Biosimilars Research

As one of Canada’s leading patient voices on biosimilars, ACE continues to monitor their ongoing research and development to provide patients the latest, unbiased, evidence-based information on this medication treatment for inflammatory arthritis.

Latest news on biosimilars

2017
Biosimilars – a major focus at EULAR 2017

More trial findings and updated analysis, real world reporting as well as patient education programs on biosimilars were key areas of research presentations at this year’s European League Against Rheumatism (EULAR) Congress.

At the meeting, ACE heard that more than 20 biosimilars have now been released to treat inflammatory arthritis. The big news is that there are now more than 700 biosimilars under development in the global pharmaceutical industry to treat numerous chronic diseases and cancer. For arthritis patients, here are some of the highlights from EULAR 2017:

Immunogenicity studies show comparable results between biosimilars and originator biologics

Background

Immunogenicity is the ability to stimulate an immune response in the body of a human or animal. This ability generally protects people against pathogens by recognizing and reacting to foreign proteins. It is a specific concern for biologic medications because they are primarily protein medicines that may be seen as being foreign. An immune response to a biologic medication can range from development of detectable but not clinically significant antibodies to an immune response with significant impact on patient safety. A patient's immune response may also affect a treatment's effectiveness.

Immunogenicity data from NOR-SWITCH study

Additional immunogenicity data from NOR-SWITCH study, the first randomized trial of transitioning from an originator biologic to its biosimilar, was presented at EULAR 2017 by Norwegian researchers who led the NOR-SWITCH study. The researchers found there was similar frequency of adverse events in patients transitioned from the infliximab originator (Remicade®) to the infliximab biosimilar Remsima® (approved as Inflectra® in Canada). Based on the researchers’ findings, patients doing well on infliximab (Remicade®) who were transitioned to infliximab biosimilar Remsima® reported similar frequencies of adverse events, including infusion reactions, and experienced no substantial change in anti-drug antibody (ADAb) levels compared with those remaining on infliximab (Remicade®).

Why this matters

These results from the ongoing NOR-SWITCH study show there are no concerns about transitioning patients with rheumatoid arthritis from infliximab (Remicade®) to its biosimilar Remsima® (Inflectra® in Canada).

Other studies on immunogenicity

Also at the EULAR 2017 Congress, studies showed that two biosimilar tumor necrosis factor inhibitor (TNFi) medications are no more immunogenic than their originator biologic in patients with rheumatoid arthritis.

Results of one of those studies, which involved 544 RA patients, showed 33.1% treated with SB5, a biosimilar candidate for adalimumab (Humira®), and 32% of those who were treated with adalimumab (Humira®) developed antidrug antibodies (ADAbs) after 24 weeks’ treatment.

“These findings further support the biosimilarity of SB5 to adalimumab (Humira®),” said study investigator Jonathan Kay, MD, director of clinical research, rheumatology at the University of Massachusetts Memorial Medical Center in Worcester and professor of medicine at the University of Massachusetts.

In the other study, which involved 596 RA patients, significantly fewer treated with SB4, a biosimilar candidate for etanercept (Enbrel®) developed ADAbs versus etanercept (Enbrel®) (0.7% vs. 13.1%, P less than .001).

Jirí Vencovský, MD, who presented the findings of the study with the biosimilar etanercept, made similar observations as Dr. Kay, regarding the effect of ADAbs on efficacy.

“Efficacy tended to be lower in patients with ADAbs,” said Dr. Vencovský, who is vice-director of the Institute of Rheumatology, Charles University in Prague, Czech Republic.

Using the American College of Rheumatology (ACR) Criteria, which are a standard criteria set to measure the effectiveness of arthritis medications in clinical trials, Dr. Vencovský saw no differences between the patients who received biosimilar etanercept or originator biologic etanercept (Enbrel®) for both the ACR50 and ACR70 responses after 24 weeks of treatment.

Transition results surprise Danish researchers

Denmark became the first country in Europe to introduce a policy transition (i.e. a transition also known as “non-medical switching” that necessitates patients to change their medicine of choice to another, typically less expensive, medicine, not for a medical reason) for rheumatoid arthritis patients doing well or “stable” on originator biologic infliximab (Remicade®) that mandates them to be transitioned to the biosimilar infliximab (Remsima®). There was concern that an increase in the use of healthcare resources, because of patient and physician anxiety about the new class of agents, would offset the cost savings, but a study presented at EULAR 2017 showed that that offset did not happen.

"This was the first nonmedical switch (policy transition) that happened," said Bente Glintborg, MD, PhD, from the Copenhagen Center for Arthritis Research and the DANBIO registry. Speaking at the EULAR 2017 Congress, Dr. Glintbord added: "Patients were anxious, physicians were anxious, and the patient societies were anxious. I expected some worrying, and that the patients would call and come in a lot.”

Background

When the first biosimilar was approved in Denmark in 2015, the country’s national council for the use of expensive hospital medicines announced that they found the biosimilar infliximab (Remsima®) equal to the originator biologic (Remicade®) in efficacy and safety. Based on this, the council made a recommendation for hospitals to use the less expensive (64% lower) infliximab biosimilar for both treatment-naïve patients and patients already on infliximab (Remicade®), unless there were medically justified reasons not to do so. By the first quarter of 2016, this biosimilar covered around 97% of infliximab consumption in Denmark. There are now two biosimilars of originator biologic infliximab approved by the national authorities in Denmark, and used in the treatment of patients with arthritis.

What did the study find?

In their study, Dr. Glintborg and her colleagues assessed total healthcare services used and the number of days with healthcare services used in the 6 months before and the 6 months after the policy transition.

During the 12-month study period, 1484 outpatient visits were made by 769 patients with rheumatologic inflammatory diseases. In total, 19,752 individual services were provided, and about 10% of those were on the transition date.

And of the 9243 days on which at least one service was provided, 693 — or approximately 7% — occurred on the transition date. There was a slight increase in the mean number of days with services from before the transition to after (5.4 vs 5.7; P = .0003).

"We found that there were some significant differences in higher use after than before," Dr. Glintborg explained, "but the numbers were very similar." The difference was statistically significant because of the large number of patients, "but not clinically meaningful."

"I was surprised, actually. I had expected a higher use of services after," she added. "These patients were well treated for almost seven years with the originator biologic, so of course they were worried. It's another drug from another company with a different name."

Differences between the two time periods were not significant for services related to nursing activity, methotrexate treatment, blood pressure measurement, conventional synthetic disease-modifying antirheumatic drugs (DMARDs), venous needle, conversation about treatment, ultrasound over extremity joint, or ultrasound under extremity joint.

"This analysis showed that there were only small differences in the rate of days with outpatient services and rates of services 6 months before and after the switch from original to biosimilar infliximab," the researchers write in their abstract. "Thus, it is unlikely that the switch is associated with substantially higher cost of healthcare resources."

"The clinical significance of the findings is that the services used before and after switching to a biosimilar from a bio-originator were not different," said Désirée van der Heijde, MD, from the Leiden University Medical Center in the Netherlands.

What it means for Canada

These data, and the experience of thousands of patients on biosimilars in Europe over the past 10 years should assure inflammatory arthritis (IA) patients in Canada that policy transitions are in fact safe, effective and cost effective. ACE believes these savings should mean more inflammatory arthritis patients will be provided reimbursement access to biosimilars and new therapies for IA will be added to public and private formularies in a timely manner. That is equity in treatment.

Educating patients about biosimilars: Best practice spotlight

One of the benefits for ACE in attending world leading scientific meetings is the opportunity to meet representatives from other arthritis patient organizations and share experiences, perspectives and best practices. At this year’s EULAR Congress, for example, ACE held meetings with the Danish Rheumatism Association (DRA), a non-governmental organization with an 80,000-person membership. The DRA were at the meeting to present its patient biosimilar education experience based on participation in a national program for patients that guide the way for future best practices for the Canadian arthritis community.

Identifying patient concerns about biosimilars

The Danish government’s decision to transition patients to a biosimilars was based on its reasoning that this policy would save money for the healthcare system, while ensuring the same benefits for patients. However, this decision caused considerable insecurity among Danish patients, who were reluctant to transition from more familiar originator biologics to less expensive biosimilars. According to an initial small study by the DRA of how this transition from biologic to biosimilar had taken place in different regions, many Danish patients felt anxious about the policy transition based on several factors, including:

  • Concerns about the safety and efficacy of biosimilars
  • Physicians’ discomfort with explaining the concept of biosimilarity to patients
  • The varying and different information on biosimilars posted on Danish healthcare websites
  • The fact that the national database of patients receiving biological treatments did not monitor drugs by batch, leading to concerns about biosimilar monitoring

Even when clinicians shared data pointing to the clinical equivalence of a new biosimilar, many patients remained unhappy. They understood the economic reasons for the switch, but didn't like the element of surprise, their lack of involvement in the decision, or the relatively short amount of time they were given to process the change. The Danish government required everyone to switch within a 2-month period, so there was limited time for patients to get their questions answered.

What was done to address patient concerns

To address the fear and insecurity over being transitioned from a biologic to a biosimilar treatment for their arthritis, the program was designed to ensure patients received independent information about biosimilars, along with closer monitoring of prescriptions to provide reassurance about their safety.

"In order to change this situation, we started a dialogue with politicians and the authorities on a national level and hospital administrations on a regional level," said Ms. Lene Mandrup Thomsen from the Danish Rheumatism Association. "The purpose was threefold: to improve the registration of biologics and biosimilars on a batch-level, the provision of more independent patient information and the involvement of patients in the decision-making process," she explained.

Engaging with politicians, medical authorities, and hospital administrations, the DRA plan, launched in August 2015 and completed at the end of 2016, consisted of four parts:

1) Monitoring efficacy and safety of biologics and biosimilars on a batch level
2) Information campaign targeting both health professionals and patients
3) Digital solutions to aid easy reporting of side effects from health professionals and patients
4) Focus on monitoring patient safety by the authorities

In addition to this national plan, hospitals on a regional level have invited a representative from the DRA to participate in a working group, with the objective of including the patient perspective in future national recommendations concerning originator biologics, biosimilars and transitioning.

Why this matters for Canadian policy makers and patients

The Canadian healthcare system differs significantly from the government-sponsored, single payer, Danish system, in which patients could be made to transition unless a medically justified reason prevented treatment with a biosimilar. In Canada, patients living with inflammatory arthritis may have more say in their own treatment options and the right to ask for and expect the best care possible through shared decision-making between themselves, their rheumatologist and other healthcare providers. ACE believes patients should be fully informed about policy decisions transitioning them to a biosimilar. They should be able to assess treatment (or no treatment) risk against benefit, and have tools to enable them to discuss the pros and cons of all treatments with their healthcare team.

We also encourage both public and private payers, who are considering policy transitioning, to consider the DRA’s example in advocating for and making more accessible greater education and safety monitoring as a means of alleviating any concerns Canadian patients may have about biosimilars. 


New research on biosimilars shows comparable safety and efficacy 
 

The latest research on inflammatory types of arthritis, osteoarthritis, and other hot topics in rheumatology was presented to 17,000 North American and international participants, including rheumatologists, patients, allied health professionals, and industry partners from over 100 countries who attended the American College of Rheumatology (ACR) 2016 Annual Scientific Meeting in Washington, DC. Arthritis Consumer Experts (ACE) attended oral and poster presentations of dozens of studies, including those focused on biosimilars compared to their originator biologic. Here are some of the highlights:

Norway’s NOR-SWITCH study

Data from the first randomized trial of switching from an originator biologic to a biosimilar of the originator was presented at the ACR Annual Meeting by Norwegian researchers who led the NOR-SWITCH study.[1] The researchers found there were no differences in disease worsening between patients who were switched from the infliximab originator (Remicade) to the infliximab biosimilar Remsima (approved as Inflectra in Canada). Based on the researchers’ findings, disease worsening occurred in 26.2% of patients who stayed on infliximab (Remicade) and 29.6% of patients who switched to infliximab (Remsima).

Lead author Guro L. Goll, MD, a rheumatologist at Diakonhjemmet Hospital in Oslo, said: “I do think that the NOR-SWITCH study helps to build confidence in biosimilars as a concept, and I do think that our study supports that you can safely switch your infliximab originator Remicade patients to infliximab biosimilar Remsima even though we have not answered all questions, such as the multiple switching issue, and it would be nice to do further studies in gastroenterology patients as well.”

One primary question remains around the use of biosimilars:

  • What happens to people’s immune systems when they make multiple transitions from originator biologic to its biosimilar, and then to another originator biologic or biosimilar with a different mechanism of action?

This question and others are traditionally answered after a medication receives its Health Canada approval and is monitored once in wide use in the approved patient population. Questions about safety, effectiveness, therapy persistence (how long a patient stays on the medication) and immune responses remain even for originator biologics, though some have been in use for 15 years and in thousands of patients worldwide and new research continues to be reported at the scientific meetings.

In media interviews from the ACR annual meeting, Cheryl Koehn, President and Founder of Arthritis Consumer Experts, was one of several voices calling for the real need for real world data collection of the outcomes of transitioning back and forth between infliximab (Remicade) and infliximab (Inflectra), transitioning from one infliximab biosimilar to another infliximab biosimilar, and transitioning from other originator biologics to their biosimilars.

“In speaking to our Canadian rheumatology colleagues attending the ACR, we learned that there is growing confidence in the safety and efficacy of biosimilars, the newest class of biologics to come to market” said Koehn. “They, like ACE, are closely watching both the emerging clinical trial and real world data. Deciphering real world research results and understanding the impact biosimilars may – or may not – have on one, a few or thousands of patients is vitally important. I remember when originator biologics first came onto the market,” said Koehn. “Patients were leery to take them even though their disease was ruining their health and their lives. But one by one, patients around the world grew confident in biologic therapy and started to take them, and for so many, their lives were transformed.”

“And the end of the day, scientists, rheumatologists and patients are looking for the same thing: Enough proof that a patient’s chance of responding to a biosimilar is high, and that their chance of the biosimilar losing its effectiveness or causing a rare but significant side effect is very low. The NOR-SWITCH trial offers some of that proof. But not all.”

[1] Tore K. Kvien, Guro Lovik Goll, et. al., “Biosimilar Infliximab (CT-P13) Is Not Inferior to Originator Infliximab: Results from a 52-Week Randomized Switch Trial in Norway,” 2016 ACR/ARHP Annual Meeting. Abstract Number: 19L


Results of Danish study of infliximab biosimilar

Presenting findings at the ACR Annual Meeting from an observational Danish trial of infliximab biosimilar Remsima (known as Inflectra in Canada) larger than the NOR-SWITCH study, investigator Merete Lund Hetland, MD, from Copenhagen University Hospital in Hvidovre, Denmark, said the results were "extremely similar." [2]

Dr. Hetland and her colleagues used the DANBIO registry to identify 802 patients — 279 with spondyloarthritis, 403 with rheumatoid arthritis, and 120 with psoriatic arthritis — who received the infliximab biosimilar as part of a nationwide mandated switch. The study team compared disease activity and flares 3 months before and 3 months after the switch and found no significant changes for any of the three diseases. Adherence rates at 1 year were similar for each disease, and the 16% non-adherence rate was similar to historic non-adherence rates with the infliximab originator.

It is important to note that both researchers from the NOR-SWITCH and DANBIO studies cautioned that the results for the infliximab biosimilar should not be extrapolated to biosimilars for etanercept or adalimumab.

"They are completely different molecules and we cannot know it will be the same story," said Dr. Hetland.

[2] Bente Glintborg, et. al., “Non-Medical Switch from Originator to Biosimilar Infliximab in Patients with Inflammatory Arthritis – Impact on s-Infliximab and Antidrug-Antibodies. Results from the Danish Rheumatologic Biobank and the Danbio Registry,”  2016 ACR/ARHP Annual Meeting. Abstract Number: 1997


What is real world data?

There are many, varied definitions of “real world data” (RWD). Essentially, RWD is a measurement of the efficacy of a medication after it receives approval by Health Canada, when prescribed and used in a practical, real-life settings that go beyond what is normally collected in pre-approval clinical trials and studies. RWD comes from various sources and includes patient data, data from clinicians, hospital data, data from payers and social data. Through its use alongside traditional data sources (such as clinical trials), RWD has the potential to provide new insights into medicines and their effects in the context of different larger patient populations.

In the context of biosimilars, tracking the efficacy, safety and value to patients and the health care system of both originator biologics and their biosimilars is important. Patients and their physicians rely on this “real world data” when they are discussing and making treatment decisions.

Currently, there are a number of ongoing biosimilar studies, including “real world” tracking of patients, to monitor for any increase in immunogenicity when transitioning from an originator biologic to a biosimilar. This will help determine if transitioning patients can be considered a safe practice before it can be medically recommended or mandated through reimbursement policy.

When you are having a conversation about biosimilars as a treatment option with your healthcare professional or payer, ask them about these important real world data discussion points:

  • What has been your experience with prescribing biosimilars?
  • Are you satisfied they are a safe and effective treatment option for me? Why?
  • Does the biosimilar you are recommending to me have a patient support program?
  • Where can I find reliable, easy-to-read information on biosimilars?
Assessing safety, efficacy of transitioning from originator biologic to biosimilar

A study summarizing the current literature presented at the 2016 ACR Annual Meeting has concluded transitioning from an originator biologic to a biosimilar for rheumatic diseases results in similar efficacy and safety data. [3]

With more biosimilars scheduled to enter the market in 2017 and beyond, clinical and real world data on the effects of transitioning are limited to transition studies of approved biosimilars. To address this gap in understanding the transitioning process – both originator to biosimilar and between biosimilars – Robert J. Moots, MB, BS, PhD, department of musculoskeletal biology, University of Liverpool and colleagues searched MEDLINE/Web of Science to identify studies where healthy volunteers or patients receiving infliximab, etanercept, adalimumab, or rituximab transitioned from originator biologics to their biosimilars.

In his conclusion, Dr. Moots said: “While initial transition data confirm maintenance of efficacy and safety, additional data from clinical and real world switching studies, especially switching between biosimilars, are required, as is continuing pharmacovigilance.” He added: “Any switching should remain a clinical decision made jointly by the treating physician and patient on an individual patient basis supported by scientific evidence.”

[3] Robert Moots, et. al. “Switching to Biosimilars in Rheumatology Evidence-Based Practice,” 2016 ACR/AHRP Annual Meeting. Abstract Number: 639


Influences on patient attitudes towards biosimilars in Germany

Based on a survey of patients taking biosimilars and originator biologic patients in Germany (“Patient Attitudes Towards Being Prescribed Biosimilars in Inflammatory Autoimmune Diseases in Germany”), study authors found patients need a greater understanding of why they were prescribed biosimilars for rheumatoid arthritis, axial spondyloarthritis and psoriatic arthritis.[4]

Of 174 biosimilar patients, 78% were satisfied their disease was under control, compared to 85% of 87 patients receiving originator biologics. Biosimilar patients demonstrated lower understanding of their treatment with 39% stating they didn’t know enough about the medication when they started taking their treatment compared to 28% for patients receiving originator biologics. Patients’ lack of understanding of biosimilars was also found as 42% didn’t know their medication was based on an alternative originator product. Biosimilar patients who had not previously received an originator biologic (also referred to as biologic naïve patients) stated the most common reasons they accepted biosimilars was cost (30%) and physician’s recommendations (30%). Those patients who transitioned from an originator biologic to a biosimilar accepted the change due to their doctor’s recommendations (73%) and cost or insurance reasons (43%).

Commenting on the study’s real world finding of the lack of understanding surrounding patient attitudes to being prescribed biosimilars by their physicians, Cheryl Koehn said: “This study underlines the information gap and need for patient education on biosimilars. That is what led ACE to launch its Biosim•Exchange in September 2016. With research-based information and education, patients can have a full therapy conversation with their rheumatologist (or other arthritis specialist) to best decide on their choice of medication, including originator biologics and biosimilars.”

[4] James Piercy, et. al. “Patient Attitude Towards Being Prescribed Biosimilars in Inflammatory Autoimmune Diseases in Germany,” 2016 ACR/AHRP Annual Meeting. Abstract Number: 1428


2016
EULAR Annual Scientific Meetings

One of the “hot topics” at the 2016 American College of Rheumatology Annual Meeting and European League Against Rheumatism (EULAR) Annual European Congress of Rheumatology was biosimilars. Based on the research presented, biosimilars offer patients and rheumatologists another choice in the treatment of inflammatory arthritis.

Biosimilars data from abstracts published or presented at the annual EULAR Annual European Congress of Rheumatology meeting in London in June 2016 show that the safety and efficacy profiles for biosimilar versions of etanercept, infliximab and adalimumab were similar to the originator biologic in rheumatoid arthritis and ankylosing spondylitis patients who were transitioned from the originator biologic to the biosimilar version.

However, another study at EULAR showed that when antibodies develop in response to the biological treatment Infliximab (Remicade), they cross-reacted with the biosimilar of infliximab (Inflectra). The study’s lead authour said: “Our results have shown that all the antibodies that developed in patients being treated with Remicade cross-reacted with the biosimilar. The presence of these anti-infliximab antibodies is likely to enhance clearance of the drug from the body, potentially leading to a loss of response, as well as increasing the risk of side effects. Therefore, in patients where biological infliximab is ineffective due to the presence of circulating antibodies, switching to its biosimilar will lead to the same problems.” 

Due to limited sample size of patients and the need for further research to better understand the potentially different immune responses in arthritis patients, this study represents early stage research in the area of “switching” or “transitioning” patients from originator biologic to biosimilar. 


Post Marketing Surveillance Research
Tracking the efficacy, safety and value to patients and the health care system of both originator biologics and their biosimilars is important. Patients and their physicians rely on this "real world data" when they are making treatment decisions.

In August 2016, the Annals of Internal Medicine published a study by researchers at Johns Hopkins University and Brigham and Women’s Hospital that evaluated a series of biosimilar studies that treat inflammation for patients with rheumatoid arthritis and inflammatory bowel syndrome, called TNF-alpha inhibitors. The researchers systematically reviewed 19 studies to determine how these biosimilars compared with the originator biologics, focusing on safety and efficacy. They concluded the biosimilars are “biosimilar” and “interchangeable” with the original versions, such as infliximab (Remicade) and adalimumab (Humira).

Earlier in 2016, commenting on the Food and Drug Administration announcement on April 5, 2016 of the approval of infliximab (Inflectra), the first biosimilar to receive approval in the U.S. for the treatment of inflammatory arthritis, Joan Von Feldt, MD, MSEd, President of the American College of Rheumatology said: “The safe adoption of biosimilars into the U.S. marketplace remains a top priority for the American College of Rheumatology. Biologics are a lifeline for patients living with rheumatic disease, helping many to avoid pain, long-term disability, and life-threatening complications. Unfortunately, many of our patients struggle to afford these complex therapies due to their high cost. The ACR welcomes the introduction of biosimilars to the U.S. healthcare system and is hopeful that the decrease in cost resulting from the availability of safe and effective biosimilars in the U.S. will increase our patients’ access to life-changing therapies and improve their overall health."

Learn more about biosimilars research

To stay informed, go to these sources and use the search function for “biosimilars” for the latest research in North America and Europe:

American College of Rheumatology

http://www.rheumatology.org

The European League Against Rheumatism

http://www.eular.org

PubMed (National Center for Biotechnology Information)

http://www.ncbi.nlm.nih.gov/pubmed/

Patient Views

Research and development of biosimilars medications is happening around the world at a rapid pace. Based on current research, what topics interest you the most?