Reprinted with AIS Health permission from the September 2023 issue of Radar on Specialty Pharmacy
Following the launch of almost 10 biosimilars of AbbVie Inc.’s Humira (adalimumab) this year, 2025 will be another big year for the U.S. biosimilar market, when no less than three versions of Stelara (ustekinumab) from the Janssen Pharmaceutical Companies of Johnson & Johnson are set to become available. Having the experience of assessing multiple competitors with varying attributes could help payers as they prepare for the launches, say industry experts.
Stelara is a human interleukin-12 (IL-12) and -23 (IL-23) antagonist indicated for the treatment of adults with moderately to severely active Crohn’s disease, adults with moderately to severely active ulcerative colitis, people at least 6 years old with moderate-to-severe plaque psoriasis who are candidates for phototherapy or systemic therapy and people at least 6 years old with active psoriatic arthritis.
Dosing is via subcutaneous injection for all of the indications except Crohn’s and ulcerative colitis, where the initial dose is via a single intravenous (IV) infusion followed by subcutaneous (SC) dosing.
“Based on the routes of administration being evaluated in clinical trials, the biosimilar manufacturers are expected to minimally seek FDA approval for an SC version initially,” says Andy Szczotka, Pharm.D., chief pharmacy officer at AscellaHealth. “At least two biosimilar manufacturers appear to be seeking approval of both SC and IV product presentations. If not part of the initial approval, IV formulations will likely follow once the manufacturers provide sufficient evidence to the FDA comparing the IV and SC formulations. Coverage for the IV formulation of Stelara should be available until an IV ustekinumab biosimilar is available in the marketplace.”
According to the Sept. 1 edition of the U.S. Biosimilars Report from Cencora (formerly known as AmerisourceBergen), there are eight ustekinumab biosimilars in various stages of development:
- Neulara from NeuClone Pharmaceuticals Ltd is in Phase I trials;
- FYB202 from Fresenius Kabi and Formycon is in Phase III trials;
- DMB-3115 from Dong-A Socio Holdings and Meiji Seika Pharma is in Phase III trials;
- BAT2206 from Hikma Pharmaceuticals PLC and Bio-Thera Solutions, Ltd. is in Phase III trials;
- ABP 654 from Amgen Inc. is in Phase III trials;
- SB17 from Samsung Bioepis — which recently said it will partner with Sandoz on commercialization of the agent — is in Phase III trials;
- CT-P43 from Celltrion USA. Inc., which submitted its Biologics License Application (BLA) to the FDA in June; and
- AVT04 from Alvotech and Teva Pharmaceuticals, Inc., whose BLA is under review by the FDA, with a decision expected by the end of this year.
In addition, Celltrion and Rani Therapeutics said earlier this year that they are developing an oral formulation of ustekinumab for psoriasis, Crohn’s and ulcerative colitis known as RT-111 that utilizes the latter’s robotic RaniPill capsule. The technology allows the capsule to break down in the small intestine, delivering the drug to that organ by injecting it into the intestinal wall.
“If this dose formulation eventually gains FDA approval,” says Szczotka, “this may provide another therapeutic option for autoimmune diseases and may compete with other available oral agents” such as Janus kinase (JAK) inhibitors.
Manufacturers Are Reaching Settlements With Johnson & Johnson
As of mid-September, three of the companies with a ustekinumab biosimilar in development had unveiled the settlement of patent lawsuits with Johnson & Johnson, allowing them to launch in the first half of 2025.
In May, Amgen said that it would be allowed to launch ABP 654 “no later than January 1st, 2025.” Then in June, Alvotech and Teva said that their AVT04 has a license entry date “no later than February 21, 2025.” Most recently, Fresenius Kabi and Formycon revealed that they can launch FYB202 “no later than April 15, 2025.”
Fresenius Kabi/Formycon said they expect to submit their BLA later in 2023. Amgen and Alvotech/Teva have said they anticipate a decision on their agents by the end of this year, says Szczotka, but “there is no assurance that either of the products will receive FDA approval. Considering the recent issues and two complete response letters that Alvotech/Teva have received with their adalimumab biosimilar approval, FDA approval is not assured.”
Other staggered launches have demonstrated that “sometimes being ‘first’ to market can be an advantage,” says Fran Gregory, Pharm.D., vice president of emerging therapies at Cardinal Health. “However, this is not always the case. Sometimes prescribers or PBM decision-makers may wait for a specific version of the product to come to market. This was perhaps the case with the adalimumab biosimilars. The first-to-market product was not the most highly utilized version of the reference product. The most widely used version was a high-concentration, citrate-free Humira, but the first launch didn’t match this exactly. It is possible that these attributes impacted the speed of adoption. We may continue to see these types of dynamics play a role in future biosimilar launches. Attributes such as injection devices, interchangeability status or even inactive ingredients could make a difference in product acceptance.”
With potential Stelara biosimilar launches still more than a year away, payers have time to “review and evaluate each of these products and make preparations for product placement, similar to the adalimumab biosimilars in 2023,” Szczotka tells AIS Health, a division of MMIT. “Having multiple ustekinumab biosimilars that provide clinically comparable products to Stelara will allow for market competition and hopefully provide cost savings opportunities for payers and patients.”
Gregory points out that spending on autoimmune conditions such as the ones Stelara is approved for has grown more than 450% from 2011 to 2021, with annual spending in the U.S. of more than $40 billion. “Because of this significantly high level of health care spend, there is much attention on these treatments. The health care system in the U.S. can benefit greatly from a biosimilar in this category.”
“Availability of multiple biosimilars in high-spend categories can bring significant changes to the marketplace,” concurs Amy Martin, Pharm.D., vice president of the access experience team at PRECISIONvalue. “There is an expectation that reduced costs and improved access will follow with the introduction of multisource competitors.” Payers should closely evaluate the timing of the launches, plus different attributes of the biosimilars, including “dosage form, strength availability and excipients, interchangeability,” as well as their “site of care, costs and price concessions.”
How Important Are Interchangeability, Manufacturer?
While the interchangeability designation “may support pharmacy point-of-sale substitutions, there are state-by-state differences on how interchangeability is defined and subsequent communication requirements, which may limit its value,” she continues.
Still, says Szczotka, “biosimilar agents that gain an interchangeable designation from the FDA with their additional studies will assist with the potential conversion and acceptance by the physicians. This will also enable substitution to occur at the point of dispensing by the specialty pharmacy where state laws allow.”
Based on the experience of the one interchangeable Humira — Boehringer Ingelheim’s Cyltezo (adalimumab-adbm) — “it may be too early to determine the value of the interchangeable designation,” states Gregory. Some payers have added that drug to their formularies, but it has one of the highest price tags of the new agents. “This begs the question [of] does the cost of gaining the FDA interchangeability designation translate to a higher price of the drug once on the market? And is it worth it? We are still waiting for the adalimumab market to develop to help us answer these questions.”
According to Madelaine A. Feldman, M.D., FACR, a clinical assistant professor of medicine at Tulane University School of Medicine and provider with The Rheumatology Group in New Orleans, “As far as the PBMs are concerned, I don’t think it makes a difference unless of course they happen to make more money on the interchangeable biosimilar — then they can use it for optics, claiming they are picking a drug that has more switching studies, when we know that doesn’t make any difference to them. After all, they are willing to switch patients to an entirely different medication (through exclusions and changing in tiering) for profit, so why should something like interchangeability affect coverage?”
Asked how important payers may find the manufacturer of an agent, Martin replies, “biosimilars have established clinical value, so payers will look at the various stakeholders and evaluate both access and demand levers for formulary placement. For example, costs, rebates and discounts of both the reference and biosimilar products, dosage form availability, the manufacturer’s strategy to pull through market share and biosimilar pipeline.”
“Biosimilar manufacturers that have either current and/or prior biosimilar manufacturing experience will help ease any payer concerns with product supply and existing distribution channels,” asserts Szczotka.
“Most of the manufacturers developing biosimilars are reputable companies with long track records in biologic development; therefore, there aren’t necessarily any obvious leaders or losers here,” declares Gregory. “When it comes to injection devices and other patient-centric features, these can be appealing but may not be considered critical to a PBM or payer making a benefit coverage decision.”
“In addition to interchangeability and manufacturing supply, pricing will be a key product attribute,” states Szczotka. “If the biosimilar does not provide a cost savings opportunity for payers and patients, it will likely struggle to gain market acceptance.”
Stelara Has Multiple Competitors
While Stelara is currently the only IL-12/-23 inhibitor with FDA approval for inflammatory conditions, its biosimilars will be entering a crowded class with multiple competitors.
“Medications such as secukinumab (Cosentyx) and ixekizumab (Taltz) work by blocking the IL-17A protein that also causes inflammation. These medications are indicated for treating plaque psoriasis and psoriatic arthritis,” explains Szczotka. “IL-23 antagonists like risankizumab (Skyrizi) block the interleukin 23 protein and are indicated for plaque psoriasis, psoriatic arthritis and Crohn’s disease. Therapies known as TNF inhibitors block tumor necrosis factor, which is also part of the inflammatory response. Examples of these medications include adalimumab (Humira) and infliximab (Remicade), which are also indicated for plaque psoriasis, Crohn’s disease, ulcerative colitis and psoriatic arthritis. Finally, JAK inhibitors such as tofacitinib (Xeljanz) and upadacitinib (Rinvoq) interfere with signals in the body that are thought to cause inflammation. Tofacitinib has several indications including ulcerative colitis and psoriatic arthritis, while upadacitinib is FDA approved to treat all of Stelara’s FDA-approved indications and more.”
“Depending on the indication, there are multiple biologic competitors for Stelara,” sums up Gregory. “This is a crowded market, and it’s growing rapidly. Because of the number of treatment options and the high spending on this group of drugs, the entry of biosimilars is even more important than ever. With increasing biosimilar availability and adoption, we can break the exponential spending trend in some cases. This is a critical contribution to creating a more sustainable U.S. health care system.”
Stelara, declares Gregory, is an important therapy for many immunologic conditions. While its approximately $14 billion in annual sales — “which is not insignificant” — is less than Humira’s $20 billion, Stelara “is still a widely utilized and effective medication for many patients.”
How May Launches Compare With Those of Humira Biosimilars?
The expected ustekinumab launches “will be both similar and different than the adalimumab biosimilars in 2023,” maintains Szczotka. “It will be similar in regard to having multiple biosimilar options within a short period of time due to the announced settlement agreements. This will likely provide market competition and assist with cost-saving opportunities and multiple pricing arrangements. Likewise, the available ustekinumab biosimilars should have the same product strength and indications as Stelara, paving the way for use in multiple inflammatory disease states.”
However, he continues, the possibility exists that none of the ustekinumabs has the interchangeability designation. And since the products do not yet have FDA approval, “the delivery devices and product formulation components are not yet known.”
Payer coverage of the Humira biosimilars has been “relatively broad,” states Gregory, with many larger PBMs keeping Humira on formulary and adding biosimilars alongside it. She adds that many payers have added the first entrant, Amgen’s Amjevita (adalimumab-atto), with several also placing both a high rebate/high wholesale acquisition cost agent and a low rebate/low WAC drug on formulary, giving the PBMs “flexibility with rebates and patient out-of-pocket dynamics". It does appear that PBMs are attempting to offer all dosage forms and concentrations to match Humira. For example, most plans seem to be selecting a high-concentration formulation with no citrate, which have been touted as market advantages for Humira.”
The Humira biosimilar launches, Martin asserts, have “changed the landscape significantly. Newly launched biosimilars offer different WAC price points; various levels of rebating; new distribution channels, such as Mark Cuban’s Cost Plus Drug Company; and an interchangeable option. Payers have had varying reactions, with many choosing to offer at least two different biosimilars, and some partnering to develop white-labeled biosimilar options to compete with channel disruptors.”
Coherus BioSciences, Inc. is partnering with Cost Plus Drugs to sell Yusimry (adalimumab-aqvh) for $569.27 plus dispensing and shipping fees. That move, says Feldman, who is also president of the Coalition of State Rheumatology Organizations, “sent a shiver down the spine of some manufacturers, as well as the PBMs counting on being able to continue favoring only the higher priced biosimilars. Now we have CVS considering investing in the manufacturing of biosimilars because they realize self-insured employers may ‘dump’ their PBMs who are preferring drug that ultimately cost the employer more. Who needs a $3,500 rebate on a $7,000 drug when you can buy it for $600?”
One takeaway for payers from the Humira biosimilars’ launches to apply to the Stelara biosimilars is that “education is still key,” maintains Gregory. “Prescribers, pharmacists and patients are all stakeholders in the health care continuum, and all are critical to the success of biosimilars. The comfort level and the confidence in the biosimilar from the health care team must be consistent in order to ensure patient acceptance and adherence.”
“Maybe they have learned a lesson that self-insured employer plans may drop them as the PBM if the employer can get true savings by using a lower priced drug,” remarks Feldman.
Aside from fairly recent launches of insulin biosimilars, the adalimumabs were the first big launches of self-administered biosimilars. Agents administered by a health care provider “have established broad access and have significantly reduced overall health care costs since their introductions,” observes Martin. “There are differences in the distribution model, costs, price concessions, reimbursement and dispensing compared to self-administered biosimilars.”
Because Stelara is both self-administered and physician-administered, “the administration and billing of the ustekinumab biosimilars may vary from that of the adalimumab biosimilars,” points out Gregory, so there will be “more of a mix of pharmacy and medical benefit with ustekinumab. This will be one key difference.” And because the Humira biosimilars “have paved the way on the pharmacy benefit path, Stelara biosimilars may have a slightly smoother journey. That said, the path will not necessarily be easy.”
Still, notes Szczotka, “physicians who treat inflammatory-related diseases have been exposed to biosimilars for some time since the introduction of infliximab and, most recently, adalimumab biosimilars. There has been a gradual acceptance for the adoption and use of these autoimmune biosimilar agents and will likely aid in the adoption of ustekinumab biosimilars in 2025.”
Contact Feldman at firstname.lastname@example.org, Gregory via Shreya Bhola at email@example.com, Martin via Andie Lunkenheimer at firstname.lastname@example.org and Szczotka via Caroline Chambers at email@example.com.
By Angela Maas