Cover Story

Biosimilars Set to Take a Big Market Share in the US

The European Medicines Agency approved the first biosimilar therapies for rheumatologic diseases in 2006, yet it took the passage of the Affordable Care Act in 2010 for the United States to begin playing catch-up. The FDA followed the pathway and framework the EMA set, culminating in the approval of biosimilar Zarxio (filgrastim-sndz, Sandoz) — an oncology drug — in 2015. Since this preliminary approval, there are now a handful of biosimilars approved in rheumatology with several more in the pipeline. However, as these drugs emerge, questions about pricing and what payers might be willing to pay in the complex structure of the U.S. health care system are becoming more pressing.

Traditionally, biosimilar treatments, like generic drugs, are cheaper than the bio-originators they replicate, but whether those savings will be passed on to patients remains to be seen. Pharmacy benefit managers are frequently included in transactions involving these drugs and will surely have a say, as will insurers. Formal guidelines or recommendations could help dictate how the drugs are used and what patients ultimately pay. The ACR has a position statement on the use of biosimilars for U.S. rheumatologists to follow, with a more comprehensive Special Article in press, that may aid many U.S. clinicians who have knowledge gaps compared to their European counterparts in the use of these drugs.

Currently approved biosimilar therapies for rheumatologic diseases in the U.S. include Inflectra (infliximab-dyyb, Celltrion/Pfizer), Renflexis (infliximab-abda, Samsung and Merck) and Ixifi (infliximab-qbtx, Pfizer), each of which replicates infliximab (Remicade, Janssen); Amjevita (adalimumab-atto, Amgen), which replicates adalimumab (Humira, AbbVie); and Erelzi (etanercept-szzs, Sandoz), which replicates etanercept.

Angus B. Worthing, MD
Angus B. Worthing

“We went from having one approved biosimilar in 2015 to having multiple approvals in 2016 and 2017,” Jonathan Kay, MD, professor of medicine, Timothy S. and Elaine L. Peterson Chair in Rheumatology, and director of clinical research in the Division of Rheumatology at the University of Massachusetts Medical School, told Healio Rheumatology. “The number of biosimilar approvals are increasing exponentially.”

However, even with this leap in the number of drugs, misconceptions may persist among U.S. clinicians, according to Kay. He suggested that there may be confusion between biosimilars and biomimics — copies of biologic medications that are widely available in the developing world but have not undergone the same rigorous clinical trial process and have not been reviewed or approved according to a specific regulatory pathway as biosimilars.

“Physicians initially might have confused biosimilars with these ‘knock-offs,’ for lack of a better term,” he said. “Also, patients were worried that they would be treated with an inferior medication, if prescribed a biosimilar. But now that multiple biosimilars are on the market in the U.S., knowledge about biosimilars is increasing, and clinicians are eager to learn about these new versions of existing medications. U.S. rheumatologists are catching up very quickly to their counterparts in Europe.”

The next issue will be one of cost, according to Angus B. Worthing, MD, chair of the ACR Government Affairs Committee and clinical assistant professor of medicine at Georgetown University Medical Center. “Price is the main reason biosimilars exist,” he said. “The price of biologics is too high; with biosimilars, everyone who needs a biologic can get it.”

Signs indicate that biosimilars will either be less expensive, or drive the price of biologics down, or both. But, with so many players involved in a complicated system, clinicians and patients remain uncertain about how that pricing situation will play out.

Following Europe’s Lead

Worthing stressed the importance of having the European legal framework in place in the process of approving these therapies in the U.S. “They took their time to do it in a transparent way,” he said. “It’s a useful thing for U.S. doctors and patients to have some hindsight from the European experience.”

Stanley B. Cohen, MD, medical director at the Metroplex Clinical Research Center in Dallas, addressed the process.

“FDA and the EMA and other regulatory organizations have set up parameters for evaluating the critical attributes of the biosimilar and originator molecules to be considered similar,” he said. “Analyses of the structural and functional characteristics of multiple batches of the biosimilar and the originator are conducted to determine if any significant differences between the molecules exist. If no meaningful difference in structure and function are identified, additional studies in the development process are performed. Animal data and nonclinical studies can be done where warranted, but generally, very little of that is necessary in biosimilar development.”

The next step in evaluation is one of clinical pharmacology, according to Cohen. “Looking at pharmacokinetics and possibly pharmacodynamics when available,” he said. “These studies generally are conducted in healthy volunteers with single dose exposure and are crucial in demonstrating bioequivalent PK for the biosimilar and the originator molecule. Immunogenicity is a major issue in biosimilar development, and it is expected that similar immunogenicity be seen in the clinical trials for the biosimilar and the originator molecule and is evaluated both in the PK studies and the subsequent clinical trial.” Cohen added that the biosimilar is then assessed in a single phase 3 head-to-head clinical trial using pre-specified parameters to demonstrate similarity in efficacy utilizing outcomes such as ACR20 response in RA or PASI75 response in psoriasis in addition to evaluation of safety and immunogenicity.

Beyond the legality, there may be a financial benefit to following the EMA’s path, as well, according to Cohen. In countries where the government controls health care delivery, such as Norway, aggressive promotion of biosimilar use in inflammatory diseases has been significant, he said.

“The cost savings in Norway has been significant, in the range of 50% to 60% for biosimilar infliximab. In other countries, where the government has less control of health care delivery, the uptake of biosimilar infliximab/etanercept has been slower.”

Transition Data

Stanley B. Cohen, MD
Stanley B. Cohen

U.S. clinicians have been exposed to a host of studies of these drugs in peer-reviewed journals over the last 2 years, and in particular, at the 2017 ACR Annual Meeting.

In a phase 3, double-blind parallel group, multicenter study, Smolen and colleagues compared SB2 (Samsung Bioepsis) with reference infliximab, including a cohort of 291 patients treated with SB2 and 293 treated with the reference product. Results indicated similar outcomes in terms of ACR responses, DAS28, Clinical Disease Activity Index, and Simplified Disease Activity Index between the two drugs through 54 weeks. Additionally, researchers found adverse events were similar, as well as anti-drug antibodies.

In a similar study published in Arthritis & Rheumatology, Weinblatt and colleagues reported the results of a phase 3, randomized, double-blind, parallel-group study on the use of SB5 (Samsung Bioepsis), a proposed biosimilar to adalimumab, in 544 patients with RA. There were 269 patients in the study drug group and 273 treated with the reference product. Results at week 24 showed ACR20 response rates of 72.4% for SB5 and 72.2% for adalimumab, with a 0.1% difference (95% CI, –7.83 to 8.13). ACR50 and ACR70 results showed similarly comparable outcomes, as did DAS28 findings; pharmacokinetics, treatment-emergent adverse events, and antidrug antibodies also were comparable.

Cohen and colleagues conducted a 58-week, double-blind, multicenter, phase 3, clinical equivalence of BI 695501-adalimumab biosimilar (Boehringer Ingelheim) and adalimumab in terms of ACR20 response at 12 and 24 weeks in patients with moderately-to-severely active RA. The analysis included 645 patients randomly assigned to the study drug or adalimumab every 2 weeks through 24 weeks, at which point re-randomization occurred. At this point, 147 originator adalimumab patients switched to BI 695501, 148 remained on the originator adalimumab, and 298 patients on the adalimumab biosimilar were dummy re-randomized and continued on treatment.

At 48 weeks, Cohen and colleagues found that DAS28-ESR changes from baseline were –2.71 for patients in the switch group, –2.60 for those who continued on the bio-originator, and –2.70 for those who continued on the study drug. At week 48, the proportion of patients with antidrug antibodies was 36.2% for the switch group, 49.6% for those who continued adalimumab and 41.8% for those who continued BI 695501. Transition did not impact efficacy, safety or immunogenicity, according to the researchers. Among the safety outcomes, serious infectious events occurred in 0.6% of patients in the BI 695501 group and 4.0% of those receiving adalimumab, with no fatalities reported in either arm.

In a 2016 study, Attipoe and colleagues switched all patients in the rheumatology department to an etanercept biosimilar after informing patients of the switch. They followed up with a questionnaire to determine how this transition may be improved. The cohort comprised 68% of patients with RA, 16% with psoriatic arthritis and 11% with ankylosing spondylitis. Rheumatology clinicians informed 65% of the cohort, while nurses or delivery companies informed the remaining. Face-to-face visits were used to inform 90% of patients, while phone or letters were used for the rest.

Results showed that the proportion of patients who found the switch experience to be excellent or very good was 45%, but 9% reported that the experience was poor or very poor. The “satisfactory” rate was 44%. Of the dissatisfied patients, 32% reported that they would have preferred to have been given the option of switching, while 21% required more information and 39% reported adverse events. Longer disease duration was associated with a poor switching experience (P = .042), along with not feeling sufficiently supported (P = .000000079) and experiencing adverse events after switching (P = .0018).

“Switching onto [biosimilars] is a phenomenon that is likely to continue with a need to improve patients’ experience of switching,” the researchers concluded. “Adequate information given in advance, having opportunities to ask questions and having a point of contact after switching are factors that patients express as important.”

According to Worthing, the FDA is currently considering “real-world” data. However, it’s unclear whether these data are being used in the approval process.

“Post-marketing data will be important to show how adverse events get tracked. Drugs can be approved in one of two ways. The first is when the biosimilar is shown to be similarly safe and effective as its bio-originator. The second shows interchangeability in which a drug is proven safe after alternating with the bio-originator, where they start on the original drug and then switch. The first pathway has been established, with several biosimilars approved. The interchangeability pathway is in draft form now.”

Many clinicians like Worthing are eager to see the final interchangeability pathway emerge. “The draft form was rigorously assembled and is likely to create a lot of good data,” he said.

Cohen said that the goal of the studies in developing a biosimilar is to determine that these minor differences in the molecular structure have no impact on efficacy of the molecule, safety of the molecule and immunogenicity.

“The FDA regulatory requirements look at the totality of the evidence; but in contrast to new molecule development, which depends heavily on clinical studies, in biosimilar development, the crucial evaluation is done pre-clinically with an analytical evaluation comprising structural analysis of the biosimilar in comparison to the originator molecule, along with functional analyses looking at multiple batches of medicine over time.”

Worthing said that clinicians are hoping more data sets like this will come along. Once these clinical criteria are met, the application process begins.

“New biologics are evaluated and approved by the FDA under a Biologics License Application (BLA) or 351(a) pathway,” Allan Gibofsky, MD, JD, professor of medicine and public health at Weill Cornell Medicine and attending rheumatologist at the Hospital for Special Surgery, said in an interview. “The Affordable Care Act of 2010 included the Biologics Price Competition and Innovation Act, also known as the Biosimilars Act. This created an abbreviated pathway — 351(k) — that can be used for agents that are highly similar to an FDA-licensed biologic.”

Pricing Issues

A number of questions surround how biosimilar therapies will be priced, and how insurers and pharmacy benefit managers (PBMs) will make their decisions. For Stanford Shoor, MD, clinical professor of medicine in immunology and rheumatology and rheumatologist at Stanford Health Care, future guideline changes will determine how biosimilars impact patient cost-savings.

“The guideline currently says to use methotrexate first,” he said. “Insurers will follow that guideline because it is the standard bearer, it has high efficacy and relatively low toxicity.”

When methotrexate reaches the end of its effectiveness, insurance companies will pay for the least expensive product, which could be a biosimilar if there is not inferiority, according to Shoor. “What will happen at the next level is that if it comes down to etanercept or its biosimilar, the insurer will cover the biosimilar because it is cheaper,” he said.

Allan Gibofsky, MD, JD
Allan Gibofsky

However, Gibofsky noted, the picture begins to muddy when PBMs get involved. “With regard to biosimilars, although a manufacturer may offer a discount from average wholesale price, that is not the full determinant of use, as rebates and volume pricing must be factored in as well,” he said. “Candidly, how they will be priced to the payer and PBM will be less important to the prescribing clinician than to what degree the cost-savings benefit the individual patient.”

Kay pointed out that the first infliximab biosimilar, infliximab-dyyb, was initially priced about 15% less than the reference product and is currently priced about 19% less than the reference product. However, determining the actual cost of the drug is complicated in the U.S. health care system.

“The actual cost of a drug in the U.S. is difficult to ascertain because PBMs negotiate discounts and rebates with the manufacturer,” he said. “For example, if a PBM puts the infliximab reference product on formulary, the manufacturer may bundle other medications at much lower prices — so the PBM may agree to the ‘package.’ Biosimilar manufacturers are less likely to be in a position to do that, especially if the biosimilar is their only product.”

The process of getting a biosimilar onto the formulary of a PBM, however, is complex, according to Worthing. He also addressed the rebate and volume pricing system. “It is the price of the drug times the rebate plus the market share,” he said. “It doesn’t allow another company to come in and undercut the drug on the formulary. Anecdotal reports suggest that PBMs have been telling people to raise prices.”

That said, Worthing noted that an initial drop in prices for infliximab has been reported, which may bode well for patients. “The overall goal is to make sure our patients pay less,” he said. “Hopefully, the PBM system will allow price reductions to pass savings along to patients.”

Shoor also emphasized a practice management component to the story. “I would imagine there will be difficulties in reimbursement, based on the history of reimbursement of drugs in the U.S.,” he said. “I don’t know where they will settle themselves on the market vs. where they are in Europe, because it is easier for European clinicians to get approval for a biologic agent — the U.S. doesn’t have standard for such a thing.”

One way of achieving reduced drug prices is to have a more scientific basis for formularies, according to Worthing. But due to the complexities of the equation and the overall trend that drug prices are not dropping as planned, alarm bells are ringing for many experts. “When patients can’t get medicines that are too expensive, you start looking under the hood,” he said.

Cohen addressed the issue of reduced pricing as well. “At present, there is significant uncertainty about what the actual discount on the price of the drugs will be,” he said. “Clearly in European countries such as Norway, where the government runs the health care purchasing, there have been discounts of up to nearly 70%. In the U.S., with the PBMs controlling drug pricing along with pharma, the actual discounts will be difficult to determine.”

However, the newest infliximab biosimilar may be priced at more than a 35% discount, according to Cohen. “I suspect that Janssen will match the discount or through their contracts with PBMs limit the penetration of the infliximab biosimilars,” he said. “Ultimately, as there are more biosimilar infliximabs and etanercepts available, the price should drop. The patient’s copay will remain an issue and we look forward to seeing if patients receiving the biosimilar will have lower copays to stimulate use.”

Kay echoed this point, noting that biosimilars have already demonstrated a significant impact in the drug marketplace. “It is certainly true that actual pricing comes down to the deals made by PBMs with pharma,” he said. “But this does not mean that biosimilars do not play an important role in the marketplace. Janssen likely would not have lowered the price of Remicade if biosimilars of infliximab were not on the market. If the bio-originator comes in at a lower price, then a PBM is going to put it in a preferred position on its formulary. So far, in the U.S., biosimilars have gained only a very small share of the infliximab market, but they have effectively reduced the cost of reference infliximab.”

Another issue that may be associated with pricing is the self-administered nature of biosimilar therapies, according to Worthing. “Patients like them because they are easy to use and don’t necessarily require a doctor visit, which should help reduce cost, but distribution will still go through PBMs,” he said.

For Kay, semantics matter, particularly when perceptions about and knowledge of biosimilars among U.S. clinicians remains somewhat problematic. “I would use the term ‘lower cost,’ since ‘cheaper’ implies lower quality,” he said. “The ideal biosimilar would be identical to the reference product but less expensive.”

Gibofsky brought the issue back to the clinic. “By definition, biosimilars are neither more effective nor safer; they cannot be,” he said. “Thus, they will compete solely on cost, and one can anticipate that — similar to how insurers evaluate branded drugs and generics — they will seek to pay the lowest amount for any comparable product, including a biologic.

Knowledge Among U.S. Clinicians

During a 2016 survey, Gibofsky and colleagues posed a series of 20 questions to 131 physicians — including 102 rheumatologists — regarding their familiarity with biosimilars, the concept of biosimilarity, and the approval process for biosimilars in the treatment of immune-mediated chronic diseases. Results showed that 84% of respondents were aware that an infliximab biosimilar was approved by the FDA, but only 47% were aware of adalimumab biosimilars and 34% knew of the product replicating etanercept.

The researchers found that 38% reported being extremely familiar with the FDA’s definition of a biosimilar, while 36% reported moderate familiarity with this definition. Understanding that an approved product did not automatically denote interchangeability was reported among 71% of respondents. Interchangeability was very or moderately important to 74% of respondents, while 96% considered effectiveness and safety as important, and 95% valued durability of response. Two-thirds of the cohort reported that they would be extremely likely or likely to initiate therapy using a biosimilar with comprehensive data available, while just 5% said they would start treatment for a different condition than the one on the indication.

For clinicians treating a patient responding well to a bio-originator, 60% reported being unlikely to switch to a biosimilar. For those treating a patient who was responding poorly to a reference product, 21% reported being likely or extremely likely to switch.

“This survey supports a need to further educate U.S. rheumatologists about biosimilars, extrapolation, and interchangeability,” Gibofsky reported. “Knowledge gaps include a lack of understanding of biosimilarity based on switching, and the availability of currently approved biosimilars.”

“There is an increasing desire by clinicians to learn more about biosimilars,” Gibofsky said. “Clinicians seem less interested in the manufacturing processes of biosimilars than their use in clinical practice.”

Gibofsky suggested that prescribers should deal with several unanswered questions. “Is the durability of a biosimilar similar to that of the bio-originator over time?” he said. “What is the effect of repeated switches on durability and efficacy? Can biosimilars be switched among themselves with the same level of comfort as a switch between a bio-originator to a biosimilar? What is meant by ‘interchangeability’ and how will that affect biosimilar use?”

In two other data sets presented at the 2017 ACR Annual Meeting by Radtchenko and colleagues, 24 community rheumatologists and 20 rheumatology practice managers in the U.S. were assessed for perceptions of biologics. They found that just 51% understood the concept of interchangeability, while 76% were unaware of compatibility requirements after a manufacturing change. Just 40% believed that efficacy and safety were matched between a biosimilar and its bio-originator. In addition, 20% said they would not prescribe a biosimilar at all, 23% reported that they would switch from a reference product and 57% would initiate a treatment-naïve patient with a biosimilar.

The researchers found that regulation associated with substitution was the most concerning issue for these respondents, followed by understanding of when to use a biologic vs. a bio-originator, and coordinating with pharmacists. Most wanted more information on both clinical and reimbursement information. “Significant barriers to biosimilar adoption for rheumatologic conditions exist due to physicians’ perceptions,” they concluded.

In another study, Radtchenko and colleagues evaluated early uptake of infliximab-dyyb in RA following its approval in April and launch in November of 2016. Biologic or biosimilar therapy was initiated in 78,481 patients since that time, but just 0.1% (n =90) were treated with the drug. The researchers reported that 6.6% of those patients were treated with the infliximab reference product.

“Adoption of [infliximab-dyyb] in the US so far has been low and has not yet significantly impacted the reference biologic,” they wrote. “The majority of [infliximab-dyyb] patients received it as first biologic, however a third of them switched from [infliximab]. Duration of therapy on [infliximab-dyyb] is relatively short due to delayed launch.”

Worthing is hopeful that previous uptake of biosimilars by the oncology community indicates that rheumatologists also will improve knowledge and use of the drugs. “Oncologists had higher amounts of knowledge and confidence in biosimilars than other specialists,” he said. “Now that we have these drugs in rheumatology, rheumatologists are finding out how dispensing works. The good news is that dosing will be easy, with the same dosing and administration as the bio-originators.”

Moving Forward

“There are multiple biosimilars in development for inflammatory arthritis as well as for inflammatory bowel disease and psoriasis,” Cohen said. “There will be multiple biosimilars for Humira and Remicade as well as Enbrel and Rituxan approved over the next several months to years. As patents lapse for other biologic therapies, such as Actemra/Orencia, biosimilars will be developed for these drugs as well. None of these are major game changers as far as therapeutics are concerned and we must be cognizant of the fact that the only reason to use a biosimilar is cheaper cost.”

The ACR Position Statement and subsequent guidance documents will be helpful, according to Worthing. “We just need to have as much information as we can on the science, the economics and the dispensing,” he said.

For Kay, keeping an eye on PBM formularies and the negotiations they conduct will be critical. “Patients do not get back the money from the rebates and discounts that PBMs negotiate — even third-party payors do not get back the entire rebate and discount,” he said. “PBMs are for-profit companies that are neither transparent nor necessary participants in the process of providing health care.”

Shoor emphasized the need for ongoing education regarding biosimilars. “The answer for U.S. clinicians is to share as much information as possible with our European colleagues,” he said. “We will understand how to use and manage these drugs by talking to them. This will happen from person to person.” – by Rob Volansky

Disclosures: Cohen reports a consulting relationship with Pfizer. Gibofsky reports he is a stockholder in AbbVie, Amgen, Bristol-Myers Squibb, Pfizer, Johnson & Johnson, GSK and Regeneron and is a consultant to AbbVie, Amgen, AstraZeneca, Pfizer, Horizon, Iroko, Relburn, Celgene, Takeda, Sandoz, Merck, Celltrion, Speaker-AbbVie, Merck, Pfizer and Celgene. Kay reports receiving research support paid to the University of Massachusetts Medical School from AbbVie, Ardea Biosciences, Eli Lilly and Company, Genentech, Pfizer, and UCB; and is a consultant to Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Crescendo Bioscience, Eli Lilly and Company, Janssen Biotech, Merck Sharp & Dohme, Pfizer, Roche Laboratories, Samsung Bioepsis, Sandoz, and UCB. Shoor and Worthing report no relevant financial disclosures.

The European Medicines Agency approved the first biosimilar therapies for rheumatologic diseases in 2006, yet it took the passage of the Affordable Care Act in 2010 for the United States to begin playing catch-up. The FDA followed the pathway and framework the EMA set, culminating in the approval of biosimilar Zarxio (filgrastim-sndz, Sandoz) — an oncology drug — in 2015. Since this preliminary approval, there are now a handful of biosimilars approved in rheumatology with several more in the pipeline. However, as these drugs emerge, questions about pricing and what payers might be willing to pay in the complex structure of the U.S. health care system are becoming more pressing.

Traditionally, biosimilar treatments, like generic drugs, are cheaper than the bio-originators they replicate, but whether those savings will be passed on to patients remains to be seen. Pharmacy benefit managers are frequently included in transactions involving these drugs and will surely have a say, as will insurers. Formal guidelines or recommendations could help dictate how the drugs are used and what patients ultimately pay. The ACR has a position statement on the use of biosimilars for U.S. rheumatologists to follow, with a more comprehensive Special Article in press, that may aid many U.S. clinicians who have knowledge gaps compared to their European counterparts in the use of these drugs.

Currently approved biosimilar therapies for rheumatologic diseases in the U.S. include Inflectra (infliximab-dyyb, Celltrion/Pfizer), Renflexis (infliximab-abda, Samsung and Merck) and Ixifi (infliximab-qbtx, Pfizer), each of which replicates infliximab (Remicade, Janssen); Amjevita (adalimumab-atto, Amgen), which replicates adalimumab (Humira, AbbVie); and Erelzi (etanercept-szzs, Sandoz), which replicates etanercept.

Angus B. Worthing, MD
Angus B. Worthing

“We went from having one approved biosimilar in 2015 to having multiple approvals in 2016 and 2017,” Jonathan Kay, MD, professor of medicine, Timothy S. and Elaine L. Peterson Chair in Rheumatology, and director of clinical research in the Division of Rheumatology at the University of Massachusetts Medical School, told Healio Rheumatology. “The number of biosimilar approvals are increasing exponentially.”

However, even with this leap in the number of drugs, misconceptions may persist among U.S. clinicians, according to Kay. He suggested that there may be confusion between biosimilars and biomimics — copies of biologic medications that are widely available in the developing world but have not undergone the same rigorous clinical trial process and have not been reviewed or approved according to a specific regulatory pathway as biosimilars.

“Physicians initially might have confused biosimilars with these ‘knock-offs,’ for lack of a better term,” he said. “Also, patients were worried that they would be treated with an inferior medication, if prescribed a biosimilar. But now that multiple biosimilars are on the market in the U.S., knowledge about biosimilars is increasing, and clinicians are eager to learn about these new versions of existing medications. U.S. rheumatologists are catching up very quickly to their counterparts in Europe.”

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The next issue will be one of cost, according to Angus B. Worthing, MD, chair of the ACR Government Affairs Committee and clinical assistant professor of medicine at Georgetown University Medical Center. “Price is the main reason biosimilars exist,” he said. “The price of biologics is too high; with biosimilars, everyone who needs a biologic can get it.”

Signs indicate that biosimilars will either be less expensive, or drive the price of biologics down, or both. But, with so many players involved in a complicated system, clinicians and patients remain uncertain about how that pricing situation will play out.

Following Europe’s Lead

Worthing stressed the importance of having the European legal framework in place in the process of approving these therapies in the U.S. “They took their time to do it in a transparent way,” he said. “It’s a useful thing for U.S. doctors and patients to have some hindsight from the European experience.”

Stanley B. Cohen, MD, medical director at the Metroplex Clinical Research Center in Dallas, addressed the process.

“FDA and the EMA and other regulatory organizations have set up parameters for evaluating the critical attributes of the biosimilar and originator molecules to be considered similar,” he said. “Analyses of the structural and functional characteristics of multiple batches of the biosimilar and the originator are conducted to determine if any significant differences between the molecules exist. If no meaningful difference in structure and function are identified, additional studies in the development process are performed. Animal data and nonclinical studies can be done where warranted, but generally, very little of that is necessary in biosimilar development.”

The next step in evaluation is one of clinical pharmacology, according to Cohen. “Looking at pharmacokinetics and possibly pharmacodynamics when available,” he said. “These studies generally are conducted in healthy volunteers with single dose exposure and are crucial in demonstrating bioequivalent PK for the biosimilar and the originator molecule. Immunogenicity is a major issue in biosimilar development, and it is expected that similar immunogenicity be seen in the clinical trials for the biosimilar and the originator molecule and is evaluated both in the PK studies and the subsequent clinical trial.” Cohen added that the biosimilar is then assessed in a single phase 3 head-to-head clinical trial using pre-specified parameters to demonstrate similarity in efficacy utilizing outcomes such as ACR20 response in RA or PASI75 response in psoriasis in addition to evaluation of safety and immunogenicity.

Beyond the legality, there may be a financial benefit to following the EMA’s path, as well, according to Cohen. In countries where the government controls health care delivery, such as Norway, aggressive promotion of biosimilar use in inflammatory diseases has been significant, he said.

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“The cost savings in Norway has been significant, in the range of 50% to 60% for biosimilar infliximab. In other countries, where the government has less control of health care delivery, the uptake of biosimilar infliximab/etanercept has been slower.”

Transition Data

Stanley B. Cohen, MD
Stanley B. Cohen

U.S. clinicians have been exposed to a host of studies of these drugs in peer-reviewed journals over the last 2 years, and in particular, at the 2017 ACR Annual Meeting.

In a phase 3, double-blind parallel group, multicenter study, Smolen and colleagues compared SB2 (Samsung Bioepsis) with reference infliximab, including a cohort of 291 patients treated with SB2 and 293 treated with the reference product. Results indicated similar outcomes in terms of ACR responses, DAS28, Clinical Disease Activity Index, and Simplified Disease Activity Index between the two drugs through 54 weeks. Additionally, researchers found adverse events were similar, as well as anti-drug antibodies.

In a similar study published in Arthritis & Rheumatology, Weinblatt and colleagues reported the results of a phase 3, randomized, double-blind, parallel-group study on the use of SB5 (Samsung Bioepsis), a proposed biosimilar to adalimumab, in 544 patients with RA. There were 269 patients in the study drug group and 273 treated with the reference product. Results at week 24 showed ACR20 response rates of 72.4% for SB5 and 72.2% for adalimumab, with a 0.1% difference (95% CI, –7.83 to 8.13). ACR50 and ACR70 results showed similarly comparable outcomes, as did DAS28 findings; pharmacokinetics, treatment-emergent adverse events, and antidrug antibodies also were comparable.

Cohen and colleagues conducted a 58-week, double-blind, multicenter, phase 3, clinical equivalence of BI 695501-adalimumab biosimilar (Boehringer Ingelheim) and adalimumab in terms of ACR20 response at 12 and 24 weeks in patients with moderately-to-severely active RA. The analysis included 645 patients randomly assigned to the study drug or adalimumab every 2 weeks through 24 weeks, at which point re-randomization occurred. At this point, 147 originator adalimumab patients switched to BI 695501, 148 remained on the originator adalimumab, and 298 patients on the adalimumab biosimilar were dummy re-randomized and continued on treatment.

At 48 weeks, Cohen and colleagues found that DAS28-ESR changes from baseline were –2.71 for patients in the switch group, –2.60 for those who continued on the bio-originator, and –2.70 for those who continued on the study drug. At week 48, the proportion of patients with antidrug antibodies was 36.2% for the switch group, 49.6% for those who continued adalimumab and 41.8% for those who continued BI 695501. Transition did not impact efficacy, safety or immunogenicity, according to the researchers. Among the safety outcomes, serious infectious events occurred in 0.6% of patients in the BI 695501 group and 4.0% of those receiving adalimumab, with no fatalities reported in either arm.

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In a 2016 study, Attipoe and colleagues switched all patients in the rheumatology department to an etanercept biosimilar after informing patients of the switch. They followed up with a questionnaire to determine how this transition may be improved. The cohort comprised 68% of patients with RA, 16% with psoriatic arthritis and 11% with ankylosing spondylitis. Rheumatology clinicians informed 65% of the cohort, while nurses or delivery companies informed the remaining. Face-to-face visits were used to inform 90% of patients, while phone or letters were used for the rest.

Results showed that the proportion of patients who found the switch experience to be excellent or very good was 45%, but 9% reported that the experience was poor or very poor. The “satisfactory” rate was 44%. Of the dissatisfied patients, 32% reported that they would have preferred to have been given the option of switching, while 21% required more information and 39% reported adverse events. Longer disease duration was associated with a poor switching experience (P = .042), along with not feeling sufficiently supported (P = .000000079) and experiencing adverse events after switching (P = .0018).

“Switching onto [biosimilars] is a phenomenon that is likely to continue with a need to improve patients’ experience of switching,” the researchers concluded. “Adequate information given in advance, having opportunities to ask questions and having a point of contact after switching are factors that patients express as important.”

According to Worthing, the FDA is currently considering “real-world” data. However, it’s unclear whether these data are being used in the approval process.

“Post-marketing data will be important to show how adverse events get tracked. Drugs can be approved in one of two ways. The first is when the biosimilar is shown to be similarly safe and effective as its bio-originator. The second shows interchangeability in which a drug is proven safe after alternating with the bio-originator, where they start on the original drug and then switch. The first pathway has been established, with several biosimilars approved. The interchangeability pathway is in draft form now.”

Many clinicians like Worthing are eager to see the final interchangeability pathway emerge. “The draft form was rigorously assembled and is likely to create a lot of good data,” he said.

Cohen said that the goal of the studies in developing a biosimilar is to determine that these minor differences in the molecular structure have no impact on efficacy of the molecule, safety of the molecule and immunogenicity.

“The FDA regulatory requirements look at the totality of the evidence; but in contrast to new molecule development, which depends heavily on clinical studies, in biosimilar development, the crucial evaluation is done pre-clinically with an analytical evaluation comprising structural analysis of the biosimilar in comparison to the originator molecule, along with functional analyses looking at multiple batches of medicine over time.”

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Worthing said that clinicians are hoping more data sets like this will come along. Once these clinical criteria are met, the application process begins.

“New biologics are evaluated and approved by the FDA under a Biologics License Application (BLA) or 351(a) pathway,” Allan Gibofsky, MD, JD, professor of medicine and public health at Weill Cornell Medicine and attending rheumatologist at the Hospital for Special Surgery, said in an interview. “The Affordable Care Act of 2010 included the Biologics Price Competition and Innovation Act, also known as the Biosimilars Act. This created an abbreviated pathway — 351(k) — that can be used for agents that are highly similar to an FDA-licensed biologic.”

Pricing Issues

A number of questions surround how biosimilar therapies will be priced, and how insurers and pharmacy benefit managers (PBMs) will make their decisions. For Stanford Shoor, MD, clinical professor of medicine in immunology and rheumatology and rheumatologist at Stanford Health Care, future guideline changes will determine how biosimilars impact patient cost-savings.

“The guideline currently says to use methotrexate first,” he said. “Insurers will follow that guideline because it is the standard bearer, it has high efficacy and relatively low toxicity.”

When methotrexate reaches the end of its effectiveness, insurance companies will pay for the least expensive product, which could be a biosimilar if there is not inferiority, according to Shoor. “What will happen at the next level is that if it comes down to etanercept or its biosimilar, the insurer will cover the biosimilar because it is cheaper,” he said.

Allan Gibofsky, MD, JD
Allan Gibofsky

However, Gibofsky noted, the picture begins to muddy when PBMs get involved. “With regard to biosimilars, although a manufacturer may offer a discount from average wholesale price, that is not the full determinant of use, as rebates and volume pricing must be factored in as well,” he said. “Candidly, how they will be priced to the payer and PBM will be less important to the prescribing clinician than to what degree the cost-savings benefit the individual patient.”

Kay pointed out that the first infliximab biosimilar, infliximab-dyyb, was initially priced about 15% less than the reference product and is currently priced about 19% less than the reference product. However, determining the actual cost of the drug is complicated in the U.S. health care system.

“The actual cost of a drug in the U.S. is difficult to ascertain because PBMs negotiate discounts and rebates with the manufacturer,” he said. “For example, if a PBM puts the infliximab reference product on formulary, the manufacturer may bundle other medications at much lower prices — so the PBM may agree to the ‘package.’ Biosimilar manufacturers are less likely to be in a position to do that, especially if the biosimilar is their only product.”

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The process of getting a biosimilar onto the formulary of a PBM, however, is complex, according to Worthing. He also addressed the rebate and volume pricing system. “It is the price of the drug times the rebate plus the market share,” he said. “It doesn’t allow another company to come in and undercut the drug on the formulary. Anecdotal reports suggest that PBMs have been telling people to raise prices.”

That said, Worthing noted that an initial drop in prices for infliximab has been reported, which may bode well for patients. “The overall goal is to make sure our patients pay less,” he said. “Hopefully, the PBM system will allow price reductions to pass savings along to patients.”

Shoor also emphasized a practice management component to the story. “I would imagine there will be difficulties in reimbursement, based on the history of reimbursement of drugs in the U.S.,” he said. “I don’t know where they will settle themselves on the market vs. where they are in Europe, because it is easier for European clinicians to get approval for a biologic agent — the U.S. doesn’t have standard for such a thing.”

One way of achieving reduced drug prices is to have a more scientific basis for formularies, according to Worthing. But due to the complexities of the equation and the overall trend that drug prices are not dropping as planned, alarm bells are ringing for many experts. “When patients can’t get medicines that are too expensive, you start looking under the hood,” he said.

Cohen addressed the issue of reduced pricing as well. “At present, there is significant uncertainty about what the actual discount on the price of the drugs will be,” he said. “Clearly in European countries such as Norway, where the government runs the health care purchasing, there have been discounts of up to nearly 70%. In the U.S., with the PBMs controlling drug pricing along with pharma, the actual discounts will be difficult to determine.”

However, the newest infliximab biosimilar may be priced at more than a 35% discount, according to Cohen. “I suspect that Janssen will match the discount or through their contracts with PBMs limit the penetration of the infliximab biosimilars,” he said. “Ultimately, as there are more biosimilar infliximabs and etanercepts available, the price should drop. The patient’s copay will remain an issue and we look forward to seeing if patients receiving the biosimilar will have lower copays to stimulate use.”

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Kay echoed this point, noting that biosimilars have already demonstrated a significant impact in the drug marketplace. “It is certainly true that actual pricing comes down to the deals made by PBMs with pharma,” he said. “But this does not mean that biosimilars do not play an important role in the marketplace. Janssen likely would not have lowered the price of Remicade if biosimilars of infliximab were not on the market. If the bio-originator comes in at a lower price, then a PBM is going to put it in a preferred position on its formulary. So far, in the U.S., biosimilars have gained only a very small share of the infliximab market, but they have effectively reduced the cost of reference infliximab.”

Another issue that may be associated with pricing is the self-administered nature of biosimilar therapies, according to Worthing. “Patients like them because they are easy to use and don’t necessarily require a doctor visit, which should help reduce cost, but distribution will still go through PBMs,” he said.

For Kay, semantics matter, particularly when perceptions about and knowledge of biosimilars among U.S. clinicians remains somewhat problematic. “I would use the term ‘lower cost,’ since ‘cheaper’ implies lower quality,” he said. “The ideal biosimilar would be identical to the reference product but less expensive.”

Gibofsky brought the issue back to the clinic. “By definition, biosimilars are neither more effective nor safer; they cannot be,” he said. “Thus, they will compete solely on cost, and one can anticipate that — similar to how insurers evaluate branded drugs and generics — they will seek to pay the lowest amount for any comparable product, including a biologic.

Knowledge Among U.S. Clinicians

During a 2016 survey, Gibofsky and colleagues posed a series of 20 questions to 131 physicians — including 102 rheumatologists — regarding their familiarity with biosimilars, the concept of biosimilarity, and the approval process for biosimilars in the treatment of immune-mediated chronic diseases. Results showed that 84% of respondents were aware that an infliximab biosimilar was approved by the FDA, but only 47% were aware of adalimumab biosimilars and 34% knew of the product replicating etanercept.

The researchers found that 38% reported being extremely familiar with the FDA’s definition of a biosimilar, while 36% reported moderate familiarity with this definition. Understanding that an approved product did not automatically denote interchangeability was reported among 71% of respondents. Interchangeability was very or moderately important to 74% of respondents, while 96% considered effectiveness and safety as important, and 95% valued durability of response. Two-thirds of the cohort reported that they would be extremely likely or likely to initiate therapy using a biosimilar with comprehensive data available, while just 5% said they would start treatment for a different condition than the one on the indication.

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For clinicians treating a patient responding well to a bio-originator, 60% reported being unlikely to switch to a biosimilar. For those treating a patient who was responding poorly to a reference product, 21% reported being likely or extremely likely to switch.

“This survey supports a need to further educate U.S. rheumatologists about biosimilars, extrapolation, and interchangeability,” Gibofsky reported. “Knowledge gaps include a lack of understanding of biosimilarity based on switching, and the availability of currently approved biosimilars.”

“There is an increasing desire by clinicians to learn more about biosimilars,” Gibofsky said. “Clinicians seem less interested in the manufacturing processes of biosimilars than their use in clinical practice.”

Gibofsky suggested that prescribers should deal with several unanswered questions. “Is the durability of a biosimilar similar to that of the bio-originator over time?” he said. “What is the effect of repeated switches on durability and efficacy? Can biosimilars be switched among themselves with the same level of comfort as a switch between a bio-originator to a biosimilar? What is meant by ‘interchangeability’ and how will that affect biosimilar use?”

In two other data sets presented at the 2017 ACR Annual Meeting by Radtchenko and colleagues, 24 community rheumatologists and 20 rheumatology practice managers in the U.S. were assessed for perceptions of biologics. They found that just 51% understood the concept of interchangeability, while 76% were unaware of compatibility requirements after a manufacturing change. Just 40% believed that efficacy and safety were matched between a biosimilar and its bio-originator. In addition, 20% said they would not prescribe a biosimilar at all, 23% reported that they would switch from a reference product and 57% would initiate a treatment-naïve patient with a biosimilar.

The researchers found that regulation associated with substitution was the most concerning issue for these respondents, followed by understanding of when to use a biologic vs. a bio-originator, and coordinating with pharmacists. Most wanted more information on both clinical and reimbursement information. “Significant barriers to biosimilar adoption for rheumatologic conditions exist due to physicians’ perceptions,” they concluded.

In another study, Radtchenko and colleagues evaluated early uptake of infliximab-dyyb in RA following its approval in April and launch in November of 2016. Biologic or biosimilar therapy was initiated in 78,481 patients since that time, but just 0.1% (n =90) were treated with the drug. The researchers reported that 6.6% of those patients were treated with the infliximab reference product.

“Adoption of [infliximab-dyyb] in the US so far has been low and has not yet significantly impacted the reference biologic,” they wrote. “The majority of [infliximab-dyyb] patients received it as first biologic, however a third of them switched from [infliximab]. Duration of therapy on [infliximab-dyyb] is relatively short due to delayed launch.”

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Worthing is hopeful that previous uptake of biosimilars by the oncology community indicates that rheumatologists also will improve knowledge and use of the drugs. “Oncologists had higher amounts of knowledge and confidence in biosimilars than other specialists,” he said. “Now that we have these drugs in rheumatology, rheumatologists are finding out how dispensing works. The good news is that dosing will be easy, with the same dosing and administration as the bio-originators.”

Moving Forward

“There are multiple biosimilars in development for inflammatory arthritis as well as for inflammatory bowel disease and psoriasis,” Cohen said. “There will be multiple biosimilars for Humira and Remicade as well as Enbrel and Rituxan approved over the next several months to years. As patents lapse for other biologic therapies, such as Actemra/Orencia, biosimilars will be developed for these drugs as well. None of these are major game changers as far as therapeutics are concerned and we must be cognizant of the fact that the only reason to use a biosimilar is cheaper cost.”

The ACR Position Statement and subsequent guidance documents will be helpful, according to Worthing. “We just need to have as much information as we can on the science, the economics and the dispensing,” he said.

For Kay, keeping an eye on PBM formularies and the negotiations they conduct will be critical. “Patients do not get back the money from the rebates and discounts that PBMs negotiate — even third-party payors do not get back the entire rebate and discount,” he said. “PBMs are for-profit companies that are neither transparent nor necessary participants in the process of providing health care.”

Shoor emphasized the need for ongoing education regarding biosimilars. “The answer for U.S. clinicians is to share as much information as possible with our European colleagues,” he said. “We will understand how to use and manage these drugs by talking to them. This will happen from person to person.” – by Rob Volansky

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Disclosures: Cohen reports a consulting relationship with Pfizer. Gibofsky reports he is a stockholder in AbbVie, Amgen, Bristol-Myers Squibb, Pfizer, Johnson & Johnson, GSK and Regeneron and is a consultant to AbbVie, Amgen, AstraZeneca, Pfizer, Horizon, Iroko, Relburn, Celgene, Takeda, Sandoz, Merck, Celltrion, Speaker-AbbVie, Merck, Pfizer and Celgene. Kay reports receiving research support paid to the University of Massachusetts Medical School from AbbVie, Ardea Biosciences, Eli Lilly and Company, Genentech, Pfizer, and UCB; and is a consultant to Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Crescendo Bioscience, Eli Lilly and Company, Janssen Biotech, Merck Sharp & Dohme, Pfizer, Roche Laboratories, Samsung Bioepsis, Sandoz, and UCB. Shoor and Worthing report no relevant financial disclosures.