FDA Approves First Interchangeable Biosimilar; Impact Remains Uncertain

More than 10 years after the passage of the Biologics Price Competition and Innovation Act of 2009 (BPCIA) as part of the Affordable Care Act, the FDA finally has approved the first interchangeable biosimilar. But while many in the industry are hailing the move, at least one expert wonders whether interchangeables will hamstring use of biosimilars that do not have that designation.

On July 28, the FDA approved Viatris Inc. and Biocon Ltd. subsidiary Biocon Biologics Ltd.’s Semglee (insulin glargine-yfgn) to improve glycemic control in adults and pediatric patients with Type 1 diabetes mellitus and in adults with Type 2 diabetes mellitus. It is a biosimilar to and interchangeable with its reference product, Sanofi Aventis’ Lantus (insulin glargine), a long-acting insulin analog. The product will be available in 10 mL vials and 3 mL prefilled pens and is administered subcutaneously once daily. It also has 12 months of exclusivity under section 351(k)(6) of the Public Health Service (PHS) Act during which the FDA cannot approve another biosimilar that is interchangeable with Lantus.

The FDA also issued three fact sheets to help improve understanding of biosimilars and interchangeable biosimilars.

“This is a momentous day for people who rely daily on insulin for treatment of diabetes, as biosimilar and interchangeable biosimilar products have the potential to greatly reduce health care costs,” said Acting FDA Commissioner Janet Woodcock, M.D., in a statement. “Today’s approval of the first interchangeable biosimilar product furthers FDA’s longstanding commitment to support a competitive marketplace for biological products and ultimately empowers patients by helping to increase access to safe, effective and high-quality medications at potentially lower cost.”

As of early August, the FDA has approved 30 biosimilars for 10 reference products.

Most States Have Substitution Laws

Interchangeable status means that the biosimilar may be substituted for the reference product without prescriber intervention. However, as of 2019, 45 states and Puerto Rico have passed biosimilar substitution laws, many of which require pharmacist notification of the patient and provider about the substitution.

The FDA initially approved Mylan — which merged with Pfizer’s Upjohn business in 2020 to form Viatris — and Biocon’s Semglee (insulin glargine) on June 11, 2020, and the companies launched the drug Aug. 31. The agency approved the drug through the 505(b)(2) new drug application (NDA) pathway, but in line with the BPCIA’s requirement that the FDA transition certain protein products approved under the Federal Food, Drug, and Cosmetic (FD&C) Act to the PHS Act on March 23, 2020, the drug was deemed to be an approved biologics license application (BLA) under section 351(a) of the PHS Act.

While most biologics are licensed under the PHS Act and approved through a BLA, some protein products — including insulins — have gained FDA approval under the FD&C Act through an NDA. The BPCIA did two things to impact this: First, it modified the definition of a “biological product” to include a “protein (except any chemically synthesized polypeptide).” Second, it said that biologics approved under the FD&C Act on or before March 23, 2020 — 10 years after the BPCIA was enacted — would transition over to the PHS Act. Thus, an approved marketing application for one of these drugs under section 505 of the FD&C Act would be deemed to be a license for the product under section 351 of the PHS Act.

Shortly before the transition date, the FDA released a final rule on the change that specifically clarified that insulin falls under this definition of “protein.” In a statement accompanying the rule, then-FDA Commissioner Stephen M. Hahn, M.D., noted that while insulin products are biologics, they have faced limited competition, “resulting in fewer choices and higher prices for patients. This transition will open new pathways for manufacturers to bring biosimilar and interchangeable versions of insulin and other transitioning products to market, facilitating greater competition in the marketplace. These critical therapies often carry a heavy price tag; the cost of insulin has risen over the past decade. Opening these products to increased competition is expected to bring down prices and help patients have access to more choices for these life-saving drugs. We will continue to communicate relevant information, including the resources we’ve issued today, to make the transition from one statutory framework to another as seamless as possible.”

Decision is ‘Monumental Approval’

Interchangeable Semglee “is a monumental approval, which adds to the confidence of evidence and utility for biosimilars,” maintains Lynn Nishida, R.Ph., head of clinical operations at Evio. “Its interchangeability with Lantus also increases price competition.”

According to David Steinberg, Pharm.D., director of pharmacy insights at Scripta Insights, “with an AWP [i.e., average wholesale price] of $118.38 for the Semglee vials, it comes in at nearly one-third the cost of the Brand Lantus (AWP $340.27). Similar to Lantus, Semglee also offers a $75 copay assistance program for a 30-day supply.” It’s uncertain whether the interchangeable Semglee will be priced similarly to the noninterchangeable product.

Nishida also says that “the impact that an interchangeable biosimilar brings from a practical perspective will allow pharmacies/pharmacists to substitute between the biosimilar and brand name reference product, without having to call the prescriber to get the medication change. This gives a lot more latitude in product selection by the pharmacy (barring any state-specific laws that limit this ability) at the point of sale, working directly with the patient, as well as payers who rely on the dispensing pharmacy to consider medications that will be effective, safe and least costly.”

An “important implication of an FDA interchangeable designation is to provide PBMs and payers additional rationale for preferencing interchangeable biosimilars over the reference products — and over approved biosimilars that do not have interchangeable designation,” explains Elan Rubinstein, Pharm.D., principal at EB Rubinstein Associates. “I’m saying ‘additional rationale’ because PBMs already designate formulary status to preference some biosimilars and coverage policies that require ‘fail first’ on some biosimilars before the originator products will be approved.”

Asked if it will make a difference that Semglee already has been on the market vs. an interchangeable biosimilar new to the market, Nishida replies that “because Semglee is likely to continue to be recognized as a brand by most PBMs and health plans, traditional formulary and utilization management (e.g., step therapy) will still likely dictate (all things being equal by way of safety/efficacy) which brand products regardless of interchangeability are considered preferred insulins and covered. It will come down to negotiated cost, discounts and rebates.”

Drug Will Launch by End of Year

In a press release on the approval, Viatris and Biocon stated that the interchangeable Semglee will launch before the end of 2021 and that “commercial preparations for launch are underway. Over the next few months, Viatris will transition the current product to the 351(k) interchangeable product.”

Asked what this statement could mean, Nishida says she is “not familiar with all the requirements from a regulatory perspective. However, I would trust that this would include things like update of their website, prescriber/patient materials and their product labeling. It will be interesting to see how much their prescribing information resembles that of Lantus.”

The statement, however, “may mean that the manufacturer intends to withdraw noninterchangeable Semglee from the U.S. market,” says Rubinstein.

That is exactly what will happen. A Viatris spokesperson tells AIS Health that “once we release the interchangeable product, pharmacies can begin ordering and transitioning to this product over a few months as the existing Semglee inventory is depleted.”

So for a period of time, says Rubinstein, there will be two “differently licensed products” with the same name available on the market. The products have different National Drug Code numbers, and only the interchangeable agent has a four-letter suffix. Pointing to the Purple Book entry for the new product, Rubinstein explains that while both Semglees are available, “there will be a Semglee that is interchangeable only with Lantus and another Semglee that is a biosimilar, not interchangeable with any other insulin glargine.”

Viatris Can ‘Essentially Relaunch’ Drug

In a May 10 first-quarter 2021 earnings call, Viatris President Rajiv Malik referred to challenges with Semglee picking up market share and how an interchangeable designation would give Viatris the opportunity to “essentially relaunch” the product: “Once we have an interchangeable [insulin] aspart, once we have interchangeability around there, it’s our opportunity to basically relook into the challenges which we have faced so far in picking up the market share, which we have been slowly and steadily picking up, spending around 2.5%, but it’s not where we want to be. So that’s going to give us an optionality and opportunity to look into this product in a very different way, and essentially relaunch the product, as we go further.”

The approval could have far-reaching implications.

“I expect that the first FDA interchangeable designation will spur manufacturers to hurry applications into the FDA — particularly if PBMs and payers more aggressively preference an interchangeable biosimilar over a biosimilar without that designation, in terms of formulary status and coverage policies,” states Rubinstein.

Adds Nishida, “this may be just the start with other biosimilar manufacturers following suit and pursuing FDA approval for interchangeable status for their biosimilar products now that there is a better understanding of the level of rigor and study that the FDA considers necessary for a biosimilar to deem itself interchangeable with its reference brand product.”

“Market share of biosimilars has been increasing over time, and that will continue — along with a trend to lower net prices for biosimilars and for originator products, the result of market competition between these products,” Rubinstein says. “FDA approval of the first interchangeable biosimilar will increase attention to biosimilars generally, for PBMs, payers, prescribers and patients — and may both increase confidence in and uptake of biosimilars.”

Will Drugs Cause Misunderstanding?

However, at least one industry expert has a different take on that. In an article published May 13 on the Center for Biosimilars website, Albert Kim, vice president of the commercial division at Samsung Bioepis Co., Ltd., said that “we at Samsung Bioepis believe a class of interchangeability products may cause misunderstanding and misinterpretation of the scientific rigor that goes into the biosimilar approvals process” by giving the impression that interchangeable biosimilars are superior to biosimilars without that designation, essentially creating two classes of drugs.

Samsung Bioepis has five biosimilars approved and launched around the world and three others in development. According to the article, the company feels that the evidence required to approve biosimilars should be enough to qualify them for interchangeable status. “Biosimilars have been around now for more than a decade around the world, and there has been no evidence of altered pharmacokinetics data, or heightened immunogenicity response, or increased safety risk, or improved or diminished efficacy in patients who switch back and forth from reference drugs to biosimilars or between biosimilar drugs,” Kim said.

Rubinstein points out that the FDA is not allowed to disclose information about filed applications, but Nishida says that based on the pharma pipeline, there are “several manufacturers” in discussion with the FDA about obtaining approval for both biosimilars and interchangeable biosimilars.

2021 could see at least two more interchangeable biosimilars approved. In a recent press release, Biocon said that a preapproval inspection of its interchangeable insulin aspart manufacturing facility in Malaysia is scheduled for third-quarter 2021. Viatris partners with the company on that product as well.

And on April 23, Boehringer Ingelheim, Inc. unveiled results from a Phase III randomized study that showed switching several times between its biosimilar Cyltezo (adalimumab-adbm) and the reference drug, AbbVie Inc.’s Humira (adalimumab), resulted in similar outcomes for pharmacokinetics, efficacy, immunogenicity and safety in people with moderate-to-severe chronic plaque psoriasis.

Interchangeable Cyltezo Could Be OK’d

The FDA approved Cyltezo on Aug. 25, 2017, for seven of Humira’s indications, and the drug’s license period in the U.S. will begin July 1, 2023. Boehringer Ingelheim has submitted a supplemental BLA for the drug as an interchangeable biosimilar and says the action date is in the fourth quarter of this year.

“The [interchangeable designation] opportunity is there for just about any biosimilar,” contends Nishida. “But the characteristics of biosimilars that are likely to be prioritized to the top for consideration are likely to be those in which levels of the drugs on a unit per unit basis and drug levels can easily be correlated to quantifiable impact. Such in the case of insulin, this was a good model, since dosing could be established on a unit per unit basis and studies that could easily correlate to a lab result (e.g., blood sugar; A1C) are easily measured.”

Insulin prices have been in the news for years as manufacturers have continued to raise them. In January of this year, the Senate Finance Committee released a report based on a bipartisan investigation into the drugs’ prices.

“We found that the business practices of and the competitive relationships between manufacturers and middlemen have created a vicious cycle of price increases that have sent costs for patients and taxpayers through the roof,” said Chairman Chuck Grassley (R-Iowa) in a press release unveiling the report.

When asked if an interchangeable biosimilar will result in lower insulin prices, Rubinstein comments that “if the reducing (over time) net price pattern for other originators and their biosimilars holds, as I expect it will for interchangeable biosimilar insulin glargine, then, yes, this should result in a trend to lower insulin prices.”

However, “interchangeable Semglee’s launch price and net price are not known relative to noninterchangeable Semglee, relative to Lantus, the originator product, and relative to other brands of insulin glargine,” he says. The Viatris spokesperson says pricing information will be available when the product launches.

Contact Nishida at lynn@evio.com and Rubinstein at elan.b.rubinstein@gmail.com.

This story was reprinted from AIS Health’s monthly publication RADAR on Specialty Pharmacy.

© 2024 MMIT
Angela Maas

Angela Maas

Angela has an extensive background of editing, reporting and writing for trade and consumer publications. She has written Radar on Specialty Pharmacy since she joined AIS Health in 2005 and has broad knowledge of the various issues at play within the space. She also has written for Spotlight on Market Access since its 2017 launch. Before joining AIS Health, she was managing editor at Employee Benefit News and Employee Benefit News Canada and managing editor at Hem Aware (a hemophilia publication), Lupus Living and Momentum (a multiple sclerosis publication). She has a B.A. in English and an M.A. in British literature from Arizona State University.

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