|Company/Partner||Drug Name||Launch Date|
|Samsung Bioepis/Merck||SB5||June 2023|
|Mylan/Fujifilm Kyowa Kirin Biologics||Hulio||August 2023|
|Fresenius Kabi||MSB11022||September 2023|
|*Received FDA Approval.|
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.
On occasion, we profile some biosimilar manufacturers about whom our readers may not be familiar. This generally refers to companies that have products that are in earlier-stage research or those who simply have not been in the news as often as their colleagues. In this post, we highlight a Guangzhou, China–based company, Bio-Thera Solutions.
Established in 2003, Bio-Thera Solutions “is dedicated to researching and developing innovative and biosimilar therapeutics for the treatment of cancers, autoimmune, cardiovascular diseases, and other serious medical conditions.” It claims several biosimilar and innovative therapies in its pipeline. According to its website, Bio-Thera’s leadership team members spent extensive time in the US. The CEO and Founder Shengfeng Li was also a founder of a California company Abmaxis, which was acquired by Merck, and worked at COR Therapeutics, which became part of Milennium. Chief Medical Officer Li Zhang worked for eight years at the Food and Drug Administration’s Center of Drug Evaluation and Research.
Why you may be hearing more about this company: Bio-Thera has advanced one of its key molecules, a biosimilar of bevacizumab (reference product, Avastin®) into a phase 3 study against EU-licensed Avastin. The company’s objective is to file a 351(k) application for this product, BAT-1706, with the US FDA and the European Medicines Agency in 2020.
The company announced a new partnership with Mumbai, India-based Cipla Ltd, to market this product in emerging markets. It is not yet known whether Bio-Thera intends to partner with another organization to market in North America or attempt to build its own sales structure.
Other products in research and development include an adalimumab biosimilar (BAT-1406), for which an application for approval has been filed for the Chinese market, and a phase 1 tocilizumab (Actemra®) biosimilar (BAT-1806) for the treatment of autoimmune diseases. The company’s information does not indicate whether either of these products will be targeted for the US market. In a 2018 press release, Bio-Thera indicated that biosimilars of secukinumab (Cosentyx®), golimumab (Simponi®), and ustekinumab (Stelara®) were also in the pipeline. Regardless of the success of its bevacizumab and adalimumab biosimilars, the company seems to be well-aligned to address patent expirations of next-generation biologics.
In other biosimilar news… Regulatory Focus reported Pfizer’s announcement that the drug maker has reevaluated its biosimilar drug pipeline. It has dropped plans to develop 5 biosimilars in preclinical development. The products themselves were not disclosed and were not listed in earlier available version of Pfizer’s drug pipeline. Five other biosimilars in clinical development will continue moving forward, according to the company. This does not affect biosimilars already approved by the FDA. No reason for the decision was given, other than that this was part of an “R&E investment review.”
Earlier this month, Pfizer notified the European Medicines Agency (EMA) that it was withdrawing one of its two applications for approval of its biosimilar adalimumab.
According to Pfizer’s Director of Global Media Relations, Thomas Biegi, the company had submitted two applications for this biosimilar, one for a limited set of indications, and the other for the full array of autoimmune indications of the reference product Humira®. Pfizer has decided to focus on gaining approval for the full slate of indications and withdrew the other application. Under the “skinny label,” the product would have been marketed as Fyzoclad™ in Europe. The potential brand name of the biosimilar if approved with all of the reference product’s indications was not disclosed. In the US, the biosimilar is still known as PF-06410293 .
Although Pfizer would not confirm its plans for the US filing, phase 3 trial results for PF-06410293 have been published, establishing the biosimilar’s equivalency to Humira in terms of efficacy, safety, and immunogenicity.
Pfizer noted in its December 5th letter to EMA that their decision was not related to safety or efficacy. No doubt, Pfizer is surveying the heavy competition for adalimumab in Europe today. Pfizer did not elaborate on why the decision was made to submit applications for both the skinny label and the full set of indications.
Pfizer signed a licensing deal with Abbvie on November 30 to market this adalimumab biosimilar in the US. It will be the sixth biosimilar to enter the market in 2023, based on this deal. Therefore, Pfizer must believe that a sixth biosimilar entrant to the US market at that time may still yield relevant revenues and marketshare.
According to EvaluatePharma, Humira US sales estimates (published in 2018) for 2020 will be about $21 billion. By 2024, this company believes Abbvie’s share of the revenue will be a bit more than $12 billion (which is not much different than today’s figures). If this guess is accurate, that leaves $9 billion for seven or so biosimilar makers. If the guess is very inaccurate, and Abbvie is left with far less revenue because of the competition and falling prices, then any number of adalimumab biosimilar manufacturers could attain more than $1 billion in sales.
In other biosimilar news…Amgen has announced the filing of a new biosimilar version of infliximab. ABP 710 was the subject of a phase 3 trial in patients with moderate-to-severe rheumatoid arthritis; researchers concluded that the drug was equivalent to Remicade® in terms of efficacy, safety and immunogenicity. Today’s filing would put this biosimilar on a path to a late Q3 or early Q4 2019 decision by the FDA. If approved, ABP 710 would be the fourth infliximab biosimilar approved in the United States (Pfizer’s Inflixi® is also approved but will only be sold overseas).
This post was updated and corrected on December 18, 2018.
On November 28, 2018, the Food and Drug Administration (FDA) announced the approval of rituximab-abbs (Truxima™), produced by Celltrion and marketed by Teva.
Approval for this rituximab biosimilar was overwhelmingly recommended by the FDA’s Oncology Drug Advisory Committee by a vote of 16-0 in October. It is the first biosimilar agent approved for the treatment of relapsed or refractory, low grade, or follicular non-Hodgkin’s lymphoma—specifically in adult patients with the CD20+ B-cell variety. The drug makers did not seek approval for the Rituxan’s autoimmune indications, and the FDA did not grant extrapolated approval for them.
According to the FDA’s announcement, the most common side effects of Truxima are infusion reactions, fever, abnormally low level of lymphocytes in the blood (lymphopenia), chills, infection and weakness (asthenia). Health care providers are advised to monitor patients for tumor lysis syndrome (a complication of treatment where tumor cells are killed off at the same time and released into the bloodstream), cardiac adverse reactions, damage to kidneys (renal toxicity), and bowel obstruction and perforation.
This leaves a wide open marketing window for Celltrion and Teva, as Sandoz announced in late October that it was halting its effort to bring its own rituximab biosimilar to the market. There is no word as of this writing regarding the launch and pricing of Truxima in the US. This also represents the second FDA approval for Celltrion; its infliximab biosimilar, Inflectra, was approved in 2016.
In Other Biosimilar News… As BR&R reported in our October discussion with Molly Burich, MS, Director, Public Policy: Biosimilars and Pipeline, Boehringer Ingelheim had decided to forego marketing its adalimumab biosimilar Cyltezo® in the EU. This is likely owing to the highly competitive environment and the huge pricing discounts being signed by European countries. However, Boehringer has now announced its intention to discontinue all efforts to market and develop any biosimilars outside of the US market. This may come as little surprise, as the Boehringer biosimilar pipeline was not aggressively stocked. Instead, it has been focused on seeking interchangeability status for Cyltezo and to launch this product as soon as possible.
Since the October expiration of Abbvie’s EU patent, the potential Humira savings seem to be truly mind-blowing. After implementing its contracts for adalimumab, the UK National Health Service (NHS) should save about three quarters of the $514 million (£400 million) it spends each year on this product alone.
In a fixed-budgeted system like that in the UK, the real implications of these savings become clear. According to the NHS, this additional $385 million (£300 million) will enable it to pay for 11,700 community care nurses or 19,800 treatments in patients with breast cancer.
And to earn these Humira savings, the NHS does not exclude using the originator product Humira. It has signed contracts (with large price cuts) with Abbvie, as well as with biosimilar manufacturers Amgen, Biogen, Mylan and its partner Fujifilm Kyowa Kirin, and Sandoz.
Could the US see such savings on adalimumab in 5 years? Although the competition may be fierce when the brand loses patent protection in 2023, Abbvie has created a stepped-launch scenario with its licensing agreements. Rather than a jailbreak of competition, as we are seeing in the EU with patent expiration there in October 2018, the timing of the licensing agreements may limit the drop in per-unit price, at least for the first year or so.
After that time, payers will be able to choose from all biosimilar adalimumab manufacturers, which should then drive pricing down (or rebates up) considerably, resulting in long-sought lower net costs. However, this will happen only after years of price increases by Abbvie. Abbvie has not claimed, while it is drastically slashing its price in the EU, that it will be losing money. In part, that is because its US revenues on Humira will continue to be at over $10 billion a year. Furthermore, its revenues largely reflect pure profit on the manufacturing of the product today, as its research and development costs were covered 15 years ago and ongoing marketing costs are a tiny fraction of this figure.
Despite repeated protestations in the US that healthcare resources are not unlimited, our system is not based on a fixed budget. It is not disingenuous to consider savings in the terms posed by NHS. Defining the large savings in terms of other useful expenditures give people a concrete idea of how the money can be better used. The need for savings on drug expenditures is acute in this nation, and biosimilars will eventually lead the way.
Just a few short weeks ago, Abbvie announced that it intended to rely on discounts as deep as 80% in parts of the EU to retain Humira® marketshare. One bellweather EU member country has signaled that it is signing tenders with other biosimilar adalimumab manufacturers.
The Center for Biosimilars reported an Email exchange with the Danish national tendering authority Amgros, which manages the country’s bidding system. Amgros confirmed that Abbvie did not provide the best bid for two tenders for adalimumab (covering January to March 2019 and covering April to December 2019). Five companies (including Abbvie) competed for the national tenders. Although Abbvie did not rank best for pricing, agreements were signed with all five companies.
According to the report, a spokesperson for Amgro said, “In both tenders for adalimumab 40 mg, we have entered into agreements with 5 companies—the agreements are ranked according to price. In both tenders, we have signed an agreement with Abbvie for Humira—but Humira does not have the lowest price (ie, is not the winner with the highest ranking).”
The importance of this action may extend beyond Denmark, as several European countries utilize others’ pricing decisions as a benchmark for their own. For example, the price for adalimumab in Bulgaria by policy cannot exceed that in 17 other EU countries.
We previously reported that Momenta Pharmaceuticals reevaluated its biopharmaceutical strategy going forward, deciding to move forward only with its investigational adalimumab and aflibercept biosimilars. Yesterday, Momenta announced that it has joined the long queue of pharmaceutical manufacturers signing a biosimilar licensing deal with Abbvie, which will allow commercialization of M923, its biosimilar to Humira, should it obtain regulatory approval. Momenta’s licensing deal is the fifth one signed by prospective biosimilar marketers in the US.
This agreement was pretty much a no-brainer for Momenta. The company did not have the stomach for attempting either an extended patent fight or an at-risk launch. However, the biosimilar licensing agreement only allows Momenta to market its adalimumab biosimilar in the US after December 2023, which will make it the fifth Humira biosimilar that will launch under the licensing agreements (Table). The main patents for Humira have expired in Europe, and these agreements have generally allowed the European launches to occur as of October 16 of this year.
Of the manufacturers signing biosimilar licensing deals with Abbvie , only Amgen and Sandoz have earned FDA approval for Amjevita® and Hyrimoz®, respectively. And Boehringer Ingelheim is still duking out patent litigation with Abbvie in the courts over its approved biosimilar agent Cytelzo®, for which it hopes to receive an interchangeability designation. The second through fifth agents entering the fight will be likely pounding away at subsequently smaller slices of revenue.
Perhaps the most frustrating part is that Abbvie is running a lucrative game; it will collect royalties from all of these manufacturers in 2023 and beyond, which will help offset declining marketshare from its biggest revenue contributor.
In Abbvie’s Web: Who Has Signed Licensing Agreements for Biosimilar Adalimumab?
Mylan/Fujifilm Kyowa Kirin Biologics
|*Received FDA Approval.|
Note: This post was revised and corrected, November 8, 2018.
The Food and Drug Administration (FDA) announced yesterday the approval of adalimumab-adaz from Sandoz. The new agent, dubbed Hyrimoz™, will not be launched in the US until 2023. The approval of Hyrimoz is the third for Sandoz (but only one, Zarxio®, is available for prescription in the US).
The FDA approval of adalimumab-adaz covered several indications, including adult Crohn’s disease, ankylosing spondylitis, juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis. The drug’s approval was based partly on the findings of a phase 3 clinical trial in patients with chronic plaque psoriasis, in which the biosimilar was found to be noninferior to the originator product Humira® in terms of efficacy (i.e., PASI 75 score) and safety.
Hyrimoz is the third approved adalimumab biosimilar, none of which have been marketed due to patent litigation. Abbvie has signed licensing agreements with Amgen and Samsung Bioepis to delay US launches.
HUMIRA PRICE DISCOUNT IN THE EU
This biosimilar is being marketed in the EU, competing with several others for the Humira marketshare overseas. However, signs of real competition are heating up in Europe, as Abbvie has offered a Humira price discount of as much as 80%.
According to an article published in Fierce Pharma, Abbvie is hoping to squash the biosimilar competition and prevent it from gaining valuable European experience ahead of US launches in 2023. The article cited a report by Bernstein analyst Ronny Gal, indicating that even at an 80% discount, Humira will still be profitable for Abbvie. “The objective is to defend the US market by denying the biosimilars in-market experience [in Europe] and then arguing the Europeans ‘chose’ Humira over the biosimilars for quality reasons beyond price,” according to Gal’s report.
On the other hand, this puts the biosimilar makers in a tight spot on the continent. They need to earn back their R&D costs and may be unwilling to face an immediate low-profit reality. Revenues within the EU for Humira are $4 billion. Even if it offered tenders of 80% for every member country (and they were accepted), revenues would still be in the range of $800 million. This would drastically reduce the size of the revenue slices for the European biosimilar competitors. It could be possible that some may drop out of the market, at least until the time of the US launches.
In part two and the conclusion of this interview, Molly Burich, MS, Director, Public Policy: Biosimilars and Pipeline, speaks to Boehringer Ingelheim’s progress in Cytelzo interchangeability studies, its plans for the product in Europe in the face of several adalimumab biosimilars launches in the EU, and also the complexity inherent in CMS’s plans to move biologic agents from part B to part D coverage.
BR&R: Boehringer Ingelheim indicated that it started the study on Cytelzo interchangeability last year. What’s the progress on this effort?
Burich: The trial is continuing to progress. It’s a high bar and a big commitment. We will certainly publicize relevant information in due course.
We feel that for Cyltezo, in particular, interchangeability is an important component. It may drive switching. The study will also show a complement of clinical data around that topic. We hope to have information to share in the future. [Editor’s Note: The VOLTAIRE-X study, which will evaluate the effect of switching between Cyltezo and Humira in patients with plaque psoriasis, has an estimated primary study completion date of March 2020 and full study completion of July 2020, according to ClinicalTrials.gov]
BR&R: Speaking about Cyltezo, I have a question about the marketing floodgates being opened in the EU for adalimumab biosimilars. At least 4 are being launched in the EU after the October 16th patent expiration. Does Boehringer Ingelheim plan to join the fray?
Burich: Boehringer Ingelheim had planned to bring Cyltezo to patients in the EU. Due to the patent litigation with AbbVie in the US, we will not commercialize Cyltezo in the EU. Boehringer Ingelheim will continue all activities for our biosimilar in the United States. We are committed to making Cyltezo® available to U.S. patients as soon as possible and certainly before 2023.
PART B TO PART D TRANSITION BY CMS
BR&R: Medicare has indicated that it will move many Medicare part B drugs into part D. To what extent will this affect biosimilar access and utilization?
Burich: It is a very hot topic these days. We have some pretty significant concerns on conceptually around what it means for moving from part B to part D. The key reason revolves around the access question, including patient cost sharing.
A move from part B to plan D could mean that patient cost sharing may jump significantly. We know that part B beneficiaries have wraparound or Medigap coverage to protect them from cost sharing issues. In part D, there is not such protection. Aside from the biosimilar question, the move from part B to part D really has to be explored and discussed a lot more to understand how we can ensure that patient access is not reduced through high cost sharing. That needs to be ironed out as it applies to any part B drug before we can speculate whether this is an opportunity for a biosimilar. Time will tell what that really looks like.
Last month, CMS released the Medicare Advantage guidance allowing for step therapy for part B drugs. That could be a potential opportunity for biosimilars, if we know how some of the access concerns will be addressed. We just don’t have the full picture at this point.
BR&R: Is it possible that this move to part D might spur some payers to create biosimilar tiers? These would require lower cost sharing for patients compared with reference biologics, assuming contracts with the reference manufacturer permits it.
Burich: In my opinion, we’ll need access to more biosimilars before we see a lot of that activity. It’s hard to foresee what big benefit design changes will be coming, but it’s certainly possible. We’ll need a mature market in the US before that will happen.
BR&R: The devil is in the details with this switching issue but there’s also an access issue. Plans can make midyear formulary changes, this would then apply to biosimilars and reference drugs covered under part D.
Burich: This is an important issue. The latest guidance that we saw from CMS, which is now a couple of years old, allowed positive formulary changes. Adding the biosimilar to a formulary is always allowed mid-year. The question involves removing an originator product or changing its tier.
CMS has said that those situations would be reviewed on a case-by-case basis. These rules preventing negative formulary changes midyear are there to protect patient access. It will take CMS some time to iron out what the process looks like for this type of potential formulary change midyear. For now, we’ll have to rely on CMS’s case-by-case review
BR&R: In general, payers do not consistently fund and manage self-injectable specialty drugs in the same way. In some cases, they cover these agents under the pharmacy benefits, medical benefit, or even both. Further, they can be managed under either benefit as well. However, it seems we are moving toward pharmacy management of these agents. How does this affect biosimilar access, if at all?
Burich: There will be more benefit design changes once we have a more robust biosimilar market. More specifically, when we have pharmacy benefit biosimilars.
We’ve mentioned CMS’s intention to move more of these products from part B to part D. It is possible that commercial plans will have different benefit designs and treat injectables differently than Medicare does. We want to make sure that biosimilar or not, the access piece is really at the center of those changes; it will not be beneficial to the biosimilar market if this move causes significant patient access issues (e.g., actual access to this drug or big swings in cost sharing). All of those things will be equally problematic for a biosimilar as they are for an originator, so we want to make sure we have our eye on the access component.
BR&R: Health and Human Services Secretary Azar and FDA Commissioner Gottlieb have loudly stated their desire to improve biosimilar patient and market access. The Biosimilar Action Plan was released earlier in the summer to that end. What is the one aspect of the Biosimilar Action Plan that appeals most to manufacturers like Boehringer Ingelheim?
Burich: The aspect of education, tackling both proactive education and countering misinformation is very critical from our perspective. We’d like to see more materials moving forward that focus on switching and on interchangeability. We haven’t really scratched the surface on those topics from an education standpoint.
The reality is that the FDA has an important voice and bringing validity to educational materials is so critical for patients, physicians, and health plans as well. We hope that the FDA will stand by its public commitment to release more reading materials, more videos, more web info, etc. It is especially important at this juncture; we are seeing misinformation and a lack of clarity on certain things.
IS THE BIOSIMILAR ACTION PLAN ACTIONABLE?
BR&R: One of the biggest barriers to biosimilar access is the patent thickets. The rebate trap problem is another story. What power does HHS have to clear out the patent thickets? Or is this an area that can only be addressed by Congress?
Burich: This is the most difficult part of the Action Plan, because it is unclear who can truly implement change and what change might be realistic. We have to protect true innovation that’s important to all stakeholders.
At the same time, there’s no question that patent litigation is the leading barrier to biosimilar accesss. Some makers of branded pharmaceuticals have constructed patent thickets so that they could sustain prolonged, expensive litigation against competitors, while stifling competition. Humira is the prime example: More than 15 years after the molecule was approved , no biosimilar is being marketed – in the U.S. What the answer is and which government agency can effect change has yet to be determined.
BR&R: That change won’t come quickly, in any case. Whether enacted by Congress or the Office of the Inspector General, which may have to reinterpret the safe harbor statutes, this may only first apply to the second-generation of biosimilar agents, beyond 2021 perhaps. It seems likely that this will be a very deliberate process.
Burich: I do believe Commissioner Gottlieb is thinking about both how to get more products launched in the short term and also the long-term vision of a sustainable biosimilar market. That is such an important part of the problem.
We were very happy that the FDA had their public hearing. The FDA panel asked a lot of thoughtful and probing questions to the individual speakers. We are fully supportive of the Action Plan and its individual components. If we saw all of those things come together and start to see action, including finalizing the interchangeability guidance and providing more education, the biosimilar market would be in a far better place.
BR&R: We say that biosimilar manufacturers can make their products attractive to payers, but payers need to play a positive role here. Commissioner Gottlieb has said that payers have to help in this process by taking the long-term view, by not automatically sticking with the reference product because of the rebate revenue. They have to be open to using the biosimilars and nurturing the health of the industry. Is there anything else the biosimilar manufacturer can do to convince payers to make this market viable?
Burich: Certainly, biosimilar manufacturers have to approach these payer negotiations and conversations with competitive and innovative contracting approaches. That does not just include pricing but also how do you drive volume and true savings to both payers and patients. That kind of innovative approach is necessary, because we know it’s a challenging market.
Biosimilar manufacturers have to look at the whole picture as well. That means providing targeted patient/physician services to really help ensure that the switching experience is seamless for the patient and the physician so that biosimilar utilization is not viewed as something very disruptive.