Cameron Santoro is an associate editor for The Center for Biosimilars

Cameron Santoro

Patients with rheumatoid arthritis (RA) who switched from the etanercept originator to a biosimilar had similar disease activity and drug persistence as those who remained on the originator, indicating that nonmedical switching does not negatively impact treatment outcomes, according to a Danish study.

, investigated clinical outcomes associated with switching between etanercept products. Patients were monitored for changes in 28-joint disease activity scores (DAS28) at 6 and 12 months.

Although FDA and European Medicines Agency approval of a biosimilar confirms the safety and efficacy of the product in comparison with its originator in a particular patient population, switching studies can provide additional context into the safety of moving a patient off of the originator and putting them on a biosimilar. | Image credit: AI generated using Dall-E3

Reference etanercept, marketed as Enbrel, has been on the European market since 2000, making it one of the first tumor necrosis (TNF) inhibitors to be approved in the European Union for the treatment of RA.

 The prevalence percentages of RA in the US and Northern European countries are typically higher than the worldwide prevalence percentage (0.5%-1.0% vs 0.24%).

 The annual incidence of RA in the US and Northern Europe is estimated to be about 40 per 100,000 persons.

After the patent for the Enbrel expired in 2015, biosimilar versions were introduced, leading to many patients being switched from the originator to the biosimilar for cost-saving reasons. While small studies on other TNF inhibitors have shown mixed results regarding treatment discontinuation and the nocebo effect, there is limited research comparing patients who switch from the etanercept originator to a biosimilar with those who do not. The present analysis aimed to address this gap by investigating drug survival and disease activity in RA patients after switching from the originator to the biosimilar.

The study was conducted using data from the British Society for Rheumatology Biologics Register for RA (BSRBR-RA), an observational prospective cohort that tracks patients with RA who start biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs).

Patients were matched based on factors such as gender, age, and disease duration. Data on disease activity and drug persistence were collected at the time of switching, as well as 6 and 12 months afterward. Statistical methods were used to assess drug survival, while logistic regression and multiple imputation were employed to analyze changes in disease activity. Sensitivity analyses were also conducted to ensure the robustness of the findings.

In this study, 1024 patients who switched from etanercept originator to a biosimilar were matched 1:1 with patients who remained on the originator. At the point of switching (or the index date for the originator cohort), both groups were similar in age (median, 64 years), gender (female, 76%), and disease duration (median, 19 years). Most patients (71% in the biosimilar cohort and 69% in the originator cohort) had initiated etanercept as their first-line b/tsDMARD therapy. The median time on the originator before switching was 9.3 years for the biosimilar cohort and 9.6 years for the originator cohort. The biosimilar group had a slightly longer median follow-up after the switch (2.7 years) compared to the originator group (2.2 years).

Kaplan-Meier estimates showed that 81% of biosimilar patients and 84% of originator patients remained on treatment after 1 year, 72% and 74% remained on treatment at 2 years, and 65% and 65% remained on treatment at 3 years, respectively. The HR for discontinuation was 1.06 (95% CI, 0.89-1.26), indicating no significant difference between the groups.

In the originator cohort, 326 patients (32%) switched to a biosimilar during the follow-up period, while 205 patients (20%) stopped etanercept treatment altogether. In the biosimilar cohort, 346 patients (34%) discontinued therapy, with 127 of these patients (37%) switching back to the originator, and 95 of them (9% of the entire biosimilar group) doing so within the first year. Most biosimilar patients stopped treatment due to ineffectiveness (n = 161), with 42% switching back to the originator and 55% changing to another b/tsDMARD. Among those who stopped due to adverse events (n = 96), 48% remained off b/tsDMARD therapy at their last follow-up.

For the 505 patients in each cohort with available disease activity data, disease activity at the index date was low and similar across both groups. The median tender joint count was 1, the median C-reactive protein level was 5 mg/L, and the median DAS28 score was 2.9. After 6 months, disease activity remained stable, with no significant differences between the cohorts.

The median DAS28 was 3.1 in the biosimilar group and 2.8 in the originator group, with no median change in DAS28. The proportion of patients in DAS28 remission was 34% in the biosimilar group and 42% in the originator group. At 1 year, the median DAS28 was 2.8 for the biosimilar cohort and 3.0 for the originator cohort, with 42% and 38% in remission, respectively. Additionally, 36% of the biosimilar patients and 31% of the originator cohort experienced an improvement in DAS28 by more than 0.6 units.

Similar results were observed when the analysis was restricted to patients who started etanercept as their first b/tsDMARD therapy.

1. Kearsley-Fleet L, Rokad A, Tsoi M-F, et al. Outcomes following switching from etanercept originator to etanercept biosimilar in 1024 patients with RA: a matched-analysis of the BSRBR-RA. 

. 2024;63(8):2082-2092. doi:10.1093/rheumatology/kead470

2. Hassett B, Singh E, Mahgoub E, O’Brien J, Vicik SM, Fitzpatrick B. Manufacturing history of etanercept (Enbrel): consistency of product quality through major process revisions. 

. 2018;10(1):159-165. doi:10.1080/19420862.2017.1388483

3. England BR, Mikuls TR. Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis. UpToDate. Updated February 19, 2024. Accessed August 20, 2024. 

https://www.uptodate.com/contents/epidemiology-of-risk-factors-for-and-possible-causes-of-rheumatoid-arthritis#:~:text=Estimates%20of%20RA%20prevalence%20in,persons%20%5B2%2C4%5D

Articles

Patients with rheumatoid arthritis who switched from the etanercept originator to a biosimilar exhibited similar disease activity and drug persistence compared with those who remained on the originator, indicating that nonmedical switching does not negatively impact treatment outcomes.

Switching From Originator Etanercept to Biosimilar Version Proves Safe, Effective in RA

In an interview with The Center for Biosimilars

, Jeffrey Casberg, senior vice president of pharmacy at IPD Analytics, discussed key products facing upcoming generic and biosimilar competition. He highlighted the importance of monitoring ustekinumab biosimilars, which are set to launch in early 2025, and aflibercept biosimilars, which may be delayed until 2025 or later. Casberg also addressed the impact of the Inflation Reduction Act (IRA) and pharmacy benefit manager (PBM) legislation on drug pricing, predicting increased transparency and changes in benefit designs.

He touched on the potential of value-based pricing models, suggesting they may offer opportunities, particularly for high-cost therapies, but are unlikely to become the dominant pricing strategy. Casberg identified three promising specialty drugs: donanemab for Alzheimer disease, resmetirom for nonalcoholic steatohepatitis, and Winrevair for pulmonary arterial hypertension.

Regarding the FDA approval of denosumab and tocilizumab biosimilars, Casberg noted their potential impact but cautioned that pricing competition might be limited due to the small number of manufacturers. Finally, he observed that pharmacy and therapeutics committees are now focusing more on orphan drugs, given their unique challenges in efficacy, safety, and cost evaluation.

With brand patents expiring, which products about to face upcoming generic and biosimilar competition do you think stakeholders should be keeping their eye on?

Yeah, there are a couple products coming down the road that would be losing exclusivity. The first one I'll hit is 

 [liraglutide], it's a GLP-1 [inhibitor]. You can't talk about pharmaceuticals today without talking about GLP-1 [inhibitors] and weight loss.

So, Victoza was kind of a big advance back in its day. It was the first once daily GLP-1 [inhibitor], once daily subcutaneous administered injectable product. It has less nausea associated with it than its previous predecessor, 

 [exenatide]. It was also the first GLP-1 [inhibitor] that had cardiovascular positive studies for cardiovascular effect. Great drug but I don't see it really helping with this whole GLP-1 [inhibitor] shortage and weight loss issue.

 [dulaglutide], they both have about 50% the weight loss that 

 [tirzepatide] have so I don't see all of a sudden a big rush to go to Victoza generic because number 1: it's once a day, and number 2: it doesn't have the weight loss that some of the big products that you're hearing about every day have. So, that's Victoza, that'll be coming shortly here in June. I think there could be quite a few generics.

 [dasatinib]. They're both tyrosine kinase inhibitors similar to 

 [imatinib mesylate], great drugs in oncology, pretty expensive therapies, and we should get quite a few generics and a good amount of price reduction there.

Then moving over to the biosimilars side, 

 [ustekinumab] biosimilars are coming. Everybody's been talking about 

 [adalimumab] and 9 or 10 companies bringing those [biosimilars] to market but almost just as big, Stelara is a big drug—$15 to $20 billion product—and it also has 8 or 9 manufacturers lined up to bring products to market. We'll have to see if the adoption by payers is similar or quicker, we're just starting to have some success and conversion of Humira to biosimilars. We'll have to see how the payers adopts Stelara [biosimilars]. Maybe they've gained some more confidence and learned a little bit from the Humira introduction. We'll have to see and Stelara will be coming early in 2025. Amgen has the first product out but then pretty quickly thereafter, several other products will hit.

 [aflibercept] biosimilars in the ophthalmology area, for age-related macular degeneration. We had 

 [ranibizumab] biosimilars come out with a couple of biosimilars recently and those biosimilars have done pretty well.

Eylea, we're watching, we don't know if it's going to come out this year, or in a year or 2. There's an opportunity this year, but IPD, the company I work for does a lot of predicting of this and we think it actually may not be in 2024, it might be 2025 or 2026 before we get Eylea, but watch for that. I had mentioned Victoza, Trulicity is a $16 billion GLP-1 [inhibitor], and it's biosimilar [could be] out in 2027. Something to plan for by the payers.

Do you foresee any policy changes or market forces that could significantly alter the cost landscape for both branded and generic drugs in the near future?

So policy or legislation, everything is about politics. I guess I'll mention 2 things. I'll mention the 

. Those would be the 2 hot ones on the IRA side, we just had the first release of the negotiated drugs and which drugs they are. We'll be getting 

, a new acronym for drug pricing, those will be announced coming up soon.

We're going to have the out-of-pocket cost of Part D reduced to the max of an out-of-pocket cost to $2,000. That's big for patients, impactful to manufacturers, and payers. Now they're going to have to deal with different benefit designs and how they're going to market the drug and price the drug or how payers are going to make the benefits work with the new $2,000 max, so there is something for everybody there.

Then 2025 redesign, for the Inflation Reduction Act, there's also quite a few different benefit designs changing for 2025. There's 

 so the manufacturers have to watch how much they're raising the prices of their drugs. If they go up too high, too quickly, then they get these penalties against them. The IRA has a number of different things, pretty complex, and everybody's paying attention to that.

Then on the second hand, it would be PBM legislation. I guess it depends on who you are and your feeling towards PBM legislation. I think it probably just comes down to more transparency. Every business has to make money and PBMs have done it. Somebody could argue they did it okay. Some say it was all smoke and mirrors but I think there's legislation now to have more transparency on PBMs. We'll see how that rolls out but a lot of discussion up in Washington on that these days.

Value-based pricing models are increasingly being explored. How do you think value-based pricing will impact the development, approval, and access to new drugs?

So value-based pricing, you hear a lot about it. You hear people trying to implement it, manufacturers bring proposals to payers on value-based pricing models. What we don't hear of are the results and if they are working or not.

I don't know in the long run, if value-based pricing will be the 'be all and end all' and change the way drugs are paid for in the United States. I'm going to say no but I think there's some value to value-based pricing and in how you look at drugs and evaluate them.

I think especially some of these high cost therapies have opportunities for some value-based models. As I was saying earlier, there's more and more of these high cost, really expensive products and looking at outcomes and measuring outcomes, that kind of thing are for these gene therapies and other expensive therapies.

I'm not saying value-based pricing will take over but I think there's opportunity in the future for use of them.

In your view, what are the top 3 promising specialty drugs currently coming down the pipeline and why should stakeholders be keeping an eye on them?

The first one I'll talk about is donanemab for Alzheimer's disease by 

; it's an amyloid-β inhibitor for early Alzheimer's disease. It would be a little bit different than 

 from Biogen, which was fully approved more recently.

Donanemab was originally going to be approved beginning of 2023, so over a year ago, but it has had a little bit of a storied pathway to approval. We were watching for an approval here any day during this last month or so, then out of the blue, there was an announcement that the FDA has requested an 

If I'm a manufacturer, not really happy about that; you never really want extra scrutiny on your drug. I'm sure they're going to talk about the dosing regimen, the potential for shorter duration of therapy compared to Leqembi probably the ARIA [amyloid-related imaging abnormalities] side effect profile. They haven't given us a date for that FDA Advisory Committee meeting. I would anticipate a date being announced any day and I still think there's opportunity for approval before the end of 2024.

I think one of the other products that is exciting is resmetirom, or Rezdiffra. for NASH [nonalcoholic steatohepatitis]. First product approved for NASH. Again, a therapeutic area we've been waiting for therapies now for maybe 10 years. Finally we do have an approval. Congratulations to 

 on that, getting their product over the finish line.

A once daily, oral product. It showed signs of efficacy and NASH resolution and fibrosis improvement. Prescribing information did not include discussion of the need for biopsy in diagnosis. So, to diagnose NASH, now called MASH [metabolic dysfunction-associated steatohepatitis], the gold standard is liver biopsy, but that's pretty invasive. You can also use noninvasive therapy testing to get diagnosis of staging of NASH in the liver. They did not have that, which was a plus for Madrigal.

It would be interesting to see how the payers set up their criteria for approval. There's a whole lot of population out there that could be treated with this, so that's another big approval that just occurred.

I'll just mention one other recent approval. It's called 

 for pulmonary arterial hypertension, sotatercept, by Merck. Winrevair is the brand name.

It's a new product for PAH, pulmonary arterial hypertension. It's a new mechanism of action, and has the potential to be more disease modifying—the other therapies out there are more symptomatic treatments—and probably early on will be used as add-on or [in the] second or third line. But I think as physicians get used to it, they could move it up in therapy.

It is pretty expensive: $240,000 for most patients, could be $480,000 for some patients. It's a weight-based dosing, so 1 vial or 2 vials. I think it's subcutaneous every 3 weeks, and it can be self-administered or professionally administered.

What is your reaction to the FDA approval of the first denosumab biosimilars?

So denosumab biosimilars, there was 2 approved; 

Wyost [denosumab-bbdz] and Jubbonti [GP2411]

. The Jubbonti is for Prolia, the Wyost is for Xgeva. One is more oncology based, one is more osteoporosis based.

They were approved, but there's no announcement on when they're going to be launched. We're thinking they might even be delayed in launch till 2025.

With only one manufacturer coming out, Sandoz, with both of those, we'll get some discount on the brand and reference drug but it's not going to be significant. It's not going to be like the 

Humira [adalimumab] situation with 9 or 10 biosimilars.

What are your thoughts on what the launch of the first tocilizumab biosimilar means for patients with autoimmune conditions?

 is actually IV [intravenous] and sub-q [subcutaneous]. I think that the 2 products launched, 

 is both IV and sub-q, and that's from Fresenius Kabi.

For the most part, Actemra is used in rheumatoid arthritis, a couple other conditions as well. Getting biosimilars in a different therapeutic area, including Actemra, that will be a big advancement. That's 2 biosimilars, so we will get a little competition there on pricing, but I don't know if I can predict what the discounts will be—maybe, 20% to 30% off.

How are pharmacy and therapeutics committees likely to approach new pipeline drugs, considering factors like efficacy, safety data, and potential cost compared to existing options?

P&T [pharmacy and therapeutic] committees are pretty standard in their approach on how they review drugs for formulary inclusion. It really comes down to safety, cost, and efficacy.

I think in today's world, the only difference is that there's a lot of these new orphan drugs which don't have a lot of competitors, so the P&T committees have to look at a drug on its own or a small number of patients, so they really look at the efficacy opportunity—which patients should get the drug, and what the criteria can be.

It's a lot less managing 4 or 5 drugs in a therapeutic area and comparing the pros and cons of drugs that are very similar. Nowadays, we're comparing a million-dollar drug which has no competition and who the patient should be and what the criteria should be. So there is a little shift in reviewing drugs from multiple drugs in 1 therapeutic class to orphan drugs.

Jeffrey Casberg discusses key upcoming biosimilars and specialty drugs, the impact of the Inflation Reduction Act on drug pricing, and the evolving role of pharmacy benefit managers in the market.

Upcoming Biosimilars and the Impact of IRA: Key Takeaways From Jeffrey Casberg

This article was originally published by 

Biosimilar uptake in the US has not met the expectations of many health care professionals who believe 

 can lead to reduced spending, according to a study published in 

As prices have increased for biologic drugs, these medications made up 46% of US prescription drug spending in 2022, despite only making up 3% of prescriptions. Originally, the assumption about biosimilars was they would help lower costs and improve patient access to biologic therapies through market competition. However, the first decade following the Biologics Price Competition and Innovation Act of 2009, which established an FDA approval pathway for biosimilars, did not have successful biosimilar competition as policy makers expected. Within the first 2 years, biosimilars had less than 30% of the market share compared with most biologic drugs facing competition.

In 2023 alone, specialty medicines accounted for 54% of spending, an increase from 49% in 2018.

 Market uptake of biosimilars has ranged based on the medication, from 8% for insulin lispro to 82% for bevacizumab. By the end of last year, adalimumab biosimilars accounted for 2% of volume, likely due to contracts the originator products are under and the differences in biosimilar formulations.

Economic factors that hinder biosimilar uptake in the US include the absence of financial rebates for biosimilars, leaving payers disinterested in supporting biosimilars.

 Additional factors like access to health insurance, clinics, and transportation can also hinder biosimilars.

The study found several patient factors that were independently associated with higher odds of initiating a biosimilar. | Image credit: Kiattisak - stock.adobe.com

Noneconomic factors, such as complex naming conventions, health care provider knowledge gaps, and safety concerns, have hindered biosimilar uptake in the US. Despite these challenges, global studies demonstrate increased patient access and treatment options through biosimilar utilization.

“The reasons for slow biosimilar uptake remain unclear,” the authors of the new study wrote.

 “Existing studies have suggested that there may be important variation in biosimilar initiation across patient characteristics and sites of care, but these studies have been limited in terms of the number and types of biosimilars investigated.”

Their study aimed to provide a better understanding of the reasons for inadequate biosimilar uptake in the US by analyzing characteristics of patients and prescribers initiating biosimilars for 7 biologic drugs from 2013-2022.

The cross-sectional study began on November 1, 2013, when the first biosimilar entered the market, and ended on March 31, 2022. Patients initiated 1 of 7 biologic medications—filgrastim, bevacizumab, epoetin alfa, trastuzumab, pegfilgrastim, infliximab, or rituximab—or corresponding biosimilars. The primary outcome was the proportion of patients who initiated the reference biologic or a biosimilar version.

A total of 196,766 patients initiated 1 of the 7 biologics or corresponding biosimilar versions during the study period. Most patients identified as White (69%) and women (58%), with an average age of 68.8 years. Patients were more likely to be enrolled in a Medicare Advantage plan (74%), receive biologic treatment in an office compared with other locations (62%), and have biologic drugs prescribed by a specialist (49%). While uptake varied between drugs, only 27% of patients overall initiated a biosimilar version.

The first biosimilar market entry dates in the US ranged from filgrastim in November 2013 to rituximab in November 2019. Patients who initiated a biosimilar increased from less than 1% in 2013 to 34% in 2022.

In 2022, more than half of patients who initiated filgrastim, trastuzumab, infliximab, rituximab, and epoetin alfa used biosimilar versions. However, less than 30% of patients initiated biosimilar versions of pegfilgrastim and bevacizumab.

Characteristics Associated With Biosimilar Initiation

The study found several patient factors that were independently associated with higher odds of initiating a biosimilar. Patients under 18 years of age were less likely to initiate a biosimilar (adjusted OR [aOR], 0.33) compared with patients 45 to 64 years old (aOR, 1.12). The only significant difference in race and ethnicity was among patients who identified as Black, who were less likely to initiate a biosimilar (aOR, 0.9) compared with patients who identified as White.

Lower odds of biosimilar initiation were associated with treatment in physician offices compared with hospital outpatient settings (aOR, 0.65). Patients who were prescribed biologics by a primary care clinician were more likely to initiate a biosimilar version compared with biologics prescribed by a specialist (aOR, 1.17). Regarding geographic variations, the highest rates of biosimilar initiation were seen in the Southern region (aOR, 1.26) and the West (aOR, 1.36) compared with the Northeast.

Initiation also varied among the 7 drugs and was associated with patient and prescriber characteristics. Patients under 18 years old were less likely than patients 65 years or older to initiate biosimilars for all drugs, except pegfilgrastim (aOR, 3.94). The study excluded 77% of the bevacizumab initiators with ophthalmologic diagnoses, and the overall number of patients initiating biosimilars increased from 27% to 37%.

Study limitations included reliance on biologic and biosimilar initiators, limited racial and ethnic data, and exclusion of other potential uptake factors. Future research should consider these factors to improve generalizability.

“Biosimilar uptake among new users has been less robust than expected in the US,” the authors concluded. “We identified that biosimilar initiation varied by patient age, insurance type, geography, and site of care, and by prescriber specialty. Targeted policy solutions to increase biosimilar uptake could result in substantial savings to patients and the health care system.”

1. Hong D, Kesselheim AS, Ameet Sarpatwari, Rome BN. Biosimilar uptake in the US: patient and prescriber factors. 

. 2024;43(8):1159-1164. doi:10.1377/hlthaff.2023.01215

2. Jeremias S. Overcoming economic, noneconomic barriers to biosimilar adoption in oncology. The Center for Biosimilars

 June 20, 2024. Accessed August 13, 2024. 

https://www.centerforbiosimilars.com/view/overcoming-economic-noneconomic-barriers-to-biosimilar-adoption-in-oncology

3. Jeremias S. Biosimilars account for 23% market share, with wide uptake disparities across molecules. The Center for Biosimilars. May 22, 2024. Accessed August 13, 2024. 

https://www.centerforbiosimilars.com/view/biosimilars-account-for-23-market-share-with-wide-uptake-disparities-across-molecules

Delayed biosimilar uptake in the US is driven by payer, provider, and patient barriers, but targeted interventions can help boost utilization and savings.

Biosimilar Uptake Lags in US Despite Potential Cost Savings

The Top 5 Biosimilar Articles for the Week of August 19

 Patients with diabetic macular edema (DME) 

 when treated with biosimilar candidate CT-P42 or reference aflibercept (Eylea) in terms of efficacy, with similar pharmacokinetic (PK), usability, safety, and immunogenicity profiles.

 for 10 drugs under the Inflation Reduction Act (IRA), sparking mixed reactions, with concerns that including drugs facing imminent biosimilar competition could hinder market access to lower-cost alternatives.

 Celltrion's adalimumab-aaty biosimilar is 

 for all Costco members, while Amgen sues Samsung Bioepis over the latter’s denosumab biosimilar candidate, and GlycoNex progresses its denosumab biosimilar SPD8 to phase 3 trials.

 for the first 6 months of 2024, a 10-fold increase from the same period the year prior. The new figures come after the company received its first 2 FDA approvals in 2024.

 to engage with the FDA on its Reddit forum—where a representative will answer complex biosimilar questions—encourages clearing misconceptions, and advocates for updates to the Biologics Price Competition and Innovation Act guidelines.

To read all of these articles and more, visit 

Videos

Here are the top 5 biosimilar articles for the week of August 26, 2024.

The Top 5 Biosimilar Articles for the Week of August 26

Strategies for Effective Biosimilar Education, Adoption

Ivo Abraham, PhD, RN, director of the Center for Health Outcomes and PharmacoEconomic Research at the University of Arizona Cancer Center discussed educational tools that could help physicians overcome biosimilar adoption hesitancy, in an interview with The Center for Biosimilars

Abraham cites instances of successful, collaborative educational approaches and emphasizes their importance for targeted learning. However, he cautions that concerns about biosimilars, rooted in fear, may persist as an obstacle.

This transcript was lightly edited for clarity. 

Physician knowledge and acceptance are crucial for biosimilar adoption. What targeted education strategies can we implement to overcome potential physician hesitancy towards biosimilars?

The reality is that today, 2024, most clinicians, and I think it goes beyond physicians, it also includes clinical pharmacists, nurses, have perhaps not accepted, but are dealing with the reality of biosimilars and the fact that they're here to stay and the payers will decide whether biosimilars and the extent to which biosimilars are adopted.

We need to look at models, not just education, but at models of good collaboration. For instance, what 

 has done, basically he sat down, I've heard him tell the story. He sat down with the medical staff and put together a model of clinical pharmacists, nurses, and physicians working together.

Yes, there will always be still some lingering reluctance or fear mongering. I think in part that is a generational issue. I would say that most clinicians now in cancer care, immunology, or immune related diseases, are very familiar with the reality of biosimilars.

It's not a matter of really advocating further, those who are going to dig in their heels are going to dig in their heels, but they're going to be overrode because prior authorization will not be granted if you are not within the formulary. The payers are for better or for worse, the key driver here.

Ivo Abraham, PhD, RN, University of Arizona Cancer Center, suggests implementing targeted educational strategies to overcome physician hesitancy towards biosimilar adoption.

 for the first half of 2024 amounted to €26.9 million ($29.4 million), showing a strong start to the year, according to the biosimilar developer’s earnings report.

An analysis of subcutaneous biosimilar and originator tumor necrosis factor (TNF) inhibitors for rheumatic diseases found 

no significant differences in survival or discontinuation

 rates due to inefficacy or adverse events, with biosimilars showing lower overall discontinuation rates and higher retention rates.

 In an interview, Ha Kung Wong, an intellectual property attorney, explained that the 

Biologics Price Competition and Innovation Act of 2009

 provides a structured but optional "patent dance" for biosimilars, which helps streamline patent disputes, potentially reducing litigation and encouraging early settlements.

, the fourth aflibercept biosimilar to be approved for Americans with age-related macular degeneration and other retinal eye diseases.

 Sarfaraz K. Niazi, PhD, argues that the S-150 bill, also known as the 

"Affordable Prescriptions for Patients Act of 2023,"

 aims to reduce drug prices by addressing anti-competitive practices, such as patent thickets and product hopping, which hinder the entry of cheaper biosimilars and generics into the market.

Here are the top 5 biosimilar articles for the week of August 19, 2024.

Biosimilar CT-P42 demonstrated comparable efficacy, safety, and tolerability to reference aflibercept in treating diabetic macular edema. | Image Credit: nazif - stock.adobe.com

Patients with diabetic macular edema (DME) displayed similar outcomes when treated with biosimilar candidate CT-P42 or reference aflibercept (Eylea) in terms of efficacy, with similar pharmacokinetic (PK), usability, safety, and immunogenicity profiles, according to a study published in 

Patients with diabetes often develop DME, a serious form of vision loss. The accumulation of extracellular fluid in the macula resulting from DME can lead to increased retinal vasculature permeability secondary to microvascular damage to the inner retinal capillaries and development of retinal microaneurysms.

A critical component to this pathophysiology is vascular endothelial growth factor (VEGF), which alters retinal capillary permeability by increasing the phosphorylation of proteins involved with tight junctions like zonula occludens.

 Endothelial cell proliferation is the aftermath of the VEGF activation of mitogen-activated protein.

Some of the recommended drugs for patients with DME include aflibercept, bevacizumab, faricimab-svoa, ranibizumab, dexamethasone, and fluocinolone acetonide.

 Providers may also suggest procedures like photocoagulation to address the leakage in the eye or vitrectomy to remove scar tissue or cloudy fluids.

Both the FDA and the European Medicines Agency (EMA) approved aflibercept for the treatment of DME.

 Originally, aflibercept was approved as a first-line therapy for patients with severe DME, when visual loss has increased because of edema involving the center of the macula.

In countries with abundant resources, patients benefit from intravitreal injection anti-VEGF therapy to treat DME. However, in underserved countries with less resources where the prevalence of DME may be higher, this option may not be available, and less expensive alternatives such as biosimilars must be considered.

To determine the therapeutic similarity of CT-P42 compared with aflibercept, patients with DME were enrolled in a randomized, active-controlled, double-masked, phase 3 clinical trial. They either received the aflibercept biosimilar candidate, CT-P42, or reference aflibercept by intravitreal injection every 4 weeks followed by every 8 weeks in the main study period.

Data collection began when the first patient was randomized on July 22, 2021, and ended at week 24 for the last patient on October 14, 2022. A total of 348 patients were randomized throughout the study, with 173 patients who took CT-P42 and 175 patients who took reference aflibercept.

The study population was mainly White (64.4%) and male (58.3%), with a median age of 63 years. Most patients had type 2 diabetes (93.1%) rather than type 1 diabetes (6.9%). More than half of the patient population (72.7%) had a baseline best corrected visual acuity (BCVA) score of at least 55 letters. The average BCVA scores were 60.3 and 60.4 in the CT-P42 and reference aflibercept groups, respectively. 

By the end of week 24, most patients completed the study from start to finish (96.3%). There were more patients who took CT-P42 that completed the study (97.1%) than the patients who took reference aflibercept (95.4%).

Very few patients discontinued the study on or before week 24 in the CT-P42 group (2.9%) or the reference aflibercept group (4.6%). Discontinuation was mainly due to withdrawal by the patient (CT-P42, 1.2%; reference aflibercept, 1.7%).

Efficacy, Pharmacokinetics, and Safety of CT-P42 in DME

Both the CT-P42 (9.43 letters) and reference aflibercept (8.85 letters) groups demonstrated improved visual acuity from baseline to week 8. The treatment difference between groups was minimal (0.58 letters) and within the prespecified equivalence margin (95% CI, −0.73 to 1.88). Similar efficacy was observed for both groups in other key retinal outcomes through week 24, confirming therapeutic equivalence.

Similar PK parameters were found among both treatment groups, with low plasma concentrations and no evidence of drug accumulation. At week 0, all injections with the vial kit were successfully administered without any user errors or close calls in either treatment group.

Treatment-emergent adverse events (TEAEs) were similar across treatment groups, at 50.3% and 53.7% of patients in the CT-P42 and reference aflibercept groups, respectively. The majority of the TEAEs were grade 1 to 2 in intensity, the most frequent being conjunctival hemorrhage (CT-P42, 1.2%; reference aflibercept, 2.3%) and intraocular pressure increased (CT-P42, 1.2%; reference aflibercept, 1.7%).

Both groups were comparable in the incidence of nonocular TEAEs reported, with 38.7% of patients in the CT-P42 group and 38.3% in the reference aflibercept group. The study population primarily comprised patients with negative antidrug antibody results for the initial 24 weeks. Immunogenicity profiles remained similar across groups during this period.

Study limitations included a small, predominantly White patient population and short-term follow-up. Long-term safety and efficacy data for CT-P42 in real-world settings are necessary.

“This study demonstrated equivalence of CT-P42 and reference aflibercept at a dose of 2 mg in 0.05 mL in terms of efficacy. The PK, usability, safety, and immunogenicity profiles of CT-P42 and reference aflibercept were also comparable in patients with DME,” the authors concluded.

1. Wolf S, Stanga PE, Veselovsky M, et al. Biosimilar candidate CT-P42 in diabetic macular edema: 24-week results from a randomized, active-controlled, phase III study. 

. 2024;1-22. doi:10.1016/j.oret.2024.06.013

2. Gupta N, Mansoor S, Sharma A, et al. Diabetic retinopathy and VEGF. 

. 2013;7:4-10. doi:10.2174/1874364101307010004

3. What is diabetes-related edema (DME)? Cleveland Clinic. February 14, 2023. Accessed August 12, 2024. 

https://my.clevelandclinic.org/health/diseases/24733-diabetes-related-macular-edema

Biosimilar CT-P42 demonstrated comparable efficacy, safety, and tolerability to reference aflibercept in treating diabetic macular edema (DME).

Biosimilar CT-P42 Demonstrates Equivalence to Aflibercept for DME

, Ha Kung Wong, JD, an intellectual property attorney and partner at Venable LLC, provided an overview of the patent legal system biosimilars must navigate under the Biologics Price Competition and Innovation Act (BPCIA) of 2009. He explained that the BPCIA establishes an optional framework for information exchange between biosimilar developers and reference product sponsors, commonly known as the "patent dance."

This process helps narrow down patent disputes before litigation, potentially reducing the number of patents involved and promoting early settlements. Wong highlighted the benefits of this system, noting that it can streamline the approval process for biosimilars, save resources, and lead to favorable outcomes for both parties. Additionally, he discussed ongoing legislative efforts that could impact the biosimilar sector, including potential reforms to patent laws and scrutiny of pharmacy benefit managers (PBMs).

Can you explain the patent legal system biosimilars are required to undergo and why this process is important to their development?

 Sure, so for biosimilars, there's the BPCIA or the Biologics Price Competition and Innovation Act of 2009, which is actually an optional framework of information exchanges between biosimilars and the reference product sponsor, or what we call the RPS, prior to filing an infringement lawsuit.

The BPCIA allows for 2 phases of litigation. One, following the biosimilars aBLA [abbreviated biologics license application] submission and the second phase triggered by the biosimilars notice of commercial marketing. Now, the idea is that the most important patents can be dealt with while the biosimilar application is under FDA review. That gives the possibility of resolving the lawsuit after only litigating a small subset of patents, instead of the RPS' entire portfolio. That can be quite large and sometimes in the hundreds.

So, to start this first phase exchange of materials, which is often referred to as the patent dance, the biosimilar notifies the RPS that the FDA has accepted its biosimilar application within 20 days of that acceptance and provides the RPS with its aBLA and "other manufacturing information".

That starts off this kind of exchange of information regarding the patents that might be infringed by the biosimilar and which they think might be likely to be licensed whether the biosimilar feels like there is an infringement, validity, or enforceability problem or not. Ultimately, what happens in the first round of litigation is that you narrow the number of patents that you actually litigate right away. If the parties can't agree, the BPCIA gives a provision for determining the list of patents that can be litigated in the first phase and the remainder gets litigated in the second phase.

For most BPCIA litigations that most parties have participated in at least some part of the dance and as I mentioned before, it was after the statute came out it was decided by the courts that this was optional.

A lot of people said, "Well, why would anybody go through this?" It turns out, it helps both sides, right? The biosimilar gets that chance to narrow it down to the patents that are most important so they're not expending an enormous amount of resources litigating hundreds of patents, and the RPS gets a chance to really zone in on the patents that are most important to them and try to protect them first, then try to seek licenses on those that can be some sort of settlement. So 24 of the litigations that have occurred, have completed this entire patent dance, 19 participated in some portion of it and didn't finish, but only 9 didn't participate.

You can see that even though it's optional, a lot of parties find some benefit to going through this process. Now, the interesting thing about it is that when it came out, I thought this is the most half-baked process ever.

That's still true, but it's better than nothing is what I think is happening. Most of the BPCIA litigations are actually ending in settlements. Thirty-one of 46, or 67%, of terminated BPCIA litigations ended in settlement or stipulated voluntary dismissals.

Very few cases have gotten the verdict, which is actually part of what we want. I think this statistic that I'm raising is demonstrating that the primary benefit of the BPCIA process is being met. That was to resolve any patent related disputes early, prior to impact on the market, thus allowing both parties to direct resources appropriately to their respective products and avoid the need to address potential damages.

In many ways, this is similar to what the Hatch-Waxman process was meant to address for small molecules. So far, it appears to be working for biologics and biosimilars, and really helping in development on both sides.

Do you foresee any potential shifts or reforms in patent law that could positively or negatively impact the biosimilars sector in the near future?

 Predicting whether there will be statutory shifts or reform in patent law is like trying to predict what will happen in the next Fast & Furious movie—you have no idea what specifically is going to happen but it's probably going to have some explosions that ultimately, will not be applicable to the real world. That being said, there are a few things I think that we might want to keep an eye on. I say "very few" only because we've seen a lot of things introduced and not a lot of follow through. There's a lot of good intentions out there, but there's not a lot of follow through. That being said, here it is.

In an interview, Ha Kung Wong, an intellectual property attorney, explained that the Biologics Price Competition and Innovation Act of 2009 provides a structured but optional "patent dance" for biosimilars, which helps streamline patent disputes, potentially reducing litigation and encouraging early settlements.