able to be switched with their reference product

According to reports, experts’ argument over ‘interchangeability’ in the US range from “whether pharmacists should be allowed to switch a biologic for its biosimilar without a doctor’s notification, to whether interchangeable biosimilars might be perceived as better or safer than their non-interchangeable counterparts.” This debate has somewhat been resolved by the US Food and Drug Administration’s (FDA) issuance of draft guidance in January 2017, specifying what should be submitted to support an interchangeable application, the report says.

The article also indicates, “the draft makes clear that switching studies to help gain this designation should evaluate changes in treatment that result in two or more alternating exposures (switch intervals) to the proposed interchangeable product and to the reference product. Study design, types of data and other considerations are also included in that draft.” Nonetheless, compliance with this regulatory requirement is expected to be highly cost intensive, too.

Quoting a senior USFDA official, a report dated June 26, 2017 mentioned: “interchangeable biosimilars will come to market within the next two years, though possibly sooner. And the first interchangeable biosimilar will likely be reviewed by an FDA advisory committee of outside experts.” Still the bottom line remains no biosimilar has yet been approved by the USFDA as ‘interchangeable’. Hence, the optics related to desirable success for biosimilars continue to remain somewhat apprehensive, I reckon.

Patent related litigations on Trastuzumab (Herceptin) were filed by Roche in India, as well. However, it’s good to note that on December 01, 2017, by a Press Release, USFDA announced the approval of Mylan’s biosimilar variety of Roche’s blockbuster breast cancer drug – Herceptin. Mylan’s Ogivri was co-developed with Biocon in India to treat breast or stomach cancer, and is the first biosimilar approved in the United States for these indications. It is noteworthy that Ogivri also has not been approved as an interchangeable product.

The global and local scenario for biosimilars:

Be that as it may, the July 26, 2017 study of Netscribes – a global market intelligence and content management firm estimates that the global biosimilar market will be worth USD 36 billion by 2022. Some of the major findings of this study are as follows:

• With a cumulative share of nearly 85%, North America, Europe, and Japan are the major contributors to global biological and biosimilar sales. Asia and Africa account for 13.2% and 1.2%, respectively.
• Pfizer is the leading player in the biologic market, with sales of nearly USD 45.9 billion in 2016 followed by Novartis (41.6 billion) and Roche (39.6 billion).
• Biosimilar approvals are estimated to be around of around 16 to 20 biosimilars between 2018 to 2021 in both US and EU.
• The US is not a favorable market for biosimilars due to a number of reasons, such as poor access to biologic drugs and an unfavorable regulatory environment.
• South Africa is one of the best-suited markets for biosimilars due to a favorable regulatory environment and prescriber acceptance.

According to the April 2017 analysis of Research And Markets, biosimilars have started winning key government tenders in countries like Mexico and Russia, and being purchased by a growing number of patients in self-pay markets such as India. The aggregate sales of ‘copy biologics’ in the six BRIC-MS (Brazil, Russia, India, China, Mexico, and South Korea) countries would now almost certainly exceed USD 1.5 billion. Yet Another estimate  expects the Indian biosimilar market to increase from USD 186 million in 2016 to USD 1.1 billion in 2020. It is up to individual experts to assess whether or not this growth trend for biosimilars is desirable to adequately benefit a large number of patients, the world over.

Conclusion:

In my view, if what usually happens to sales and profit for small molecule blockbuster drugs post patent expiry, would have happened to the large molecule biologic drugs, the market scenario for biosimilars would have been quite different. In that scenario, one would have witnessed a plethora of biosimilar competition against high priced and money churning biologics, such as Humira, being launched with a significantly lesser price than the original brand.

Prices of biosimilars would have been much lesser primarily because, the litigation cost, now built into the biosimilar prices for successfully coming out of the labyrinth of patents after the basic patent expiry, would have been minimal. Moreover, restrictions on drug ‘interchangeability’ would not have made the target market smaller, especially in the United states.

Alongside, compliance with the regulatory need to meet the ‘interchangeability’ condition in the US, would drive the product cost even higher. More so, when this specific regulatory requirement is not necessary in other developed markets, like Europe. Both these factors would adversely impact affordability and access to sophisticated biologic drugs for patients, even after the fixed period of market exclusivity.

That said, a virtually impregnable patent labyrinth mostly ensures that going off-patent isn’t end of the road for blockbuster biologic drugs to continue generating significant revenue and  profit, any longer – and it would remain so at least, in the short to medium term.

By: Tapan J. Ray 

Disclaimer: The views/opinions expressed in this article are entirely my own, written in my individual and personal capacity. I do not represent any other person or organization for this opinion.