Tony Hagen is senior managing editor for The Center for Biosimilars

Two bills in Congress meant to address “product hopping,” or the anticompetitive practice of introducing a changed product to steer consumers away from an older product and competing versions, illustrate the unique scrutiny that drug manufacturers are subjected to, panelists said at the American Conference Institute’s (ACI) 11th Summit on Biosimilars and Innovator Biologics.

“This is something that’s very specific to the drug industry,” said Melissa Brand, assistant general counsel and director of intellectual property for Biotechnology Innovation Organization, a large trade association.

“You don’t see this sort of thing when a company introduces a new brand of shoe and can’t say anything bad about the old shoes or has to keep marketing the old shoes; or every time a new smartphone comes out, you don’t see a company having to go out and still market its old phone product, so I think it emphasizes the scrutiny on the industry these days,” Brand said.

 were introduced in May 2019 and address product hopping, although there are important differences between the two, said David Korn, vice president of intellectual property and law with Pharmaceutical Research and Manufacturers of America.

Both bills address “hard switching,” which is when a pharmaceutical company introduces a follow-on product and discontinues an older-but-similar product, and “soft switching,” when a company introduces a follow-on product but “takes action to unfairly disadvantage the older product in a manner that impedes competition for generics or biosimilars,” Korn said.

Current law does not clearly address the practice of soft switching, “and having such a concept could raise significant uncertainty for companies when thinking about planning alternative versions—new innovations—after initial approval,” he asserted.

“Both bills could kill innovation by requiring manufacturers to demonstrate that actions with respect to subsequent innovative products are not as competitive,” he said.

The House bill exempts certain products from the definition of follow-on products, including ones that qualify for Hatch-Waxman Act product exclusivity protections, Korn said. “That’s not in the Senate bill.”

“The House bill also has an exemption for certain activities not constituting unfairly disadvantaging the earlier product under definition of the soft switch,” he added. This exemption covers truthful, nonmisleading promotional activity, and there’s no exemption for this in the Senate bill, Korn said.

“You can imagine a situation where someone comes up with an alternative version and raises a question about what they can or cannot say about what’s truthful and nonmisleading, so there are a lot of questions that would need to be considered,” Korn said.

The Senate bill also includes broader legal remedies, such as disgorgement of “unjust enrichment” gained by the manufacturer and “restitution,” or damages, whereas the House bill does not specify remedies but indicates that enforcement will be in accord with provisions of the Federal Trade Commission Act.

ACI panelist Karin Hessler, assistant general counsel for the Association for Accessible Medicines, a trade group representing large biosimilar developers and manufacturers, said that from the biopharmaceutical industry perspective, there’s a concern that that soft switches may become “overregulated,” and this may discourage innovation. 

“You may not see the sort of really beneficial follow-on products where someone has really improved a formulation or has a new route of administration, a new indication, so that’s something that I think is definitely a concern,” she said.

from House Judiciary Committee Chairman Jerrold Nadler (D-New York), in justification of the House legislation, explained that preexisting antitrust laws have been a poor fit for addressing product hopping abuses. “Unfortunately, courts have struggled to consistently apply the antitrust laws to this conduct. Moreover, antitrust litigation to address anticompetitive behavior in pharmaceutical markets is costly and slow, often taking years—if not decades—to stop the abusive behavior.

“HR-5133 would prohibit product hopping by establishing that it is an unfair method of competition in violation of the Federal Trade Commission Act. In doing so, not only would this legislation help deter such conduct in the first place—through the FTC’s ability to obtain equitable monetary relief—it would also expedite judicial proceedings by providing much needed clarity to the law,” Nadler said.

According to the Congressional Budget Office, the companion bills, if enacted, will save taxpayers more than half-a-billion dollars over a 10-year period, the statement said.

 for more coverage of the ACI virtual 2020 conference.

Brand M, Korn D, Hessler K, Pearson M. Biosimilars state of the union: regulatory and legislative developments impacting the biopharmaceutical industry. Presented at: ACI 11th Summit on Biosimilars & Innovator Biologics; September 23, 2020.

Articles

ACI 11th Summit on Biosimilars & Innovator Biologics

Two bills in Congress meant to address the anticompetitive practice of product hopping drew fire at the American Conference Institute's annual biosimilars conference.

Biopharmaceutical Industry Representatives Discuss Product Hopping Legislation

Eva Temkin, acting director for policy at the 

Office of Therapeutic Biologics and Biosimilars (OTBB), provided a snapshot of how the FDA's new office is faring

 in her keynote talk at the American Conference Institute’s 11th Summit on Biosimilars & Innovator Biologics.

The OTBB was established in 2018 to help usher the development of biosimilars and thereby lower health care spending and improve patient access. “What we really wanted to do was say, ‘We’re committed to this. We recognize that there are a lot of things that the agency can do to help this marketplace grow and become stable,’” Temkin said in the discussion that was moderated by Amanda Hollis, JD, a patent litigator with Kirkland & Ellis of Chicago. 

One of the OTBB’s missions was to explore the use of data based on studies of reference products abroad to help bring down the development cost for biosimilar companies seeking to launch products on the US market, where the emphasis has been on doing local studies with locally sourced reference product material.

Hollis noted in her questions that reference product sourcing for US biosimilar applications can amount to almost half the cost of developing biosimilars for this marketplace.

Temkin noted that broadening the scope of resources available to biosimilar manufacturers in this context remains, very much, a work in progress. “I think we have made some progress and we’re still working on it,” she said. Discussions with foreign regulators are a part of this ongoing effort she said.

The FDA is tracking roughly 570 drug development programs underway related to potential coronavirus disease 2019 (COVID-19) therapies and has reviewed 270 trials. The pandemic has caused a massive shift in FDA priorities, Hollis noted, in a series of questions about priorities, resources, and election year politics.

Temkin responded that the resources at the OTBB remain adequate to the task of reviewing biosimilar applications, although she is “always” looking to hire more staff. The office currently has a staff of about 24, including legal and scientific professionals.

Since the beginning of 2020, the FDA has approved 2 new biosimilars, down from 10 last year; 28 have been approved since 2015. Currently there are about 90 biosimilar development projects for roughly 35 reference products, Temkin said.

With so much work on the OTBB’s plate, Hollis asked how the OTBB prioritizes these projects and decides which to review first. “As with a lot of things in government, there are limited resources and a lot of needs. One thing we take very seriously is to get stakeholder input in how we prioritize,” Temkin responded.

Hollis also asked whether patents and pending patent expirations play any role in the FDA’s decisions on which product development projects to prioritize. Temkin said that is not a central focus at the FDA. “If that is something that folks feel is something that should be taken into consideration, I would certainly encourage people to submit comments.”

A current goal at the OTBB is improving the efficiency of the biosimilar and interchangeable biosimilar approval process, and Temkin’s office has sought to create a “more tangible understanding” of what the scientific needs are for granting approvals for biosimilars, and this has included making clear what types of evidence are not acceptable for the approval of biosimilars, she said.

Temkin E, Hollis A. Biosimilars and interchangeable products: insights on FDA's perspective on implementation. Presented at: ACI 11th 

Summit on Biosimilars & Innovator Biologics. September 23, 2020. 

The FDA's Office of Therapeutic Biologics and Biosimilars balances a large number of biosimilar development projects with limited resources and is making progress, says Eva Temkin, acting director of policy.

FDA's Eva Temkin Discusses Biosimilar Approvals at ACI

Recent attempts at reform across the biosimilar and generic drug landscape have not had unanimous support, legal experts noted at the American Conference Institute’s 11th Summit on Biosimilars & Innovator Biologics.

Last year, for example, California, enacted Assembly Bill (AB) 824, which enabled it to evaluate “pay for delay” settlements between biosimilar developers and reference product companies and bring enforcement actions for what it perceives as anticompetitive terms.

“That legislation is doing what the Supreme Court declined to do, which is impose a presumption that an agreement that includes certain terms has an anticompetitive effect,” said ACI panelist Karin Hessler, assistant general counsel for the Association for Accessible Medicines (AAM). The AAM has filed a series of court actions designed to overturn AB 824, but has thus far been

The AAM represents many large biosimilar developers and contends that California has improperly assumed the right to reject corporate settlements reached outside the state and also given itself leeway to impose excessive fines on individual companies (minimum of $20 million).

Another reason the pharmaceutical industry opposes this law is that it gives California the ability to review and evaluate all individual past settlements between drug companies, not just new settlements, said panelist David Korn, vice president of Intellectual Property and Law with the Pharmaceutical Research and Manufacturers of America.

If other states join in with regulations of their own, the operational environment for pharmaceutical companies could become far too restrictive, he said. “This should be left up to Congress, because if you have multiple state-based frameworks, it could create a patchwork [of laws] that would be harder to comply with.”

Hessler said there’s potential that patent settlements between companies will be “stifled” by this legislation. “If you have that sort of impact, then you may see generic and biosimilar companies not as frequently challenging patents, which ultimately could result in higher rather than lower drug prices,” she said.

In addition, California Governor Gavin Newsom has until the end of this month to sign or veto AB 852, a bill that would enable the state to contract for the manufacture of generic and biosimilar drugs. One of the driving thoughts behind this bill is that “there has to be a more viable pathway for producing an affordable insulin,” Hessler said.

The legal and pharmaceutical industries are watching this bill closely, the panel said.

“There are certainly provisions in the bill that talk about sales to California payers, but I think the assumption is that (drugs) would be distributed potentially nationally,” Hessler said.

Panelists at American Conference Institute's (ACI) 2020 virtual summit discuss California's legislative attempts to improve competition in the drug industry. 

California's Anticompetitive Legislation Is Scrutinized at ACI

Recent clinical and real world evidence for Samsung Bioepis biosimilars for bevacizumab and trastuzumab support use of these products in place of the reference versions, David Planchard, MD, and Mark D. Pegram, MD, said at the European Society for Medical Oncology Congress Virtual 2020, in a review of study findings.

“People may know that biosimilars save money overall, but want to see that the data prove clinical similarity in a very controlled setting as well as in the real world,” said David Planchard, MD, of Institut Gustave Roussy (IGR) in Villejuif, France. Planchard serves as associate professor of medicine with the Thoracic Tumor Board at IGR.

The Samsung Bioepis bevacizumab biosimilar Aybintio (SB8) was approved in August for marketing by the European Commission. Samsung Bioepis’ trastuzumab biosimilar Ontruzant was launched in the United States in April.

Planchard noted that SB8 and the bevacizumab reference product (Avastin, BEV) have an “identical primary amino acid sequence and have demonstrated highly similar structural, physiochemical and biological properties.” A phase 3 trial randomized 763 patients with non–small cell lung cancer roughly equally to SB8 and BEV.

 Of those, 258 completed induction treatment with SB8 and 277 with BEV. The mean age of patients was 60.2 vs 60 in the respective arms.

In the full analysis set (FAS), equivalence was demonstrated in terms of best overall response rate (ORR) risk ratio and risk difference. The ORR in the FAS was 47.6% for SB8 vs 42.8% for BEV. In the per protocol set (PPS), the best ORR was 50.1% for SB8 vs 44.8% for BEV.

Median progression-free survival (PFS) in the FAS was 8.5 months for SB8 vs 7.9 months for BEV, and in PPS the median PFS was 8.5 months vs 7.9 months, respectively. Median overall survival (OS) in the FAS was 14.9 months vs 15.8 months, respectively; and in PPS, 14.8 months vs 15.8 months. Mean duration of response was 6.38 months vs 6.79 months, respectively, in the FAS; and 6.33 months vs 6.81 months in PPS.

Tumor burden change at 24-weeks from start of induction therapy in FAS was 0.6% (95% CI, –4.18% to 2.99%).

Overall responses also helped to demonstrate comparative efficacy in the trial arms. At cycle 2, there were 96 (28.5%) partial responses (PRs) in the SB8 group vs 88 (26.8%) in the BEV group; and stable disease was achieved by 202 (59.9%) and 201 (61.3%), respectively.

By cycle 6, the numbers were still close, demonstrating comparability. There were 97 (57.1%) and 83 (49.4%) PRs, respectively; and 60 (35.3%) and 70 (41.7%) SDs, Planchard said. At cycle 6, there was 1 (0.6%) complete response in the BEV group.

In terms of treatment emergent adverse events of special interest, proteinuria was observed in 2 instances in the SB8 arm (0.5%) and 7 patients (1.8%) in the BEV group. Hypertension was noted in 29 (7.7%) and 16 (4.2%) of each group, respectively.

Pharmacokinetic profiles also were highly comparable, Planchard said.

Pegram, director of the Breast Cancer Oncology Program at Stanford Women’s Cancer Center, Stanford University Cancer Institute, California, discussed real world data for biosimilar trastuzumab (SB3, Ontruzant) plus reference pertuzumab in early stage breast cancer.

He noted that a 56% pathological complete response rate (pCR) was noted in 215 Danish patients with HER2-positive breast cancer who received neoadjuvant chemotherapy plus SB3 plus pertuzumab, which he said was exactly comparable to historical trial evidence for the reference drug (Herceptin).

“Indeed, 68% of patients treated in the neoadjuvant setting with node-positive disease converted from lymph node–positive disease to lymph node–negative disease after treatment, so that’s also very reassuring and demonstrates the activity of this trastuzumab biosimilar when combined with pertuzumab,” he said.

In a separate study involving real-world outcomes of 35 patients from Austria with HER2-positive breast cancer who received chemotherapy plus SB3 plus pertuzumab, the safety and efficacy profile of SB3 plus pertuzumab was consistent with that of the reference product in that combination. Significantly, 22 patients treated in the neoadjuvant setting achieved a pCR of 50%; none of the 35 patients had a decline in left ventricular ejection fraction (LVEF) of more than 10%; and 2 patients had an LVEF decline of ≤ 5% after treatment. “This is also very reassuring in terms of cardiac safety signals,” Pegram said.

Importantly, Pegram said, “this recent real-world evidence supports the extrapolation of trastuzumab-dttb [SB3] to include combination [therapy] with pertuzumab.”

1. Planchard D, Pegram MD. Navigating the optimized oncology treatment options in colorectal cancer, lung cancer and breast cancer through multidisciplinary discussions: clinical evidences of biosimilars. Presented at: ESMO Congress Virtual 2020. 5389.

2. Reck M, Luft A, Bondarenko I, et al. A phase III randomized double-blind multicenter study to compare the efficacy, safety, pharmacokinetics, and immunogenicity between SB8 (proposed bevacizumab biosimilar) and reference bevacizumab in patients with metastatic or recurrent nonsquamous non-small cell lung cancer. Lung Cancer. 2020.

ESMO Virtual Congress 2020

Biosimilars from Samsung Bioepis have demonstrated equivalency in clinical trial and real world settings, according to 2 prominent cancer specialists. 

Planchard, Pegram Review Evidence for Samsung Bioepis Biosimilars

At the European Society for Medical Oncology (ESMO) Virtual Congress 2020 this week, detailed presentations will be 

biosimilar studies for agents from Mylan, Samsung Bioepis, and Shanghai Henlius Biotech.

Investigators plan to report phase 3 efficacy and safety data for Mylan’s proposed bevacizumab biosimilar MYL-14020 versus the reference product, Avastin, in the first-line treatment of patients with stage IV nonsquamous non–small cell lung cancer.

Investigators randomized 671 patients to the biosimilar candidate (n = 337) and Avastin (n = 334). In the preconference abstract, they reported that the confidence intervals for objective response rate (ORR) were within the predefined equivalence margins, demonstrating equivalence for MYL-14020.

 that the FDA had accepted its 351(k) filing application for MYL-14020. An application decision date was scheduled for December 27, 2020.

A poster on a randomized equivalence study for the Shanghai Henlius Biotech trastuzumab biosimilar (HLX02) also will be presented at ESMO. The multicenter study randomized women (N = 649) 1:1 to receive intravenous HLX02 or a European Union–marketed version of reference trastuzumab combined with docetaxel, with the primary end point being ORR at week 24.

In their preconference abstract, the investigators reported a 71.3% ORR for HLX02 vs 71.4% for the reference product. The group difference of 

7.0% to 6.9%) was “completely within the predefined equivalence margins of ±13.5%.”

In June, Henlius and Accord received a positive 

 for marketing approval for HLX02 from the European Medicines Agency.

Samsung Bioepis reported phase 3 exploratory 

 for its bevacizumab biosimilar (Aybintio) ahead of the scheduled ESMO poster presentation.

Positive results emerging on oncology biosimilars will be presented at the European Society for Medical Oncology Virtual Congress 2020 this week . 

Positive Equivalency Data for a Trio of Biosimilars Are Reported

positive phase 3 exploratory study results for its bevacizumab biosimilar, Aybintio, which received European Commission 

The findings are set for presentation at the European Society for Medical Oncology (ESMO) Virtual Congress 2020, which begins this week.

The Incheon, Republic of Korea–based company said the study results supported preexisting evidence in support of equivalence between Aybintio and reference bevacizumab in patients with metastatic or recurrent nonsquamous non–small cell lung cancer.

“The data observed in the phase 3 exploratory analyses reinforce equivalent clinical efficacy between Aybintio and reference bevacizumab,” said Seongwon Han, vice president and leader of the Medical & Lifecycle Safety Team at Samsung Bioepis.

The exploratory study enrolled 665 patients, of whom 337 received Aybintio and 328 were treated with reference bevacizumab with paclitaxel and carboplatin every 3 weeks for up to 6 cycles, followed by Aybintio or reference bevacizumab maintenance monotherapy. The risk difference was analyzed in the per-protocol set (PPS) within a predefined equivalence margin of ±12.5%.

The primary end point was overall response rate (ORR) after 24 weeks of induction therapy. In a previous analysis, the ORR in the PPS was 50.1% for Aybintio and 44.8% for reference bevacizumab, and the risk difference by week 24 was 5.3% (95% CI, 

2.2% to 12.9%). The risk difference is a comparative measure of the likely harms and benefits of therapies.

In the current study, the risk differences in best ORR by weeks 11 and 17 was 2.2% (95% CI, 

The mean reduction in tumor burden by week 24 was 

27.3% for reference bevacizumab, with a difference of 0.59% (

Samsung Bioepis said the results of the phase 3 exploratory analyses would be presented in an e-poster at ESMO during the virtual event’s Science Weekend on Thursday, September 17 at 9 AM Central European Summer Time.

Samsung Bioepis' bevacizumab biosimilar demonstrates equivalence in analyses to be presented at the European Society for Medical Oncology Virtual Congress 2020.

Samsung Bioepis Reports Positive Phase 3 Results for Aybintio

Biosimilar trastuzumab (Herzuma) in combination with pembrolizumab and chemotherapy was highly effective in reducing tumor size in patients with HER2-positive advanced gastric cancer, according to results of a phase 1b/2 clinical trial.

 trial was designed to evaluate the potential of the combination therapy in light of a growing body of evidence on the positive effects of monoclonal antibodies such as trastuzumab in treating solid tumors.The findings have implications for reducing the costs of care, the authors said.

“With the costs of oncology treatments being so burdensome, the availability of biosimilar trastuzumab could reduce the overall cost by combination treatment with innovative new drugs and chemotherapy,” said Sun Young Rha, MD, PhD, chief of medical oncology at Yonsei University College of Medicine and the lead investigator of the trial, during her presentation on the results at this year's virtual 2020 American Society of Clinical Oncology Annual Meeting.

Investigators in the Republic of Korea enrolled 43 patients and treated them with pembrolizumab (200 mg, day 1), biosimilar trastuzumab (6 mg/kg, day 1), capecitabine (1000 mg/m

 twice daily, days 1-14), and cisplatin (80 mg/m

The treatment duration ranged from 1.4 to 24 months, with a median follow up of 16.1 months. The trial enrolled 43 patients and 11 remained on the regimen.

Investigators found significant tumor shrinkage in 95.3% of patients, and the overall response rate was 76.7%. They said 16.3% of patients experienced a complete response and 60.5%, a partial response. Additionally, the median progression-free survival was 8.6 months (95% CI, 7.2-16.4), and the median overall survival (OS) was 19.3 months (95% CI, 16.5-NA). The investigators also found that positive status for the PD-L1 protein for patients at diagnosis did not significantly affect OS rates.

Treatment-related adverse events (AEs) ≥ grade 3 occurred in 32 (74.4%) patients, including 17 (39.5%) cases of grade 3 or grade 4 neutropenia. Immune-related AEs occurred in 4 (10%) patients. The most common hematologic AEs were decreased neutrophil count and anemia, which occurred in 46.5% and 32.6% of patients, respectively.

Herzuma, developed by Teva Pharmaceuticals USA and Celltrion Healthcare, is indicated for treatment in patients with HER2-positive metastatic breast cancer, early breast cancer, and metastatic gastric cancer.

It was approved for use in the United States in December 2018 and 

 in March 2020, making it the fourth trastuzumab biosimilar to be approved in the United States.

The drug was approved in the European Union in November of 2017 and 

 there in May 2018. Herzuma also is approved in the Republic of Korea, Japan, and Brazil.

Rha SY, Lee CK, Kim HS, et al. Targeting HER2 in combination with anti-PD-1 and chemotherapy confers a significant tumor shrinkage of gastric cancer: A multi-institutional phase Ib/II trial of first-line triplet regimen (pembrolizumab, trastuzumab, chemotherapy) for HER2-positive advanced gastric cancer (AGC). 

. 2020;38(suppl 15; abstract 3081). doi:10.1200/JCO.2020.38.15_suppl.3081

ASCO

A phase 1b/2 trial evaluating a trastuzumab biosimilar as part of a first-line triplet regimen demonstrated significant tumor shrinkage in HER2-positive advanced gastric cancer.

Biosimilar Trastuzumab Effective in Triplet Regimen for Gastric Cancer

What do UK patients think about the process and communication used to switch to adalimumab biosimilars by the National Health Service (NHS) and the local home care trusts?

 at the European Hematology Association (EHA)’s 25th Annual Congress, EHA25 Virtual, not very much.

, even before the results of the tender for adalimumab (reference product Humira) had taken place. The United Kingdom has made no secret of its hopes of significant cost savings on a switch to biosimilar adalimumab, aspiring to save £300 million (approximately US $386 million) of its £400 million (approximately US $514 million) annual spending on adalimumab as a result of using biosimilars.

In the UK setting, self-administered biologics are delivered to patients in their homes by commercial companies that are paid for by pooled funds from the pharmaceutical industry. Once a prescription is initiated by a hospital prescriber, nurses deliver the products and teach patients how to inject their therapy at home.

Nearly 2 years in, researchers sought patient feedback on the switch process with the intent of reporting findings to NHS England. In addition, they sought to give organizations representing rheumatology, dermatology, and gastroenterology patients information to develop any future resources to help improve shared decision making (SDM).

These organizations had worked with National Health Service (NHS) to produce the materials for disseminating information to prescribers and patients, and they now wanted to know how the process was implemented and if SDM was practiced.

A working group of 4 organizations created an online survey asking questions about:

How the individual was communicated with regarding their treatment being switched to a biosimilar

Was there any choice or perceived input into the decision making process

Overall satisfaction on how the individual felt their personal preferences/needs were met

The results demonstrate how challenging the switch process turned out to be.

899 useable responses, with patients identifying as 52% rheumatology, 42% gastroenterology, and 5% dermatology patients; the remaining 1% were “more complex specialties,” the researchers said.

More than half of patients were not asked for their consent before their treatment was switched to a biosimilar adalimumab, while 40% said they gave consent. A minority (7%) couldn’t remember or were unsure if consent was given.

Three-fourths were not at all satisfied or not satisfied with the ability to decline being switched. Just 12% felt that they had been given an option to refuse the switch.

SDM “needs to be put into action not just words,” concluded the authors, who represented the National Rheumatoid Arthritis Society, 1 of the 4 organizations that created the survey. The other organizations were the National Axial Spondyloarthritis Society UK; Crohns’ & Colitis UK; and the Psorarsis Association, UK.

They said they will continue to work with NHS and other stakeholders to make SDM “a reality not just rhetoric.”

EULAR

The UK results show how challenging switching to a biosimilar can be, according to patient groups.  

Looking Back, UK Patients Unhappy With Adalimumab Biosimilar Switch

Upon admission to hospital, patients who had been taking insulin degludec (iDeg) at home may receive inappropriate dosing when switched to another insulin, and this is because physicians tend to have a poor understanding of the pharmacodynamics (PD) and pharmacokinetics (PK) of iDeg, investigators concluded in a study presented at the American Diabetes Association 80th Scientific Sessions online conference.

Lead investigator Jing H Chao, MD, and Irl B. Hirsch, MD, observed widely variable practice in transitioning patients from iDeg to insulin glargine U100 (iG100) upon admission, but for various reasons, patients with type 1 diabetes were found to be at much higher risk of developing hypo- and hyperglycemia than patients with type 2 diabetes.

A key reason for the complexity of transitioning patients from iDeg to iG100 is that iDeg has a half life of 25 hours, more than twice that of iG100, meaning it remains in the body at higher concentrations for longer, up to 42 hours versus 24 for iG100, Chao explained. Hospital-based physicians may not understand this and give patients too much or too little iG100 to maintain insulin levels following home dosing. “Physicians should judiciously determine the amount of insulin to be given,” Chao said.

Part of the reason for the knowledge deficiency may be that iDeg, a Novo Nordisk product, was FDA approved just 5 years ago. An advantage of IDeg is that it enables physicians to achieve a more stable background level of insulin in the body relative to insulin glargine, which “waxes and wanes,” Chao said.

So, when switching to iG100 upon admission, it is important to take into account the different rate at which iDeg is excreted from the body. “By the 24th hour, there is still 50% of the background degludec on board. By contrast, when you have glargine, most of the glargine has already been washed out,” Chao said. “If patients were to receive a 100% glargine dose at the 24-hour mark, that would raise their basal [or background] insulin to 150% of the basal insulin that’s on board at that point.”

In the study, Chao and Hirsch noted that clinicians gave iG100 at 0% to 100% of the home-based iDeg dose anytime between 24 hours and 72 hours after the last iDeg dose, “demonstrating a general lack of understanding of the PK and PD of iDeg and a great need to standardize this transition.”

“Physicians are giving 100% of the glargine at the 24th hour, leading to over-basalization of the insulin,” she said.  Excessive insulin can lead to hypoglycemia and, consequently, altered mental status and potential cardiovascular events, including heart attack.

“Not only do physicians vary the time at which they give the first dose of glargine, they also vary the amount of the glargine they give as compared to the home dose. That part was not surprising to us,” Chao said.

“What is surprising to us is that despite such variable practice, we did not see hypoglycemia in patients with type 2 diabetes, and the reason is that compared with type 1 diabetes, patients with type 2 diabetes have a better buffer in that they continue to secrete a small amount of insulin and continue to secrete some glucagon. These are countering hormones that buffer them and help prevent them from getting hypoglycemia as much as patients with type 1 diabetes,” she said.

Mild hypoglycemia was observed in 2 patients with type 1 diabetes, or 28.6%. there were no cases of hypoglycemia in the type 2 group (n = 32).

Another factor to consider is that patients when admitted tend to be under higher levels of physiologic stress, which causes them to require increased amounts of insulin. So, the tendency on the part of physicians to provide too much iG100 is counterbalanced by the body’s need at this point for more insulin than usual, Chao said. “For these reasons we don’t see hypoglycemia in patients with type 2 diabetes.”

“We found that, to counter the amount of stress-induced hyperglycemia, when patient receives 50% to 75% of the glargine at the 24-hour mark, which leads to total of 100% to 125% background basal insulin level at that time, their blood sugar is actually better controlled,” she said.

“If you give anything up to 49%, that gives them less than their home dose, and is insufficient to cover their basal insulin requirement during a stressful hospitalization.”

Chao and Hirsch are hoping that their study prompts physicians to think more carefully about the PD and PK of iDeg and carefully assess other factors when determining follow-up dosing, such as meals taken, stress from hospitalization, renal function, and whether patients were on a sufficient home dose of insulin to begin with. Renal considerations are key with iDec, because it is not excreted via the kidneys.

The investigators also would like to see further studies conducted, leading to the development of guidelines.

“We’re hoping that prospective trials can be conducted to take a better look at the transition to determine the recommendations on how much insulin glargine to give at what point of their patients’ hospitalization that will ensure patients safety during this complicated transition,” Chao said.

For more about insulin degludec, see these stories about 

Chao JH, Hirsch IB. degludec-to-glargine transition: the first real-world study. Poster presented at: American Diabetes Association 80th Scientific Sessions; June 12-16, 2020. Poster 1025-P.

There is much inconsistency in the way physicians transition patients from insulin degludec to insulin glargine upon hospital admission, leading to higher risk especially for patients with type 1 diabetes, according to a study presented at the American Diabetes Association 80th Scientific Sessions online conference.
 

Doctors Manage Insulin Degludec-to-Glargine Transition Poorly, ADA Study Says

Hi, I’m Skylar Jeremias for The Center for Biosimilars®, your resource for clinical, regulatory, business, and policy news in the rapidly changing world of biosimilars.

The European Hematology Association recently held its 25th Annual Congress, EHA25 Virtual, from June 11 through June 21. The meeting was conducted on a digital platform due to the coronavirus disease 2019 (COVID-19) pandemic and featured some key study findings and presentations on the up-and-coming world of hematology biosimilars.

The following is a summary of our biosimilar coverage from this event:

Investigators produced what they described as the 

 the use of biosimilar erythropoiesis-stimulating agents (ESAs) in patients with myelofibrosis (MF)-related anemia.

Investigators said ESAs are used to manage anemia in hematological malignancies, but scarce evidence exists for the use of these agents in the treatment of MF, and available results are divergent: Response rates range from 23% to 69%, according to the abstract presented at EHA25 Virtual. Until this study, there were no data on the use of biosimilar ESAs in this setting, investigators said.

Investigators reported an 88% overall response rate for a Sandoz rituximab biosimilar in combination with chemotherapy in patients with CD20-positive diffuse large B-cell lymphoma. At the end of treatment, the complete response was 57% and partial response was 31%. Investigators said 61% and 29% of patients experienced enlarged lymph nodes and disease-related pain, respectively.

 presented this month at EHA25 Virtual confirmed findings from the REFLECT study released in 2019, which was the first prospective postapproval study to evaluate a rituximab biosimilar in this context.

 that a rituximab biosimilar developed by Celltrion Healthcare (Truxima) in combination with lenalidomide and acalabrutinib (R2A) in patients with relapsed or refractory aggressive B-cell lymphoma was tolerable and effective.

The addition of rituximab, a targeted therapy, to chemotherapy agents can improve patient outcomes but adds to the financial burden of treatment. Investigators said that exploring the use of biosimilar rituximab may be an avenue to bring down costs.

To read all of these articles, visit our EHA 

Videos

EHA is the annual meetting for the European Hematology Association.

Here is a summary of our coverage from EHA25 Virtual, the annual meeting for the European Hematology Association (EHA).

Latest Conference Articles