Last month, the European Medicines Agency (EMA) approved Samsung Bioepsis/Biogen’s biosimilar version of Johnson & Johnson’s $6-billion-per-year biologic, Remicade (inflximab). Flixabi (an infliximab biosimilar referencing Remicade), which was approved for all of Remicade’s indications, is the second Remicade biosimilar approved in the EU. Celltrion won approval for its biosimilar Remicade, Inflectra (infliximab dyyb), in that market in 2013.
Remicade is indicated for treatment of Crohn's disease, ulcerative colitis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and rheumatoid arthritis. It was first approved in 1998 for the treatment of Crohn’s disease, and in 1999 for treatment of rheumatoid arthritis. The other indications followed in subsequent years.
Flixabi is the 21st biosimilar approved in the EU in the last 10 years. According to Stacie Ropka, an IP attorney at Axinn, Veltrop & Harkrider, “Approval of another biosimilar in Europe is business as usual.The EMA is willing to approve biosimilars. There is a well-established roadmap in Europe for getting biosimilars approved."
Is FDA approval of Inflectra a turning point?
Admittedly, the roadmap in the US is less established. The first biosimilar,Sandoz’s Zarxio (filgrastim-sndz) -- a biosimilar version of Amgen's Neupogen -- was approved a little more than a year ago. In April, Inflectra became the second approved biosimilar in the US.
Ropka says Zarxio was an ideal candidate for a first biosimilar approval in the US. It was already approved in more than 40 countries and there was extensive post-marketing surveillance data tracking about 6,000 doses of Zarxio. It is also a relatively uncomplicated protein.
However, Inflectra is considerably more complicated. Ropka sees the approval of a Inflectra as an important breakthrough for the US-based biosimilars market.
“It’s exciting that the FDA was able to find a comfort level approving a monoclonal antibody. They are much more complex than a drug like Zarxio. They are larger, and have additional tertiary and quarternary structures,” said Ropka, who holds a PhD in microbiology and immunology.
“The FDA seems to be more comfortable with reviewing biosimilars, as noted by the evolution of the briefing documents from Zarxio to Inflectra," said Dr. Bertrand Liang, the founding chief executive officer of Pfenex and chair of the Generic Pharmaceutical Association Biosimilars Council.
When will biosimilar discounts increase in the US?
Now that Inflectra has been approved in the US, there is a growing sense of momentum and increased demand. There is also a growing expectation that as the market matures, and competition comes into play, discounts will be on par with those in Europe. Those discounts vary from country to country, and are highest in Norway, where Remsima (the brand name for infliximab-dyyb in the Scandinavian countries) is discounted 70% compared to the originator drug.
Not surprisingly, Remisima has 80% of the total infliximab market share there and has all but pushed branded Remicade out of the market.
Tom Hutchings, business insights analyst at Decision Resources Group (DRG), predicts that the entry of another Remicade biosimilar into the EU market will put even more downward pressure on prices.
He said, “In order to win tenders in the EU, Samsung/Biogen will have to offer a greater discount for Flixabi than Celltrion and Hospira. Our research with EU payers suggests that Inflectra and Remsima have entered the market with a discount of 25%-35%. On this basis, we project that Flixabi will be 30%-40% cheaper than Remicade.”
By contrast, Zarxio was only discounted 15% when it launched, but there was no biosimilar competition in the US. That’s going to change eventually, probably sooner than expected, according to Ropka.
“As more biosimilars enter the market, third-party payers are going to become more active. They will help inform, educate and ultimately persuade patients to choose biosimilar options, because they simply won’t pay for brand-name products if there is a therapeutic biosimilar equivalent,” she said.
The biosimilars market in the US is poised for growth. As of April 20, there were 60 products in the FDA biosimilar product development program.
Overcoming barriers to slow uptake
Even if patients are open to using a biosimilar, many physicians are reluctant to prescribe them. When SERMO, a global social network of physicians, polled 3,849 physicians in May, 53% said they would not prescribe biosimilars to their patients at this point in time—although 43% of the respondents said that they would be interested in obtaining more educational information about biosimilars before prescribing.
Overall only 10% of respondents signaled an unwillingness to adopt, while 47% said that they would be willing to prescribe biosimilars as they became available. Given that the biosimilars industry in the U.S. is young, these adoption rates would be considered normal.
As Liang said, “A similar scenario was seen with generic drugs after Hatch-Waxman in the 1980s and early 1990s. Today, approximately 88% of dispensed drugs are generics.”
As a scientist, Ropka remembers the early skepticism around monocolonal antibodies, which she said “are still in their infancy.” It took years for researchers to unravel the puzzle around identifying specific targets, and identifying the appropriate antibody or ‘shut-off valve.’
Ropka noted that in the last 20 years, there has been a full-swing towards acceptance of and reliance on antibodies. Liang noted a similar dynamic with generic drugs. Ultimately, long-term experience and an evidence base that can be consulted are definitely part of what will shift attitudes among skeptics.
“The US has the opportunity to learn from the EU, where there have been over 400 million patient days of safe and effective use of biosimilars since the first approval in 2006,” said Liang.
Closing the messaging gap
Like the early days of antibodies, physicians and other stakeholders need to be educated and assured that biosiimlars are safe and effective. They also need to understand that bridging studies and indication extrapolation are not short-cuts, but rather based on sound science.
In the EU and the US, a biosimilar product must have the same amino acid sequence as the originator product to be defined as a biosimilar. It must also possess the same glycosolation patterns, and other structural features. Biosimilars don't have to be exactly the same as their originators, but they do have to be very close in terms of efficacy and safety.
When SERMO interviewed physicians about their concerns, one US rheumatologist expressed his concern that fast-tracking biosimilars through the approval process is like ‘high-stakes gambling.’ There are also concerns about indication extrapolation.
Ropka pointed to several messaging points that must be conveyed, including the message that the processes that underscore the biosimilar testing and approval process are not only stringent, but scientifically sound and informed by long-term experience in the rest of the world, particularly in Europe.
“Physicians need to know that the biosimilars target the same receptors and latch onto the receptors with the same strength. They should also know that immogenicity is part of the testing process---since immunogenicity is such a significant concern," she added.
Even as payers, patients and ultimately physicians adopt biosimilars, patent challenges can impede launch timelines. Janssen maintains that its patent is valid through September 2018 and that Celltrion cannot launch Inflectra until that date. However, last February, the US. Patent and Trade Office (USPTO) rejected Janssen’s patent.
In response to the USPTO’s decision, Janssen issued a statement vowing to “continue to defend its intellectual property rights, and if necessary…pursue all available appeals.” However, according to Hristina Ivanova, Associate Analyst at DRG, “We expect that Janssen's appeal will be rejected. On this basis, we anticipate that Inflectra will launch this year.”
According to Liang, however, patent disputes are part of the process. Litigation was anticipated both in the development of the generics pathway as well as that of biosimilars via the BPCIA,” he explained.
“While there is litigation ongoing, there are various mechanisms both within the BPCIA itself, and through other means, that will facilitate marketplace entry of these important medications. While it is anticipated branded drug companies will work to protect their products, education of stakeholders about biosimilars has largely been well-accepted and provided support for biosimilar momentum.”
This entire conversation ultimately comes back to patients who need biologics to treat debilitating, painful, life-threatening immunologic, inflammatory conditions, as well as certain cancers.
Large-scale adoption happens in waves, and adoption of biosimilars is no exception. As physicians gain better understanding of and more experience with biosimilars, attitudes will change---especially with the pressure brought to bear from payers and patients whose ability to access a biologic treatment is price driven.
Although the development of a robust biosimilars industry in the US may unfold differently than it did in Europe, Liang looks to that market as an example of how biosimilars can significantly increase access.
He said, “Perhaps most notable, is the increased patient access that Europe has experienced. For example, since biosimilar filgrastim was introduced to the UK, the number of patients who have been able to receive this drug has doubled. It is hoped that the ability for biosimilars to increase patient access as seen in the EU can translate to policies within the US to enable similar access for US-based patients, as well.”