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?
Mylan/Fujifilm Kyowa Kirin Biologics
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
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
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.
Embroiled in patent litigation, the
partnership of Amgen and Allergan have waited for the opportunity to launch
Mvasi® since September 2017. During this time, the competition has
not been stagnant, with Pfizer moving towards an FDA decision. The next 6 months
may prove critical, but when will providers, patients, and payers have access
to Avastin® biosimilars? That may be based more on guesstimates than
WHAT DO WE KNOW?
(1) Amgen and Allergan received its FDA approval for Mvasi (bevacizumab-awwb) September 17, 2017. The approval covered all of the reference product’s indications. The drug was approved for use by the European Medicines Agency in January 2018.
(2) In court
documents filed during its patent battle with Genentech, Amgen had
originally stated that it planned to begin marketing Mvasi once the last 8
patents it considered valid expired on December 18, 2018.
(3) Amgen then revised this potential launch
date, according to the court filing, saying that it could launch several months
earlier, on April 5, 2018.
(4) In either case, the launch has not
occurred. According to the Purple
Book, Avastin was first approved by the FDA February 26, 2004. That is
approximately 15 years, and counting.
(5) The US District Court handling
the litigation is expressing impatience
with the back and forth between the two parties (read the Judge’s concluding
remarks). A trial court date was set for June
(6) Pfizer completed its phase 3 trial for PF-06439535 in
nonsquamous non–small cell lung cancer and filed for FDA approval in August
2018. An FDA decision is expected in the second quarter of this year.
(7) In November 2018, Boehringer Ingelheim completed its phase 3 trial in lung cancer for BI 695502.
(8) Samsung Bioepis completed its phase 3 trial in lung cancer in October 2018 (compared with EU-licensed Avastin).
So much for what we know. Here are some things we know less well.
At a drug pipeline update at the Academy of Managed Care Pharmacy in October 2018, Express Scripts’ Aimee Tharaldson, PharmD, Senior Clinical Consultant—Emerging Therapeutics, offered a projected launch date of July 2019. In an E-mail communication with Biosimilars Review & Report, Dr. Tharaldson clarified that this estimate was based on the anticipated expiration of a key patent on Avastin that month.
When we contacted a senior Amgen executive, he
stated that the company declined to discuss potential launch dates.
Goodwin’s Big Molecule
Watch, which keeps a close eye on biosimilar-related patent litigation,
does not list any ongoing suits between Genentech and Pfizer or Boehringer
Ingelheim regarding Avastin (which may be surprising in itself).
We would anticipate that Pfizer will launch as soon as feasible, if they receive an FDA approval by June. Pfizer has an established record of moving their biosimilars quickly to market (e.g., Inflectra® [with Celltrion], Retacrit®, and Nivestym®).
Samsung Bioepis has not yet revealed their plans around an FDA filing for their investigational biosimilar of bevacizumab.
Boehringer had not yet filed a 351(k) application for approval of BI 695502. Comments by Molly Burich, Director, Public Policy: Biosimilars and Pipeline, in our interview last Fall, made it clear that the company is laser focused on bringing its adalimumab biosimilar (Cytelzo®) to market. In fact, this bevacizumab biosimilar was no longer posted on their pipeline at that time.
WHAT WE FOUND OUT
Today, Susan Holz, Director, Communications, Specialty Care, confirmed that the company decided that this agent was not in its strategic plans and it simply allowed the study to be completed. She said, “Boehringer Ingelheim made the decision to terminate all activities related to the BI 695502 program, a biosimilar candidate to Avastin. It is important to note that this decision was not based on any safety or efficacy findings with the investigational medicinal product BI 695502. Boehringer Ingelheim continuously evaluates our business portfolio and assesses potential strategic partnerships to help enhance our pipeline and development capabilities.”
Perhaps several of these unknowns will be
resolved by the end of July, and the clouds will lift a bit. I suspect at that
time, we’ll be much closer to biosimilar access for this biologic, which racked
billion worldwide in sales in 2017.
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.
In the first portion of a two-part interview with Molly Burich, MS, Director, Public Policy: Biosimilars and Pipeline, Boehringer Ingelheim, we cover the challenges of driving biosimilar uptake, as well as the unique situation that has focused this manufacturer’s attention on biosimilars and interchangeability.
BR&R: The viability of the US biosimilar industry is being challenged if companies cannot rely on revenue from switching, especially for the autoimmune category.
Molly Burich: Yes, biosimilar uptake is certainly going to be dependent on switching. But switching comes in a few different types. One case involves patients who are going to be switched to a therapy with a different mechanism of action. Perhaps their existing therapy no longer works (or didn’t work in the first place).
Another case is medication substitution by the physician. The doctor drives that decision to switch the patient either to a biosimilar or to an interchangeable.
Lastly is automatic substitution, which will come as a result of interchangeability and enabled by state laws. However, that is only in play once a product gains the interchangeability designation.
All of those are important components, but certainly switching overall is an important part of the market viability.
BR&R: When we’re talking about automatic switching, multiple stakeholders are involved, including the prescribers, pharmacies, payers, patients. And none of it matters if we don’t have an interchangeable product or even final guidelines from the FDA on interchangeability. In retrospect, should we have made automatic switching for biosimilars based on something other than interchangeability?
Burich: There are a lot of stakeholders involved and this is. why multiple ways of switching will likely occur. In terms of switching, interchangeability allows pharmacists to switch one reference product prescription for an interchangeable one without intervention of the physician at the front end—pending state laws of course. The physician must be notified of the change.
In our opinion though, automatic switching is certainly not the only way to drive uptake of biosimilars. We believe physician-driven switching and payer-drive substitution via formulary decision-making are very important to drive the uptake of biosimilars.
BOEHRINGER INGELHEIM’S SINGULAR PRODUCT FOCUS
BR&R: Biosimilar utilization, and the overall market, has been growing slowly since the first biosimilar approval. Prospective biosimilar manufacturers have tended to jump into the market with both feet, filling their pipelines with multiple biosimilar agents. Boehringer Ingelheim may be the only major manufacturer with a single biosimilar listed on its pipeline web page. Is the company in a wait-and-see mode, to see if the industry will survive? Or is Boehringer making further investments in biosimilar development behind the scenes?
Burich: We are constantly in an evaluation process of our portfolio. Obviously, we are focused on our approved biosimilar Cyltezo® (adalimumab-adbm) and also on interchangeability, here in the U.S. That is our focus area. We believe that the introduction of biosimilars will improve the lives of patients, as well as contribute to the quality and economic sustainability of healthcare systems.
INTERCHANGEABILITY: MISUNDERSTOOD BUT NO SILVER BULLET
BR&R: The issues around interchangeability are particularly frustrating. At the time the BPCIA was written, was the concept of interchangeability (which does not exist in EMA regulations) an attempt to give prescribers and consumers a warm and fuzzy feeling of an AB-rated generic?
Burich: It’s an important question. As you said, when the BPCIA was written, interchangeability was viewed as a sort of silver bullet. The reality is that interchangeability is an important concept, but perhaps it makes more sense for only certain products. As we gain experience in the biosimilar market, we’re starting to see this.
We believe in the concept of interchangeability and in what the FDA has put forth about interchangeability. We do think there are questions about how an interchangeable product may be perceived compared with one that is not interchangeable. In our comments to the FDA, we encouraged the FDA to come out with educational materials that are geared toward talking about interchangeability, and talking about switching. These are all important questions and need to be addressed for the broad stakeholder community. The FDA is obviously best positioned to bring that type of education in the next round of materials they develop.
BR&R: We’ve heard a great deal about people mischaracterizing interchangeable products as being superior to biosimilars (for the same reference product). Why is this differentiation so important?
Burich: This issue speaks to education. All people engaging in the biosimilar space must realize that the designation of interchangeability does not mean it’s a higher-quality, safer, or more-efficacious product. It means that the manufacturer has conducted additional studies required by the FDA to enable that automatic substitution at the pharmacy level.
The FDA has issued clarifying pieces of information and education on their website about this, but there is room for more. The reality is that when a drug is approved as a biosimilar, it has attained the foundational designation proving that the drug is highly similar to the reference biologic, without any clinically meaningful differences. On the other hand, gaining the interchangeability designation is about conducting trials of multiple switches within the patient and expecting the same results in any given to patient. Those are two different distinctions. It proves something different, allowing for automatic substitution to occur.
In part two and the conclusion of this interview, which will be published in a separate post, Molly Burich speaks to Boehringer Ingelheim’s progress in Cytelzo’s 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.