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, Pennsylvania based Janssen Biotech’s Remicade when co-administered
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.
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.
Substitution concerns
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.
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 provoke an immune
response, until the drugs are out on the market and being used in large
populations, explained Jean Sathish, lecturer, molecular 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.
Alissa Fleck
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.