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Patent Expiry No Longer End of The Road

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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 4th 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 17th 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 5th place in the global ranking. Five years after it goes off patent, Remicade is expected to feature in the 6th 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.

A Great News! But…Would This ‘Golden Goose’ Lay Golden Eggs?

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On December 9, 2014, international media flashed across the world a great news item from the Indian pharma industry:

“The first biosimilar of the world’s top-selling medicine Humira (adalimumab) of AbbVie has been launched in India by Zydus Cadila.”

This exhilarating news has undoubtedly got frozen in time flagging a well-cherished moment of pride for the Indian pharmaceutical industry. Along side, taking note of many contemporary factors in this area, a lurking apprehension too does creep in. It raises an awkward and uncomfortable question – would this ‘Golden Goose” born out of a laudable ‘reverse engineering’ effort be able to lay ‘Golden Eggs’, signaling its global commercial success for the company?

In this article, I shall try to dwell on on this important issue.

In one my earlier blog posts of August 25, 2014 titled, “Scandalizing Biosimilar Drugs With Safety Concerns”, I discussed another related concern in this area.

Born a ‘Golden Goose’:

Just to recapitulate, the original product Humira (Adalimumab) of Abbvie, a fully human anti-TNF alpha monoclonal antibody was first globally approved for marketing in 2002. Since then Humira has emerged as the most preferred therapy to reduce the signs and symptoms of patients suffering from moderate to severe rheumatoid arthritis, moderate to severe polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, moderate to severe Crohn’s disease and moderate to severe ulcerative colitis. However, Humira is not available in the Indian market, at present.

Zydus Cadila has announced that its biosimilar version of Humira (Adalimumab), has been approved by the Drug Controller General of India (DCGI) and will be marketed under the brand name ‘Exemptia’ for the treatment of autoimmune disorders as indicated for Humira.

As claimed by the company, ‘Exemptia’ is a ‘fingerprint match’ with the original drug Humira in terms of purity, safety and potency. Zydus Cadila has also stated that the novel non-infringing process for Adalimumab and a novel non-infringing formulation have been researched, developed and produced by scientists in its own Research Centre.

With this the world took note of the ‘Golden Goose’, born out of brilliant ‘Reverse Engineering’ in India. However, the apprehension of many continued to linger: Would this ‘Golden Goose’ be able to lay ‘Golden Eggs’?

The product and the price:

According to an estimate, over 12 million patients in India suffer from the above chronic conditions of autoimmune disorders, which progressively deteriorate and lead to lifelong pain and in some cases, even disability. To treat these indications, Exemptia is recommended as a 40 mg subcutaneous injection once every alternate week. Patients normally would have to take the treatment for six months.

Media reports indicate that ‘Exemptia’ of Zydus Cadila will be priced in India equivalent to US$ 200 a vial against Humira price in the United States of US$ 1,000. Initial overall reaction for this local price does not seem to be quite favorable for India.

The global market:

A recent report from Thomson Reuters indicates, as blockbuster drugs with sales turnover of around US$100 billion lose patent protection, the global biosimilars market is expected to grow around US$ 25 billion by the end of the decade.

According to a 2013 report of the credit rating agency Fitch, eight of the current 20 top-selling global pharmaceuticals are biologics that will face patent expiry by 2020.

EvaluatePharma reported that the current the anti-rheumatics market makes up the second largest treatment area by sales, with worldwide revenues of US$ 41.1 billion, closely behind the oncology therapy area, which registered sales of US$68 billion in 2012 with a high growth rate.

The report also states, despite biosimilar entry Anti-rheumatics segment is expected to record a Compound Annual Growth Rate (CAGR) of 4 percent with a turnover of around S$52.1 billion in 2018.

The local potential:

Over the last several years, China and India have been emerging as the promising destinations for international outsourcing of biopharmaceutical manufacturing. In the recent times, China and India are reportedly showing promises to become the industry’s top potential destinations for offshoring over the next five years, ahead of traditional bio manufacturing hubs in the US and Western Europe.

More than 40 biosimilar products are now available in the Indian market. Over 10 pharma players are competing in this area with around 15 epoetin, 8 G-CSF and 4 insulin “biosimilars”, besides a few others.

Although India has the second largest USFDA approved drug manufacturing plants next to the United States, none of the products manufactured in these facilities can possibly be considered as “true biosimilars”.

Humira expected to remain strong:

EvaluatePharma also forecasts that Humira of AbbVie would continue to remain the best selling drug of the world at least till 2018 with sales of US$12.8 billion, despite its US patent expiry in 2016.

Moreover, to succeed Humira that will go off patent between end 2016 and 2018 (Europe), AbbVie reportedly has seven new drugs in clinical development for Rheumatoid Arthritis. These patented new drugs could also significantly cannibalize the sales of Humira.

Physicians’ attitude towards biosimilars:

According to an October 2014 Report of IMS Institute from Europe’s perspective, within each country’s health system, physicians display a range of attitudes and behaviors that influence their prescribing of biosimilars.

IMS observed three broad segments of prescribers as follows:

  • Conservative prescribers: These doctors tend to be late adopters of new technologies, are more likely to follow published clinical treatment guidelines, and may not be aware of or educated on the availability of potential use of biosimilars.
  • Open-minded prescribers: This archetype includes physicians who tend to be the most responsive to new information about treatment options, particularly where experience and knowledge of biologics may be low and educational program can be effective in impacting usage.
  • Enterprising prescribers: This segment of prescribers is most likely to search out information from all sources, and be open to trying different options for patient care including biosimilars as well as innovative treatments.

In addition to these archetypes, the report states, physicians’ attitudes and prescribing behavior may also be influenced or determined by prescribing guidelines, if any, the use of prescribing incentives, as well as the use of promotional activities by either originator or biosimilar manufacturers.

The US biosimilar challenge:

According to reports, despite two pharma players filing biosimilar applications at the USFDA, there are still many issues to be sorted out in this space by the drug regulator of the country.

Though an interchangeable biosimilar in the United States still appears to be several years away, there are initiatives in some American states to restrict interchangeable biosimilar for substitution against the reference product.

Moreover, USFDA’s draft guidance on clinical pharmacology of May 2014 has invited strong adverse comments from the innovator companies, lobby groups and the industry associations.

However, just in the last week, both the innovator companies and biosimilar manufacturers have reportedly agreed to support state legislation that allows pharmacies to automatically substitute biosimilars for corresponding branded biologics. But pharmacies must give prescribers a heads up afterward “within a reasonable time.”

For biosimilars makers, it’s a big improvement on the alternative, as the biotech developers wanted to require pharmacists to check with doctors before making the switch.

That said, the USFDA is yet to determine exactly how to classify biosimilars and their “reference products” as interchangeable. This guidance for classification would be necessary for the above mentioned pharmacy switches. This guidance is important especially for the statutory language, which dictates that interchangeability is proven for “any given patient”. This could also be construed as requiring studies in all the approved indications for a brand name biologic, i.e. Humira has around five different indications.

Thus, the path ahead still remains challenging for the biosimilar players in the United States, and more so for the Indian Companies, as compared to other global pharma majors with deep pockets.

Several other Humira biosimilars under development too:

As indicated earlier, the US and Europe patents of Humira with worldwide sales of US$ 11.02 billion in 2013 would expire by end 2016 and 2018, respectively. Thus, the product has become among the most sought-after biosimilar target prototypes for many pharma and biotech companies across the world.

The global biotech major Amgen has already indicated that its ABP 501 biosimilar has shown comparable efficacy and safety to Humira (adalimumab) in a late-stage trial in patients with moderate-to-severe plaque psoriasis after treatment duration of 16 weeks. The product, reportedly, has also matched Humira in stimulating immune response in patients.

Experts believe, Amgen could be in a position to compete directly with Humira when it loses patent protection, if similar results are obtained in the second phase III trial.

Moreover, according to available reports, Boehringer Ingelheim, Sandoz (Novartis) and Coherus are also progressing well with the development of Humira biosimilars.

Zydus Cadila expects that in 2019 it would be ready to launch the biosimilar of Humira (Adalimumab) in the United States.

Marketing challenges for biosimilars:

Today, the global biosimilars market is indeed in a nascent stage, even for the Indian players.

For successful commercialization of biosimilars, I envisage, a well-crafted hybrid marketing-model of small molecule generics on the one hand and large molecule biologics of the originators’ on the other would be appropriate, in the years ahead.

In the early marketing phase, biosimilar marketers are expected to follow the same branding, communication and detailing strategies of the originators, which ultimately would transform into a generic matrix as more players chip in with the price competition intensifying.

Unlike small molecule generics, affordable price of a biosimilar would be just one of the many critical considerations for its commercial success in the biologics market.

Sustained efforts and initiatives to allay safety concerns with biosimilars among both the doctors and also the patients would be a dire necessity. Providing in-depth medical, technical and domain knowledge to the sales team should never be compromised, though these would require additional initial investments. Post marketing surveillance or pharmacovigilance for biosimilars must be ongoing, even in India. Here too, Indian players do not seem to be very strong, as yet.

Thus, unlike small molecule generics, marketing a large molecule biosimilar would require clear, razor sharp and focused strategies across the value chain to unlock its true potential. Crafting impactful value propositions, avoiding complexities, for each stakeholder, would decide the commercial fate of the product.

‘Made in India’ issue for pharma needs to be addressed expeditiously:

High credibility clinical trial data and manufacturing quality standards would also play a decisive role, especially for India made biosimilars.

This is mainly due to widespread reports of frequent USFDA allegations related to falsification and doctoring of manufacturing data in several manufacturing plants of India.

Ethical and quality issues for drugs made in India, such as these, assumed even greater dimension, as the regulators in France, Germany, Belgium and Luxembourg reportedly suspended marketing approval for 25 drugs over the genuineness of clinical trial data from India’s GVK Biosciences. This is yet another blow to ‘Made in India’ image for medicines, which has arrested the global attention, for all the wrong reasons, just the last week. 

Conclusion:

Considering all the above points, let me now try to make a fair personal guess on whether or not the ‘Golden Goose’ would be successful enough to lay ‘Golden Eggs’, as required by the company.

Firstly, in the Indian perspective, the key point that strikes me is the cost of a treatment course with ‘Exemptia’ per patient in the country. On a rough calculation, it comes around Rs. 1,50,000 per course/per patient. This appears rather high according to the income level of an average Indian.

However, Zydus Cadila expects sales between Rs.1 billion (US$16.16 million) and 2 billion for ‘Exemptia’ only from the Indian market.

I reckon, with relatively high per course treatment cost with Exemptia, it may be quite challenging for the company to achieve this goal in the domestic market.

Thus, the global success of this biosimilar brand would mainly depend on its degree of success in the United States and Europe, post patent expiry of Humira.

Going by the possible availability of other Humira biosimilars from manufacturers with robust global marketing muscle, skill sets, experience and other wherewithal, the path of global success for Exemptia of Zydus Cadila, if the company decides to fly solo, appears to be strewn with many odds.

I would now stick my neck out to zero in with specificity in this area, while envisaging the possible future scenario.

Considering the evolving macro scenario together with the commercial success requirements in this space, I reckon, despite presence of several possible competitors of Humira biosimilars, including one from Zydus Cadila, the biotech domain expertise of Amgen, fuelled by its marketing muscle, would in all probability make its ABP 501 biosimilar the toughest competitor to Humira after its patent expiry in the US and Europe…and then…why doesn’t it try to succeed in India too?

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.