Tony Hagen is senior managing editor for The Center for Biosimilars

In a study of use of infliximab biosimilars among patients with gastrointestinal and rheumatologic conditions, investigators found high adherence.

The retrospective study, presented at the American College of Rheumatology (ACR) annual meeting, involved 533 patients in the IBM MarketScan commercial insurance database who were treated with infliximab from 2014 to 2018. Investigators characterized those who initiated use of infliximab biosimilars after treatment with the reference product or no prior infliximab treatment.

Patients were divided according to never having used infliximab reference product, early switchers with less than 2 years of reference product use, and late switchers with greater than 2 years of reference product use.

Investigators said 41.6% to 47.4% of patients had inflammatory bowel disease and 34.2% to 48.7% had rheumatoid arthritis. Psoriasis patients accounted for 8.8% to 14.2% of the population.

Roughly half of patients were highly adherent to infliximab biosimilars at 12 months of treatment with these alternative agents. Among those with ≥ 12 months of follow-up care, 53.6% of naïve users, 44.3% of early switchers, and 56.1% of late switchers remained highly adherent at 12 months.

High adherence among patients with at least 18 months of follow-up amounted to 59.3% for naïve infliximab biosimilar users, 50% for early switchers, and 40.7% for late switchers.

Investigators found that there was no significant difference in adherence among those who initiated biosimilar infliximab.

Investigators divided comorbidity rates according to patient type. Among infliximab naïve users, 14.3% had diabetes; 42.9%, hypertension; 17.3%, depression; chronic obstructive pulmonary disease, 19.4%; and cancer, 11.2%.

The respective percentages for early switchers were 17.5%, 37.7%, 21.1%, 7%, and 3.5%; and for late switchers, 15.9%, 38.1%, 10.6%, 15.9%, and 11.5%.

The adjusted odds ratio for high adherence among naïve infliximab biosimilar users was 1.68 (

 = .35), meaning the former group was far more likely to adhere to infliximab biosimilar than the latter group.

Sarvesh S, Alanaeme JC, Curtis JR, Yun H. Utilization and adherence among infliximab biosimilar initiators in a U.S. national commercial insurance database. Presented at: ACR Convergence 2020; November 5-9, 2020. Poster 0555.

Articles

ACR Convergence 2020

Investigators looked at adherence in patients who switched from reference infliximab during treatment for rheumatologic and gastrointestinal treatment. 

High Adherence Noted Among Infliximab Biosimilar Users

The coronavirus disease 2019 (COVID-19) pandemic has stretched health care systems but may also create room for improving utilization of biosimilars, according to a presentation at the Terrapinn Festival of Biologics Basel 2020. 

“Interestingly, for 2020, this crisis is also the greatest opportunity we have to rethink, rebuild, and reshape. We have a new normal to face, and I think that's what we need to consider,” said Julie Maréchal-Jamil, director of Biosimilar Policy & Science at Medicines for Europe and an advisory board member for The Center for Biosimilars®.

In the presentation, Maréchal-Jamil discussed what steps need to be taken to develop policies that will foster sustainable access to the biosimilars market for patients and allow European health care systems to get the greatest benefit from biosimilar use.

She laid out 3 things that regulators should consider to achieve these goals, including developing a vision where savings are reinvested into measures that improve health by improving access for patients; targeting policy frameworks to individual countries; and incorporating components to make sure the policies function efficiently.​ 

A vision for health involves addressing health and access needs by developing roadmaps to achieve objectives, which is what France and the United Kingdom have done, explained Maréchal-Jamil.

She said the United Kingdom implemented a policy to expand access to off-patent biologics. The policy allows for reference products to compete alongside biosimilars for market access, meaning that patients exclusively use whatever product is deemed to be the “best value biologic.”

According to Maréchal-Jamil, in the United Kingdom, targets for adoption of the best value biologic are 90% for new patients within 3 months of a biosimilar launch and 80% for existing patients within 12 months.

The French implemented a policy to increase the development of innovative biologics by encouraging that 80% of existing patients transition to a biosimilar by 2022. The French theorize this would encourage innovator companies to develop new medicines once they lose patent protection for older ones.

Maréchal-Jamil said Norway and Poland also have unique strategies for how they increase biosimilar utilization.

In Norway, biosimilars were widely used in the hospital setting but rarely used in the community pharmacy setting. Maréchal-Jamil said Norway had reflect on how to adjust its framework to achieve mass use.

Maréchal-Jamil also said the Poland’s baseline biosimilar access rate is lower than the average for the European Union despite having good use rates for some biosimilars, suggesting that reforming drug programs or imposing budget caps would be more effective in addressing biosimilar use than implementing biosimilar regulatory policies.

Additionally, Maréchal-Jamil said that originators that are expected to lose patent exclusivities in the future will require policy adjustments and new policies to be added over time.

Maréchal-Jamil said that successful policy changes must build awareness, trust, and confidence, drive biosimilar use, and translate cost efficiency gains to better health.

To increase awareness, trust, and confidence in biosimilars, Maréchal-Jamil suggested that easy-to-understand educational information must be given and made continuously available to the public. Additionally, trust can be built by continuously involving stakeholders in policymaking.

According to Maréchal-Jamil, nearly half of medicines agencies in Europe still do not have biosimilar educational resources listed on their websites, even though Europe as a whole has 20 years of experience using biosimilars.

Maréchal-Jamil said that studying what other countries have done could inspire policies that drive biosimilar use. Maréchal-Jamil mentioned that IQVIA’s country 

 published in June would be a good source of inspiration because they detail the policies of 12 European countries regarding biosimilar switching, tender systems, utilization incentives, and pricing regulations.

Lastly, Maréchal-Jamil mentioned Germany as an example of how to translate cost efficiency to impact treatment access to biologics. The Bavaria study on treatments for rheumatoid arthritis found that the introduction of biosimilar competition to the market decreased the amount of time before a patient could get access from 7.4 years to just 4 months, suggesting competition can play a major role in increasing access for patients.

Festival of Biologics Basel

In Europe, the pandemic has revealed problems within health care systems and the need to increase access to biosimilars and reform health care policies.



Prioritize Biosimilar Uptake in Europe, Conference Speaker Says

In a keynote speech to a generic and biosimilar drug industry group, Alex M. Azar, secretary of HHS, gave a pat on the back to outgoing President Donald Trump, praising his policies and executive orders aimed at reducing prescription drug costs.

In addition, accelerated approvals of biosimilars and generic drugs combined with growing market competition since 2017 have contributed to a plateau in drug price inflation the past several years, Azar said at the Association for Accessible Medicine (AAM) GRx+Biosims virtual conference.

He attributed this trend not to pricing restraint on the part of manufacturers but, specifically, to market dynamics and drug policies promoted by Trump.

“Since we released the president’s drug pricing ‘

’ in May 2018, the official government measurement of drug price inflation has been flat. That measure saw the largest drop in nearly 50 years from June 2018 to June 2019. Now, I don’t think that’s because of the goodness of drug companies’ hearts. In fact, I worked at a drug company myself, and I can more or less assure you it’s not. In significant part, it’s because of the market discipline that your companies provide,” Azar said.

study published earlier this year indicate list prices for prescription drugs climbed sharply from the start of the Trump administration through 2018, but net drug prices increased much more moderately during those years, according to the study. The study did not describe drug price behavior after 2018.

“I believe we’ve seen more efforts to promote competition in prescription drug markets from HHS and our colleagues at FDA than we’ve seen since the passage of Hatch-Waxman in the 1980s,” Azar said. The Hatch-Waxman Act (1984) encouraged the manufacture of generic drugs and created a regulatory system for these agents.

“We’ve set records for approvals of generic drugs in 2017 [937], 2018 [971], and 2019 [1171], while also accelerating approvals of biosimilars. The savings that these drugs deliver are massive,” Azar said. There were 10 biosimilar approvals in 2019, a record number, but just 2 so far in 2020.

There are roughly 90 ongoing biosimilar development projects on file with the FDA, which has not officially given any explanation for the reduced number of approvals this year, although in general remarks FDA officials have stated that efforts to approve trials and review treatments related to coronavirus disease 2019 have required a massive shift of priorities and resources.

Generic drug savings totaled $313 billion in 2019, $96.1 billion of that for the Medicare program and $48.5 billion under Medicaid, Azar said, quoting from a 2020 

. “We’ve also taken steps to drive not just faster generic and biosimilar approvals but also faster adoption of these options, and we’ve allowed Part D plans to accelerate substitutions of generic drugs for brand drugs, and we’ve given Medicare Advantage plans new tools to negotiate lower prices that they’ve already used to substitute lower cost biosimilars.”

Azar said a 2018 HHS report identified $3 billion in potential savings on $9 billion that Medicare Part D plans are spending annually on name brand drugs that have generic alternatives. Achieving those savings involves eliminating “kickbacks” to middlemen in the drug supply chain and fixing the “broken rebate system” that rewards payers and pharmacy benefit managers for preferring certain drugs, whether or not they are lowest cost, he said.

“We’re also working to propose rules around Part B drugs that have the potential to be equally significant for American drug costs, especially with regard to rapidly rising expenditures on biologics, which today represent almost 40% of prescription drug spending,” Azar said.

He said biosimilar uptake in the health care marketplace has been “slower than we’d like, in part because the Part B system actually encourages prescribing more expensive options. If we can bring to the biologics market just a fraction of the savings that generic drugs have brought to American patients, that will be a transformative shift.”

Hernandez I, San-Juan-Rodriguez A, Good CB, et al. Changes in list prices, net prices, and discounts for branded drugs in the US, 2007-2018. 

. 2020;323(9):854-862. doi:10.1001/jama.2020.1012

AAM GRx+Biosims

HHS Secretary Alex M. Azar said efforts and policies to counter a sharply upward drug price trend have been successful, in a talk with the Association for Accessible Medicine.

Azar Says Trump's Drug Price Shake-up Is Working

Highlighting challenges and ongoing efforts, Sarah Yim, MD, director of the Office of Therapeutic Biologics and Biosimilars (OTBB) delivered a progress report on the FDA’s Biosimilars Action Plan (BAP) at the Association for Accessible Medicine (AAM) GRx+Biosims annual conference.

The BAP was created in 2018 to support biosimilar development by improving efficiency of the development and approval process; improving scientific and regulatory guidance; improving education about biosimilars for patients, clinicians, and payers; and improving the competitive environment by “reducing gaming of FDA requirements or other attempts to unfairly delay competition,” Yim said.

The FDA continues work to develop indices of critical quality attributes for biosimilars, identify pharmacodynamic (PD) biomarkers, and investigate in silico modeling, in which computers are used to model pharmacologic or physiologic processes. Each of these qualifies as a potential development tool, “but because of resource limitations related to [coronavirus disease 2019], we are not yet ready to release the first batch of biosimilar product recommendations. Hopefully, we’re close,” Yim said.

 to help biologics developers and other stakeholders to understand at what point the exclusivity protection clock begins to tick for a reference product. The guidance was also intended to help innovator companies know what information to provide the FDA to help the agency decide when product exclusivity begins. Six years later, that guidance is still in draft form, although progress continues, Yim said. “We’re still working on biologic product regulatory modernization and finalizing guidance on reference product exclusivity and post-approval manufacturing.”​ 

The FDA would like to make various improvements to improve biosimilar development, and these include optimizing review staff time, exploring PD markers and assays that can help ascertain biosimilarity between biosimilar candidates and reference products, providing product specific guidance, and partnering with international regulatory authorities to reduce redundant activities. “To take product development and review to the next level in efficiency, more will need to be done,” Yim said.

“We’ll need to improve the status of biosimilar-related knowledge management and expand its scope to ensure not only consistency but provide space for ideas regarding improvements in best practices to be easily known and shared,” she said.

Another area of focus that could lead to important gains for biosimilars is patient education and reduction of anticompetitive messaging, she said. This can be achieved, in part, “by figuring out how to best exploit the educational gold mine of information that’s already available from real world experience with biosimilars. More than a decade of experience is available for some biosimilars in Europe, and at least several years of information should be available for some of the US-approved biosimilars.”

Yim noted the FDA’s achievement in modernizing the Purple Book, which originally was a bare bones listing of FDA-licensed biological products and now is an expanded, searchable, online database.

Also, in 2019, the FDA published guidance on biosimilar interchangeability with reference products and on the design and evaluation of comparative analytical studies for determining biosimilarity.

“We’ve made significant strides in advancing educational resources and activities and have recently begun a 2-year curriculum development project,” Yim said. “We also plan to begin work this year on developing additional, wide-reach education forums.”

Yim also said the FDA and the Federal Trade Commission have made “significant progress” combating anticompetitive behaviors by innovator companies and others that seek to oppose the advancement of biosimilars.

“Moving forward, we will be looking toward identifying and expanding high value activities that could help take biosimilar and interchangeable product access to the next level in the 2020s,” she said.

Sarah Yim, MD, director of the Office of Therapeutic Biologics and Biosimilars (OTBB), highlighted the ways the FDA is working to remove blocks and wedges hindering biosimilars.  

OTBB Director Discusses FDA's Roadmap for Biosimilars

Investigators have presented evidence of what they say are successful, first-time tests of a multibiomarker disease activity (MBDA) score in patients with rheumatoid arthritis (RA). Separate comparative studies of infliximab and adalimumab biosimilars vs their reference counterparts were presented at the American College of Rheumatology (ACR) Convergence 2020 meeting.

The value of the MBDA score (Vectra) is that it consists of measures of 12 serum proteins and is highly sensitive, thereby offering an alternative to “subjective” clinical observation of patient progress, they explained.

“Comparison of MBDA scores between treatment groups may provide additional evidence of biosimilarity using an objective, quantitative assessment of disease activity that is independent of the potential subjectivity of joint counts or patient or physician global assessments,” said Jonathan Kay, MD, of the University of Massachusetts Medical School, who served as lead investigator for both studies.

Both studies involved Pfizer biosimilars and were sponsored by Pfizer.

In the first study, patients were randomized to treatment with an infliximab biosimilar (Ixifi) vs reference infliximab (Remicade) sourced from the European Union.

Investigators enrolled 650 patients who met 2010 ACR/EULAR disease classification criteria and had ≥ 4 months of RA duration. They received 3 mg/kg of infliximab intravenously at weeks 0, 2, 6 and then every 8 weeks, in combination with methotrexate (MTX). MBDA scores were on a scale of 1 to 100, with 100 being the highest level of disease activity. They reported initial treatment period activity for weeks 0 to 30.

Baseline mean scores for patients receiving the infliximab biosimilar were 61.3 vs 58.8 for the reference product. For the overall population, the mean scores at 30 weeks were 46.9 for both biosimilar and reference groups.

The proportions of patients with high MBDA scores at baseline in both the biosimilar and reference cohorts were similar: 66.0% vs 66.9%, respectively. At week 30, the proportions of patients with high MBDA scores decreased to 42.3% and 40.2%, respectively.

Investigators said the decreases in individual serum biomarker levels that formed the composite MBDA score also were similar between biosimilar and reference groups. They identified 3 biomarkers for which this was true—serum amyloid A, tumor necrosis factor receptor 1, and VEGF-A—but they said it held true also for other biomarkers included in the MBDA score.

Mean MBDA scores decreased 15.2 and 14.1 points, respectively from baseline to week 6 in the 2 groups, and disease stability between cohorts was noted through week 30.

In the second study, investigators enrolled 597 patients with RA by 2010/EULAR criteria and disease duration of ≥ 4 months. They were randomized to adalimumab biosimilar (Abrilada) or European Union–sourced adalimumab reference product and received 40 mg subcutaneously every other week, in combination with MTX.

Mean MBDA scores were calculated at baseline and weeks 6, 12, and 26. At baseline, the mean MBDA scores for the biosimilar and reference groups were 57.2 and 58.3, respectively. “Mean values of MBDA scores were comparable between treatment groups at all measured time points through 26 weeks,” the investigators wrote.

The proportions of patients with high MBDA scores decreased to 45.5% and 41.7% at week 26. Mean MBDA scores dropped from baseline by 11.9 and 12.4 points, respectively, by week 6; by 11.7 and 12.4 points at week 12; and by 14.3 and 15.5 points at week 26, respectively. Again, individual serum biomarker levels tracked one another closely between biosimilar and reference cohorts.

The mean scores over the 26 weeks for both cohorts were similar, leading adalimumab investigators to conclude: “MBDA score based on 12 serum biomarkers provides a sensitive and objective clinical assessment of biosimilarity that does not require physical examination of the patient or subjective patient global assessment of DA."

1. Kay J, alvarez D, Rehman MI, Zhang M, Iikuni N. Use of multi-biomarker disease activity scores to assess biosimilarity in a phase 3, randomized controlled trial comparing biosimilar infliximab-qbtx (PF-06438179/GP1111) with EU-sourced reference infliximab in patients with active RA. Presented at: ACR Convergence 2020; November 5-9, 2020. Abstract 1204.

2. Kay J, Bock A, Iikuni N, Zhang W, Alvarez D. Use of multi-biomarker disease activity scores to compare biosimilar adalimumab-afzb (PF-06410293) with EU-sourced reference adalimumab in a phase 3, randomized, double-blind trial in patients with active RA. Presented at: ACR Convergence 2020; November 5-9, 2020. Abstract 1233.

A multibiomarker disease activity score looks at serum protein activity for a more sensitive evaluation of biosimilarity, investigators said at the American College of Rheumatology Convergence 2020 meeting.

Multibiomarker Test Reads Out Positive in 2 Pfizer-Sponsored Studies

Biosimilar developments reported at the American College of Rheumatology (ACR) Convergence 2020 virtual meeting included data from safety and efficacy trials for Pfizer and Celltrion versions of adalimumab.

Positive safety, immunogenicity and efficacy findings were reported for the Pfizer adalimumab biosimilar PF-06410293 (Abrilada, ADL-PF) in a study of patients with moderate-to-severe active rheumatoid arthritis (RA).

In an earlier study, ADL-PF, which has been approved in the United States and European Union, was compared with reference adalimumab sourced from the European Union (ADL-EU) and demonstrated therapeutic equivalence in patients with active RA. Comparable safety, efficacy, and immunogenicity was maintained up to week 56, and no differences in outcomes were observed for patients who underwent a blinded switch to ADL-PF at week 26.

At the ACR Convergence 2020, updated findings were presented for weeks 52 to 92 in patients who continued ADL-PF (N = 552). At week 52, all patients remaining on ADL-EU were switched to ADL-PF. Investigators said efficacy response rates at week 78 were 84.2% for all patients, and 83.4%, 85.8%, and 84.3% for the biosimilar, week 26 switch, and week 52 switch groups, respectively.

Investigators said response rates according to the ACR20 scale, which defines positive change as a 20% improvement in a core set of measures, were comparable across the 3 groups.

On safety, investigators said ADL-PF was generally well tolerated across groups with comparable safety profiles. With regard to immunogenicity, investigators reported comparable rates of antidrug antibodies (ADAs) and neutralizing ADAs.

In a separate study presented at ACR Convergence 2020, investigators demonstrated efficacy and safety equivalence of the adalimumab biosimilar candidate CT-P17 to reference adalimumab in patients with moderate-to-severe active RA.

CT-P17 is a high concentration (100 mg/mL), citrate-free formulation of the reference product. Investigators sought to show equivalence by efficacy at week 24 and by pharmacokinetics and overall safety over the first 24 weeks of administration.

Investigators randomized 648 patients 1:1 to reference and biosimilar adalimumab. They found that the ACR20 response rate at week 24 was 82.72% in both groups. Confidence intervals for treatment difference were fully within parameters set by the European Medicines Agency and the FDA. Secondary efficacy end points also were similar between cohorts.

Investigators noted a slightly higher serum trough concentration in patients receiving CT-P17 vs reference adalimumab at week 24: 5.3 μg/mL vs 4.3 μg/mL (

Safety profiles between groups also were similar. Most events were grade 1/2. Among the CT-P17 cohort (n = 324), there were 5 treatment-emergent adverse events leading to study discontinuation, vs 8 for the reference group (n = 324). Events leading to discontinuation considered related to the adalimumab treatment were 2 vs 4, respectively.

The number of patients who developed ADAs was lower at week 24 for those on CT-P17 vs reference (32.3% vs 35.8%, respectively). Among patients receiving CT-P17, 83 (25.6%) had neutralizing ADAs, vs 103 (31.8%) receiving reference product.

In March 2020, Celltrion applied for CT-P17 marketing authorization in the United States and Europe. Those applications are still pending.

1. Fleischmann R, Alvarez D, Bock A, et al. A randomized, double-blind phase 3 study comparing the efficacy, safety and immunogenicity of PF-06410293 (Abrilada™), an adalimumab (ADL) biosimilar, and reference ADL (Humira®) in patients with moderate to severe active RA: results from weeks 52-92. Presented at ACR Convergence 2020; November 5-9, 2020. Abstract 0798.

2. Kay J, Jaworski J, Wojciechowski R, et al. A randomized, double-blind, phase 3 study to compare the efficacy and safety of a proposed high concentration (100 mg/mL) adalimumab biosimilar (CT-P17) with reference adalimumab in patients with moderate-to-severe active rheumatoid arthritis. Presented at ACR Convergence 2020; November 5-9, 2020. Abstract 0800.

Poster presentations at the American College of Rheumatology (ACR) Convergence 2020 meeting shed light on performance of adalimumab versions. 

ACR Abstract Roundup: Pfizer and Celltrion Agents Demonstrate Safety, Efficacy

A study of Celltrion’s CT-P17 adalimumab biosimilar candidate demonstrated 

 and safety equivalence to US and EU samples of reference adalimumab

; and a separate study of difference administration methods for CT-P17 demonstrated equivalent outcomes

, in findings presented at American College of Rheumatology (ACR) Convergence 2020, the ACR’s virtual annual meeting.

Adalimumab reference product is indicated for arthritis, plaque psoriasis, ankylosing spondylitis, Crohn disease, and ulcerative colitis. CT-P17 was developed as a high concentration (100 mg/mL) citrate-free formulation of the reference product.

PK and safety of CT-P17 relative to US- and EU-marketed reference adalimumab were evaluated in a healthy population (N = 312) randomized to a single dose in each of the 3 arms.

Investigators said the 90% CI intervals for each of the PK parameters were within the predefined equivalence margin of 80% to 125%; and secondary PK parameters were similar among the 3 treatment groups. Mean serum concentrations up to day 71 were comparable among the trial cohorts, they said.

Investigators also described a comparable safety profile among the 3 cohorts. Most treatment-emergent adverse events (TEAEs) were grade 1/2. The most frequent of these was injection site reaction, but no clinically notable differences were observed in lab results, vital signs, electrocardiogram results, or physical examinations among the patient groups.

With regard to immunogenicity, patients testing positive for antidrug antibodies (ADAs) and neutralizing ADAs were comparable in each cohort. In addition, each group followed a similar curve as numbers of patients testing positive increased over the study term.

Investigators concluded that PK equivalence of CT-P17 relative to high concentration (100 mg/mL), citrate-free formulations of the US- and EU-samples of reference product was demonstrated. Safety was also comparable, they said.

In a separate, phase 1 randomized, single-dose study in healthy participants comparing PK and safety of CT-P17 auto-injector (AI) and prefilled syringe (PFS) products, investigators observed comparable findings for mean peak and total drug exposure as well as for secondary PK parameters, safety, and immunogenicity.

The trial randomized enrollees 1:1 to 40 mg of CT-P17 AI (n = 98) or PFS (n = 95). Investigators said 92 patients completed treatment on AI and 83 completed treatment with PFS.

In both groups, mean peak and total systemic exposure were equivalent because the 90% CIs were within the predefined equivalence margin of 80% to 125%, investigators said. Maximum dose duration (Tmax) occurred at 132 hours for both treatment groups. Secondary PK parameters also were comparable between the AI and PFS groups, as were mean serum concentrations.

On safety, 60.2% and 51.7% of patients reported ≥ 1 TEAE in the AI and PFS groups, respectively. There were 2 TEAEs (grade 3), and all other TEAEs were grade 1/2. TEAEs considered related to CT-P17 were reported by 47 (50.5%) and 38 (43.7%) of patients in the AI and PFS groups, respectively. The most frequent were headache (11.8% and 9.2%) injection site reactions (8.6% and 6.9%).

1. Pharmacokinetics and safety of CT-P17, a proposed high concentration (100 mg/mL) adalimumab biosimilar, in comparison with EU-approved adalimumab and US-licensed adalimumab; results of a phase 1, randomized, double-blind, three-arm, single-dose study in healthy subjects. Yu KS, Jang I, Lim HS, et al. Presented at ACR Convergence 2020; November 5-9, 2020. Abstract 0204.

2. A phase 1, randomized, open-label, parallel group, single-dose study to compare the pharmacokinetics and safety of the auto-injector and pre-filled syringe of CT-P17, a proposed, higher concentration biosimilar (100 mg/mL) adalimumab, in healthy subjects. Keystone EC, Furst D, Kay J, et al. Presented at ACR Convergence 2020; November 5-9, 2020. Abstract 0199.

Separate studies including one on application methods for CT-P17 were reported at the American College of Rheumatology Convergence 2020 meeting.

Celltrion's CT-P17 Adalimumab Biosimilar Candidate Demonstrates Equivalence

Following the launch of its Biosimilars Initiative in December 2019, Alberta, Canada, has succeeded in switching 16% of patients from use of 7 reference products to approved biosimilar versions, according to a presenter at the Terrapinn Festival of Biologics Basel 2020.

Alberta’s switching program launched 6 months after British Columbia began a similar initiative, which is further ahead with converting patients to biosimilars.

Alberta hopes to switch all patients on the 7 reference drugs to biosimilars by January 15, 2021, a deadline that was extended as a result of the coronavirus disease 2019 pandemic. Originally, authorities had hoped to complete the full conversion by July 1, 2020, said Graham Statt, the assistant deputy minister of the Pharmaceutical and Supplementary Benefits Division for Alberta Health, in the presentation.

According to a breakdown of the switching progress so far, 30% of patients receiving infliximab in Alberta switched to a biosimilar and 56% of those enrolled in a biosimilar patient support program.

Alberta officials hope the program will help save money on health care and improve access to biosimilars.

The 4 most frequently used reference products accounted for 75% of the province’s total net payment for biologics from 2019 to 2020, or US $200 million. Those products are Remicade (infliximab), Humira (adalimumab), Enbrel (etanercept), and Stelara (ustekinumab). In Alberta, there are etanercept and infliximab biosimilars available, but not for adalimumab and ustekinumab.

Also, the average annual growth rate of biologics 

use in Alberta over the last 5 years was 13.9%.

“Over the next 4 years, this initiative will save us between [US $173 million and US $290 million] once fully implemented. These savings will go back into the health system to help ensure we can provide the high-quality care Albertans deserve,” said Tyler Shandro, Alberta’s minister of health, in a 2019 

According to Statt, the Canadian province’s plan is 

 to British Columbia’s, where physicians are given a window of time to prepare patients for the switch from selected reference products to biosimilars. Physicians were encouraged to use research and educational materials to help manage patient concerns about medication changes. “We provided the numerous research and clinical studies on the efficacy and safety of switching patients from [originator] biologics to biosimilars, so people could be confident in the change,” said Statt.

The reference products that patients are being switched from include Remicade, Enbrel, Lantus (insulin glargine), Neulasta (pegfilgrastim), Neupogen (filgrastim), Copaxone (glatiramer), and Rituxan (rituximab). Alberta Health added Rituxan to its list after biosimilar Riximyo 

 regulatory approval from Health Canada in June 2020. Riximyo 

 across Canada in August 2020. Two other rituximab biosimilars, Truxima and Ruxience, were also added to the list of alternatives for Rituxan.

The switches aren’t mandatory. Statt clarified that according to the plan, patients enrolled in one of the Alberta Blue Cross government sponsored plans will no longer receive coverage for the reference product. Patients may submit an exception request to continue being administered the reference product, and if approved, pay out-of-pocket under their current plan policy or can change to another form of drug coverage under Alberta’s Blue Cross programs.

“I think this is actually an important point. We’re not forcing people to take a certain drug here in Alberta

. "What we're saying is that if you want to maintain coverage for the drugs, it has to be the drugs that we provide. In some cases, people may choose to stay on a particular drug, and they're welcome to do that."

As of early October, only 1.4% of patients had submitted exception requests and approximately one-fourth of those were approved, according to Statt.

In preparation for the switching deadline, he said that patients and physicians were sent reminder letters in October. Statt added that the next steps for the program include tracking patient drug usage, health outcomes of patients, and feedback from physicians and patients.

Alberta, Canada’s deadline for switching patients to biosimilars is months away, but the province has already seen some success with the new program.

Alberta, Canada, Sees Early Success From Switching Patients to Biosimilars 

There is much effort these days to conduct real-world studies of biosimilars, but findings from these initiatives are not really suitable for confirming safety and efficacy trials used to gain biosimilar approval, said Uwe Gudat, head of clinical safety and pharmacovigilance for Fresenius Kabi, a Germany-based maker of oncology, diabetes, critical care, digestive, and medical products, including biosimilars.

Real-world evidence (RWE) is better suited to answer questions about practical use of products in the real world, Gudat explained at the Terrapinn Festival of Biologics Basel 2020 virtual conference.

RWE cannot do the job of detailed physicochemical characterization and functional assays, he said. “Do we really think that real-world evidence can reassure us more than well-controlled randomized clinical trials? I don't believe so.”

The value of a clinical trial is that it screens out random variables, or “noise,” such as patient comorbidities, that distort whatever “signal” the biosimilar is giving that it can successfully treat the target disease conditions, Gudat said. You can’t get the same results in the real world, because there the background noise is strong, he said. “For the most part, when we’re answering questions, the signal clarifies and the noise distracts.”

In the clinical trial setting, the efficacy of a drug candidate is being evaluated; and in the real world, the actual effectiveness of the drug under conditions of everyday medical practice is being judged.

The analytical comparison of a biosimilar candidate done in a controlled setting can be compared to development of a car and the systematic testing of its constituent parts, he said. In the real world, “we’re taking the car out for a spin.” But it’s then that many other factors come into play. Continuing the car analogy, he explained that road conditions, driver fitness, driving skills, and time of day are variables that have the potential to “confound your comparison,” and the variations from what you observed in a controlled setting could be extreme and not the fault of your product.

Even in a drug trial, it is unlikely that clinicians will get the same results every time. It is a fundamental of statistics that patient outcome samples will vary, and these must be pooled to form a more comprehensive picture of how the biosimilar will perform, Gudat said.

He noted that clinical studies of US- and EU-sourced samples of reference adalimumab (Humira) have demonstrated variations that could be explained by local conditions under which the drugs were administered—not by variations between the US and EU biosimilars. “We don’t believe that studies conducted by one sponsor vs another sponsor are fundamentally different and the products used are fundamentally different; much more, we think there are certain circumstances that the study introduces that drive the observation,” Gudat said. "We have to acknowledge that there’s randomness."

Genuine product characterization involves pooling multiple samples of patient outcomes to form a statistical curve. Most of the samples will cluster in the center of this curve, but inevitably there will be outliers. The confidence interval, or the probabilistic margins of drug performance, cuts away the outliers, but those outliers still reflect what could happen when patients use the drug being studied, he said. “This is important, because it helps us understand what kind of numbers we’ll be looking at and what they mean or don’t mean.”

The real-world differences observed between US- vs EU-sourced Humira could be explained by non-drug–related variables, such as improper drug administration or the geographic dispersal of study populations and their epidemiological history—ie, tuberculosis, Gudat said.

For those reasons, he said, RWE doesn’t really help evaluate for biosimilarity. “It compares the products embedded in a multitude of circumstances. You have to look at the whole package. I’m really illustrating why the signal-to-noise ratio in the real-world setting is actually not necessarily conducive to generating comparative evidence for a biosimilar. You’ve just got so much noise; and if you do see a difference, you’ve got no idea where it’s coming from.”

That doesn’t mean RWE is of no value. There are questions that RWE can answer and should be used to answer, he said.

RWE studies can provide important information along the lines of who has gained access to the biosimilar, when is it being used in real world practice, how it is administered, and in what settings the biosimilar has been embraced, Gudat said.

By following this line of inquiry, real-world studies can complement clinical efficacy studies, he said.

Gudat suggested a number of potential real-world studies that would accomplish this objective:

Characteristics of patients treated with biosimilars

Health care practitioners’ attitudes and acceptance of biosimilars

Practitioners’ knowledge of biosimilars

Changes in the order of use of biologics (treatment lines)

Impact on patient outcomes (public health consequences)

“These are other questions equally important or also important that [RWE] can help us to answer,” Gudat said.

Expecting real-world evidence to confirm safety and efficacy of biosimilars is asking too much, Uwe Gudat, a pharmacovigilance expert from Fresenius Kabi, said at the Terrapinn Festival of Biologics Basel 2020.

Expert Cautions on What to Expect From Real-World Biosimilar Evidence

Orphan drugs are often significantly more costly than other biologics, and the presumption might be that biosimilar orphans could bring down the cost of these agents significantly, but the realities undermine that theory, said Roman Drai, MD, PhD, research and development director with Geropharm of Saint Petersburg, Russia.

However, it’s possible that with some modifications in evidence requirements by regulators, the cost of developing biosimilar orphans could be bought down significantly, and this savings could be passed on to patients, Drai said at the Terrapinn Festival of Biologics Basel 2020.

Under ordinary circumstances, competition helps to spur innovator companies to develop better drugs, with patients reaping the benefit, Drai said. “An innovator company might produce first-in-class and best-in-class drugs if they have someone pushing behind them, such as a biosimilar company.”

This doesn’t necessarily happen with orphan drugs, and the costs of development are the reason, Drai said. The costs of developing orphan drugs may be 4 times higher than costs for nonorphan drugs, he said. “The cost for ultra-orphan drugs could be 12 to 20 times higher.”

Orphan drugs are priced high in large part because they are intended for rare conditions and a small population of patients is eligible for treatment with these drugs. Further, the high costs of development must be offset within the same product exclusivity window as applies to common originator and biosimilar drugs, depending on patents, Drai said. This need for a return on investment is factored into the price of orphan drugs.

Another reason for the high cost of developing orphan drugs, both biosimilars and originators, is that for pharmacodynamic (PD) and pharmacokinetic (PK) studies, roughly 40 patients would be needed, but residual uncertainty needs to be resolved via efficacy, safety, and immunogenicity studies, and for this as many as 380 patients would be needed, he said. “You could not just enroll 50 patients to compare with a biosimilar; this is not enough to exclude the uncertainty.”

For that combined patient population (N = 420), an estimated $7.74 million would be needed to perform the PK/PD, efficacy, safety, and immunogenicity studies in Russia—roughly 7 times higher than for nonorphan drugs. In addition, those confirmatory studies would come after more basic studies to establish pharmaceutical and comparative quality and to perform comparative nonclinical evaluation.

Time is another factor that adds to the cost. Enrollment is prolonged because it isn’t easy to get patients to switch to a biosimilar for an orphan drug study, and enrollment may have to be conducted across multiple geographic zones to get the minimum number of patients. An immunogenicity study alone might stretch out to 12 months, Drai said.

Getting past these issues is possible with some structural changes in the way this development work is traditionally performed, he said. This can be accomplished by lowering residual uncertainty prior to phase 3 studies: Phase 3 studies could be waived altogether, they could be postponed until after marketing authorization, and a smaller-than-usual number of patients could be enrolled for phase 3 studies, Drai said, suggesting 3 alternatives.

The prerequisites for allowing such a bypass would be as follows: the existence of a simple molecular structure; high binding affinity between the molecule and antigen; low disulfide bridges; and moderate hydrophobicity, or molecular attraction to water. If these conditions are met, the phase 3 studies could be deemed unnecessary, Drai said.

Further, identifying biomarkers could ease the process by providing surrogate clinical end points for helping understand the drug’s mechanism of action, he said.

“We need to have smart approach to orphan biosimilars and develop guidelines for orphan biosimilars,” he said. “This would lower costs, and often a biosimilar orphan drug could cost less than an originator and it would make the therapy available all over the world.”

Biosimilar orphan drugs might not be cheaper than innovator orphan products, owing to multiple factors, but modifications to regulatory policy could change this, a presenter said at the Terrapinn Festival of Biologics Basel 2020.

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