Bluff or Serious Biosimilar Bet?

Few aspects of the pharma industry get as much attention as biosimilars. Because the impact extends across all phases of a biopharmaceutical product’s lifecycle, it’s one of the hottest topics in recent memory. The issue of biosimilars is sure to be raised in discussions as varied as cell line development, manufacturing, analytical characterization, and commercialization. 2015 was a landmark year with the FDA’s approval of its first biosimilar monoclonal antibody, and 2016 is ending with a long list of products under regulatory review – and more approvals imminent in the US and Europe. So while the stakes have always been high, the game is about to change massively. And this is where the analogy with the game of poker comes into play; the two worlds are more closely linked than they may initially appear and the commonalities between them are striking.

What is a game without players? How do they stack up against each other? In this case, the companies developing and commercializing biosimilars are counting their chips (financial resources) and holding their cards (individual assets) close to the chest. There will be winners and losers in this high-risk, high-rewards game, but the strongest hand (biosimilars portfolio) has yet to be revealed. A few leaders have surged ahead, on the basis of first approval in a specific product class or country; but being first does not necessarily determine the victor. To get a clue on who is most likely to command this game, we must examine who is at the table, peak at their cards, and imagine how they might play.

Player 1: Celltrion

Limited experience and limited chips, but could their one ‘“high card” and two “low cards” be enough to win?

Celltrion was the first company to lay a face card on the table in the biosimilars poker game. In gaining European Commission (EC) approval for Remsima (formerly CT-P13) – its biosimilar version of Remicade (infliximab; Merck Sharpe & Dohme) – in September 2013 (1), and subsequently launching it in key Western European markets in February 2015 (2), the Korean biotech trumped its biosimilar rivals. Few expected Celltrion to pull ahead and beat other more experienced companies to the punch with a biosimilar monoclonal antibody. It’s a young company with a true “poker face,” revealing little and making the collection of competitive intelligence a challenge. Was it beginner’s luck? Not likely. The quality of data from the pivotal PLANETAS (Phase I) and PLANETRA (Phase III) studies provided the foundation for the product’s approval in Europe. The US has also welcomed the biosimilar; in February 2016, an FDA advisory panel voted 21 to 3, backing approval of Inflectra for all indications for which Remicade is currently approved.

When it comes to other cards, however, Celltrion appears to be struggling: CT-P6, a proposed biosimilar Herceptin (trastuzumab; Roche), and CT-P10, a proposed biosimilar Rituxan/MabThera (rituximab; Roche). These assets began development at roughly the same time as CT-P13, but progress has been slow. Phase III data for CT-P6 in the metastatic breast cancer (mBC) setting was presented at St Gallen 2013, but no regulatory filing has been made. In fact, clinical trials in early breast cancer have  been initiated, suggesting Celltrion was unhappy with its cards. By generating more data for CT-P6, one could argue that Celltrion is trying to build a stronger hand. Likewise, CT-P10 seems to have stalled. Rumours surfaced in April 2013 suggesting that Celltrion had terminated the product’s development completely (3). However, clinical development on CT-P10 continues, and Celltrion submitted CT-P10 for approval in Europe in November 2015 – albeit only for rheumatoid arthritis. The assumption is that data generated from two Phase I studies, both completed in Q4 2015, supported the submission (4). On the face of it, this is a huge gamble and it remains to be seen if Celltrion is bluffing or has a trick up its sleeve.

Celltrion has also lost a key commercial partner in recent months. Following Pfizer’s $17-billion acquisition of the biosimilar player Hospira, which was completed in September 2015 (5), Celltrion have been forced to leverage other commercial partners, including Mundipharma, Biogaran, Kern Pharma, and Orion. While these other partnerships may not be as ‘meaty’ as that with Hospira, they still afford Celltrion ‘boots on the ground’ outside of Korea and provide critical mass that allows them to drive sales of its marketed portfolio. We find it notable, however, that Pfizer has returned rights for CT-P6 and CT-P10 back to Celltrion. While not an EC or US Federal Trade Commission (FTC) requirement of the deal, the timing does suggest that Pfizer does not believe the cards are valuable.

Player 2: Boehringer Ingelheim

An experienced player with lots of chips on the table and a potential “ace in the hole”

Boehringer Ingelheim is one of the largest contract manufacturing organizations in the world. From a commercial perspective, however, the company’s primary care heritage in areas such as cardiovascular and respiratory means that it has limited experience in terms of developing and commercializing biologics. Despite having enough chips to stay in the game and bags of patience (thanks to being privately owned), does Boehringer Ingelheim have the cards to play a decent hand?

Some sceptics have honed in on Boehringer Ingelheim’s decision to trim its already-small biosimilars portfolio. In October 2015, Boehringer Ingelheim made the decision to fold and terminate development of its rituximab biosimilar (B1 695500) following a “strategic portfolio review” (6). Many believe that this has left Boehringer Ingelheim with a weaker hand compared to other major players. Perhaps this is true, but Boehringer Ingelheim also has a potential ‘ace in the hole’ that could see it become one of the leading biosimilar players in the future. This potential wild card is BI 695501, a proposed biosimilar of Humira (adalimumab; AbbVie). Development of this wild card is fairing well, and keeping the company in the game. BI 695501 is currently progressing in a pivotal Phase III study, as well as in other open-label safety and device testing studies. Also in its favour is the size of the Humira prize and the potential for commercial differentiation with a pre-filled syringe.

But we must also consider the fact that Amgen has submitted its proposed Humira biosimilar, ABP 501, to the EMA and FDA already. Although other companies are ahead from a regulatory perspective, the intellectual property that protects Humira from biosimilar competition isn’t expected to expire until 2020 in Europe and 2022 in the US (7) – which gives Boehringer Ingelheim plenty of time to catch up.

And let’s not forget that Boehringer Ingelheim also holds two other cards: BI 695502, a proposed biosimilar Avastin (bevacizumab) in Phase III clinical trials, and Abasaglar, a biosimilar version of Sanofi’s Lantus (insulin glargine), which was approved in Europe in September 2014 and launched in Western Europe in August 2015 in partnership with Eli Lilly (8), (9). It will be interesting to watch how these cards are played.

Player 3: Sandoz (Novartis)

Highly experienced; the ability to play it cool and take its time, and plenty of chips on the table, but will its current market leading status mean future expectations become unrealistic?

Sandoz has been commercializing biosimilars in Europe since 2006 and commands approximately 50 percent of the global biosimilars market. In 2015, sales of biopharmaceuticals (which include biosimilars) grew by 39 percent to $772 million (10). Moreover, the company will go down in the history books as being the first to secure a biosimilar approval in the US with Zarxio (filgrastim-sndz) (11). Coming to the game with seven biosimilars (including Omnitrope, EPO-alfa and Zarxio/Zarzio) and the second largest biosimilar pipeline after Pfizer, Sandoz is in possession of the poker equivalent of a Full House.

Clearly, of all the payers at the table, Sandoz has the most biosimilar experience and heritage. Does this enable Sandoz to read other players and play more strategically? Perhaps. Another significant advantage comes from the diversity of its portfolio, which ranges from simple biologics, such as Omnitrope (somatropin), all the way through to oncology mAbs. Despite being one of the first to start clinical development of a rituximab biosimilar (GP2013), it appears to have a taken a slow and steady approach, which has allowed others to catch up. Sandoz was the second to file a rituximab biosimilar with the EMA in May 2016, 7 months after Celltrion’s CT-P10 filing (12) Sandoz’s strongest cards appear to be in the anti-TNF category, and include etanercept (GP2015) and adalimumab (GP2017). GP2015 is under regulatory review in Europe and the US, and the company also has its proposed biosimilar Neulasta (pegfilgrastim; Amgen) under review in the US. Sandoz’s laser focus on its biosimilar portfolio, combined with Novartis’s technical expertise and deep pockets, make this company a formidable opponent.

Player 4: Samsung Bioepis

Limited experience, but a high number of chips; will rapid regulatory progress and a broad portfolio enable it to take command of the market?

Think Samsung and vivid thoughts of the latest smartphone and television technologies spring to mind. Certainly, the South Korean tech giant’s increasing prowess in the life sciences arena is not at the forefront of many peoples’ minds. But the company, set up as a joint venture between Samsung Biologics and Biogen in 2012 (13), has already played some quick cards by becoming the first company to secure regulatory approval for Benepali, a biosimilar version of Enbrel, (etanercept; Pfizer), in January 2016 (14). Could Samsung Bioepis be the dark horse at the poker table? Perhaps. Is Samsung Bioepis a company that needs to be taken seriously? Absolutely. Indeed, early losses including the failure of its rituximab biosimilar (SAIT101 – now reactivated with a new partner AstraZeneca) (15) – seem only to have made Samsung Bioepis a better player. It has five biosimilars in its pipeline, including biosimilar versions of Remicade (SB2), Humira (SB5), Herceptin (SB3), Avastin (SB8) and Lantus (MK-1293; being developed by Merck, Sharpe & Dohme). Rapid progress across all of its mAb and fusion protein programmes means Samsung has been able to quickly catch up with its opponents and suggests it could get to market sooner than all others. A strong upside for the company is the potential for early mover advantage in the oncology setting with their Herceptin (SB3) biosimilar development programme, which was filed in Korea with the Ministry of Food and Drug Safety (MFDS) in September 2016,  and with the EMA in October 2016 (16).

Player 5: Amgen

A highly experienced biologics player with lots of high value chips on the table, but having just lost a key partner will its “straight flush” be enough to reign supreme?

Undoubtedly, Amgen has a very strong hand that includes some high value cards; a proposed biosimilar mAb under regulatory review in Europe and the US (ABP 501; adalimumab), four proposed biosimilar mAbs in clinical development (bevacizumab [ABP 215], infliximab [ABP 710], rituximab [ABP 798] and trastuzumab [ABP 980]) and another four in non-clinical development (cetuximab [ABP 494], plus three undisclosed mAbs). However, ABP 501 is likely to be first to gain regulatory approval in Europe and the US, and delays to commercialization until 2020 in Europe and 2022 in the US are on the cards due to AbbVie’s patent suite on Humira (see section on Player 2: Boehringer Ingelheim). With the announcement in November 2015 that Pfizer intends to acquire Allergan for $160 billion (17), Amgen’s biosimilar oncology portfolio (i.e., bevacizumab, trastuzumab, rituximab and cetuximab) has certainly suffered a setback now it is without a key commercial partner – this partnership would have contributed toward the cost of development of its assets in return for royalties and commercialization options. However, this setback will not affect the programmes being managed internally (i.e., anti-TNFs). In fact, Amgen may not need a new partner to add more chips (financial backing) to the table; everything will depend on how it plays the game, which means that execution is key. Contracting and lifecycle management is a key skill of Amgen’s, but it remains to be seen if they bring another partner onboard. Recently, Amgen has partnered with Celltrion so we’ll have to see how this plays out.

Player 6: Pfizer

Highly experienced; lots of high value chips and an ability to take risks make Pfizer’s “royal flush” hard to beat 

With the largest biosimilar portfolio – boosted by selecting Hospira’s best cards – Pfizer appears to be going all in. In addition to the six mAbs (adalimumab [PF-06410293], bevacizumab [PF-06439535], infliximab (PF-06438179; US only), ranibizumab [PF582], rituximab [PF-05280586] and trastuzumab [PF-05280014]) that Pfizer is developing independently, its acquisition of Hospira added four new, carefully selected cards to the deck: Remsima (in Europe only), Retacrit (EPO-zeta), Nivestim (filgrastim) and HSP-130, a proposed pegfilgrastim biosimilar. The acquisition of Hospira could well accelerate the spin-off of Pfizer’s Global Established Pharmaceuticals (GEP) into a separate company comparable to the Novartis/Sandoz set up. This would mean Pfizer moving toward a hybrid innovator/generic business model; with the largest biosimilar portfolio as a central pillar of its strategic focus and revenue stream, which makes a lot of sense. Pfizer arguably has the edge over Amgen’s portfolio as they are able to offer biosimilars across all key molecules. Using the poker analogy, this is a Royal Flush – usually considered the highest hand possible, except for when wild cards are in use. Add to this stacks of chips on the table and the experience to remain cool and play a patient game… and it could be that Pfizer is in the driver’s seat.

Endgame

The biosimilar competitive landscape has evolved dramatically over the last decade, but the game that is about to play out in the next decade will be even more fascinating. What was initially an opportunity for generics companies has now evolved into a market where generics companies, originator companies and everyone in between seems to want a piece of the very lucrative action. Early players, such as Teva, have walked away from the table to reassess their options, but could potentially return if the opportunity presents itself. Other companies, like Merck, Sharpe & Dohme, have been re-born and companies like Boehringer Ingelheim and Celltrion have persevered despite having hands that other players may consider folding on. Meanwhile, the three kings of Pfizer, Amgen and Sandoz have consolidated their positions and firmed up their seats at the table. But there are new players to watch out for too, highlighted by Samsung Bioepis’ entry in which it has rapidly made its presence very well known.

As to who will finally win? Well, that depends on what each company defines as “winning. The  most sales? Highest volume? First to market? Largest portfolio? The most profit? All of these are valid metrics, but only time will tell which one will take prominence. The biosimilars market is certainly not for the faint of heart; nerves of steel have become de rigueur, as has patience, lots of cash and a long-term strategy. And of course the ability to see you have a bad hand and fold. As Kenny Rogers says in the lyrics to his hit The Gambler, “You’ve got to know when to hold ‘em, know when to fold ‘em, and know when to walk away.”

Eva McLellan (nee Furczon) works in Global Product Strategy at Roche global headquarters in Switzerland, and Martyn Smith is the Head of Global Competitive Intelligence at F. Hoffmann La Roche, Basel, Switzerland. 
The authors would like to thank Duncan Emerton, biosimilar expert and senior director at FirstWord, and Joanne Steiner, from Aprior Consulting, for their considerable input and assistance with this article.

Disclaimer: The views and opinions expressed in this article are those of the individual authors and do not necessarily reflect the views, opinions or policies of their employers or other affiliated organizations.