Tony Hagen is senior managing editor for The Center for Biosimilars

There were several firsts in 2021 for biosimilars, including the first interchangeable biosimilars and the first ophthalmology biosimilar, but under the surface an “identity crisis” has developed, said Eva Temkin, JD, a former regulator who moved recently to private law practice, in a panel discussion at the 2021 GRx+Biosims conference.

Temkin and Rachel Turow, JD, MPH, a private industry general counsel representing Teva Pharmaceuticals, agreed that many policy questions are coming to a head, such as labeling practices and defining the interchangeable designation. Interchangeable biosimilars are ones that pharmacists can dispense in place of reference brands without obtaining authorization from the prescribing physicians.

Looking from the outside in, Turow said that for regulators, this may be a time of intrigue and creative problem solving, but for the biosimilars industry, “it does seem to feel like you’re running around trying to put out many fires at once,” including legislative, regulatory, and patient and physician education problems.

The FDA is developing a regulatory science program with the goal of improving regulatory decision making and making it possible for stronger science-based recommendations in the development of applications under the Public Health Service Act 351(k) licensing process for biosimilars, said Alison Falb, JD, the sole regulatory panelist, who is counsel for the FDA's Office of Therapeutic Biologics and Biosimilars (OTBB).

The OTBB oversees regulatory policy for biosimilars, interchangeables, and other therapeutic biologic products.

Falb said a pilot program is scheduled for 2023 with the stated purpose of advancing the development of interchangeable biosimilars and improving the efficiency of biosimilar product development. The program will also help to determine what real-world evidence might be needed to establish the safety standards for interchangeable status. There will also be stakeholder meetings to review the progress made on these initiatives and determine future priorities.

The practice of “skinny labeling” (labeling carve-outs) worries Turow, who heads up regulatory law and policy divisions for Teva.

I really hope we’ll see skinny labeling addressed, coming out of [

GlaxoSmithKline v. Teva Pharmaceuticals USA, Inc]

, but I think the implications for biosimilars are really just as severe, if not more worrisome, in terms of the liability for induced patent infringement with a skinny label.

Labeling carve-outs involve marketing generics and biosimilars for a narrower range of medical indications than the brand products as a means of avoiding infringement of patents that concern only specific indications. The generic or biosimilar company may include only limited indications on its product label, which the FDA approves, but if the physician or patient assumes that the product is safe for all indications of the reference product and uses it for a patent-protected use, the question may arise whether the generic or biosimilar manufacturer “induced” the physician or patient to use the product for that indication.

GlaxoSmithKline (GSK) and Teva have battled over this issue in court, with GSK alleging induced infringement of Coreg (carvedilol) and Teva emerging as the victor. “I really hope we’ll see skinny labeling addressed, coming out of [

, but I think the implications for biosimilars are really just as severe, if not more worrisome, in terms of the liability for induced patent infringement with a skinny label,” Turow said.

There are signs that federal policy makers are going to continue to support labeling carve-outs, said Temkin, a partner in the FDA and Life Sciences practice of King and Spalding and a former director of policy in the OTBB. She said this was clear from the text of a recent HHS report on drug competition and drug pricing. “Who knows what that will mean in practice and whether it will translate into congressional action, but it does seem to be a focus, and I think it’s an important thing to consider,” she said.

In September 2021, HHS issued its Comprehensive Plan for Addressing High Drug Prices to the White House, and in this, HHS emphasized that it considers the pathway for labeling carve-outs to be an important means of lowering costs for patients and the federal government via Medicare and Medicaid spending.

The FDA has also promised to provide more clarity on the handling of the interchangeable designation. Turow said there’s a lot of ground to cover in providing the desired level of detail for stakeholders in the biosimilar sphere. Aspects of the interchangeable designation requiring clarification range from basic comparability of the biosimilar and the reference product to labeling and any product application devices used. So far, 2 biosimilars have been issued the interchangeable designation in the United States.

“I do have my favorite interchangeability question,” Turow said, “which is if biosimilar A is interchangeable to the reference product and biosimilar B is interchangeable to the reference product, are they interchangeable with each other? And I don’t think the FDA has answered that question.”

Turow said she’s encouraged that pharmacy benefit managers recently have been moving interchangeable biosimilars onto their preferred formularies, but she said that, in the health care community, there’s still a lot of basic education required about biosimilars to generate more confidence in their use.

Under the Biosimilar User Fee Act (BsUFA) reauthorization for 2023 to 2027, the FDA spells out product developer fees and goals for developing the biosimilar approvals process, and the reauthorized plan includes addressing product labeling, interchangeability, and advertising for biosimilars, Falb said. With regard to the interchangeable designation for biosimilars, this includes paying attention to postapproval manufacturing changes to products and addressing differences between drug application products. “I think it’s definitely something we consider a high priority area for guidance,” she said.

As for labeling differences between biosimilars and interchangeable biosimilars, Falb said, the FDA has previously stated that “the principles from the biosimilar labeling guidance would also apply to interchangeable biosimilar labeling,” although the interchangeable designation is somewhat different from the biosimilar definition and those standards also are relevant to how these agents should be regarded, Falb said.

Articles

GRx+Biosims

A trio of regulatory experts discuss the current standing of biosimilar policy in the United States and expectations going forward. 

Panelists Discuss Regulatory Perspective on Biosimilars

Biosimilars employed in clinical studies may reduce the costs of those studies, relative to using reference brand drugs. As clinical research tools, they may also provide answers to questions about appropriate therapy.

When it comes to treatment for breast cancer, investigators used biosimilar trastuzumab (Trazimera) to help understand whether a genetically targeted population of patients would benefit from a de-escalation of standard therapy by leaving out chemotherapy.

Improved outcomes have been derived from the addition of human epidermal growth factor receptor 2 (HER2)–targeted therapies to conventional chemotherapy, although patients sometimes are overtreated with combination therapies or suffer adverse events that might otherwise be avoided.

In KEYRICHED-1 (NCT03988036), a prospective phase 2 trial, investigators sought to determine whether comparable pathologic complete response (pCR) rates could be achieved in the neoadjuvant setting without a chemotherapy therapeutic component in patients with HER2-positive early breast cancer (EBC).

For this study, investigators enrolled patients with HER2-enriched (HER2-E) EBC, because this PAM50 molecular subtype of HER2-positive breast cancer is associated with higher pCR rates following anti–HER2-based treatment. In other words, this subgroup of patients was more likely to respond well to de-escalated treatment.

In this single-arm study, investigators enrolled pre- and postmenopausal patients (N = 48) with newly diagnosed HER2-postive stage I-III EBC with immunohistochemical (IHC) expression 2+ or 3+ and HER2-E subtype by PAM50.

Treatment consisted of 4 cycles (every 21 days) of the following:

Trastuzumab biosimilar (Trazimera, loading dose 8 mg/kg, maintenance dose 6 mg/kg)

Pertuzumab (loading dose 840 mg/kg, maintenance dose 420 mg/kg)

Pembrolizumab is an immunotherapy that blocks the programmed cell death receptor (PD-1) from binding with the PD-L1/L2 ligands, thereby preventing the tumor cell from “switching off” the immune system response against the cancer.

Pertuzumab mutes the tumor cell signaling process by locking onto HER2-expressing cancer cells, thereby arresting their growth and inducing apoptosis, or cell death.

Trastuzumab is complementary in action to pertuzumab. It attaches to HER2 receptors on breast cancer cells and prevents them from receiving growth signals.

Trial enrollment was conducted between May 2020 and March 2021. Investigators said that of 98 patients initially screened, 52 (55%) had the HER2-E subtype by PAM50, and of those, 48 entered the treatment phase.

The median age of patients was 57; 65% had tumors larger than 2 cm and 30% were positive for lymph node involvement.

Investigators said the centrally confirmed pCR rate was 52% in 46 evaluable patients (a minimum pCR rate of 50% was predetermined for recruitment continuation).

“Despite the HER2-E subtype, no pCR was observed in 4 patients with IHC HER2 2+/fluorescence-in-situ hybridization (

)–positive status in contrast with 20/39 (51.2%) pCRs in HER2 3+ tumors,” authors of the study wrote.

They said the confirmed pCR rate for HER2-positive/hormone receptor (HR)–positive tumors was 38.5% vs 58.5% for HER2-positive/HR-negative tumors. They observed no new safety signals.

The investigators said the findings were favorable in comparison with those from the 

, another de-escalation study, which compared trastuzumab and pertuzumab alone (dual blockade) with trastuzumab, pertuzumab, and paclitaxel in patients with HER2-positive/HR-negative EBC.

In WSG-ADAPT, investigators concluded that the addition of taxane therapy (paclitaxel/chemotherapy) to dual HER2 blockade over 3 months “substantially” increased pCR rates in HER2-postive/HR-negative EBC compared with dual blockade alone.

They said that in KEYRICHED-1, “The observed pCR rates compare favorably in HR-positive as well as HR-negative/ HER2-positive EBC. Moreover, KEYRICHED-1 demonstrates that with appropriate molecular patient selection, clinically meaningful pCR rates in the range of those obtained with longer, more toxic chemotherapy-containing regimens can be achieved.”

Kuemmel S, Gluz O, Reinisch M, et al. KEYRICHED-1 – a prospective, multicenter, open label, neoadjuvant phase II single arm study with pembrolizumab in combination with dual anti-HER2 blockade with trastuzumab and pertuzumab in early breast cancer patients with molecular HER2-enriched intrinsic subtype. Presented at: 2021 SABCS; December 7-10, 2021. https://www.abstractsonline.com/pp8/#!/10462/presentation/1034

Investigators said pathologic complete response (pCR) improved in a trastuzumab biosimilar/pertuzumab trial when patients were preselected for a subtype of breast cancer. 

Molecular Selection Boosts pCR Rate in Early Breast Cancer Trial

A phase 1 study of the proposed eculizumab biosimilar (SB12) vs reference product (Soliris) has demonstrated pharmacokinetic (PK) bioequivalence and comparable pharmacodynamic (PD), safety, and immunogenicity characteristics in a population of healthy volunteers, investigators reported at the 2021 American Society of Hematology meeting.

Eculizumab is a humanized monoclonal antibody that binds to human C5 complement protein and blocks hemolysis, or the breakdown of red blood cells. Eculizumab is currently indicated for paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, refractory generalized myasthenia gravis, and neuromyelitis optica spectrum disorder.

Investigators sought to demonstrate comparable PK and PD in healthy individuals aged 18 to 55 years (N = 240) who were randomized in a 3-arm trial to a single 300-mg dose of SB12 or US- and EU-sourced reference product. Blood samples for analysis were collected over 64 days.

The primary end point was PK similarity between the various agents as determined by total drug exposure, or area under the concentration-time curve. Biosimilarity for the primary end point was confirmed, as the 90% CIs were within the predetermined equivalence margin of 80% to 125%, authors of the study wrote.

Investigators said there were no deaths or discontinuation of investigational products (IPs) due to treatment-emergent adverse events (TEAEs); they said there were 2 serious adverse events: renal colic in the SB12 cohort and back pain in the US-eculizumab group. “Both events were considered not related to the IP,” investigators wrote.

They said 70.0%, 65.0%, and 71.3% of patients in the SB12 and EU- and US-sourced eculizumab cohorts, respectively, experienced TEAEs, which investigators said was similar.

The number of participants who developed postdose antidrug antibodies (ADA) to eculizumab was 2 (2.5%), 1 (1.3%), and 0 (0.0%), respectively, authors wrote. “There was no significant difference between treatment groups. None of the [participants] with post-dose ADA to eculizumab had a positive result for neutralizing antibodies.”

Lee HA, Jang H, Kim Y, et al. A randomized, double-blind, single-dose phase 1 comparative pharmacokinetic study comparing SB12 (eculizumab biosimilar) with reference eculizumab in healthy volunteers. Presented at: ASH 2021; December 11-14, 2021. Abstract 929.

American Society of Hematology  Annual Meeting and Exposition

In a pharmacokinetic (PK) and pharmacodynamic (PD) trial in healthy participants, Samsung Bioepis' SB12 eculizumab biosimilar candidate demonstrated equivalence to Soliris, the reference product. 

SB12 Eculizumab Biosimilar Candidate Demonstrates PK, PD Equivalence in Phase 1 Trial

In midterm results for a phase 2 study presented at the the 2021 San Antonio Breast Cancer Symposium, a trastuzumab biosimilar (Herzuma) in conjunction with gedatolisib, a cell-signaling inhibitor, demonstrated an overall response rate of 58.8% with manageable toxicity in patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer (mBC) with a PIK3CA aberration.

The disease control rate achieved with this combination was 82.4%, investigators said. Median progression-free survival was 5.9 months.

Trastuzumab is a monoclonal antibody that targets HER2, which is overexpressed in cancers and contributes to excessive cell growth. Trastuzumab binds to the HER2/neu receptor and reduces HER2 expression and also reduces growth of blood vessels that support tumor growth.

Gedatolisib targets the mTOR/PIK3 signaling pathway, which plays a role in tumor growth and proliferation. mTOR is a protein whose signaling regulates cell metabolism, growth, proliferation and survival. And PI3K is a group of enzymes that also regulate cell growth and are implicated in the development of cancer.

In the trial, investigators sought to elucidate the value of trastuzumab in combination with gedatolisib in patients whose cancers had progressed after multiple lines of therapy.

Resistance to anti-HER2 agents with antibody-drug conjugates (ADCs) is common, especially along the mTOR/PI3K signaling pathway. ADCs combine an antigen-specific antibody with a cytotoxic payload. At least 2 anti-HER2 ADCS have been approved for HER2-positive breast cancer. One is ado-trastuzumab emtansine, which was initially approved in 2013. Another was trastuzumab deruxtecan, approved in 2020.

In this study, patients were enrolled who had HER2-positive mBC with a known PIK3CA pathologic mutation or amplification whose disease had progressed following ≥ 2 HER2-directed therapies. Patients were treated with the trastuzumab biosimilar plus gedatolisib until progression or intolerable toxicity.

Median age of patients (N = 17) was 54.5 years and premenopausal (11.8%) and menopausal (88.2%) patients were enrolled.

Following therapy, investigators said 3 patients had progressive disease, 4 had stable disease, and 10 showed a partial response. The trial will continue with enrollment up to a target 62 patients.

Kim JW, Ahn HK, Choi JG, et al. Phase II study of trastuzumab biosimilar (Herzuma) plus gedatolisib in patients with HER-2 positive metastatic breast cancer who progressed after 2 or more HER-2 directed chemotherapy: KM-10A (KCSG BR 18-13) interim analysis. Presented at: 2021 SABCS; December 7-10, 2021. Poster PS16-03.

San Antonio Breast Cancer Symposium

In metastatic breast cancer (mBC) resistant to multiple lines, Herzuma (a trastuzumab biosimilar) plus gedatolisib, an mTOR/PI3K signaling pathway inhibitor, demonstrated value. 

Biosimilar-Gedatolisib Combo Elicits Response in Resistant mBC

Researchers who surveyed patients and oncologists about biosimilars and switches to biosimilars from reference products said they found discrepancies between patients’ perceptions and physician perceptions of whether the information provided was adequate.

The study was presented at the 2021 San Antonio Breast Cancer Symposium. Oncologists and patients were asked the same questions following a switch to a trastuzumab biosimilar.

The widest discrepancies in perceptions were the following:

Oncologists tended more often than patients to report that information about the switch was presented in an easy-to-understand way: 58% vs 42%.

Oncologists were more likely to conclude that patents had ample opportunity to ask questions: 59% vs 35%.

Oncologists tended more often to conclude that patients were given adequate information resources about the switch: 33% vs 18%.

Patients were less likely than oncologists to have the impression that their cancer would be treated as effectively with a biosimilar rather than the reference drug (Herceptin): 43% vs 79%.

Oncologists agreed less of the time that patients understood the reason for the switch to a biosimilar: 39% vs 43%.

Oncologists were more likely than patients to conclude that patients were not worried about switching: 41% vs 24%.

Oncologists tended more often than patients to conclude that switching to a biosimilar was a “minor change” in a patient’s care: 67% vs 37%.

Investigators in this study noted that 5 trastuzumab biosimilars have been approved in the United States and with two 60-item questionnaires, they sought to elucidate patient and oncologist perspectives on switching to biosimilars and the relative levels of understanding between patients and their providers.

“Ours is the first survey comparing the experiences and perspectives of oncologists and patients,” they wrote.

In other findings, 55% of patients reported being given an option to switch from the reference drug, Herceptin, to a biosimilar. Investigators said 41% of patients surveyed said they received no prior notification of a switch. In addition, 44% of patients said they learned more about biosimilars through self-directed study than from their providers, and 41% said they had wanted more time to discuss switching to a biosimilar with their oncologist.

Areas where patients and their oncologists were in close agreement were as follows:

Patients felt involved in care decisions: 18% vs 18%.

Patients trusted their oncologists: 63% of patients vs 67% of oncologists.

Patients trusted their insurance companies: 9% of patients vs 12% of oncologists.

Patients understood reasons for switching: 43% of patients vs 39% of oncologists.

Patients emotionally adjusted to the switch: 41% of patients vs 42% of oncologists.

Patients were not worried about treatment success: 29% of patients vs 33% of oncologists.

The surveys included 33 oncologists and 143 patients. The median patient age was 50 years and for oncologists, 46 years. Patients were predominantly White (91%), but oncologists were not (39%). Investigators said 56% of patients had a bachelor’s degree and 56% had metastatic breast cancer.

Papautsky EL, Carlson M, Lustberg M. The patient-centered paradox: A US-based survey of oncologist- and patient-reported experiences with trastuzumab biosimilars. Presented at: SABCS 2021; December 7-10, 2021. Poster P2-13-13.

After a switch to a biosimilar, patients and their oncologists may not always agree on how well the switch was described or whether the patient felt involved. 

Patient-Provider Surveys Elucidate Biosimilar Switching Process in Oncology

Long-term survival findings for the trastuzumab biosimilar Ontruzant (SB3) demonstrated equivalence to the reference product (Herceptin) in a 

 of patients with human epidermal growth factor receptor 2 (HER2)–positive early or locally advanced breast cancer, investigators reported at the 2021 San Antonio Breast Cancer Symposium (SABCS).

Findings were analyzed following a medium of 68 months from patient randomization, constituting the longest monitored data to date for SB3, investigators said.

Previously, at the European Society for Medical Oncology meeting in September 2021, long-term cardiac safety and efficacy results were reported for patients (n = 367) from the same trial. The findings presented at SABCS reflect outcomes for those patients plus an additional 171, as well as stratified, comparative findings for patients exposed to reference drug lots whose quality “drifted,” or was not consistent with the standard, during the trial.

“Patients treated with reference drug ‘drifted’ lots were patients who were exposed to at least 1 vial from reference lots with a downward drift in antibody-dependent cellular cytotoxicity (ADCC) during the neoadjuvant treatment period,” authors of the study wrote.

Patients who were treated with nondrifted lots were those who received reference drug at the standard strength and formulation during the neoadjuvant treatment period.

Investigators said that the 5-year event-free survival (EFS) for patients treated with SB3 vs reference product (drifted or nondrifted) was 79.8% and 75.0%, respectively (HR 0.84; 95% CI, 0.58-1.20; 

 = .335). Investigators said this still demonstrated equivalence between the biosimilar and the reference product.

The 5-year overall survival (OS) between groups also was comparable: 92.5% for the SB3 group and 85.4% for the reference product group (HR 0.61; 95% CI, 0.36-1.05; 

“However, there was a meaningful difference within reference product arm depending on the ADCC-drift status,” authors of the study wrote.

In the comparison with nondrifted trastuzumab reference product, the event-free survival for SB3 was 79.8% vs 82.5% for the reference product (HR 1.28; 95% CI, 0.73-2.22; 

 = .391), and investigators said this demonstrated equivalence.

The OS for patients who received SB3 vs nondrifted reference product was 92.5% vs 91.4% respectively (HR 0.99; 95% CI, 0.42-2.31; 

They said 5-year EFS for reference drug patients who received drifted vs nondrifted product was 70.3% vs 82.5%, respectively (HR 2.57; 95% CI, 1.28-5.14; 

 = .008). OS for these 2 groups was 81.3% vs 91.4%, respectively (HR 3.87; 95% CI, 1.37-10.93; 

“For HER2-positive breast cancer treatment, monitoring long-term outcome is important, and we hope these five-year follow-up study results in a large group of patients provide meaningful value to the oncology society by demonstrating robust comparable long-term safety and efficacy profile of a trastuzumab biosimilar,” said Dong-hoon Shin, vice president and Medical and Lifecycle Safety Team leader for Samsung Bioepis, which developed the biosimilar SB3.

In the phase 3 study, patients were randomly assigned to receive 8 cycles of SB3 or reference drug with concurrent neoadjuvant chemotherapy (4 cycles of docetaxel followed by 4 cycles of 5-fluorouracil/epirubicin/cyclophosphamide).Patients then underwent surgery and went on to receive 10 cycles of SB3 or reference drug based on previous treatment, completing 1 year of treatment.

Following the adjuvant treatment, patients were enrolled in the 5-year follow-up study.

Pivot X, Pegram MD, Cortes J, et al. Final survival analysis of a phase 3 study comparing SB3 (trastuzumab biosimilar) and reference trastuzumab in HER2-positive early or locally advanced breast cancer. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021. Poster P2-13-04.

The trial included "drifted" (nonstandard) reference product, forcing a stratified analysis to yield relevant data. 

Ontruzant Biosimilar Demonstrates Equivalence to Herceptin in 5-Year Study

Treatment of Human epidermal growth factor receptor 2 (HER)–positive early stage breast cancer with a candidate biosimilar (EG12014) yielded equivalent efficacy and safety in comparison with the reference product, Herceptin, in patients who received concurrent taxane chemotherapy.

 presented at the 2021 San Antonio Breast Cancer Symposium, investigators said neoadjuvant treatment in combination with anthracycline/paclitaxel–based systemic therapy demonstrated positive outcomes for the EirGenix candidate biosimilar in a multinational phase 3 study.

The study (NCT03433313) was conducted during the COVID-19 pandemic and yet the objectives and functioning of the trial were uncompromised, the investigators said. The last patient to enroll joined the trial in March 2020.

HER2 cancer is fast growing and spreads to the lymph nodes faster than HER2-negative breast cancer. Therefore, amplification, or overexpression, of HER2 in breast cancer is associated with poorer outcomes.

Trastuzumab is a standard therapy for HER2-positive breast cancer, and the investigators said the addition of trastuzumab to neoadjuvant treatment involving anthracyclines and taxane-based therapy has improved pathologic complete response (pCR), event-free survival (EFS), and overall survival (OS).

In this trial, they sought to verify that efficacy and safety between the reference product and EG12014 were equivalent.

In the neoadjuvant phase, investigators enrolled 807 patients and randomized them to 2 cohorts. One arm received epirubicin (90 mg/m

) every 3 weeks for 4 cycles, followed by EG12014. The second arm received the same chemotherapy regimen but with reference trastuzumab instead of the biosimilar candidate. 

Trastuzumab in both arms was administered at a loading dose of 8 mg/kg and maintenance dose of 6 mg/kg. Both arms received paclitaxel (175 mg/m

Patients subsequently underwent surgery and the trial’s primary end point of pCR was assessed.

In the adjuvant phase of the trial, following surgery, patients received the biosimilar candidate or reference product (loading dose: 8 mg/kg and maintenance dose: 6 mg/kg) to complete a total of 12 months of trastuzumab treatment.

The investigators assessed differences in study treatments and procedures resulting from the pandemic, but said no sensitivity analysis was conducted regarding COVID-19 because virus infections were not expected to affect the primary end point analysis.

They said the primary end point, pCR of eradication of tumor from both breast and lymph nodes, was reached with a relative risk ratio (RR) of 0.992 (90% CI, 0.880-1.118) between the 2 treatment cohorts. Secondary end points of tumor eradication from breast and lymph notes also were reached.

The investigators said objective clinical response was similar between the 2 treatment arms and that EFS, OS, safety end points, and toxicity assessments also were similar between arms, supporting equivalence.

They also said incidence of COVID-19 infections was spread evenly between the 2 trial arms and did not cause any discontinuations or deaths. “The influence of the pandemic on this clinical study has been relatively low considering timing and the participating countries,” the  investigators concluded.

Patients were enrolled in Belarus, Chile, Colombia, Georgia, India, Russia, South Africa, South Korea, Taiwan, and the Ukraine.

“EG12014 has shown equivalent efficacy to Herceptin in regard to clinical response and has also demonstrated a similar safety profile,” they concluded.

EirGenix, the company developing the biosimilar, is based in New Taipei City, Taiwan, and has partnered with Sandoz for commercialization of EG12014 outside Taiwan and mainland China

Grohmann-Izay B, Huang C-S, Dzagnidze G, et al. A phase III, randomized, multicenter, double-blind study to compare efficacy and safety of EG12014 (EirGenix trastuzumab) with Herceptin® as neoadjuvant treatment in combination with anthracycline/paclitaxel-based systemic therapy in patients with HER2-positive early breast cancer - a multinational phase III study conducted during the COVID-19 pandemic. Presented at: SABCS 2021; December 7-10, 2021. Abstract P2-13-17.

A trastuzumab biosimilar candidate demonstrated equivalence to Herceptin in patients with early-stage human epidermal growth factor receptor 2 (HER2)–breast cancer.

EirGenix Trastuzumab Biosimilar Candidate Demonstrates Equivalence in HER2-Positive Breast Cancer

November 2021 was a busy month on the biosimilars front, with companies announcing plans for interchangeable forms of adalimumab, the FDA stepping back into its normal routines after the COVID-19 battering, and payers putting more weight behind biosimilars.

In Washington, DC, legislators debated health care policies that would promote the use of biosimilars and generics;and biosimilar industry veterans warned of policies that might do more harm than good.

The following is the short list of leading biosimilar news articles published at The Center for Biosimilars

. Read them to ensure you’re on top of events.

 it has a trial under way to qualify its adalimumab biosimilar (Amjevita) for interchangeable status, which would give pharmacists independent latitude to dispense this product in place of the brand, Humira. 

I am pleased to say that as of July we began resuming normal operations for domestic inspections.

 that it too intends to seek interchangeable status for its adalimumab biosimilar (Abrilada). That FDA filing, it said, would come in December.

 about the difference, if any, between biosimilars that have the interchangeable designation and those that don’t. The FDA stated in a November conference that it was attempting to tie up some of the loose ends around these 2 designations. Sarah Yim, MD, director of the FDA’s Office of Therapeutic Biologics and Biosimilars, stated that the pending guidance would help with the development of interchangeable biosimilars.

Biosimilars are generally cheaper than the biologics they reference, but payer authorizations and preferences can make the difference between a biosimilar that gets used and doesn’t get used. Prime Therapeutics in November 

 it was moving Semglee, an insulin glargine biosimilar, to the pharmacy benefit manager’s preferred formulary list. Semglee became an interchangeable biosimilar this year, and in October 2021, Express Scripts also gave it preferred status.

The FDA has been distracted by COVID-19 and is now 

 to the business of reviewing biosimilar approval applications, Acting Commissioner Janet Woodcock, MD, reported in a biosimilars industry address in November. Domestic factory inspections, essential for certifying biologics manufacturing quality, are back on track, she said. 

A new concept has sprung up in the biosimilars world: tailoring. This refers to deciding evidence requirements for biosimilarity partly on a case-by-case basis. The goal is to streamline the approvals process, cut red tape and unnecessary expense, and, most important, do away with “blunt tool” measures for biosimilarity that add little or nothing to the sum total of evidence.

 reported on a European Medicines Agency 

 for trying out a tailoring approach on a handful of biosimilar approval applications. Also, the World Health Organization moved forward with an effort to revise its biosimilar guidance to incorporate a more sophisticated palette of tools for assessing biologics equivalence. The Center for Biosimilars

, policy and science officer for Medicines for Europe, about the significance of these revisions.

This formulary change reinforces Prime's commitment to increasing biosimilar adoption and also demonstrates that we are not beholden to rebates, as we're able to also prefer the lowest net cost therapy.

A Capitol Hill initiative to elbow more competition into the drug markets involved a proposal to allow Medicare to negotiate prices for a limited number of drugs and fine manufacturers who refuse to play ball. These proposals, embedded in the draft Build Back Better Act, have aroused 

 in the manufacturing community, which contends that legislators have been chanting a new policy mantra that misses the mark. The real problems are 

, they said in discussions and public statements in November.

November signified robust debate but it also included Global Biosimilars Week, an invention of the International Generic and Biosimilar Medicines Association (IGBA), which chose the occasion to raise the issue of patient access and affordability. Policies need to be 

 and perhaps redrafted, IGBA said, so that the savings from biosimilars trickle down to the individuals who are intended to benefit: the patients.

Representatives of the Community Oncology Alliance (COA) this past month discussed an interesting 

 they’ve observed among COA practices that have been using biosimilars: As biosimilars have been introduced, usage of both biosimilars and their reference products has increased. The conclusion? The competitive pricing appears to be lowering costs overall and enabling more patients to afford these products.

Biosimilars in a standalone setting can provide savings, but they can also be used in combination with other brand products. A study of sintilimab in combination with the bevacizumab biosimilar 

 was tried in the ORIENT-31 trial of patients with advanced nonsquamous non–small cell lung cancer. Savings were not evaluated, but a significant improvement in progression-free survival was reported.

 made by a biosimilar expert may not be a biosimilar, but it can still save time and money. Sarfaraz K. Niazi, PhD, wrote in a November column about his laboratory experiment to bypass the years-long whiskey aging process. It doesn’t have to take 12 years or 60 years for a whiskey to absorb the flavor from a wooden barrel, Niazi postulated. He used thermal dynamics to accelerate the process. The end point of the study was taste, and Niazi reports it was pretty good.  

For all of these stories and many more from November, visit The Center for Biosimilars

Regulators are at work clarifying biosimilar guidance and on Capitol Hill, a battle is raging over reforms that could help or hurt biosimilar advancement.

Biosimilars Roundup: November Was Dominated by Legislative and Regulatory News 

Price negotiations for biologics and forcing drug manufacturers to rebate CMS for drug costs that exceed rates of general inflation are options the federal government is considering to control drug spending.

But these policies “are in lieu of addressing the root cause” of drug cost increases, and programs that disallow rebates paid by manufacturers to pharmacy benefit managers (PBMs) and payer plans would be more effective, argued a biosimilars manufacturer representative at the recent GRx+Biosims conference sponsored by the Association for Accessible Medicines.

Some industry stakeholders contend “pay-for-delay” deals unfairly restrict competition whereas others contend they facilitate drug affordability and market access. GRx+Biosims panelist Sarah D’Orsie said that instead of seeking to curtail and regulate pay for delay deals between drug makers, the federal government should raise the bar on the quality of patents issued to drugmakers. D’Orsie is vice president of government affairs and policy for Fresenius Kabi.

If approved, the Build Back Better Act, President Joe Biden’s safety net spending initiative would allow drug price negotiations for a small number of high-cost Medicare Part D and Part B drugs that lack generic or biosimilar competition. Prices of up to 10 drugs could be negotiated in 2025, with the annual number of drug prices negotiated increasing to 20 by 2028. The proposal would also cap the upper limit of the negotiated price. Further, an excise tax would be levied on drug makers that don’t comply with negotiation and monetary penalties would apply to companies that don’t maintain negotiated prices.

Separately, a bill in Washington, DC, the Preserve Access to Affordable Generics and Biosimilars Act, would limit pay-for-delay deals that compensate drug manufacturers for withholding their products from market.

Patent thickets, which are clusters of patents that shield originator products from competition, and poor patent quality tend to impede biosimilar competition, D’Orsie said, explaining that patents, good or bad, can give the originator company leverage to negotiate pay-for-delay settlements, which keep biosimilars and generics off the market.

As D'Orsie described, rebates paid by manufacturers can become a vicious cycle if both the original brand manufacturer and the biosimilar company feel compelled to offer them.

“As a biosimilars company, we have to compete in some way with the brand, and the way it’s going, that means giving a rebate. In order to compete [with other companies] on bigger and bigger rebates, you raise your price in order to have more room. So the concept is that the manufacturer is breaking even every year and the PBM and the plan are getting a bigger rebate…and the Medicare patient ends up paying [more, as a percentage of costs] every single year,” she said.

The US Patent and Trade Office is just granting scores of junk patents, which is why we need to do settlements between biosimilar companies and the brand, because we cannot afford to litigate these scores of junk patents.

One provision of the Build Back Better Act would require drug manufacturers to rebate the federal government if their prices for biologics covered under Medicare Part B and Part D increase faster than the rate of inflation. “Everybody’s worried about the inflationary penalties,” D'Orsie said.

She said pay-for-delay settlements actually help biosimilar companies to bring their products to market. Although these agreements appear to delay biosimilar competition, the “root cause” of delayed competition is an excess of patent approvals that are granted on a weak basis of evidence of product improvement or innovation, she said.

“The US Patent and Trademark Office is just granting scores of junk patents, which is why we need to do settlements between biosimilar companies and the brand, because we cannot afford to litigate these scores of junk patents,” D’Orsie said. “The settlements actually get us closer; [they] allow us to launch, sooner than if we were just going to wait for the patent to expire.”

Panelist John Brooks, a partner with health policy consulting firm South Capitol, said reforms are needed to Medicare Part D, which he said was designed for an era when generic drugs were a significantly smaller proportion of prescriptions written and biosimilars didn’t exist.

“It’s really exciting to see the potential for significant changes here that could improve the program but also provide additional opportunities to level the playing field for products and manufacturers,” he said.

The current design of Medicare coverage, along with manufacturer rebates, “creates a series of incentives for [payer] plans that can drive them toward using higher-cost products,” Brooks said.

He suggested that policy makers level the playing field, in part, by putting biosimilars, such as adalimumab, on specialty tiers. “We’ve seen just in the past year that CMS has given plans additional flexibility to create a second specialty tier. That should improve the negotiating leverage of biosimilars.”

AAM GRx+Biosims

Specialty tiers for biosimilars and reforms that address the proliferation of poor-quality patents would help lower costs and improve access, biosimilar industry veterans said.

Biosimilar Industry Critiques Biden's Drug Pricing Reforms

Biosimilars in the United States have seen perhaps the greatest uptake in oncology, but the use of biosimilars in oncology has also broadened access, meaning that competitive pricing of these agents, relative to reference products, has enabled more patients to receive treatment, according to a recent study of biosimilar administration at 122 practices by the Community Oncology Alliance (COA).

“A few years ago, when biosimilars were entering the market, several COA practices started using these, and we started to see savings anecdotally within our own organizations,” said Kathy Oubre, MS, CEO of the Pontchartrain Cancer Center in Louisiana and a cochair of the biosimilars committee at COA.

“We as an organization decided to take this a step further and look at this from a broader perspective, with a working hypothesis that biosimilars were going to play an integral part in bringing down health care costs,” she said in a presentation at the COA 2021 Payer Exchange Summit.

For the study of biosimilar use, participating practices submitted data for over 2 million administrations of reference and biosimilar products, and in the analysis, COA focused on rates of biosimilar adoption, administrations, and access to care.

In 2019 there were 68,000 administrations of Rituxan, the originator product for rituximab. The first rituximab biosimilar was Truxima, launched in November 2019, and this accounted for 19% of administrations in the first quarter of 2020.

Biosimilar rituximabs achieved a greater presence in the market with the launch of Ruxience in January 2020, and by the fourth quarter of 2020, rituximab biosimilars accounted for 55% of all rituximab administrations, Oubre said.

There were 112,000 administrations of rituximab in 2020, and 66,000 of those involved the reference product and the remaining 46,000, biosimilars. Oubre said this amounted to an increase of 44,000 administrations from 2019 to 2020, so access to care had sharply improved within the practices included in the study.

In 2019 there were about 23,000 administrations of both reference (Remicade) and biosimilar infliximab, and of those, 20,000 were reference product administrations. At that time, biosimilars accounted for a small percentage of administrations, but the presence of infliximab biosimilars began to grow. In 2020, Remicade administrations added up to 21,000—a 5% increase—but biosimilar administrations were significantly higher, 5000, reflecting growth in biosimilar share of administrations and also an increase in access to care with infliximab, Oubre said.

In 2019, there were about 120,000 administrations of pegfilgrastim, and 100,000 of those represented reference product (Neulasta) administrations. But in 2020, the number of administrations climbed to 139,000 in total, with 98,000 (a decline) being reference drug administrations and 41,000 being biosimilar administrations. “So, quite a large increase,” Oubre said.

“Within our organization [Pontchartrain], biosimilars have offered us a lower-cost alternative without sacrificing any quality for our patients. Therefore, we continue to see increases in access to care,” she said.

The first pegfilgrastim biosimilar entered the market in July 2018 and by the fourth quarter of that year had a 2% share of the market. By the end of 2020, pegfilgrastim biosimilars had a 31% share, Oubre said. There were 4 available biosimilar pegfilgrastims by that point.

The first trastuzumab biosimilar (Kanjinti) was launched in July 2019. In the fourth quarter of 2019, there were roughly 24,000 administrations of trastuzumab, and about 16,000 of those were the reference product (Herceptin), and 8000 were biosimilar administrations.

Kathy Oubre, MS, a cochair of the biosimilars committee of the Community Oncology Alliance (COA), explains findings from a broad study of biosimilar use in oncology practices.  

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