Tony Hagen is senior managing editor for The Center for Biosimilars

Tony Hagen

Despite the hoopla surrounding the return of brazikumab, an IL-23 inhibitor in development for treatment of Crohn disease (CD) and ulcerative colitis (UC), AstraZeneca provided only a brief 

this week that did not address concerns about whether it would play its role, as hoped by the Federal Trade Commission (FTC), in upholding a competitive marketplace for such agents.

Rather, the subtle emphasis was on the value of the deal to shareholders. Brazikumab was spun off by FTC order as part of the recent $63 billion AbbVie-Allergan merger because both of those companies were developing IL-23 inhibitors in the CD and UC space, and the FTC didn’t trust that a sufficiently competitive environment for these products would result unless brazikumab were released from their possession.

AstraZeneca explained in its statement that its financial obligation under this exchange was very limited. The company will be paid by AbbVie to develop the product and bring it to market, and AstraZeneca’s only financial duty will be to pay one of the original rights holders, Amgen, “a high single-digit to low double-digit royalty on sales of brazikumab if approved and launched.”

“Other than this, AstraZeneca will own all rights and benefits arising from the medicine with no other payments due,” the company said. What makes the deal better for AstraZeneca is that it originally sold brazikumab to Allergan for $250 million and a promise of up to $1.27 billion if sales and development goals were met. That exchange occurred in 2016.

The reigning IL-23 inhibitor on the market for CD and UC is Johnson & Johnson’s ustekinumab (Stelara). Brazikumab was among products in late stage development considered to have a good chance of providing competition and bringing down the cost for consumers. 

 for ustekinumab cannot enter the US market before 2023, owing to product exclusivity protection.

In a dissenting opinion on the FTC’s 3-to-2 

of the AbbVie-Allergan merger, Commissioner Rohit Chopra said it was unclear that, having paid nothing for brazikumab, AstraZeneca would be aggressive about completing development of the product and launching it on the market. “This is a windfall for AstraZeneca, who will pay nothing for a valuable drug development project and is free to re-license the business to another company. It is unclear where this project falls in AstraZeneca’s development priorities and whether the company is committed to the project over the long-term,” he wrote.

Chopra’s stand on the issue was contrary to that expressed by the FTC panel majority, who contended that this and other “divestitures fully remedy any potential loss of competition.”  

In its statement last week, AstraZeneca did not address the concern on the board, nor did it discuss the strength of its intentions to complete development of brazikumab. The company also did not respond to a request from 

® for comment on this issue. Further, there was scant mention of brazikumab in the company’s first quarter 2020 earnings statement or related conference call with media and investors.

 with media and investors, the company did anticipate the return of the candidate product to its portfolio, but only in the context of the funding that would be received from AbbVie for development of the drug. “We will receive basically complete funding for this development, but we have to book it somewhere, and we will book it as other income,” Marc Dunoyer, executive director and chief financial officer for AstraZeneca, was quoted as saying.

Articles

If it has strong intentions to develop the IL-23 agent brazikumab for commercialization, AstraZeneca did not show its hand when it acknowledged receipt of the agent from Allergan last week.

AstraZeneca Quietly Acknowledges Receipt of Brazikumab

Amid the disruption caused by the new coronavirus disease 2019 (COVID-19) a Cranbury, New Jersey, company that is pioneering its own formulation of bevacizumab expects to begin reporting topline data from 2 clinical trials in August of this year.

Outlook Therapeutics, which formerly operated under the name Oncobiologics, provided an 

 on the development of ONS-5010 (Lytenava) this week in its first-quarter 2020 earnings statement.

The company aims to bring the product to market for the treatment of wet age-related macular degeneration (wet AMD) and other retinal diseases. Although reference bevacizumab (Avastin) is used for the treatment of these conditions, ONS-1010 would be the first on-label, or indicated, version of bevacizumab for this purpose, and so the company aims to seek innovator product status via a biologic license application with the FDA through the 351(a) pathway.

Outlook Therapeutics, which is undergoing restructuring to strengthen its financial standing as it pilots this product through the developmental stages, said safety protocols imposed to protect clinicians and patients in ongoing trials for ONS-1010 have affected progress, although the company is on track to report findings as early as late summer 2020.

“Over the course of the last quarter, we made notable progress amidst navigating the uncertainties of the evolving COVID-19 pandemic. Our team remains focused on advancing our ONS-5010 development program as efficiently and rapidly as possible while focusing on the safety, health and welfare of our employees, clinical trial site providers and the patients in our trials,” said Lawrence A. Kenyon, president, CEO, and chief financial officer, in a statement.

With wet AMD, abnormally high levels of vascular endothelial growth factor (VEGF) accumulate in the eye. VEGF promotes the growth of abnormal blood vessels, and bevacizumab is an anti-VEGF recombinant monoclonal antibody that inhibits VEGF and associated blood vessel development activity. It has become a standard-of-care treatment option around the globe, according to Outlook.

Bevacizumab is already widely used for the treatment of wet AMD and, in fact, has been shown to be highly 

 in comparison with other anti-VEGF treatments, such as aflibercept and ranibizumab. The agent is administered via injection into the vitreous fluid at the back of the eye. Avastin, the original bevacizumab, is not indicated for treatment of wet AMD although it is commonly used for that purpose.

Enrollment was completed in August 2019 for NORSE 1, a safety and efficacy trial (N = 61) for the bevacizumab candidate, and it is this trial for which the company expects to report findings during the third calendar quarter of 2020. NORSE 1 is comparing ONS-5010 with ranibizumab. No adverse effects from the COVID-19 pandemic are expected to delay progress with this trial, the company said.

NORSE 2 is enrolling 220 patients at 40 clinical sites in the United States. This trial began in July 2019, and the primary outcome is a statistically significant improvement in visual acuity. The comparator drug is also ranibizumab. August 2020 is also the anticipated date for completion of enrollment.  The company said it is not expecting COVID-19 to affect enrollment.

Contingent upon marketing approval in the United States, the product would be sold in vials and single-use prefilled syringes. Outlook also plans to commercialize the product in France, the United Kingdom, Italy, Germany, Spain, and Japan.

In other developments, the company has entered a partnership with BioLexis of Singapore, its largest shareholder and its development partner for ONS-5010, to help with the financial streamlining and ensure the partners retain 100% of any future net profits for ONS-5010.

As it emerges from organizational restructuring, Outlook Therapeutics expresses confidence in its bevacizumab candidate for retinal diseases.

Outlook Therapeutics Moves Ahead with Bevacizumab Formulation

Incheon, Republic of Korea company Samsung Bioepis reported clinical trial data from 3 studies of its trastuzumab biosimilar (Ontruzant) that demonstrate equivalency to the reference product, Herceptin, in various settings. In April, the biosimilar was 

The results will be presented at the upcoming American Society of Clinical Oncology meeting (ASCO20 Virtual Scientific Program).

Using data from the Danish Breast Cancer Cooperative Group registry, investigators 

 to assess the real-world efficacy of combining neoadjuvant chemotherapy (NACT) with Ontruzant and pertuzumab in patients with HER2-positive early breast cancer.

Overall, 56% of patients (n = 215) achieved a pathologic complete response (pCR) and 68% of patients who were node positive before receiving the combination of NACT, Ontruzant, and pertuzumab had tumor-free axillary nodes after completing the regimen.

Investigators said the pCR rate for the Ontruzant combination that was comparable to that seen in clinical studies involving Herceptin in combination with NACT and pertuzumab.

Cardiotoxicity of Ontruzant Plus Pertuzumab

Because cardiotoxicity is a concern during trastuzumab therapy, it is important to understand the safety profile of biosimilars in this regard. Investigators at the Medical University of Graz in Austria sought to 

 potential decline in left ventricular ejection fraction (LVEF) for patients with HER2-positive breast cancer receiving Ontruzant and pertuzumab.

All patients (n = 35) had a normal baseline LVEF (> 50%) prior to starting Ontruzant and pertuzumab, and the median LVEF was 60%. At the end of treatment (median 4 cycles), the median LVEF was 60%.

The safety and efficacy profile of Ontruzant and pertuzumab was consistent with Herceptin and pertuzumab, researchers said.

Cardiac Safety and Survival by ADCC Status

In a study of long-term cardiac safety and survival, investigators 

 Ontruzant versus Herceptin in patients stratified by antibody-dependent cell-mediated cytotoxicity (ADCC) status.

They enrolled 367 patients, with 186 receiving Ontruzant and 181 receiving Herceptin. During a median follow-up of 53 months, the incidence of asymptomatic LVEF decrease was low (1 patient on Ontruzant and 2 on Herceptin), with all patients recovering with LVEF ≥50%. There were no cases of symptomatic congestive heart failure, cardiac death, or other significant cardiac conditions reported.

The 4-year event-free survival rates were 83.4% for the biosimilar and 80.7% for the reference product (HR, 0.77). The 4-year overall survival rates were 94.3% versus 89.6% (HR, 0.53), respectively.

“Comparable long-term cardiac safety and survival at 4-years supports biosimilarity,” investigators wrote.

The ASCO20 Virtual Scientific Program will be presented May 29 to 31, 2020.

In a trio of studies, investigators were able to demonstrate equivalency of Samsung Bioepis’ trastuzumab biosimilar in various settings.
 

Samsung Bioepis Reports Clinical Trial Data for Ontruzant

Alvotech, of Reykjavik, Iceland, said its high-concentration adalimumab biosimilar (AVT02) has performed successfully in separate clinical trials for efficacy and pharmacokinetic (PK) similarity.

The company added that both studies demonstrated no clinically meaningful differences for safety, tolerability, and immunogenicity between AVT02 and the reference product (Humira).

Alvotech aims to eventually market AVT02 in the United States, Europe, and selected Southeast Asia markets.

In a March 2020 statement, Alvotech said it had 

 with DKSH, of Zurich, Switzerland, to commercialize AVT02. The biosimilar candidate has yet to be certified as a biosimilar or approved for marketing in any country.

AbbVie’s Humira is indicated for multiple autoimmune diseases, including rheumatoid arthritis, ankylosing spondlytis, plaque psoriasis, psoriatic arthritis, ulcerative colitis, and Crohn disease. Humira had worldwide sales of $18.4 billion in 2017.

AVT02 is being developed with a 100 mg/mL dose form that Alvotech believes will differentiate its product from “most biosimilar competitors, while matching the newest dosage forms of the reference product.”

The drug falls within the family of anti—tumor necrosis factor (TNF) agents. It contains a monoclonal antibody and blocks the activity of TNF, which normally helps the body control infection but leads to serious inflammation when produced in excess amounts.  

The total market value for TNF-inhibitors in 2018 was over $40 billion and is expected to expand at the annual rate of 16.5% through 2026, Alvotech said.

“This is an exciting time for Alvotech as we advance the first biosimilar program another step closer to patients around the world. Our goal is to provide patients and healthcare providers with a cost-effective, accessible alternative to therapies which are currently available,” said Joseph E. McClellan, chief scientific officer at Alvotech.

In its statement, Alvotech explained that a phase 1 clinical study to compare the PK between AVT02 and Humira following a single 40 mg subcutaneous injection in health adult volunteers has met its primary objective. All primary PK end points were within equivalence margins, demonstrating PK similarity of AVT02 to the reference product.

The phase 3 comparative, confirmatory study for AVT02 also met its primary objective by demonstrating equivalent efficacy. The study is evaluating efficacy, safety, and immunogenicity of AVT02 compared with Humira in patients with moderate-to-severe chronic plaque psoriasis.

Alvotech announces positive top-line results for two comparative studies for AVT02, a proposed biosimilar to Humira (adalimumab). News release. Alvotech. May 12, 2020. Accessed May 14, 2020. 

www.alvotech.com/newsroom/alvotech-announces-positive-top-line-results-for-two-comparative-studies-for-avt02-a-proposed-biosimilar-to-humira-adalimumab

Icelandic company Alvotech said clinical trials for its adalimumab candidate have demonstrated equivalence to reference product Humira.
 

Alvotech Reports Efficacy and PK Results for AVT02 

Hoping to grab a share of the increasingly competitive market for adalimumab in the European Union, Celltrion has sought marketing approval for its adalimumab biosimilar, CT-P17, from the European Medicines Agency. An immediate launch is planned once authorization is granted.

The company has tweaked the adalimumab product slightly to give it an edge in the increasingly crowded market for adalimumab.

Based on an application filing in March, the company hopes to gain approval for all indications of AbbVie’s reference product Humira, including rheumatoid arthritis, ulcerative colitis, and psoriasis.  

In Europe in 2019, sales revenue for Humira continued to decline owing to encroaching biosimilar competition that now includes a field of at least 6 products: Amgevita, Imraldi, Halimatoz, Hulio, Kromeya, and Amsparity. European net revenues for Humira amounted to $4.3 billion in 2019, down 31.1%.

 of CT-P17 that it hopes will differentiate the product from competitors.

Product differentiation has been a successful technique for Celltrion. It previously introduced a subcutaneous version of its infliximab biosimilar (sold as Inflectra in the United States and Remsima in the European Union), as opposed to intravenous.

The company said the new version had comparable efficacy and safety for patients with Crohn disease and rheumatoid arthritis.

In an early 2020 report for its investors, Celltrion reported that Remsima had achieved a 59% share of the European market for infliximab, a larger share than retained by the reference product by Janssen, Remicade.

The ambitious launch schedule for the adalimumab biosimilar is in tune with the company’s plans expand rapidly into the biosimilar space.

‘‘Celltrion boasts a strong and dynamic product portfolio and pipeline. As we chart the company’s 2030 vision, the company hopes to launch 1 biosimilar product every year, reaching a total number of 18 products by 2030. Biosimilars and value-added medicines which we call 

 [innovative biosimilars] are set to be our key growth drivers,” said Jung Jin Seo, Celltrion’s chairman, in a 

In Europe, the company’s rituximab (Truxima) and trastuzumab (Herzuma) biosimilars have achieved market shares of 38% and 15%, respectively.

In the United States, where AbbVie has managed to retain full market share for Humira, net revenues for reference adalimumab in 2019 were $14.9 billion. There are 5 adalimumab biosimilars currently approved by the FDA and these are anticipated to launch in 2023.

In March, Teva Pharmaceuticals USA and Celltrion Healthcare 

 the market availability of Herzuma (trastuzumab-pkrb), an injectable biosimilar with the same indications as the Herceptin reference product.

Celltrion is pinning its hopes on a higher-concentration formulation of adalimumab to gain elbow room among multiple competing products.
 

Celltrion Says It Will Waste No Time in Launching CT-P17

As far as innovator companies are concerned, as well as the public, Australia’s process for approving generic and biosimilar agents is too secretive. There are no strict requirements that drug makers looking to bring a rival product to market need to inform the innovator companies until very late in the process, once marketing approval has been given and the product is about to appear on the Australian register of drugs.

For innovator companies, this provides very little time, sometimes less than 2 months, to bring a legal action to halt the commercialization, and in the event the company loses its patent defense, it can be held liable for lost revenues suffered by the generic or biosimilar company. For the public, this late notification system prevents individuals from knowing whether a more affordable product is coming to market until quite late.

However, there are signs that Australian authorities are working to remedy the problem. The

Therapeutic Goods Administration is currently seeking feedback on 

prescription medicines transparency measures

 that would make it harder for pharmaceutical companies to delay notification of intent to launch a rival product.

Under current Australian law, once competitor therapeutic products have received marketing approval and been placed on the Australian Register of Therapeutic Goods, the brief interval of time before commercialization may be all innovator companies have before the product retails and starts to erode the base price for the reference product.

There are rules for earlier disclosure if a competitor’s product is likely to infringe an innovator’s patent, but these are considered too weak. For example, a company is not required to disclose to the innovator that it is bringing a rival product to market if it believes that its product will not violate 1 or more of the innovator’s “valid” patent claims. However, the opinion of the competitor company may not be unbiased.

“This has meant, in practice, that sponsors seeking marketing approval for a generic or biosimilar medicine in Australia generally do not notify the innovator of their application, and the innovator only becomes aware of the generic or biosimilar product when it is approved,” according to an 

 of the current law and proposed changes by patent law attorneys at Shelston Intellectual Property of Sydney, Australia.

The patent law attorneys offered FDA policy as an example of a significantly more effective model. “Australia's current regime for belatedly and somewhat passively notifying innovators of generic and biosimilar product approvals contrasts with the rigid and transparent processes of the US Food and Drug Administration,” they wrote.

In the United States, the FDA does not provide information about pending drug applications unless they have been publicly disclosed. Even so, this information generally becomes available long before an approval. 

 of 249 Biologic License Applications and New Drug Applications found that 89.2% were disclosed in ≥1 public medium, and 78.7% of those were announced with a press release.

Further, under the US Biologics Price Competition and Innovation Act, biosimilar applicants must provide notice to the reference product sponsor no later than 180 days before the date of the first commercial marketing of the biological product. In practice, a review of potential patent infringements begins sooner than the start of that period.

Australian regulators are fielding 2 possible solutions to the notification problem they have identified. One would require that applicants provide earlier notice to the innovator company whether or not they believe that infringement may result from marketing of the rival product, or at least make a declaration to authorities that they have “a reasonable belief” that no patent entanglement would result. This still leaves considerable power over notification in the hands of the applicant.

The second option would require applicants to provide innovators with early notification for all generic and biosimilar applications whether or not they think patent infringement is likely to result. Copies of that notification also would have to be sent to Australian regulators, in this case the Therapeutic Goods Administration. This earlier notification would be required after an application for registration passes preliminary assessment.

Authorities hope to provide more time for patent disputes to be resolved before marketing authorization is provided. Rival companies are not the only ones that can hold innovator companies liable for lost revenues.

, the Australian government sued Sanofi and Bristol Myers Squibb (BMS), contending that litigation surrounding patents for their blockbuster anti—drug clotting drug clopidogrel (Plavix, Iscover) prevented a rival generic from coming to market. The availability of a rival drug on the country’s Pharmaceutical Benefits Scheme would have triggered an immediate 12.5% price reduction. The government sought $325 million in relief, contending that, except for the patent litigation, the generic product would have become available in 2008 and generated considerable savings for the Australian health system.

However, Sanofi and BMS successfully counterargued that, among other things, it was doubtful the rival companies would have brought their drugs to market by the date on which the presumed damages would have begun to accrue.

Although Sanofi and BMS defeated this suit, their claims of patent infringement were settled out of court in a clopidogrel suit against rival drug company Apotex Australia. Apotex had sought $138 million in damages.

As a footnote to their analysis, attorneys from Shelston IP noted that there may be wider implications to the Australian notification system as it stands now. “It is open to debate as to whether Australia's current arrangements are consistent with its obligations under the Australia-United States Free Trade Agreement,” they wrote.

Chahal HS, Szeto D, Chaudhry AH, Sigelman DW, Kim S, Lurie PG. Public disclosure of the filing of new drug and therapeutic biologics applications with the US Food and Drug Administration [published online June 3, 2019]. 

Australia’s secretive drug approval system gives what some believe is an unfair advantage to rival drug companies.
 

FDA's Drug Approval System Is More Open Than Australia's

The importance of biosimilars worldwide is illustrated by the development of biosimilar manufacturing and development beyond the United States and Europe. In Iran, AryoGen Pharmed has a growing portfolio of biosimilars and aims to become a leader in the development of these medicines. Well established as a biopharmaceutical manufacturing center, AryoGen Pharmed has received a Good Manufacturing Practice certificate from the Europeans Medicines Agency.

Investigators described successful findings for the company’s bevacizumab biosimilar candidate, BE1040V, in a recent phase 3 clinical study in 

. The authors outline the product's potential value as a treatment for metastatic colorectal cancer (mCRC).

They note that 5-year survival for patients with this disease is low at just 14%. However, overall survival with systemic chemotherapy in clinical trials has risen to 30 months from 11 months, and these gains have been aided by the introduction of newer chemotherapeutic agents, such as oxaliplatin and irinotecan, in combination with combination regimens such as fluorouracil and biologic agents.

“In fact,” the authors write, “only trials that have incorporated the use of biologic agents into regimens of combination therapies have consistently reported a median survival rate of over 24 months.”

Bevacizimab is one of the biologic agents that have been employed with success in the mCRC setting. The drug works by inhibiting vascular endothelial growth factor-A, which helps in the formation of blood vessels that are essential to the growth of tumors.

A biosimilar bevacizumab such as BE1040V can play an important role in making these advanced therapeutic combinations available to patients, the authors note. Biosimilars are highly similar to innovator brands and have no clinically significant differences with regard to tolerability and efficacy. The chief advantage of a biosimilar over an innovator product is its presumed greater affordability for patients and health care systems.

“Due to the considerable cost of the reference product bevacizumab and also the high mortality rate of mCRC in Iran, BE1040v was developed as a biosimilar of the reference product bevacizumab,” investigators wrote.

The just-published study demonstrated that the candidate bevacizumab biologic was noninferior to the reference product in terms of efficacy and tolerability.

For a full discussion of the study findings, visit 

With successful findings from a phase 3 trial of its bevacizumab biosimilar candidate, Iranian company AryoGen Pharmed is a step closer to commercialization of this product.

AryoGen Notches an Advance With Its Bevacizumab Candidate

Even in a place like Europe, which is considered well ahead of the United States in terms of adoption of biosimilars and represents 80% of the global biosimilar market, biosimilars constitute only 1% of the total sales of biologic medicines.

It turns out that not all European physicians are familiar with biosimilars, and those who do know something about biosimilars tend to overestimate their knowledge of these agents, according to a new study, which encompassed information mostly on physicians in Europe but also from the United States.

These are issues that should be addressed, because physicians’ reluctance to prescribe biosimilars may restrict potential savings that would allow treatment of larger patient populations and improve efficiencies in medical treatment, the authors noted. “It is vital to study physicians’ attitudes towards and perceptions of the uptake of biosimilars,” they said.

The investigators drew their conclusions from a study of already published material from multiple sources. They evaluated physicians based on the following

Information sources about biologic medicines

Attitudes toward and experience with biosimilars

Use of biosimilars for biologic-naïve patients

Switching between originators and biosimilars for patients already treated with biologic medicines

Thoughts on pharmacist-led substitution of biologic medicines

The studies evaluated in the investigation (N = 23) were mainly from Europe (n = 16) and North America (n = 4). The studies were published between 2014 and 2019, although most (n = 20) were published in 2017 or earlier.

Most of the physicians included in the studies, which included surveys, reported that they had at least a basic understanding of biosimilars: 5% to 44% reported high familiarity; 49% to 76%, familiarity; 2% to 25%, no familiarity.

Although many indicated they had general familiarity with biosimilars, their actual measured knowledge indicated lower levels of understanding: 18% to 66% of physicians incorrectly described biosimilars as generic medicines, and 31% to 72% incorrectly thought they were structurally identical to originator medicines. Because they are biologics and differ slightly from batch to batch, biosimilars are not structurally identical to originator medicines.   

When looking for information about biologic medicines, 25% to 84% of physicians said they turned to scientific publications; 32% to 76%, pharmaceutical companies; 26% to 75%, professional society guidelines; 17% to 71%, conferences and educational events.

The authors said physicians’ attitudes toward biosimilars appear contradictory: 6% to 38% consider  biosimilars and originator products to be interchangeable, and 28% “never think so.” Some studies indicated that 65% to 67% of physicians have concerns about biosimilar use, but other studies reported that 54% to 94% of physicians feel somewhat or very confident prescribing biosimilars.

“Regardless, a positive attitude towards biosimilars does not automatically translate into prescribing, as physicians seem to prefer originator products to biosimilars,” the authors wrote.

There are also differences between specialties. “Gastroenterologists seem to be frequent prescribers of biosimilars, while dermatologists and rheumatologists seem less enthusiastic,” the authors wrote.

Physicians tended to be more enthusiastic about biosimilars if there are robust pharmacovigilance studies to support their use, easier access to treatment for patients, or regulatory approvals in place. Disadvantages that discourage use include distrust in safety, efficacy, immunogenicity, and uncertainty about using biosimilars outside their approved indications. Quality, traceability, and tolerability of biosimilars were also concerns, along with how patients feel about biosimilars.

The physicians used multiple sources of information about biologic medicines, such as scientific publications (25%—84%), self-study (35%–84%), pharmaceutical companies (32%–76%), guidelines from professional societies (26%–75%), educational events and conferences (17%–71%), other published literature (46%–68%), physician colleagues (28%–54%), safety registries (52%) and pharmacist colleagues (19%).

Physicians (39%—89%) were more willing to prescribe biosimilars for biological drug-naïve patients rather than for those already being treated with biologic medicines. “The proportion of physicians willing to switch from an originator to a biosimilar was 51% or less, except in a single study in which the percentage was 91%,” investigators said.

“Most physicians (64%—95%) were concerned about or disagreed with pharmacist-led substitution of biologic medicines,” the authors added.

They concluded that “physicians’ knowledge of biosimilars in many cases was inadequate, and this may contribute to the low prescribing and uptake of biosimilars…. It is vital that in the near future physicians and other healthcare professionals are provided targeted, evidence-based information on biosimilars to support their uptake and to gain the full cost-saving potential of these medicines.”

A 2019 study indicated that physicians ranked savings for patients as their top 

when considering whether to use biosimilars.

Sarnola K, Merikoski M, Jyrkkä J, Hämeen-Anttila K. Physicians’ perceptions of the uptake of biosimilars: a systematic review [published online May 5, 2020. doi: 10.1136/bmjopen-2019-034183.

A retrospective study of physician surveys on biosimilars demonstrated that understanding physician attitudes toward biosimilars is crucial to improving uptake of these agents.

New Survey Looks at Physician Attitudes Toward Biosimilars

Interleukin-23 (IL-23) inhibitors are an important new class of drugs for the treatment of Crohn disease (CD) and ulcerative colitis (UC), both common causes of inflammation of the digestive tract. Johnson & Johnson’s Stelara (ustekinumab) is the only IL-23 inhibitor currently approved to treat moderate-to-severe CD and UC in the United States. Although a variety of other drugs have been approved to treat CD and UC, the effectiveness of most is limited, according to the Federal Trade Commission (FTC).

Further, biosimilar competition for Stelara is at least a few years off. The patent exclusivity on this product expires in 2023. NeuClone Pharmaceuticals of Sydney, Australia, recently 

 a phase 1 clinical trial for its ustekinumab biosimilar candidate NeuLara. This agent is under development for treatment of both CD and UC.

Another ustekinumab biosimilar candidate is 

, which Formycon, of Martinsried-Planegg, Germany, is developing. In October 2019 the company announced the start of a phase 1 clinical trial of FYB202. NeuLara and FYB202 are aimed at the formidable market dominated by Stelara, which in 2019 achieved global sales of $6.6 billion. That market is expected to reach $7.8 billion in 2024, according to 

According to the FTC, there are just 3 companies with other types of IL-23 products in late-stage development for the treatment of CD and UC. Those are AbbVie, Allergan, and Eli Lilly and Company. So, it was with consternation recently that the FTC approved the $63 billion merger of AbbVie and Allergan. The panel, which 

 3 to 2, was divided over whether the arrangements made to ensure a competitive drug market in the wake of the merger were sufficient.

In explaining its decision to require the merging drug companies to divest themselves of certain assets, the FTC explained that “The proposed acquisition would likely result in substantial competitive harm to consumers in the markets for prescription drugs for the treatment of EPI [exocrine pancreatic insufficiency], IL-23 inhibitors for the treatment of moderate-to-severe Crohn’s disease, and IL-23 inhibitors for the treatment of moderate-to-severe ulcerative colitis.”

AbbVie is seeking indications for CD and UC for its Skyrizi IL-23 inhibitor, which is currently on the market with FDA approval only for plaque psoriasis. Allergan’s brazikumab IL-23 inhibitor is under development for CD and UC. Under the merger agreement with the FTC, Allergan must transfer its brazikumab business to AstraZeneca, the initial developer of the drug. In the dissenting opinion, FTC Commissioner Rohit Chopra contended that there is not enough evidence that AstraZeneca would be aggressive about completing development of brazikumab and bringing it to market, such that it becomes a viable alternative IL-23 treatment for CD and UC.

“Divesting assets is only an appropriate remedy if the buyer will fully replace the competition lost by a merger. But, merging parties have little incentive to sell to a strong competitor and, in fact, succeed more when the buyer fails,” Chopra said. “The FTC has put its faith in a proposal that AstraZeneca, who publicly reported a few years ago that it was retreating from immunology, will follow Allergan’s path to bring this drug to market.” AstraZeneca might decide to “relicense” the product to another party, which adds more uncertainty to the idea that brazikumab eventually will come to market, he said.

In a strongly worded opinion, FTC panel Chairman Joseph J. Simmons disagreed with Chopra. “The commission must have proof that [a merger’s] likely effect is ‘substantially to lessen competition.’ We cannot meet this burden of proof just by surmising there might be harm.” Explaining that he thought Chopra’s dissent was based on flawed reasoning, Simmons said he was attempting to “set the record straight.”

“No drug development is without risk and there is no guarantee today that Allergan will successfully commercialize this product,” Simmons said. He noted that AstraZeneca will receive payment from the merger partners to cover the development of brazikumab in both CD and UC indications, and that those payments are contingent on AstraZeneca’s continuing to develop brazikumab in each indication. He said AstraZeneca will be incentivized to bring the drug to market by the potential for further revenue. “AstraZeneca has a stronger financial incentive to develop brazikumab than does Allergan…under the proposed settlement,” he argued.

AbbVie and Allergan account for more than 95% of the market for drugs to treat EPI, and with regard to the panel’s division over whether there would be sufficient postmerger competition in the EPI drug market, Chopra noted that Allergan drugs Zenpep and Viokace would be divested to Nestlé under the FTC brokered plan, and Nestlé is more of a specialist in food than pharmaceuticals. “Neither the board nor management have recently stated that they intend to transform Nestlé into a major player in the pharmaceutical business,” he said. “Nestle and its nutrition subsidiary cannot match Allergan’s experience and know-how.”

Simmons responded that “a company can both sell consumer products and be a formidable competitor in the pharmaceutical industry. For example, Johnson & Johnson sells Band-Aids and baby powder and is, at the same time, a major player in pharmaceutical industry.” He said Nestlé, in fact, had executive leadership with much experience in pharmaceuticals. “Nestlé has been involved in the pharmaceutical industry for over 40 years, in various iterations,” he said, noting that the company previously owned Alcon, which Nestlé built from a $280 million business in 1977 to a $40 billion operation by the time it separated from the company in 2010.

The Federal Trade Commission was deeply divided over whether the AbbVie-Allergan $63 billion merger plan would allow for a sufficiently competitive marketplace.

AbbVie, Allergan Merger Puts IL-23 Inhibitor Competition in Doubt

Following the launch of their rituximab biosimilar (Truxima) late last year, Teva Pharmaceutical Industries and Celltrion Healthcare have broadened the conditions for which this product can be used. They are also 

 their 10%-to-reference product discount on the product despite the recent arrival of a competitor rituximab biosimilar from Pfizer, which is being offered at a 24% discount.

A patent dispute with originator company Genentech held up the availability of Truxima for treatment of rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis.

 that the product is now marketed for these indications also, following FDA supplemental approval received in December 2019.

“We are proud to make Truxima available to patients and providers as a treatment option for these indications, especially as this is the only rituximab biosimilar indicated for rheumatoid arthritis,” said Brendan O’Grady, executive vice president, North America Commercial, Teva.

It was in November of 2019 that Teva and Celltrion announced the initial launch of this product in the United States for the treatment of adults with CD20-positive, B-cell non-Hodgkin lymphoma either as monotherapy or in combination with chemotherapy. The drug was also made available for the treatment of chronic lymphocytic leukemia.

The biosimilar is patterned after Genentech’s reference product Rituxan, which is approved for all of the above indications.

In January, another rituximab biosimilar (Ruxience) was 

 in the United States, this one by Pfizer. Although launched in January at a 24% discount to the wholesale acquisition cost (WAC) of Rituxan, Ruxience is not indicated for rheumatoid arthritis.

Teva, of Tel Aviv, Israel, and Celltrion, of Republic of Korea, have entered into a partnership for commercialization of Truxima in the United States and Canada. Offered at a discount of 10% to Rituxan in the US, Truxima is available through primary wholesalers at a WAC of $845.55 for 100 mg vial and $4227.75 for 500 mg vial.

Although Pfizer has offered a more attractive discount for its rituximab biosimilar, Teva Pharmaceutical Industries and Celltrion Healthcare have decided not to match that discount for their own rituximab biosimilar, which is more costly.
 