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Continue reading for Dr. Emerton's reflections on 2013 as well a look ahead to 2014, and be sure to leave your own biosimilars predictions (good or bad) for 2014 in the comments section or via Twitter.
Note: this blog entry is entirely the work and personal opinion of Dr. Duncan Emerton. Please read and understand my customary BiotechDueDilgience Disclaimer as well as the author's Disclaimer below.
Personally, 2013 was defined largely by change. I changed my job, moving from a company I was with for nearly a decade. I left behind some good colleagues, some great friends and some excellent clients. I moved home, not only changing my house but also my home town. Again, familiarity was left behind, exchanged for uncertainty about the future. Deep down I knew change was coming, in fact needed, in my life; I could either shape change or let it shape me.
A new year always brings challenges. It also brings a renewed sense of optimism, mixed in with a small amount of anxiety. And I’m not alone here. Off the back of declining NME approvals from FDA in 2013 (1 - find web links for all references below), the biopharmaceutical (‘biopharma’) industry is facing its own challenges and uncertainties. Declining output, rising R&D costs, pressure from payers to deliver better value. These are just a few of biopharma’s ‘least favorite things’, members of a long list of issues executives are having to deal with, both now and in the future.
One of the ways biopharma companies are trying to drive and shape this change is by investing in disruptive technologies. Cancer immunotherapy is one of the hottest tickets at the moment. Identified by Science magazine as 2013’s breakthrough of the year (2), several companies have jumped on the band wagon and invested billions of dollars. Another is biosimilars. Once seen as a threat, biosimilars have emerged in recent years as a significant opportunity for a select group of large biopharma companies. Biosimilars aren’t just for generics companies. As I put it back in December 2011, some very large biopharma gamekeepers have turned poacher in a search for new opportunities.
So what's happened in 2013; much ado about nothing?
My involvement in the biosimilars sector began 2006. Despite the fact that I’ve never worked for a biosimilar company, I’ve developed a pretty decent understanding of the sector. The science, the regulations and, my specific area of expertise, the commercial issues. I’ve even been called a biosimilars opinion leader at one stage. My Mum would have been proud!
Much of what was written and debated on the subject of biosimilars has focused primarily on quality, regulatory, and scientific issues. We have seen extensive analysis of regulatory guidelines, how they affect clinical development strategy, and how they are evolving. Much discussion has also centered on the quality of biosimilars and how modern analytical techniques can effectively characterize them. Very little discussion has focused on the commercial issues.
To my delight, conversations at conferences, in the press and over social media during 2013 began to focus more on commercial issues within the biosimilars sector. I myself presented at these conferences, contributed to social media and wrote about the potential profitability of the biosimilars sector, asking if scientific excellence within the biosimilars sector could be translated into a healthy commercial return (3). And I’m not alone. Bernstein Research’s Ronny Gal published a note in December 2013 saying that there had been a definite ‘…shift to discussion of commercial issues’ during a recent biosimilars conference (4). While regulatory and scientific issues will also be important, 2013 was the year people began openly asking the question; can we actually make any money from these products?
Events during 2013 haven’t really made answering that question any easier. News has been mixed. There has been some progress and success, but there have also been some steps back, and some high profile failures.
The standout success of 2013 came in September, when the European Medicines Agency (EMA) approved its first biosimilar monoclonal antibody (mAb). Following a positive Committee for Medicinal Products for Human Use (CHMP) endorsement in June 2013 (5), Celltrion's CT-P13, a biosimilar version of Janssen Biotech's Remicade (infliximab), received formal EMA approval in September 2013 (6). The product will be branded as Remsima (Celltrion), Inflectra (Hospira) and Flammegis (Egis). Despite having been approved in Korea in July 2012 (7), the European approval of CT-P13 was a significant milestone for the biosimilars sector. It showed that highly complex biosimilars could be developed successfully. Questions remain about the commercial potential for the product, however.
Much clinical development progress was also seen, with several late-stage biosimilar mAb programs initiated by companies such as Amgen, Sandoz, Pfizer and Russia's Biocad. Amgen has three biosimilar mAb programs in Phase III, including proposed biosimilar versions of trastuzumab (ABP-980), adalimumab (ABP501) and bevacizumab (ABP215). Pfizer has four biosimilar mAb programs, covering the same molecules as Amgen with the addition of a proposed biosimilar rituximab (PF-05280586). At roughly the same time, in May 2013, Sandoz and Samsung Bioepsis confirmed the initiation of Phase III studies for their proposed biosimilar versions of etanercept, GP2015 and SB4, respectively. Sandoz also initiated Phase III trials for its proposed biosimilar version of adalimumab (GP2017), and Samsung initiated Phase III trials for its proposed biosimilar version of infliximab (SB2). This is only small selection of what happened in 2013; suffice to say, companies with the ability to sponsor late-stage clinical development of biosimilars did so in their droves in 2013.
On the downside, we’ve continued to see what Novartis called a ‘shakeout’ in the biosimilars sector (8). Case in point; efforts to develop a biosimilar version of rituximab (Rituxan/MabThera; Roche) took a significant beating in 2013, with several clinical programs being suspended or put on hold. Companies such as Samsung Bioepsis (SAIT101), Teva (TL-011) and Celltrion (CT-P10) have put the brakes on development for their programs. In addition to the news that TL-011's development has been terminated, Teva's biosimilars joint venture with Lonza was also scrapped in 2013 (9). First announced in Jan 2009, the alliance was hailed by both companies as an opportunity to ‘…deliver significant growth for each company. Critical to the success of the whole alliance was TL-011. In the cold light of day, both companies have come to the conclusion that the cost of developing (and then commercializing) biosimilars is too expensive; financial common sense has prevailed.
Regulatory evolution was pretty limited in 2013. The EMA continued to tinker with its gold-standard biosimilar development pathway (10), updating various pieces of guidance to clarify key requirements and make the clinical development phase for certain classes of products easier (e.g. low molecular weight heparin). In contrast to steady progress in Europe, however, no significant developments were seen at FDA. While there were rumors of a biosimilar submission having been made to FDA (11), there was still no movement from FDA in relation to what would be needed to develop an interchangeable biosimilar.
Many commentators have taken to social media about the potential for an interchangeable biosimilar in the US. My argument is simple; if FDA don't produce guidance, it's a moot point. While companies like Baxter and Momenta, which have bet the mortgage on being able to develop and commercialize interchangeable biosimilars, could guess and plough forward with clinical development programs, that's a huge risk that not every company will be willing to accept. And on that point, are cracks beginning to appear in the Baxter/Momenta alliance? As recent as December 2013, Baxter returned the rights for M511, a proposed biosimilar oncology mAb (which I believe to be rituximab, but other people believe its cetuximab) to Momenta (12). Again, common sense could be prevailing, but this could also indicate a change in the mood within the alliance in relation to its 'interchangeable biosimilar' strategy.
In terms of policy changes, there was a volte-face in France in relation to the policy of automatic substitution for biosimilars. In Dec 2013, the French Constitutional Council upheld provisions of the 2014 social security bill that would allow for the substitution of biosimilars in France (13). This reverses a 2007 decision to ban biosimilar substitution in France (14). While substitution may only be done if certain conditions are met (i.e. the prescriber has not ruled out the possibility of such substitution), it opens the door to increased uptake of biosimilars in a country that has historically been very brand loyal and resistent to using both generics and biosimilars. Similar moves in the US, supported by lobbying dollars from Amgen and Genentech, have received a mix response (15).
Germany's statutory health insurance system (the Kassenärztliche Vereinigung) also raised its requirements for biosimilar prescribing in 2013. There are 17 physician based regions in Germany, and the majority of regions have implemented biosimilar quotas for biosimilars. For example, the quota system for short acting EPO-alfa used in retail setting has been a critical driver of uptake of biosimilar EPO-alfa. Additional payer activity endorsing biosimilars as safe and effective via “dear doctor letters” and address potential concerns has had a significant impact on uptake (16).
While the French approach of promoting automatic substitution of biosimilars failed in Norway (14), the Norwegians came out fighting in 2013 with another plan to drive biosimilar uptake. Despite Celltrion presenting data on the safety of switching RA (and AS) patients from Remicade to its biosimilar infiximab, CT-P13, at ACR 2013 (17,18), a group of Norwegian physicians has obtained funding of $3.3m from the Norwegian Health Department to conduct a 'safe to switch to CT-P13 study' for patients already on Remicade (19). It seems that Celltrion's data doesn't provide enough reassurance regarding the switching in ordinary clinical practice. I have some serious concerns about the study, both from an ethical and reputational perspective. My view (and I’m very happy for this view to be challenged) is that the switching study has been done already. It strikes me as being unethical to repeat the study. Also, what will happen if this study shows that (in a real world setting) it’s not safe to switch from Remicade to CT-P13? Will this call into question Celltrion’s data, and the whole EMA biosimilar approval process? Only time with tell.
And finally, deal activity in 2013 showed no sign of abating over concerns about the commercial opportunities that biosimilars represent. Several new biosimilar alliances were forged, including Merck & Co. partnering with Samsung Bioepsis (20), Biocon replacing Pfizer with Mylan for its biosimilar insulin portfolio (21), Baxter joining forces with Coherus Biosciences on the development and commercialization of biosimilar etanercept (22), and Biogen Idec exercised its option to take on commercialization responsibilities for various anti-TNF biosimilars that emerged from its alliance with Samsung Bioepsis (23). Again, only small selection of the deals and alliances that were forged in 2013, and suggestive of high optimism within the industry regarding the opportunities for biosimilars.
And to 2014 and beyond; is there a pot of gold at the end of the rainbow?
As Yogi Berra once said, ‘…it's tough to make predictions, especially about the future.’ That said, I believe that in 2014 we'll see more change, more evolution of the sector. It's inevitable.
Without a doubt, we will see biosimilar insulin approved in Europe in 2014. Eli Lilly and Boehringer Ingelheim's diabetes alliance bore fruit in 2013, and a biosimilar marketing authorization application (MAA) for LY2963016, a proposed biosimilar version of insulin glargine, was submitted to the EMA for review (24). The product was also submitted to FDA, but via the 505(b)(2) pathway and not the biosimilar 351(k) pathway (25). Based on an average of 15-17 months for the EMA to review a biosimilar application, we can expect to see an approval some time in Q4 2014. We may see an approval in the US even sooner.
Will 2014 be the year when a biosimilar (i.e. 351(k)) submission is actually made in the US? As discussed previously, there were rumors in 2013 that one has already been made. There are some well documented reasons why a 351(k) submission is a huge undertaking, none more so than the patent provisions contained in US biosimilar legislation. But the US market is by the biggest biologics market globally. The size of the prize is too great to ignore. So, if not 351(k), what else? More BLA submissions like Teva's tbo-filgrastim strategy? Perhaps. Both pathways hold unique benefits, and approval via both pathways would enable companies to compete in a highly lucrative market.
The shakeout, as discussed previously, is likely to continue in 2014. While more deals are being struck, and will continue to be struck in 2014, failure and success will always walk hand in hand. One key pipeline product I've got my eyes on 2014 is Celltrion's proposed biosimilar version of trastuzumab, CT-P6. Celltrion have already submitted this product for approval in Korea (26), presented Phase I/IIb data for CT-P6 at St Gallen 2013 (27), and followed this up with Phase III data at ASCO 2013 (28). Since Celltrion's submission to Korea's Ministry of Food and Drug Safety (MFDS) in June 2013, however, nothing else from Celltrion or Hospira has been published about CT-P6. There's been plenty of other things written about Celltrion, but things have gone quiet in relation to CT-P6. Why? One could argue that the Phase III data Celltrion have generated for CT-P6, in metastatic breast cancer patients, isn't good enough to submit to EMA. There is also the possibility that EMA has requested data in early breast cancer patients. For the record, I don't know. These are just some possibilities.
Like my family, friends, fine wine, good food and great company, the sustainability of the biosimilars sector is something that I care about immensely. I want to see it succeed. I want to see it become profitable. Healthcare budgets are not getting any bigger (in fact, they’re shrinking!). We need cheaper, more cost-effective biologics. True innovation, while immensely important in the treatment of disease, comes at a price. Biosimilars offer society a ‘safety-valve’, enabling payers and governments to manage costs and maintain quality.
But I’m a pragmatist. I understand that there are some huge road blocks that sit in the way of where we are now and where we need to be for this to happen. So, my final words on the subject are these. Let’s make 2014 a year when we find that elusive common ground. Let’s get behind biosimilars, make the sector work. Sure, keep investing in true innovation, the new stuff, the products and therapies that the industry needs to develop and commercialize in order to remain in business. Let's try and overcome the clinical challenges of developing biosimilars. But let’s not lose sight of what society needs.
So, is there a pot of gold at the end of the rainbow? One thing is for certain. Like the Death Valley '49ers who searched long and hard for riches during the Californian gold rush of the 1840s, companies will always be searching for riches within the biologics market. But here's a word of caution. Like the original gold rush, it wasn't the prospectors that made the most money, it was the sellers of the tools.
The views expressed in this article are mine, and mine alone. Furthermore, all information in this article is only current as of the date of publication. If you're reading this article sometime after its original publication, it may not reflect accurately recent events. Please read and understand the complete Biosimilarz Blog Disclaimer.
- FDA drug approvals in 2013. [Accessed Jan 2014].
- Cancer immunotherapy: 2013's breakthrough of the year. [Accessed Jan 2014].
- Profitability in the Biosimilars Market: Can You Translate Scientific Excellence into a Healthy Commercial Return. [Accessed Jan 2014].
- Biosimilars: moving beyond regulatory, heading into commercialization.Bernstein Research, Dec 2013. Copy of report available upon request.
- CHMP endorsement for Inflectra (CT-P13; infliximab). [Accessed Jan 2014].
- European Commission Implementing Decision: Inflectra. [Accessed Jan 2014].
- South Korea approves Remsima from Celltrion to compete with Remicade. Accessed Jan 2014].
- Biosimilars face big delays as blockbuster knockoffs hit a roadblock. [Accessed Jan 2014].
- Teva, Lonza end biosimilars joint venture as the copycat crowd thins. [Accessed Jan 2014].
- EMA Biosimilar Guidelines. [Accessed Jan 2014].
- The Biosimilarz Blog! 11-22-2013. [Accessed Jan 2014].
- Momenta Form 8-K (19 Dec 2013). Accessed Jan 2014].
- Social security law provisions for 2014. [Accessed Jan 2014].
- The impact of biosimilars’ entry in the EU market. [Accessed Jan 2014].
- Governor Brown Vetoes California Biosimilar Bill. [Accessed Jan 2014].
- Presentation by Ken Walsh, Global Pricing & Market Access, Sandoz Biopharmaceuticals. Biosimilars’ utilization and the role payers do play in driving uptake in Europe. [Accessed Jan 2014].
- Efficacy and Safety of CT-P13 (Infliximab biosimilar) over Two Years in Patients with Rheumatoid Arthritis: Comparison Between Continued CT-P13 and Switching from Infliximab to CT-P13. [Accessed Jan 2014].
- Efficacy and Safety of CT-P13 (Infliximab biosimilar) over Two Years in Patients with Ankylosing Spondylitis: Comparison Between Continued CT-P13 and Switching from Infliximab to CT-P13. [Accessed Jan 2014].
- Norway to facilitate switch to biosimilars with $3m Remicade study. [Accessed jan 2014].
- Merck and Samsung Bioepis enter biosimilars development and commercialization agreement. [Accessed Jan 2014].
- Biocon enhances partnership with Mylan through strategic collaboration for insulin products. [Accessed Jan 2014].
- Baxter and Coherus Biosciences announce collaboration to develop and commercialize biosimilars. [Accessed Jan 2014].
- Biogen Idec and Samsung Bioepsis announce agreement to market anti-TNF biosimilar product candidates in Europe. [Accessed Jan 2014].
- Eli Lilly and Company and Boehringer Ingelheim announce regulatory submission for new insulin glargine biosimilar product. [Accessed Jan 2014].
- Eli Lilly and Company and Boehringer Ingelheim announce new drug application filing in the U.S. for new insulin glargine product. [Accessed Jan 2014].
- Celltrion files for approval of its trastuzumab biosimilar, CT-P6, in Korea. [Accessed Jan 2014].
- Phase I/IIb clinical trial comparing PK and safety of trastuzumab and its biosimilar candidate, CT-P6.[Accessed Jan 2014].
- Robust data for biosimilar trastuzumab programs presented. [Accessed Jan 2014].