Pfizer announced
November 18th that the biosimilar licensing application (BLA) for its
adalimumab biosimilar was approved by the Food and Drug Administration (FDA).
The drug will be marketed under the name Abrilada™ (adalimumab-afzb) in November
2023, according to the terms of a licensing agreement with AbbVie.
According to Pfizer, the drug was approved for the following
indications:
Ankylosing spondylitis
Crohn’s disease in adults
Juvenile idiopathic arthritis
Plaque psoriasis
Psoriatic arthritis
Rheumatoid arthritis
Ulcerative colitis
This represents a subset of reference product Humira®’s
indications (though it includes most of the major disorders).
Pfizer’s Global President, Inflammation and Immunology, Richard
Blackburn, said in a press release: “Our current portfolio of approved
biosimilar products is one of the broadest in the industry and we are proud to
offer additional treatment options for patients.”
Abrilada’s approval is the 25th biosimilar to be
licensed in the US, and fifth adalimumab approval. This will place Abrilada
as the seventh adalimumab biosimilar to launch in 2023, assuming all of the
manufacturers signing licensing agreements have gained approval by that time.
Extrapolation of indications by the Food and Drug
Administration (FDA) has been widely accepted by providers, payers, and most patient
groups. Yet how to address the approval of a narrow indication list (or skinny
label) seems less settled.
The four FDA-approved adalimumab biosimilars received the
agency’s endorsement for a large set of Humira®’s 10 indications. Amjevita®
and its brethren were approved for the treatment of moderate-to-severe
rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, moderate-to-severe
Crohn’s disease in adults, plaque psoriasis, moderate-to-severe polyarticular
juvenile idiopathic arthritis, and moderate-to-severe ulcerative colitis. Missing
are indications to treat pediatric Crohn’s disease, hidradenitis suppurativa,
and noninfectious uveitis (regardless of severity). When payers are asked whether
these missing indications (especially involving other autoimmune disorders) are
important for coverage decision making, they will likely agree that it makes
little difference to them.
In perhaps the more important biosimilar example, rituximab,
the indications are split between cancer treatment (e.g., non-Hodgkin’s
lymphoma and chronic lymphocytic leukemia) and autoimmune therapy (e.g., rheumatoid
arthritis, polyangiitis, pemphigus vulgaris). Although the dosing rate (50
mg/hr) is the same, Rituxan is given as part of a cytotoxic chemotherapy regimen
for patients with non-Hodgkin’s cancer versus methotrexate and methylprednisone
for autoimmune treatment. The two rituximab biosimilars (Truxima®
and Ruxience®) approved by the FDA do not have the rheumatoid arthritis
indication, although Ruxience has received approval for polyangiitis.
The reasons their manufacturers sought the skinny labels could
be many, including avoidance of patent infringement, quicker path to FDA
approval, or simply limited resources. However, Pfizer did complete a phase 3
trial in RA for Ruxience. Currently, Amgen/Allergan have completed phase 3
trials for both non-Hodgkin’s
lymphoma and rheumatoid
arthritis for their investigational biosimilar ABP 798. It is possible that
the partners could submit a 351(k) biologic license application at the end of Q4
2019 or Q1 2020.
For payers, the presence of skinny labels for biosimilars versus
approval for the entire set of indications matters little. In several market research
projects we have conducted with managed care medical directors and pharmacy
directors, their answers have been consistent: If the biosimilar is approved by
the FDA and is covered by the health plan or insurer, then the payer will be
far less concerned how the biosimilar is used. The reasons are simple: Payers are
gaining comfort with biosimilar use. If the reference product and biosimilar
have been demonstrated to be sufficiently equivalent to produce equivalent outcomes,
and the biosimilar is less expensive, why overmanage its use?
Further support for this view was published this month in BioDrugs.
These South Korean authors evaluated 11 head-to-head randomized, control trials
of rituximab biosimilars for use either non-Hodgkins lymphoma or RA. A total of
3,163 patients were included in the meta-analysis. Response rates in the trials
for lymphoma and RA were consistently equivalent, and no significant
differences were revealed in the formation of antidrug antibodies.
Perhaps the best opportunity for managed care organizations to restrict
the use of a biosimilar (or biologic) outside of step therapy is the ubiquitous
prior authorization (PA). Today, there is little, if no, reason for PA criteria
to be different for a reference biologic or its biosimilar(s), other than price
preference. In that case, the skinny label has little effect on a payer’s coverage.
In reporting its second quarter earnings, Momenta Pharmaceuticals stated on August 2 that it no longer plans to market M923, its biosimilar version of Humira®.
“Today,
Momenta announced the Company will cease active development of M923 at this
time, due to changes in the market opportunity associated with Humira patent
litigation settlements,” according to a company press release.
In 2018, Momenta decided to drastically scale back its biosimilar development as part of a strategic review. However, it continues to partner with Mylan on one remaining biosimilar candidate, M710. This is a biosimilar version of aflibercept (Eyela®).
Momenta’s troubles were first apparent after it completed its phase 3 trial of M923 in psoriasis. The clinical study pitted the biosimilar versus the EU-licensed version of adalimumab, and was successfully completed in 2017; however, no FDA filing ensued, despite a company announcement that it would occur in 2018. Later that year, the company stated that it delayed filing for financial reasons, but it would continue to seek a partner to commercialize the product.
In 2018, it signed a licensing agreement with AbbVie, which would have allowed it to launch in December 2023—in the back of the pack of licensed biosimilars in terms of timing (which could not have helped its efforts to seek a partner). In view of its refocusing its strategic outlook, the delay in filing a 351(k) biologic licensing application (BLA) application with the FDA may have made some sense from a couple of perspectives
First, the company may have thought twice about continuing expenditures if it was undecided as to whether it would remain committed to the biosimilar development. These expenditures could be quite significant (beyond payment of user fees) if the FDA requested additional data in an initial review of the BLA.
Second, with a potential launch date of December 2023, Momenta certainly had time to get its ducks in a row. If a commercialization partner could be lined up before the BLA filing, that company could help shoulder additional associated costs.
In any case, Momenta’s pull back is not entirely unexpected. Though it intended to file an application with the European Medicines Agency early this year (which would not have required a further delay in launch), this also did not occur (probably because of existing biosimilar adalimumab competition in Europe).
Momenta’s pipeline, beyond aflibercept, consists of other biologics for rare diseases. Its marketed products are for generics of Copaxone® and Lovenox®.
In a busy beginning of the week, the US Food and Drug
Administration approved new biosimilars for Humira®and Rituxan®. Samsung Bioepis gained approval for Hadlima™
(adalimumab-bwwd), and Pfizer scored with Ruxience™
(rituximab-pvvr).
HADLIMA
The approval for Hadlima covers the following indications:
Rheumatoid arthritis
Juvenile idiopathic arthritis
Psoriatic arthritis
Ankylosing spondylitis
Crohn’s disease in adults
Ulcerative colitis
Plaque psoriasis
Formerly known as SB5, Samsung Bioepis secured Hadlima’s approval
on the basis of phase 1 and phase 3 studies in rheumatoid arthritis.
The phase 3 investigation included over 500 patients, finding ACR20
responses to be equivalent to that of Humira (at 72%). Immunogenicity profiles
for the two agents were also similar through 52 weeks of a switching study.
According to its licensing agreement with Abbvie, manufacturer of Humira, Samsung will not be able to market this agent until end of June 2023. This agent joins Samsung’s two other approved anti-TNF biosimilars, Renflexis (infliximab) and Eticovo (etanercept). Only Renflexis is currently marketed in the US.
RUXIENCE
Pfizer’s newest biosimilar entry, Ruxience, has been
approved for a subset of indications of reference product Rituxan, including:
Treatment of adult patients with relapsed or refractory, low-grade or follicular B-cell non-Hodgkin’s lymphoma who are CD20-positive and have failed prior treatments
Patients who have nonprogressing, low-grade, CD20-positive B-cell non-Hodgkin’s lymphoma and who are stable after receiving a prior chemotherapy regimen containing cyclophosphamide, vincristine and prednisone
Patients with CD20-positive follicular lymphoma who are therapy naïve in combination with chemotherapy or who had responded to previous rituximab therapy
Patients with CD20-positive chronic lymphocytic leukemia in combination with fludarabine and cyclophosphamide
Granulomatosis with polyangiitis in adult patients in combination with glucocorticoids
The biosimilar does not include Rituxan’s labeled indication for rheumatoid arthritis, similar to the other approved rituximab biosimilar.
The application for Ruxience included the results of the
phase 3 clinical trial (REFLECTIONS), which included
394 patients with follicular lymphoma. Compared with the EU-licensed version of
rituximab (MabThera®), Ruxience was found to provide equivalent
clinical and safety outcomes.
Originally designated PF-05280586, Pfizer has not disclosed when Ruxience will be available. Pfizer signed a settlement with Roche (Genentech) over litigation for a key Rituxan patent, but terms of this agreement were not disclosed. The other FDA-approved biosimilar competitor in this space, Celltrion’s Truxima®, is similarly awaiting launch.
$44 Billion by 2024. $250 Billion by 2024. Whatever. I’ve not been very impressed by the many attempts to estimate how much money biosimilars could save the US health care system. Even the more well-known estimates of biosimilar savings, like those from RAND and Express Scripts, have been little more than games of “pin the tail on the donkey,” as the researchers were blinded as to when products would actually launch and the unproved potential for biosimilar uptake.
Of course, this was not the economists’ fault. They had little past information about the US biosimilars market on which to base their view of the future, and they could not have predicted the extent to which patent litigation prevented access to these medications.
I do appreciate the latest effort, however, by the Biosimilars Council (a subsidiary of the Association for Accessible Medicines) to understand biosimilar savings. Instead of predicting the future, the Council reviewed the past to assess how much each biosimilar would have saved the health care system and patients had they launched as expected.
The number they landed on was $7.6
billion since the introduction of the first biosimilar in 2015 through
2018. It applies not to the seven biosimilars (as of June 12, 2019) that were
launched but to the 12 that were approved but not available because of ongoing patent
litigation.
As impressive as this lost opportunity sounds, I believe that the biosimilar savings estimate is still too low. The calculation by the Biosimilars Council does not seem to include an important aspect: The reference manufacturer takes significant price annually for each year biosimilar competition does not emerge. The analysis assumed a 30% price discount and 40% uptake, split between two biosimilar competitors. Uptake was assumed to increase to 50% if three were three separate competitors. Yet the analysis was based on actual list prices from IQVIA data.
If biosimilar competition existed, these price increases would not have occurred, likely at all. For example, the availability of Inflectra® and Reflexis® did not fuel great uptake of biosimilars at the expense of Remicade®; however, the infliximab market was changed suddenly, by forcing Janssen Biotech to not only halt their price increases in 2016 but significantly lower their net pricing. As a result, average sales prices have been dropping ever since the introduction of the biosimilars (from a high of $85.81 per 10 mg in January 2018 to $69.96 in July 2019 [–19%]).
Consider the same scenario for the adalimumab biosimilars, which I wrote about previously. Without competition, AbbVie can raise its retail prices right through 2022, resulting in upwards of 50% higher list prices. Although this does not account for contracting, each new payer contract it should be remembered, is based on the current price (not the previously rebated costs). In other words, the higher prices work their way into subsequent payer contracts. How much additional biosimilar savings, on top of the calculated $7.6 billion, would that be? I’m not an economist, but it shouldn’t be too difficult to estimate, based on no future price increases (only future price reductions). Over an 18-month period, Amgen raised the price of Enbrel® four times, resulting in a 37% jump by 2016. Had biosimilar etanercept been available at the time, that would not have happened, yielding an instant 37% savings. That does not prevent the reference manufacturer from hiking the drug price in the months before biosimilar competition occurs. This practice is expected to continue. However, the earliest possible availability of biosimilars will yield compounded price savings.
It seems that AbbVie has won the battle and the war. The last remaining holdout in the fight to bring a biosimilar adalimumab to market before 2023 has capitulated, as AbbVie announced May 14 that Boehringer Ingelheim agreed to the terms of a licensing arrangement. This agreement allows Boehringer Ingelheim to enter the marketplace July 1, 2023, getting a slight jump on some other licensees, but it effectively ends the protracted patent litigation that Boehringer hoped to win.
In an interview with BR&R, Molly Burich, Boehringer Ingelheim’s Director, Public Policy, Biosimilars and Pipeline, told us in October 2018, “We are committed to making Cyltezo® available to US patients as soon as possible and certainly before 2023.”
WHICH COMPANIES HAVE SIGNED LICENSING DEALS WITH ABBVIE?
Company/Partner
Drug Name
Launch Date
Amgen
Amjevita*
January 2023
Samsung Bioepis/Merck
SB5
June 2023
Boehringer Ingelheim
Cytelzo*
July 2023
Mylan/Fujifilm Kyowa Kirin Biologics
Hulio
August 2023
Sandoz
Hyrimoz*
September 2023
Fresenius Kabi
MSB11022
September 2023
Pfizer
TBD
November 2023
Momenta
M923
December 2023
Coherus
CH-1420
December 2023
*Received FDA
Approval.
However,
at that time, Ms. Burich also disclosed that Cyltezo would not be
commercialized in Europe; in October, the stampede of biosimilar manufacturers had
just left the starting gate. In addition, Boehringer had earlier decided to
drop plans to develop other biosimilars in the pipeline and focus solely on
Cyltezo. That would seem to leave Boehringer out in the cold until July 2023.
In response to BR&R’s
query, Susan Holz, Boehringer’s Director
of Communications, Specialty Care, provided the following statement: “As
we previously shared, at this point in time, our focus remains on providing
patient access to our biosimilar Cyltezo in the US, and future biosimilars
activities will be driven out of this market. Boehringer Ingelheim continuously
evaluates our business portfolio, and we assess potential strategic
partnerships to help enhance our pipeline and development capabilities. As you
know, we have stopped development activities for the rest of the world, and I
am not able to comment on specifics regarding our biosimilar in- or
out-licensing strategy.”
Boehringer Ingelheim had
reported that it is seeking the interchangeability designation for its adalimumab
biosimilar. In the possible scenario where Cyltezo won its patent challenge,
and gained the interchangeability designation from the FDA (note that FDA only issued
its final interchangeability guidelines draft this week), the marketing potential
was rosy indeed. However, suppose the FDA approves the interchangeability label
for Cyltezo. It cannot leverage it until after Amgen’s and Samsung Bioepis’
adalimumab biosimilars have launched. Will it have the same advantage? That’s
difficult to say. Payers will be anxious to grab immediate savings on this
product, and interchangeability may not be considered such a great benefit.
That is, in four years, will payers routinely switch available biosimilar
agents anyway? My guess is that health plans and insurers will be leaning in
that direction.
On the other hand, it will be easier to automatically switch patients in nearly every state. That lever will only be used if Boehringer gives payers a real reason to use it—a significantly better deal than the existing options. AbbVie offered huge discounts (on the order of 80% in some countries) in an effort to hang on to some marketshare once biosimilars were available in the EU. After all, why worry about interchangeability and switching when you can continue to use Humira® at a 75% discount?
Ms. Holz told BR&R, “In regards to interchangeability, this is a very important issue for many stakeholders, as it is the catalyst for automatic substitution at the pharmacy level, which in turn may help drive efficient use of biosimilars and maximize the cost-saving potential of these important medicines.” She added, “We were very pleased to see the Agency finalized interchangeability guidance that retained the appropriate balance between a high-bar to prove interchangeability and product-specific flexibility to make such a status attainable.”
In the next four years, the price of Humira will undoubtedly rise. This will mean that savings gained in 2023 will be little more than money lost to the system over the previous 48 months. As significantly, it represents tens of billions of dollars into AbbVie’s bottom line from a product that was approved in the US 17 years ago.
In the biosimilars arena, at least in the US, history seems
to be truncated. Policy changes occur in rapid fire succession these days, and
access scenarios don’t evolve—they just happen or they don’t! Along this brief
journey, I’ve taken the opportunity to focus on some of the sign posts that
were exceedingly poor maps for navigating the future.
One of the first blogs I wrote for The Center for Biosimilars in early 2016, involved a defeat for Amgen in its patent litigation with AbbVie regarding Humira®. No one was sure what the implications of this decision would be. Amgen was on the road to gaining approval of the first biosimilar adalimumab. The payer and investment community sensed momentum building towards the imminent takedown of the number 1 biologic in terms of sales. I referenced 2016 Humira revenue estimates of $14 billion for AbbVie, and mentioned two other prospective biosimilar makers—Baxalta and Momenta—being hot on Amgen’s heels.
In that same article, many in the investment community was under the belief that a US marketed adalimumab biosimilar would be available by 2020. Instead, January 2023 is looking more inevitable. I wrote, “The investment community believes that Amgen will come out on top; they believe that AbbVie will have $6 billion—not $18 billion—in Humira sales by 2020.”
I’m not sure that I could have been more wrong in my
assumptions or sentiments, thinking that AbbVie’s maze of 70 patents (at the
time) could be severely damaged at that time by the process to challenge patents.
This may happen today through Boehringer’s efforts, but I wouldn’t count on it.
The other major players don’t have the stomach for fighting this battle.
In 2017, Baxalta and Momenta have dropped out of the biosimilar contention for Humira’s marketshare, replaced by Sandoz, Boehringer, Coherus, Samsung Bioepis, and perhaps others. Baxalta and Momenta , one being taken over by Shire and the other facing financial realities.
Unfortunately, it will take a miracle, in the form of a Boehringer victory or even less likely, adoption of Dr. Peter Bach’s biologic pricing proposal, to get adalimumab to the payer market. The fact that the proposal that Dr. Bach and his colleagues at Memorial Sloan Kettering laid out received as much attention as it did tells quite a bit about our serious frustration today with access to biosimilar savings.
Of course, very few actions taken by the current Administration have yet to be implemented. These are intended to bolster the biosimilar industry and move from promised to actual savings. However, the signs are telling me that we’re not in an evolutionary phase of biosimilar development–an extinction event may be around the corner.
Only Boehringer Ingelheim remains as a biosimilar maker who
has an approved version of adalimumab but who has not signed on with AbbVie.
United Food and Commercial Workers Local 1500 has filed the suit with the other
manufacturers and AbbVie, claiming that by their actions, they are trying to “divide
the market for adalimumab between Europe and the United States,” according to
the Center for Biosimilars report.
This is an interesting question. The individual motivations of the first companies to come to agreement with AbbVie (Amgen, then Samsung Bioepis) included an end to interminable patent legislation in the US. They wanted the ability to immediately plan launches in Europe (starting in October 2018). The motivations of most other subsequent signees almost certainly was to not forfeit marketshare in Europe, which was needed to help sustain biosimilar development efforts for the US market. In fact, many of these prospective US manufacturers already had received approval in the EU.
AbbVie’s principal patents on Humira® expired in Europe in October 2018. The last of the principal patents are supposed to expire around 2023 in the US anyway. Was it necessary to arrange serial US launches as demonstrated in this link? Would patent litigation have continued well past the supposed patent expiration date? Knowing AbbVie, this is likely. Their several patents involving adalimumab use to treat individual diseases would provide AbbVie a basis for forging ahead with lawsuits that would have gained them additional billions of dollars in sales while the suits meandered toward conclusion.
Does this mean that access to Humira is accelerated through the signing of the royalty agreements, rather than delayed through acts of collusion? That is difficult to say. Although should the lone holdout—Boehringer Ingelheim—decide that it makes business sense to launch at risk, it could topple the carefully orchestrated structure of the agreements. Amgen believes that it will launch the first adalimumab biosimilar, and experience a few months of exclusivity in the US. At that point, Amgen (and every subsequent adalimumab biosimilar maker) would have to decide whether (1) to do the same or risk losing its advantage, (2) start working towards marketing plan B, or (3) cede the initial marketshare and its billions in revenue and wait it out. If Boehringer obtains its sought after interchangeability designation, that may well speed up the process.
Personally, I find it hard to believe that these individual
acts represent premeditated collusion; although the resulting lack of access to
the many biosimilar versions may look to others as an orchestrated maneuver.
The multitude of companies that have lined up to sign 2023 licensing
agreements with Abbvie on sales of Humira® biosimilars has grown
again. The latest biosimilar maker added to the list is Coherus Biosciences.
Coherus has an investigational adalimumab biosimilar that completed
a phase 3 trial in 2017 in patients with plaque
psoriasis and psoriatic arthritis. CHS-1420 was found to yield similar
clinical outcomes compared with the reference product.
According to the press
release from Coherus announcing the deal, the biosimilar will be available
for marketing December 15, 2023. This will make it the eighth biosimilar version
of adalimumab to enter the market, with Amgen entering first, in January of
that year. As with the other deals signed by Abbvie, this signing concludes any
patent litigation between the parties and Coherus will pay royalties to Abbvie
on the sales of its biosimilar.
Coherus is expected to file a submission with the European
Medicines Agency, though the timing of this filing has not been disclosed. Furthermore,
it has not yet signed a deal with a marketing partner. In past conference
calls, the biosimilar maker has indicated that it will not focus its resources
on sales of its products outside the US.
COHERUS SUES AMGEN
OVER ADALIMUMAB PATENTS
To complicate matters a bit more, Coherus has launched a patent
infringement suit against Amgen, believed to be the first of a biosimilar
maker against another. Amgen’s Amjevita® was approved by the Food and
Drug Administration in 2016, and has been for sale in the EU. Coherus intends
to file for FDA approval in Q4 2019. Coherus contends that Amgen’s manufacture
of Amjevita violates Coherus’ US patents 10,155,039; 10,159,732; and
10,159,733. These patents involve the creation of stable aqueous formulations of
adalimumab.
Coherus seeks
“damages adequate to compensate for past, present, and future infringement,” which
could have implications for revenues from the European sales of Amgen’s
biosimilar, because of its manufacture in the US. In addition, Coherus seeks an
injunction from the court that permanently enjoins Amgen from engaging in
further alleged infringement.
Coherus President and CEO Denny Lanfear said in its January
25th press release, “Coherus recognized early on the central role intellectual
property would play in advancing biosimilars to market. One important element
of our IP strategy for advancing [CHS-1420] is reflected in the success we’ve
achieved in patenting our innovations in the field of adalimumab formulation.
We believe in the strength of our IP and we intend to protect it.”
Although generic manufacturers engaging in patent suits with
competitors has occasionally occurred, this may be a first in the biosimilar
community. I suppose it was only a matter of time.
