Biopharmaceutical Report I
Rheumatologists in the US eagerly anticipate biosimilars for pricey anti-TNFs and other biologics used to treat rheumatic diseases but have expressed concern over perceptions of not having full prescribing power. Others say physicians should not be concerned, as they will still have ultimate discretion, and biosimilars will not be used interchangeably.
Experts agreed they are not concerned about biosimilars having unanticipated adverse effects. Their concern lies in the belief that, until biosimilars have entered the market on a large scale, it will be difficult to determine the extent of their bioequivalence.
The PLANETRA study showed there is no justification for physician fears that biosimilars will perform worse than their originator biologic counterparts, said Dr Daniel Furst, director, rheumatology clinical research center, UCLA, Los Angeles, California. The PLANETRA study was a randomized-double-blind parallel group study to demonstrate equivalence in efficacy and safety of CT-P13 to its originator, Horsham, Pennsylvaniabased Janssen Biotech’s Remicade when coadministered with methotrexate in patients with active rheumatoid arthritis (RA) [Yoo, DH. Annals of the Rheumatic Diseases. 2013 Oct; 72(10):1613-20].
In the study, CT-P13 demonstrated equivalent efficacy to Remicade at week 30 with a comparable pharmacokinetic profile and immunogenicity and comparable safety profile, according to the Journal.
Efficacy more of a concern than safety
More rheumatic disease biosimilars are also coming up for EMA decision in 2H15, including Samsung Bioepis’ Remicade biosimilar, SB2, and its biosimilar of Amgen (NASDAQ:AMGN), Pfizer (NYSE:PFE) and Takeda’s (TYO:4502) Enbrel (etanercept), SB4, according to company press releases.
SB4 and SB2 both met their primary endpoints in pivotal Phase III studies, demonstrating equivalence to their originators and equivalent safety profiles, according to a 10 June press release.
A drug that’s exactly the same but less expensive is great as long as the physician gets to decide when to prescribe it, a rheumatologist said. Still, these are theoretical concerns at this point, she said, adding it’s a matter of waiting to see how it plays out once biosimilars enter the US market.
Europe has 20 biosimilars on the market, including anti-TNFs, which have had no unexpected adverse effects, said Brenda Huneycutt, director, Avalere’s FDA Regulatory, Strategy and Policy Practice.
Despite the PLANETRA study’s positive findings for biosimilars, the fear is pharmacies having the power to substitute biologics with biosimilars without appropriate identification, said Furst, noting that would make it impossible to track side effect profiles, should negative side effects arise.
No laws currently exist that allow for automatic substitution of biologics with biosimilars in the pharmacy and, while such a law could theoretically be drafted, it would be shocking, noted Huneycutt. Under the 2009 Biologics Price Competition and Innovation Act (BPCIA), only interchangeable biologics could be substituted at the pharmacy, and the FDA has still not laid out a clear path for having biosimilars approved as interchangeable, Huneycutt explained. To date no biosimilar has been approved as an interchangeable, she added.
Pending legislation in at least 30 states includes provisions that biosimilar manufacturers would also have to apply for interchangeability status-- similar to existing legislation for generics--before pharmacy substitution could occur, according to the National Conference of State Legislature.
Ultimately, it’s uncertain whether pharmacy interchangeability laws would be enacted at the state or federal level, said Huneycutt.
The rheumatologist agreed that pharmacy substitution at the pharmacist’s discretion would be a major concern. Another concern is insurance companies mandating switching patients from biologics to biosimilars or interchangeables when patients are doing perfectly well on brand name medication, and that’s a major worry that rheumatologists have, she said.
Price reduction similar to Europe anticipated
Physicians always have the option of having medications dispensed as written, so the physician still has a level of control, even if interchangeables were approved, explained Huneycutt. Physicians’ concerns about interchangeables are not completely unfounded though as, while there should be no clinical difference between a biosimilar and the reference product, it’s hard to believe that a product is 100% the same as the originator, she said. Every batch might not be the same, and physicians may have different comfort levels depending on the sensitivity of their patients or the nuances of different indications when it comes to interchangeability, she said.
Oncologists would typically be more open to switching their patients from a biologic to a biosimilar than rheumatologists whose patients have stabilized on a treatment, said Huneycutt. Rheumatologists are likely to try biosimilars on new patients, rather than switching patients who are stabilized on treatment, Huneycutt said.
When generic substitution became commonplace, there were physician concerns that generics were potentially not as good as originator drugs, and biologics raise a similar concern, said Huneycutt.
Anti-TNFs like Remicade are also more complex than granulocyte colony-stimulating factor (G-CSF) analogs like Amgen’s (NASDAQ:AMGN) Neuopgen (filgrastim), for which the only biosimilar is approved in the US, making immunogenicity possibly a greater concern for the more complex drug, Huneycutt noted.
Further, the administration of many biologics for rheumatic diseases, for instance infusions, happens in the hospital setting, so the drugs the hospital has available comes into play, said Huneycutt.
While physicians largely agree that fear sur - rounding biosimilars is unwarranted, it’s hard to know what impacts there might be in terms of immunogenicity, or the ability of a drug to pro - voke an immune response, until the drugs are out on the market and being used in large pop - ulations, explained Jean Sathish, lecturer, mo - lecular and clinical pharmacology, University of Liverpool, UK.
Getting a patient to respond to an anti-TNF, especially for a period of time, is a delicate balance, the rheumatologist explained. If a patient is switched to a biosimilar and does not respond to the biosimilar as well as the originator, and you try to put them back on the original antiTNF, it might not work for them again, and then you’ve missed the boat if they don’t respond to either, she noted. Still, the perception is that safety issues and immunogenicity are less of a concern than they used to be, said Sathish.
Price and uptake in the US
It’s important to remain conservative at the moment while sorting out regulatory issues around biosimilars in the US, but it’s a fervent hope that in the long run, there will be RA biosimilars that, when prescribed appropriately, will have a 25-30% cut in cost without any downsides, said Furst.
A 20% savings is likely on US biosimilars, which is not huge, but is a pretty good deal as these biologics are so expensive to start off with and so many people are on anti-TNFs, said Sathish.
It’s hard to imagine why there would be uptake for rheumatology biosimilars in the US, especially if there is no automatic substitution at the pharmacy as with small molecules, said Arti Rai, professor of law, Duke Institute for Genome Sciences & Policy, Durham, North Carolina. The price reduction is not dramatic enough, she said, adding that it will also hurt if biosimilars are not approved for all the same indications as their originators.
It’s difficult to predict what uptake will look like in the US and the European model is not necessarily the most accurate, explained Sathish. The UK, for instance, has publicly funded healthcare, and will conduct a cost/benefit analysis and view any biosimilar favorably, he said, noting that the US tends to be more individualistic when it comes to healthcare.
It may be a number of years before the US sees major anti-TNF biosimilars approved and launched due to ongoing litigation surrounding the BPCIA, this news service previously reported on 29 May. The Korean manufacturer Celltrion (KOSDAQ: 068270) is attempting to bring Remsima, a Remicade biosimilar, to market, but it could be tangled up in a legal battle with Remicade originator Janssen Biotech until at least 2018, this news service reported. Enbrel, another major anti-TNF, was also given a patent extension of an additional 16 years in the US in 2012. Furst said he is holding out hope for a biosimilar for Biogen’s (NASDAQ:BIIB) Rituxan (rituximab) to enter the US market. The patent on Rituxan expires in the US in September 2016.
Reporter, New York
Alissa is a former freelance editor and journalist who has been a regular contributor for Bankrate, the Huffington Post, Truthout, Global Post and three Straus News publications in Manhattan. She has written medical and health copy for websites including SF Gate (the San Francisco Chronicle online) and Livestrong as well as for private clients.