Switching Study Complete, Biosimilar Maker Awaits FDA Decision on Interchangeability

In an April 23 press release, Boehringer Ingelheim announced that its phase 3 switching study between its biosimilar Cyltezo® and the reference adalimumab biologic Humira® is complete. The biosimilar maker also stated that it had filed its supplemental application for interchangeability designation with the Food and Drug Administration (FDA).

The VOLTAIRE-X study randomized 238 patients with moderate-to-severe plaque psoriasis to receive either the 40 mg/0.8 mL dose of the originator product or Boehringer’s biosimilar. The study met the requirements to support interchangeability by employing multiple switches between the two products in addition to cohorts who received one agent continuously. The manufacturer is presenting its 32-week results at the 2021 virtual meeting of the American Academy of Dermatology.

The study found that clinical efficacy, pharmacokinetics, immunogenicity, and safety outcomes were similar among the patient cohorts switched between biosimilar and reference products, and those who received continuous treatment with Humira.

The VOLTAIRE-X study was initiated in July 2017 and slated to end in April 2019. Our previous communications with Boehringer Ingelheim hinted at ongoing talks with the FDA to better optimize their chances of gaining interchangeability. However, the 32-week primary outcome results are only being reported now.

The decision by the FDA on Cyltezo is expected in the fourth quarter of 2021. For the first time, the FDA has been asked to conclude whether the interchangeability designation should be provided. When contacted by BR&R, Boehringer Ingelheim representatives could not further specify the decision date.

Cyltezo is expected to launch in July 2023, making it the third biosimilar to become available among manufacturers signing settlement agreements with AbbVie.

Further Dissecting the Launch of Adalimumab Biosimilars in the US

As we inch closer to the January 2023 date for the launch of the first US adalimumab biosimilar, industry watchers are more closely scrutinizing which company, if any, will have a competitive advantage in this lucrative marketplace.

Just to reset, the series of settlements signed by AbbVie currently puts Amgen’s Amjevita® first to be released, followed by several others according to the schedule we first published in May 2019.


Company/PartnerDrug NameLaunch Date
AmgenAmjevita*January 2023
Samsung Bioepis/MerckHadlima*June 2023
Boehringer IngelheimCytelzo*July 2023
Mylan/Fujifilm Kyowa Kirin BiologicsHulio*August 2023
SandozHyrimoz*September 2023
Fresenius KabiMSB11022September 2023
PfizerAbrilada*November 2023
MomentaM923December 2023
CoherusCH-1420December 2023
*Received FDA Approval.

A few developments have occurred since then, primarily the subsequent FDA approval of Hulio®, Hadlima®, and Abrilada®. Momenta was acquired by Johnson & Johnson in October 2020 and is no longer a separate entity or operating in the biosimilar business. But Coherus filed for approval in December 2020, and Alvotech and its partner Teva filed in November 2020. Celltrion, which completed its phase 3 trial, is on the verge of filing for approval, and Fresenius Kabi may join the crowd in filing this year as well.

The more interesting question is how these products might be differentiated. First, there are two concentrations: Two agents (Celltrion’s CT-P17 and Alvotech’s) will be available at the 100-mg/mL dose (which is a dosage offered by AbbVie’s Humira®), while the others will be dispensed at the 50-mg/mL dose.

Second is the availability or importance of a citrate-free formulation. The citrate-free formulation of Humira® is supposed to be associated with less injection-site pain, at least according to anecdotal evidence, but the value of this formulation has not been proven in clinical trials. Some of the planned biosimilars, such as Amjevita and Hulio, are citrate free. Other biosimilar manufacturers may roll out citrate-free adalimumabs, but this may not have a strong effect on payer coverage decision-making. Jeffrey Casberg, MS, RPh, Vice President, Pharmacy, IPD Analytics, believes that payers could ask patients to make a trade-off based on cost sharing: Would they pay more for a citrate-free version, if the preferred product is at a lower copay?

Jeffrey Casberg, MS, RPh

Third is the issue that has been looming for a couple of years now—the potential for Boehringer Ingelheim to score interchangeability status for Cyltezo®, which would be unique among adalimumab biosimilars. Boehringer Ingelheim cannot launch until July 2023, making it the third scheduled biosimilar to market. This will hurt whatever leverage Boehringer may have as the sole adalimumab interchangeable biosimilar. For example, should Amgen seal its payer contracts prior to January 2023, Boehringer will have to offer serious discounts just to get its foot in the door for the 2024 contract year. Mr. Casberg suspects that, in the end, Cytelzo won’t be the first biosimilar to be dubbed interchangeable; he thinks one of the insulins may be more likely to earn that distinction.

At this point, neither Celltrion nor Alvotech/Teva has signed licensing agreements with AbbVie. This raises an intriguing scenario. According to Mr. Casberg and the IPD Analytics team, “There is a possibility that these two agents could launch as early as late summer or fall of 2022.” Mr. Casberg told BR&R, “This is based on an assessment of publicly available information by IPD’s intellectual property group.”

Mr. Casberg emphasized, “I’m not saying that a 2022 launch is likely to occur, but that it could occur.” If this should occur, it could seriously upset the adalimumab settlement apple cart. If Celltrion or Alvotech decided to start marketing early, it may be launching at risk—but that’s a risk that might yield riches for a biosimilar maker emboldened by the prospect of a major cut of $16 billion in sales. If we have learned anything about the biosimilar market, it is that the first to launch has a big advantage over the others.

Is Identification of Biosimilars vs. Reference Products Still an Issue?

In the past, we have addressed whether the use of the four-letter suffixes have enabled positive identification of biosimilar agents by providers and health plans or simply added to confusion over the quality of the products being prescribed. This issue had faded somewhat, with the realization that the suffixes have been superfluous in identifying which agent was prescribed—or so we assumed. A poster at last week’s Academy of Managed Care Pharmacy (AMCP) virtual annual meeting suggested this may not be the case.

Optum Epidemiology and the Biologics and Biosimilars Collective Intelligence Consortium (BBCIC) jointly presented findings on data sources that can be used to conduct real-world observational studies on oncology. This preliminary investigation is required, so the BBCIC can fulfill its mission: to generate reliable real-world evidence that examines the safety and effectiveness of biologics in order to improve public health.

The BBCIC relies on its distributed research network, composed of national and regional health insurers and integrated delivery networks that encompass administrative health care claims data on nearly 95 million patient lives, as its primary data source.

For the oncology biologic study, the investigators distributed questions to 18 potential real-world data sources, gaining responses from seven (39%). Two respondents relied on electronic health record (EHR) data, one was primarily based on claims, and four used a combination of claims and EHR data.

BBCIC Update
Cate Lockhart, PharmD, PhD

The survey included a hypothetical case study on the use of trastuzumab in patients with breast cancer. Here is what was truly fascinating about the results of this study: of the seven respondents, two (28%) reported that they could not positively identify which biologic or biosimilar was used. Perhaps less surprising is that only four (57%) could identify biomarker information (such as estrogen-receptor status).

One might assume that at this point in time, delivery systems, health plans, insurers, and claims data warehouses would be able to pinpoint the agent used through either the four-letter suffixes, national drug codes, brand names, or a combination of these. One of the data sources responding indicated that they have a “partial” ability to identify the exact biologic used.

We followed-up with Cate Lockhart, PharmD, PhD, Executive Director of the BBCIC, about this finding. Dr. Lockhart responded to BR&R via Email, “There are still some non-specific codes floating around out there that contribute to the challenge in differentiating products—and sometimes there is still a lag between launch and specific code assignment, and then updated coding in EHR/claims documentation.

“We know from our own research that suffixes, code modifiers, and NDCs are not uniformly captured in medical claims data,” stated Dr. Lockhart. “Some of the sources are relying on structured EHR data, so it is dependent upon how treatment is captured across clinics, for example. Even the two sources that suggested differentiation was not readily captured in their curated data did say it would be feasible to do so. You wouldn’t think product differentiation would be a problem, but that is why we specifically asked the question in the request for information.

“Data sources are getting much more robust in recent years as more and more research is being conducted with these data,” she wrote, “but we still have the legacy of trying to do research with data that were not originally captured for research purposes.”

Source: Seals RM, Lockhart CM, Lin L, et al. Characterization of real-world data sources to support observational studies of biologics, including biosimilars in oncology. Poster presented at the Academy of Managed Care Pharmacy 2021 annual meeting. April 12-16, 2021.

In Other Biosimilars News…Last week, Genentech and Centus Biotherapeutics, Ltd (a joint venture between AstraZeneca and Fujifilm Kyowa Kirin Biologics) filed a joint motion that settles their patent infringement litigation regarding a biosimilar for bevacizumab. This biosimilar received European approval for marketing in October 2020.

Oncology Biosimilars Are Proof That the Market Works

If there is anything that Ted Okon, MBA, Executive Director, Community Oncology Alliance, and Peter Bach, MD, from Memorial Sloan Kettering agree upon, it is that hospital systems make more profit by prescribing high-cost drugs than they do with lower-cost agents, like biosimilars.

Ted Okon

Beyond that, these two wouldn’t be expected to agree on much when it comes to the pharmaceutical market. In his presentation at the World Biosimilar Congress in late March, Mr. Okon tried to dispel Dr. Bach’s main argument, that the biologics market is broken in the US and the best way to address it is through statutory regulation.     

“The fact is,” claimed Mr. Okon, “that the US biosimilar market is working. The market could be stronger and produce more savings, but there is a good deal of price competition.” He cited Bernstein Research’s latest figures, showing strong net price reductions in all biologic areas with biosimilar competition. In addition, bevacizumab and trastuzumab biosimilar marketshares are around 60%.  

The problem is that for select drugs—especially biologics—the mark-ups paid before rebate can average 250%, he said. Hospitals get high rebates, which lower the net cost down to a reasonable average selling price (ASP). “This makes biosimilars financially unattractive to the hospital,” according to Mr. Okon, and as a result, a substantial proportion of hospitals carry only the innovator product. However, the amount the hospital is paid by the insurer varies considerably across payer. For example, Wake Forest Medical Center may receive between $7,000 and $15,800 when billing for Neulasta®, depending on whether the payer has negotiated a good deal with the manufacturer. When it comes to 340B institutions, the hospital systems receive additional discounts that make the reference product even more attractive, he pointed out. Biosimilar makers would have great difficulty getting 340B hospitals to utilize their products.   

Even today, Mr. Okon said, biosimilars are still subject to a fictional narrative, like “physicians don’t want to prescribe them,” or “patients don’t want to take them.” These are demonstratively false, said Mr. Okon, as is the assertion that biologics are a natural monopoly and have to be regulated as one.

The type of mandated price fixing that Dr. Bach and colleagues propose “has never worked long term, and always has unintended consequences,” said Mr. Okon. Indeed, the need for this regulatory approach does not seem to be grounded in the facts. “But biosimilar growth and savings are being held back,” he said, by rebate traps, patent litigation, and other factors.

Biosimilars, Employers, Medicaid, and Rebates

At last week’s World Biosimilar Congress, much of the content revolved around increasing access to biosimilars. That topic automatically invokes the controversial use of rebate contracting. Robert Popovian, PharmaD, Former Vice President, Govt Relations, Pfizer, asserted that access for oncology biosimilars is much greater than that for infliximab biosimilars because of the latter’s reliance on rebates. “Rebate contracting is a huge barrier,” he said, “and not just for biosimilars, too. Rebates equal formulary access.” Dr. Popovian believes that “employers are the lynchpin to really turning the tide [towards biosimilar uptake].”

Robert Popovian, PharmD

That will require employers to take a stand on the rebate issue. Employers are also not immune to the lure of rebate traps, however. For many pharmaceutical contracts, self-funded employers demand the lion’s share of rebates from their pharmacy benefit manager or health plan vendor.

Asked if we can wean our system away from rebates, Dr. Popovian said that if biosimilar price discounts result in extremely low  net prices, plans and PBMs will no longer be able to turn a blind eye—they will have to go for the lowest net price as well. He pointed out, “Price competition doesn’t exist today. It’s rebate competition.”

Dr. Popovian believes that better adoption of lower-cost products will be necessary, because without it, “there will be no space within the benefit design for gene therapies and other game changers.”

Medicaid Preferred Drug Lists Also Focus on Rebates That Hold Back Lower-Priced Biologics and Biosimilars

Inmaculada Hernandez, PharmD

The rebate issue has snarled the Medicaid program as well, according to Inmaculada Hernandez, PharmD, Assistant Professor, Pharmacy and Therapeutics, University of Pittsburgh. States are incentivized to use originator drugs with high list prices, that after rebates, have lower net prices than biosimilars. According to her 2020 paper published in the Journal of Managed Care and Specialty Pharmacy, prior to 2010, states only received rebates for drugs administered through the fee-for-service Medicaid program. Since the passage of the Affordable Care Act, states also received rebates through Medicaid managed care organizations (MCOs).

In order to be listed on states’ Medicaid preferred drug lists (PDLs), the manufacturer must provide significant rebates to the program. Dr. Hernandez illustrated the problem with the follow-on insulin glargine Basaglar® version of the originator product Lantus®. “All nine states that included glargine in their PDLs favored Lantus over Basaglar. We analyzed Basaglar use between states with only fee-for-service Medicaid, states with managed care plans not subject to PDLs, those subject to them, and states with MCOs where drug benefits are carved out through fee-for-service drug benefit.” The uptake of Basaglar was minimal in all situations, except in MCOs not subject to PDLs. “Medicaid PDLs prevented uptake of Basaglar by listing it as nonpreferred. These results reflect the strong financial incentives of rebates,” Dr. Hernandez concluded, and “more states are implementing PDLs.” This has continued implications for the uptake of Basaglar as well as biosimilar versions of insulin glargine yet to be introduced.

The Congress was held as part of the 2021 Festival of Biologics USA virtual conference.  

Mandatory Price Slashing After Biologic Exclusivity Expires: Much Lower Prices but at What Cost?

Peter B. Bach, MD
Peter Bach, MD

There may be few areas of the biosimilar industry more frustrating to payers, manufacturers, and observers than the delays in market access due to patent mazes and litigation. Attempts to manage address intellectual property rights of biologic makers ranged from the insertion of the “patent dance” process in the BPCIA to calls for the Federal Trade Commission to step in and declare certain patents anticompetitive and thus invalid.

Peter B. Bach, MD, at Memorial Sloan Kettering Cancer Center, has been at the forefront of efforts to address high oncology drug prices. With Mark Trusheim, MS, from the MIT Sloan School of Management, they published a column in the New York Times on March 15, which reiterated an extremely aggressive approach to the dual problems of patents and pricing. We first reported on this approach in 2019, and thought it was worthwhile reassessing, based on the biosimilar situation in 2021.

P-Quad or the Pequod?

Under Production Plus Profit Pricing (P-quad), the 12-year period of market exclusivity would set a stronger standard for the biologic product lifecycle. “After 12 years, and regardless of patents, the maker of the original biologic would set a price that guarantees a 10% profit over and above the cost of making and distributing its product,” according to Dr. Bach’s plan.

This would, in effect, obviate life-cycle extension as an incentive for creating patent thickets for a particular product. There would likely be other reasons to file new patents to protect intellectual property, including for potential licensing of a pharmaceutical or its manufacturing process, newer formulations (e.g., routes of administration or less-painful versions of an injectable). The all-consuming, retain-multibillion-dollar-sales-at-any-cost drive for share value growth would be gone. Maybe overnight.

By the time 12 years of market exclusivity are complete, the manufacturers of biologics have generally earned multiples of their initial research and development costs on the product. The vast proportion of revenues late in a pharmaceutical product’s lifecycle is profit. For a biologic agent like Humira® this may be a tiny fraction. (Note: This is a pure guess on my part, but with $16 billion of US revenue alone, how much could production and distribution be? $200 million is only 1% of the total.)  

There are societal costs and benefits to the P-quad approach. One will likely be a rapid winding down of originator-sponsored research to improve a drug once marketed. Another would be a scuttled biosimilar industry. Drs Bach and Trusheim write that a 10% profit is more than most U.S. industries generate. That may be so, but we’re not talking about just any industry here. If this leads, as intended, to a gargantuan cut in total drug revenue at the end of the 12-year exclusivity period, there may be too little to sustain interest by the biosimilar makers of today. This effect is magnified if more than one biosimilar maker will have to share the smaller pie.

A Biosimilar Market to Ensure Drug Supply

On the other hand, the existence of a biosimilar market may no longer be based on the need for competition; rather it would be focused instead on ensuring supply, once the biologic maker is no longer interested in maintaining a 10% margin for a specific drug.

On the really big plus side, such an approach would undoubtedly reduce biologic prices. It would seriously hinder patents beyond those defining composition of matter and original manufacturing processes from delaying drug launch. In fact, the patent courts would have a lot fewer cases relating to biologics.

Furthermore, such a plan could also eliminate the use of rebates for older agents—if a price has been so discounted, what’s the point of offering a further rebate?

I wouldn’t be persuaded by the potential argument that the search for innovation will be harmed by reducing the opportunity for handsome profits beyond the 12-year period. The pharmaceutical industry is well able to earn considerable profits on a drug and contribute value to shareholders over the course of 12 years.

The authors’ stipulate that biosimilar competition has not yet resulted in anticipated drug price reductions. Based on data from IQVIA and Bernstein Research, this is not really the case in terms of marketed biosimilars in 2021. They argue that the price of trastuzumab today remains 26% higher than the 2007 price of Herceptin in today’s dollars. That may be true, but the prices are coming down. Just not as quickly as many expect they would. The real problem is that the price of biologics facing delayed biosimilar introductions has gone up. In past columns, I’ve expressed how the initial reductions in the cost of Enbrel® or Humira® will only reflect modest rollbacks. For example, based on yearly WAC increases of 9%, initial net price discounts on Humira in 2023 would have to be 54% to reflect the product’s cost in 2018. With that product, however, this may actually occur because of the intense competition upon biosimilar launch.

Maybe a restriction to 10% profit margins is not the right level for obtaining a balance between drug pricing and sustainability of the biosimilar industry. The immediate effects of decisive measures like P-quad are hard to gauge. The longer-term implications are even harder to estimate.

NCCN Biosimilar White Paper Advocates Against Single Preferred Products by Payers

A policy paper from the National Comprehensive Cancer Network (NCCN), released in early March, asks payers to refrain from preferring single agents for the treatment of cancer.

Based on a survey of cancer center pharmacy directors and policy development by these health executives at NCCN institutions, the white paper expressed concerns particularly around both storage issues and concerns about the health of the biosimilar industry.

Payer coverage restrictions were a focus of the white paper. Cancer centers have to stock adequate supplies of any biologic or biosimilar in a drug class that may be preferred by the several plans covering members who might visit the center for care. For example, one health plan may cover Herceptin® and not its biosimilars, yet another may prefer Herzuma® over the reference product and the other biosimilars. Still another may cover Kanjinti® only or all of the drugs in the category at parity. If a cancer center like Mayo Clinic contracts with six or more plans, the probability rises that many if not all of these products will need to be stored. The inability to automatically interchange these products with one another prevents an easy solution to the problem.

Further, payer restrictions “can threaten the continued availability of biosimilar products in the marketplace if payers refuse to reimburse for, without exclusions or restrictions, at parity, all biosimilar products within a therapeutic class,” state the authors. “In some cases, certain payers require use of the higher cost (to the hospital) reference product, to the detriment of the less-expensive biosimilar.” The principal reason for this situation, they believe, is likely rebates paid by manufacturers to the payers.

Who’s P&T Committee Holds Sway?

Another interesting challenge faced by the cancer centers is that payer coverage of products limits to an extent the institution’s options during its own Pharmacy & Therapeutic Committee deliberations.

“Insurance company restrictions, which are generally not visible to the cancer center physician or pharmacist and often are not known ahead of time by the finance department prior authorization (PA) or pre-certification staff members.” The white paper continues, “When PA is performed, the inevitable result is payment denial with resulting appeals, draining time and resources from healthcare providers and contributing nothing to improve patient outcomes or safety, or decreasing the cost of health care. Policies such as these may also lead to medication errors and/or financial toxicity for patients.”

A larger problem, NCCN points out, is that some manufacturers may exit the biosimilar market because “lack of parity and lack of equal access to hospitals (since hospitals cannot administer medications that they know will not be reimbursed). This may lead to less competition and possible loss of cost savings—the original reason for the BPCI Act.”

It is true that health systems have had to address the patient’s health care coverage restrictions for many years. Hospitals maintain their own drug formulary for inpatient and outpatient care. Once patients are discharged or cared for in the community setting, the drug formulary of the patient’s health plan or insurer then dictates which medications are covered. This often results in changes in treatment with small-molecule medicines.

Of course, this is not the case for biologics (at least other than insulin). And not for cancer centers, who treat the patient through the entire episode of care. They have to be highly cognizant of which product is covered by which insurer and ensure that the patient doesn’t wind up having to pay an enormous bill for treatment with noncovered agents. If all biosimilars and reference products were covered, this implies that the health system can persuade its clinicians to prescribe one of the limited number of agents on its own formulary, thus alleviating the storage issue.

Lower Prices or Fewer Storage Requirements

The white paper from NCCN does seem to suggest a question about the value of biologic competition for payers, however, and it is closely related to the topic of an article posted recently. If there is to be coverage at parity, this would tie the hands of payers to get the best deal possible.

Although we agree that the sustainability of the biosimilar industry is still at risk, it may be more a risk for certain manufacturers who must fight harder for uptake. This will likely be the case for those drug makers who are late to the market; this has always been the case for brand or generic medications struggling for marketshare in a crowded drug category.

NCCN’s point about drug storage is well taken. Biologic medicines often require refrigeration and sometimes special handling. Yet, the pharmaceutical pipeline is stocked with biologic products (many of which are cancer therapies), and this particular problem will not go away if stocking all biosimilar and reference products were not required.

Forcing Payers to Cover Biosimilars? Beware of Unintended Consequences

One of the problems that has stalled greater uptake of biosimilars in the US has been payers’ reluctance to give up their rebate revenue from manufacturers of reference biologics. When payers prefer branded reference agents with higher wholesale acquisition costs (WAC), they retain often substantial rebate revenue, with little benefit to consumers.

A proposed bill was introduced into the Minnesota state legislature in February that attempts to remedy the situation. Although the sponsors seem to have their hearts in the right place, they may have not considered how this move could backfire on them, and potentially have negative results for biosimilar manufacturers.

Referred to as SF 990, sponsors Jennifer Schultz (DFL-Duluth) and State Senator Carla Nelson (R-Rochester) introduced the bill into the Minnesota state legislature in mid-February. The objective of the bill is to make more biosimilars accessible to a greater proportion of the state’s residents. Specifically, the bill will require pharmacy benefit managers or health plans/insurers to “not require or demonstrate a preference for a pharmacy or healthcare provider to prescribe or dispense any of the following: (1) a reference biologic, (2) any product that is biosimilar to the reference biologic product, or (3) any product that is an interchangeable biological product, relative to the reference biologic product.” The clause also says, “if a PBM or health carrier elects coverage of a product listed [above], it must also elect equivalent coverage [for all other products in its class].” This requirement would not be applicable to health plans that are part of public programs or those providing coverage through the State Employee Group Insurance Plan.

Under the Minnesota proposal, plans operating in the state would be required to provide equal coverage for biosimilars, reference agents, and interchangeable products in the same drug category, with the expectation that this would make biosimilars more accessible. It may be true. Over the long term though, it could also have the reverse effect.

Consider this hypothetical example: If a plan in Minnesota preferred a reference biologic X, because it costs less than biosimilar Y after rebates and discounts. That level of preferred coverage came with a 20% copay to the consumer (to a maximum out-of-pocket limit). The biosimilar is currently excluded. Now, if SF 990 is signed into law, the biosimilar is now covered at that same 20% copay to the consumer, regardless of what the WAC and net cost may be. That could remove the incentive for the biosimilar manufacturer to lower its WAC cost. It could also remove the incentive for the maker of reference drug X to add discounts and increase rebates to provide the lower net cost. In other words, the prices of both drugs may not be driven down as far by competition. In that case, no one benefits. In fact, there would be more incentive to raise prices, because the law states that the managed care organization would have to cover all if it covers any (even if the price goes up). The law explicitly takes away the payer’s ability to use medical management and formulary tools to control costs. Either way, the bill’s sponsors wouldn’t have intended this to happen.

Undercutting Biosimilar Competition

The better scenario is that the payers prefer the biosimilar agent because they want to, not because they have to. And they will want to because the biosimilar gives them the lowest net cost (either through the introduction of more biosimilars that generate additional competition or through the elimination of rebates). As it stands today, most biosimilar coverage is at parity with reference brands, according to a research letter published in June 2020 in JAMA.

Ms. Schultz said of this bill, “Biosimilars could save families hundreds, or even thousands, of dollars per month. Coverage for lower-cost biosimilars is a must-do.” What if the biosimilars are no longer the lower- cost product?

A wise teacher once counseled me that any time a piece of legislation is passed, unintended consequences will soon be evident, and will surprise everyone—even its critics. And one consequence of this bill could be to undercut competition, which is the reason for biosimilars’ existence.

Biosimilar Bytes for This Week

Although big biosimilar news has been lacking in the last couple of weeks, there are several newsbytes that are of interest to industry followers. Here are a few of the more notable biosimilar news items.  

The COVID pandemic hadn’t had significant implications for biosimilar developers, but news of a deferred FDA approval decision for an investigational bevacizumab biosimilar may have broken the streak. The approval of product MYL-1402O from partners Biocon and Mylan (now Viatris) will be delayed because the FDA has not yet inspected Biocon’s manufacturing facility. According to a regulatory filing, Biocon does not yet have a schedule as to when the inspection will occur. We originally projected an FDA decision in the first quarter of 2021, based on a 351(k) application in March 2020. Biocon and Mylan are vying to become the third Avastin® biosimilar to be approved and launched in the US.  

Coherus has discontinued its aflibercept biosimilar development program (CHS-2020) as it diverts finances to developing a new PD-1 inhibitor with Junshi Biosciences. This leaves Coherus with three biosimilars in their pipeline: adalimumab, ranibizumab, and bevacizumab. The latter two are licensed from other biotech developers; CHS-1420 is a homegrown biosimilar version of Humira®.

Earlier this month, we highlighted Outlook Therapeutics, a company that is seeking to challenge the branded biologic and biosimilar ophthalmology market with a manufactured intravitreous injection of bevacizumab. Outlook recently announced the completion of recruitment of its final safety study, an open-label investigation. The results should be announced in the second quarter of this year, according to the manufacturer. Combined with the upcoming release of its phase 3 trial results, Outlook confirmed that it is on target to submit a 351(a) application to the FDA in the fourth quarter of 2021.Celltrion has begun its phase 3 trial of its aflibercept biosimilar CT-P42. This trial will be recruited through 13 countries and should serve as the pivotal trial for its regulatory applications. In addition, the company received approval in Canada to market its subcutaneous version of etanercept. Considering it was approved in Europe in 2019, the agent Remsima SC seems to be poised for a 351(a) FDA filing perhaps as early as this year. It cannot be considered a biosimilar, because a subcutaneous version of the reference product Remicade® does not exist.    

(Note: This article was corrected and updated February 18, 2021).

Ophthalmology Biosimilars May Face a Formidable Challenger

In researching an update on Oncobiologics, an organization that once had an interest in producing biosimilars (adalimumab and bevacizumab), I found a compelling issue that could seriously affect the likelihood of success for several other biosimilar manufacturers.

It turned out that Oncobiologics was rebranded Outlook Therapeutics in 2018. At the time, the newly rechristened company announced that it would no longer develop biosimilars for the US market. Although it dropped its interest in an Avastin® biosimilar, if successful, Outlook Therapeutics may undermine the expectations of ophthalmologic biosimilar makers.

Compounded Bevacizumab Still Number 1 for Wet Macular Degeneration

According to Outlook’s data, Avastin’s off-label use dominated the age-related wet macular degeneration market in 2016, at roughly half of the patient volume. In a 2018 survey of 740 US retinal specialists, off-label Avastin use for this disorder was even greater, at 70%. This off-label version must be compounded by a pharmacy to create the lower-dose solution required for intravitreal administration.

A study published in 2011 in the New England Journal of Medicine found that the compounded formulation of bevacizumab and the biologic ranibizumab (Lucentis®) were of equivalent efficacy for this indication. This makes sense, because ranibizumab and bevacizumab are derived from the same monoclonocal antibody; ranibizumab is a fragment of the full bevacizumab molecule. Another clinical trial found that compounded bevacizumab was as effective as aflibercept (Eylea®) in treating central retinal vein occlusion–associated macular edema. When compounding pharmacies created the ophthalmic formulation from a single vial of Avastin, the yield was dozens of doses, costing a fraction of that for Lucentis and Eylea. The only issue was whether the compounding pharmacies could ensure a contaminant-free product for patient use.

Outlook Therapeutics’ lead pipeline product is a manufactured ophthalmologic form of bevacizumab (ONS-5010). In commercializing a cGMP-produced ophthalmic formulation of bevacizumab, Outlook seeks to retain the drug’s value and efficacy while ensuring its safety. The drug maker is hoping to file a 351(a) biologic licensing application in the second half of 2021. A phase 3 trial was completed in August 2020 in which 61 Australian patients with choroidal neovascularization secondary to age-related macular degeneration were given either ranibizumab or ONS-5010. A larger phase 3 trial of 227 patients is set to wrap up in July 2021.   

Shrinking Market Expectations

This development may certainly affect the sales potential for the developing Lucentis and Eylea biosimilars marketplace. As covered last year, Lucentis’ sales are slipping, mostly due to competition with Eylea. Roche indicated an estimated annualized 2020 US sales of approximately $1.7 billion. Eylea’s 2020 annualized US sales may be about $4.8 billion, based on Regeneron’s third-quarter 2020 net sales figures. A corporate presentation by Outlook indicated that Eylea’s share is more than 30% of the wet macular degeneration market.

Assuming Outlook Therapeutics is successful in obtaining approval of its 351(a) application with the FDA, this could first occur in late 2022. The earliest any aflibercept biosimilar will come to the market will be around that same time. Two ranibizumab biosimilars may be ready for launch in 2021. If Outlook prices its new ophthalmologic formulation of bevacizumab at a solid discount to the aflibercept and ranibizumab biosimilars, payers would be justified in requiring the reference brands and biosimilars be stepped through ONS-5010. Such a prior authorization requirement or step edit, especially in the Medicare space, could significantly limit the projected revenues of ranibizumab and aflibercept biosimilars.

Since compounded bevacizumab is the dominant treatment in the age-related macular degeneration category, providers have already experienced ramifications on buy-and-bill practices relative to Eylea or Lucentis prescribing. After obtaining FDA approval, payers would need little incentive to utilize specialty pharmacies for product purchase and delivery of ONS-5010 to the physicians’ offices.

This rosy scenario for Outlook Therapeutics may not last, however. Investigational anti-VEGF treatments are being studied for their improved duration of action, requiring less-frequent intravitreal injections. This characteristic alone could make them more attractive than today’s options.

It is possible that developers of ranibizumab and aflibercept biosimilars are solely focused on their smaller reference targets with multibillion-dollar sales. Yet, the manufacturer of ONS-5010 may gain additional, significant marketshare at the expense of the biosimilar makers, if they play their cards right.