Four-Letter Suffixes May Be FDA’s Own Brand of Misleading Information on Biosimilars

Its intent was to improve tracking and reportability, but the Food and Drug Administration’s decision to employ four-letter suffixes for biosimilars may have created its own misleading information. This would be truly ironic, considering FDA’s own efforts to restrict or eliminate misleading information that could deter biosimilar utilization.

New evidence has been published recently that suggests that the four-letter suffix will likely succeed—in confusing the public and misleading consumers.

Four-letter suffixes

Interestingly, the study appeared in Diabetes Spectrum, and involved biosimilar insulins (of which none have been officially approved by the FDA). It is easy, however, to see how these findings may apply to the biosimilars approved and available for prescription in the US.

Researchers from the Johns Hopkins School of Public Health, Clemson University, and Brigham Young conducted experiments in which more than 1,300 individuals volunteered to playact the role of patients with type 2 diabetes whose glycemic levels were well controlled with a reference insulin product. They were randomized to review one of two versions of advertisement for an imaginary biosimilar insulin. One version of the ad mentioned a four-letter suffix, the other did not. The advertisements also varied in one other way: They (1) stated that the biosimilar requires a new prescription (i.e., not interchangeable), (2) did not require a new prescription from the doctor (interchangeable), or (3) did not disclose any information about interchangeability.

Participants were then required to rate the following probabilities on a seven-point scale:

  • They would ask their doctor or health plan about the biosimilar
  • They would find out more information about the biosimilar on the Web
  • The clinical effectiveness of the biosimilar relative to the reference drug
  • The degree of similarity of the biosimilar compared with the reference insulin
  • They would switch to the biosimilar

Interchangeability, Four-Letter Suffixes, and Impressions

The researchers found that these hypothetical patients would be more open to asking about or using a biosimilar when they believed it was interchangeable with the reference insulin product. If they were informed that the product did not require a new prescription from their doctor, they considered the biosimilar “more similar” to the reference product. However, in the scenario in which a new prescription was needed, the patients were more likely to use the biosimilar if it was discussed without a four-letter suffix. When the four-letter suffix was included, participants’ likelihood of switching to the biosimilar dropped significantly.

The authors concluded, “Absent the mention of needing a new prescription, adding four-letter suffixes to biosimilars’ nonproprietary names decreased participants’ likelihood of using the biosimilars.”

Let us put aside the interchangeability question, because there are no interchangeable biosimilar insulins currently approved (or biosimilar insulins or interchangeable biosimilars of any type in the US).

Since its initial draft guidance, the FDA’s rules on biosimilar nomenclature—specifically the four-letter suffix—has raised my blood pressure and the ire of many payers. Although this study does not consider the most recent iteration of the rule, which includes four-letter suffixes on new reference biologics as well, there are no suffixes applied to the reference products for insulin glargine or aspart. The researchers give ample argument to those who believe the damage has already been done.

There is little reason to believe that these research results involving diabetes should not be applicable to other diseases for which patients receive chronic treatment. However, it is nearly impossible to calculate the effect the naming system has had on actual biosimilar uptake.

The authors do suggest that FDA may have taken a wrong turn on the path to biosimilar acceptance and uptake. They wrote that “future research could examine whether the new policy translates to reducing barriers to use biosimilar insulins and whether the naming convention adds more value than complexity for patients.”

A Profile on Lesser-Known Player in the Biosimilar Space: NeuClone

On occasion, we profile some biosimilar manufacturers about whom our readers may not be familiar. This generally refers to companies that have products that are in earlier-stage research or those who simply have not been in the news as often as their colleagues. In this post, we highlight an interesting company based in Sydney, Australia.

NeuClone has been operating since 2007, with its founding CEO, Noelle Sundstrom, at the helm. The company has historically focused on clinical trial development of biologics and biosimilars. It has not yet brought a product to market, but that may change soon. On its website, NeuClone describes itself as a “clinical-stage biopharmaceutical company with an exclusive focus on the development and commercialisation of high-quality biosimilar products.”

Why you may be hearing more about this company: NeuClone’s pipeline is considerable but mostly early stage; two products (trastuzumab and ustekinumab) completing phase 1 trials in healthy volunteers in December 2019 and April 2020, respectively. Both trials used US- and EU-licensed versions of the reference products, which implies the possibility for marketing them in the US and elsewhere. The company emphasizes its conduct of clinical trials using Australian participants only, which it believes gives it some inherent advantages over other biosimilar developers.

Other biosimilars in the early-stage pipeline for NeuClone include adalimumab, denosumab, palivizumab, and pertuzumab, but also two other interesting products—nivolumab (reference product, Opdivo®) and pembrolizumab (Keytruda®) are listed as in the preclinical stage of development. These two agents account for about $20 billion in sales globally each year. Bristol Myers Squibb has registered 184 patents on Opdivo, and stated in a document from 2016 that patent expiration is likely in 2027 for the US and in 2026 for the EU. Merck, the manufacturer of Keytruda, has filed a mere 154 patents, but the main patent expiration is 2028 for both the US and EU. NeuClone has signed an agreement with the Serum Institute of India as strategic manufacturing partner for each of the above-mentioned biosimilars. NeuClone will retain marketing rights in the US and other major markets, according to a press release. In addition, NeuClone says that it has another 12 (unnamed) biosimilar candidates in early stage development. This indeed represents one of the deepest portfolios in the biosimilar industry.

If the patent thickets can be managed, nivolumab and pembrolizumab could be highly enticing oncology targets for several biosimilar manufacturers.

It will be very interesting to watch the progress and evolution of this Australian upstart.

Who Are the Key Aflibercept Biosimilar Players to Watch?

One of two biologics injected intravitreally to treat forms of macular degeneration, edema, or retinopathy, Eylea® (aflibercept) was first approved by the US Food and Drug Administration (FDA) on November 18, 2011. Originally approved as a single-dose vial, its manufacturer, Regeneron, received FDA approval of a prefilled syringe in December 2019. We covered the potential biosimilar competitors for the second product, Lucentis® (ranibizumab), in January 2020.

Eylea has significantly greater sales (and growing) than Lucentis. Regeneron reported Q4 2019 US revenues for the innovator product Eylea at $1.22 billion, which represented a 14% increase over the same quarter of 2018. Total US sales for 2019 were $4.64 billion. In its most recently reported quarter (Q2 2020), sales slipped to $1.114 billion, but this was likely attributable to the COVID-19 outbreak discouraging physician office visits. In comparison, Lucentis sales are roughly a quarter of this figure.

Aflibercept belongs to the class of vascular endothelial growth factor agents, and there are two forms currently prescribed. Eylea is indicated for ophthalmologic uses only. Zaltrap® (also known as ziv-aflibercept) was approved for use as an intravenous infusion for oncology patients to address specific cancer mutations. Regeneron and partner Sanofi Genzyme own the rights to Zaltrap.

Several aflibercept biosimilar candidates are in development, hoping to market after the 2020 US patent expiration. The following is a summary of the publicly disclosed players.   

AFLIBERCEPT BIOSIMILAR CANDIDATES

Company NameDrug NamePossible FDA Submission Dates
MylanMYL-1701PQ1-Q2 2021
Samsung BioepisSB15Q1 2022
AmgenABP 938Q1-Q2 2022
FormyconFYB203Q3–Q4 2022
AlteogenALT-L92023
Coherus BiosciencesCHS-20202024

Mylan. MYL-1701P (also referred to as M710, as part of a partnership with Momenta Pharmaceuticals) is perhaps the aflibercept biosimilar that is furthest along in the development process. It is currently the subject of a 324-patient phase 3 trial. The patients in this study, which started in 2018 and is scheduled to be completed in December 2020, have diabetes-related macular edema. Earlier this month, Momenta was acquired by Johnson & Johnson, and M710 was the sole biosimilar remaining in its portfolio. Mylan is to handle development and commercialization.  Mylan believes that it will file a 351(k) submission by early 2021, which could mean an FDA decision in early Q1 2022.

Samsung Bioepis. SB15 is an aflibercept biosimilar candidate that began a phase 3 trial on June 23, 2020. The recruitment objective is 446 participants with neovascular age-related macular degeneration, with a scheduled completion date of February 2022 (primary completion date of March 2021). Samsung completed its phase 3 trial of its Lucentis biosimilar SB11 in December 2019, which is interesting, because of the direct competition between the Lucentis and Eylea brands.

Amgen. ABP 938 is Amgen’s aflibercept biosimilar candidate. A phase 3 trial of this agent began in June 2020, comparing ABP 938 with US-licensed Eylea in 566 patients with neovascular age-related macular degeneration. The study is scheduled to conclude in July 2022, with primary results reported in September 2021.

Alteogen We first reported on theSouth Korean company Alteogen in January 2018, when it had completed preclinical testing on the investigational aflibercept biosimilar ALT-L9. The phase I trial for this aflibercept biosimilar was slated to begin October 2019 in patients with patients with neovascular age-related macular degeneration. The completion date is December 2020.

Formycon. Bioeq GmbH is responsible for managing Formycon’s pharmaceutical development program for its aflibercept biosimilar FYB203. Bioeq began a phase 3 trial on July 23, 2020 to compare FYB203 to Eylea in 400 patients with neovascular, age-related macular degeneration. With a primary completion date of August 2021, this should enable Formycon to file an application with the EMA in 2025 and/or the FDA sometime in 2022 and potential US introduction in 2023.

Coherus Biosciences. Coherus BioSciences, the maker of the pegfilgrastim biosimilar Udenyca®, is still in the preclinical development stage with its aflibercept biosimilar candidate CHS-2020. According to Coherus, clinical trials for this biosimilar is slated to begin in 2021. Based on this timeline, FDA submission may not occur until the 2024 timeframe, which could make Coherus one of the late arrivals to market.

Biosimilar Bytes

The biosimilar news streaming over the past couple of weeks has been interesting, with an important update of a crucial story to the biosimilar field. We commented on some of the more noteworthy items below.

Date Set for Supreme Court Arguments in ACA

November 10 is the date now set by the US Supreme Court to hear oral arguments over the constitutionality of the Affordable Care Act (ACA). This date will be a week after the presidential election. The Supreme Court will have to determine whether the individual mandate to have health insurance, which was removed three years ago, renders the entire ACA unconstitutional. In doing so, it could invalidate the Biologics Price Competition and Innovation Act (BPCIA), which authorizes the pathway for biosimilar approval by the Food and Drug Administration. As covered earlier in BR&R, the courts have not been in agreement as to whether the ACA can be severed from the individual mandate, and also whether the BPCIA (among other sections of the ACA) can be severed from the parent legislation. The November court date may translate to a Supreme Court decision in June 2021.

Creative Scoring System on Biosimilar Use in Europe

Industry consultant IQVIA has introduced a simple scorecard for understanding the differences among European countries regarding their approach and experience with biosimilars. Rated by level of competition, how prices have been affected, and biosimilar uptake, the scorecards have a look that is reminiscent of NCCN’s Evidence Blocks. IQVIA’s scoring system also address the sustainability of biosimilars in each country, through a number of measures. These include the type of tenders and contract length (and whether these contracts are exclusive), physician switching policies, the existence of patient incentives to use biosimilars, the inclusion of biosimilars in clinical guidelines, among others.

Celltrion Seeking Oral Infliximab Next

Last November, Celltrion received EMA approval to license its subcutaneous form of infliximab in Europe. The South Korea–based biosimilar maker isn’t stopping there. It recently announced that it is in the early phases of developing an oral form of infliximab, as well. An oral form could well have a dramatic effect on the market for this drug (along with some gastrointestinal side effects that often accompany the transition to this route of administration).

Although Celltrion has not mentioned any intention of bringing this oral product to the US market, it does intend to submit a 351(a) application for FDA approval of the subcutaneous form. That approval could upend the biosimilar market for infliximab (depending on pricing), because of its implications on site of care as well as pharmacy versus medical benefit management.  

In other Celltrion news, it is starting phase 1 clinical trials of CT-P41, a biosimilar version of denosumab for the treatment of osteoporosis. This biosimilar is not expected to complete clinical trials until 2025, with a marketing application submitted in 2026.

Johnson & Johnson Purchases Momenta

Johnson & Johnson announced on August 24 that it has entered into a definitive agreement to acquire Momenta Pharmaceuticals, Inc, formerly a player in the biosimilar market for $6.5 billion. Momenta still has one biosimilar under development, M710, which is a biosimilar version of aflibercept (Eylea®) to treat wet age-related and diabetic macular degeneration. This agreement places J&J in bed with Mylan, which was contracted to develop M710 on Momenta’s behalf. Mylan confirmed in late February that it is still moving forward with development of the agent, also known as MYL-1701P. A phase 3 trial in the treatment of diabetic macular degeneration is scheduled to be completed in December 2020 (primary completion was in February), and Mylan says it expects a 351(k) submission by early 2021.

AAM Names New Executive Director

On August 25th, the Association for Accessible Medicines (AAM) announced that its new President and Chief Executive Officer will be Dan Leonard, former President and CEO of the National Pharmaceutical Council (NPC). Mr. Leonard takes over for Chip Davis, whose tenure with AAM ended in February.

Carol Lynch, President, Sandoz US and Head, Sandoz North America, and Vice Chair of the AAM Board of Directors, said in a press release, “We are confident that Dan will lead the association’s talented team to support our work with the Administration and Congress to further secure the pharmaceutical supply chain and create market conditions that will ensure the long-term viability of the generic and biosimilars industry.”

Employers, Biosimilars, and Pharmaceutical Benefits: Something’s Gotta Give

This week, we asked veteran employer benefit advisor and consultant F. Randy Vogenberg, PhD, RPh, to write about the employer’s role in encouraging the use of biosimilars. Dr. Vogenbergs’ recent work with business coalitions and individual employers around the management of the medical or drug benefit, and specialty pharmaceuticals in particular, allows him to address the key reasons employers have not been early advocates for the greater biosimilar uptake.

Over the last several years, the number of biologic drugs being approved by the FDA for the treatment of chronic and rare diseases has outpaced the number of approvals for conventional small- molecule agents. Typically priced at higher than these non-biologic drugs, the cost impact of biologic drugs has become a major concern among employers with self-funded or fully funded health plans. Although employers value vendor management for these drugs, their high claims costs have prompted many employer coalitions to target biologic spending for action.

Randy Vogenberg, employers and biosimilars
F. Randy Vogenberg, PhD, RPh

The scientific issues involving the development of biosimilars were sorted out years ago, allowing the FDA to evaluate and approve biosimilars versions of branded (reference) biologic drugs. Former FDA Commissioner Scott Gottlieb, MD, was a champion of biosimilars, and that momentum has not been lost with his departure, according to Juliana Reed, MS, Vice President and Global Corporate Affairs lead for Pfizer, one of many traditionally branded companies (such as Amgen, Sandoz/Novartis, Merck) now marketing biosimilars.

Why Have Employers Not Embraced Biosimilars?

Several lessons can be learned from the marketing of generics, which received a big boost from the Hatch–Waxman Act of 1984. Provisions of that legislation spurred the development of generics while preserving incentives for innovator companies to develop new products. Hatch–Waxman kept the United States in the forefront of drug innovation but also enabled tremendous savings. Today, 89% of prescriptions filled in the US are with generic drugs. On the other hand, the value proposition for biosimilars remains mired in benefit transactions managed primarily by third-party vendors with little to no oversight by their employer clients. Employers have not strongly asserted their pharmaceutical benefit management oversight and their ability to leverage biosimilars as part of their benefit strategy. Additionally, employers have been confused early on about which biosimilars were available for use, owing to patent litigation. Opaque rebate agreements and pricing differentials have contributed to delays by employers in expanding biosimilar coverage and allowed vendors to keep the status quo.

Another key point is that aside from the above issues, employers cannot quickly make changes to benefit policies. Benefit policy alterations can require 2 to 3 years for implementation and communication, meaning that corporations may experience significant delays before biosimilars savings are registered.

Overall, these issues have led us to the current day situation, where we have lost considerable cost-saving opportunities from the introduction of biosimilars.

Right now, biologic products represent the minority of all prescriptions dispensed in the US, but a major driver of total benefit spend. And that latter figure is growing as the number and claims cost of prescriptions increase along with new biologic products approved by FDA. According to industry estimates, the US purchases 60% of all biologics globally, but 90% of all biosimilar sales occur in Europe. Typically, employers receive reports from their PBMs on top drug spending. Often, anywhere from four to seven of those most costly drugs will be biologics. However, biosimilars for these drugs have yet to achieve more than a toehold in the US marketplace. That represents a very significant savings being missed by employers and not registered on their balance sheets. Furthermore, this also results in higher out-of-pocket monies paid by their plan members.

What Employers Can Do

Since 2010, the National Employer Initiative on Specialty Drugs, led by Midwest Business Group on Health with the Institute for Integrated Healthcare, began addressing employer concerns about the costs of biologic or specialty drugs while supporting the clinical outcomes they have been able to achieve in patient care. In 2018, the Employer–Provider Interface Council (EPIC) of the Hospital Quality Foundation (HQF) was launched to assist more directly in making market change happen on a number of key benefit plan challenges, including coverage of biologics and biosimilars.

Employers can take action in their own benefit plans and support efforts by others. One way is to incentivize biosimilar uptake, by introducing policies that cut patient out-of-pocket costs, share savings with providers who prescribe biosimilars, and increase the average sales price add-on paid to physicians for biosimilar purchases. Additionally, employers can target anticompetitive practices that can cause patients and providers to lose confidence in the safety and efficacy of biosimilars despite the fact that FDA approval assures that biosimilars are as safe and efficacious as originator drugs.

Employers should refocus on changing their own benefit plan. This includes checking contracts for policy language that does not disadvantage biosimilars (or instead prefers them); auditing PBM coverage recommendations; designing biologic and biosimilar elements of coverage language in the vendor-contracting strategy; determining if site of care strategy is beneficial to your company, as many biosimilars may be prescribed by care setting; and a continuous communication strategy executed to all plan members about biosimilar coverage and what it means to the employee plan member.

From the employer’s perspective, the future of pharmacy benefit design should include at least three consistent elements: (1) formularies based on clinical efficacy, not rebates, discounts, exclusive contracts, or narrow networks; (2) drug costs based on net amounts, preferably at the time of dispensing or use; and (3) clinical outcomes balanced with drug costs to maximize savings with the highest quality of care possible. For employers as plan sponsors, the science and economics of biologic therapies illustrate clearly that doing nothing is no longer an option.

___________________________________________________________________

F. Randy Vogenberg, PhD, RPh, is principal of the Institute for Integrated Healthcare (IIH), Greenville, SC, where he focuses on commercial employee benefits, care delivery and outcomes research, education, and strategic benefit consulting on medical-legal, clinical, or economic issues in commercial health care. He currently serves as Co-Leader, National Employer Biologics & Specialty Initiative with the Midwest Business Group on Health. His most recent publication, Integrated Pharmacy Benefits for Specialty Pharmaceuticals: Access and Management, was published in 2019. e-book.

The Next-Generation Biosimilar Race: A Tale of Two Autoimmune Biologics

To date, prospective biosimilar makers have had plenty of chances to hone their business skills. They have calculated opportunity costs, projected constantly updated financial projections, worked their legal departments and partners overtime, and tested new communication skills with the FDA. Among the factors that manufacturers have to address when deciding on new biosimilar targets: patent dances and mazes, commercialization partners (if they don’t do it themselves), potential competition from other biosimilars, and of course potential risk (i.e., investment) versus reward (i.e., revenue). Overall, this can be a test of both the manufacturers’ and payers’ patience.

Drug rebates

When considering biosimilar targets, it makes sense to follow the money. Focus on today’s high-revenue products that can support acceptable sales for multiple competitors. In other words, one cannot expect to obtain approval and remain the sole biosimilar manufacturer for a product with annual US sales of $1.5 billion.

The autoimmune space is one of most lucrative in terms of pharmaceutical sales. To a great degree, this is attributable to the performance of Humira®, Enbrel®, and Remicade®. However, the later wave of entrants, including other TNF-inhibitors and the interleukin products have also posted sales of $1 billion or more.

This article addresses two specific products with impending patent expirations, one with multiple potential biosimilars and one without. The biosimilar candidates are not listed in any particular order or ranking.

USTEKINUMAB (STELARA®) BIOSIMILARS IN DEVELOPMENT

The main patent for Stelara expires in September 2023 in the US (January 2024 in Europe). Whereas the US sales of Janssen’s product were a prodigious $4.3 billion in 2019, EvaluatePharma estimated that this could be 80% higher (or $7.8 billion) by the time of patent expiration. On that basis alone, it should be a highly attractive target for biosimilar development.

Ustekinumab is an interleukin 12/23 inhibitor, and it was first approved in September 2009 for the treatment of plaque psoriasis, after an initial filing in 2007 and FDA complete response letter in 2008. Janssen received subsequent approvals for psoriatic arthritis and Crohn’s disease. Janssen has filed 54 patents on the reference product.

Formycon AG. Formycon partnered with Aristo Pharma GmbH on the manufacture and testing of this interleukin 12/23 inhibitor (also known as FYB 202). This product is in early-stage analytic evaluation.

Celltrion. Experienced biosimilar player Celltrion seems to have begun phase 1 trials earlier this month for its ustekinumab biosimilar candidate CT-P43, The trial of 270 healthy volunteers, which will include US- and EU licensed versions of Stelara, is scheduled for completion in February 2021. Interestingly, Celltrion does not include this investigational biosimilar on its pipeline page.

NeuClone Pharmaceuticals. Australian firm NeuClone has a biosimilar product (referred to as NeuLara). According to the company, it has successfully passed the analytical and characterization stage of development and has obtained positive preliminary results of its phase 1 study (though not listed in http://www.clinicaltrials.gov). This study included 200 healthy volunteers who received doses of the biosimilar or US- or EU-licensed Stelara. The final clinical study report is anticipated in the third quarter of 2020.

Bio-Thera Solutions. Bio-Thera Solutions, based in Guangzhou, China, has just begun a phase 1 clinical study on its biosimilar BAT2206. It is not clear whether the biosimilar, if successful, will be commercialized in the US, and with any potential marketing partner.

Alvotech. Only recently announced, Alvotech had signed a commercialization agreement with Teva on its full pipeline of 6 biosimliars, including adalimumab, and likely, ustekinumab. There is no indication as to whether Alvotech’s potential biosimilar has made it past the analytic and characterization stage of development.

Celerion AG. A poster presented by Celerion in 2018 announced a successful evaluation of similarity between an investigational biosimilar ustekinumab and the reference product (EU and US versions). However, it is unknown as to whether this product was developed by Celerion or the study was completed on behalf of another manufacturer. Celerion’s primary role seems to be that of a contract research and manufacturing organization.   

CERTOLIZUMAB PEGOL (CIMZIA®): ANOTHER STORY

First approved in April 2008 for the treatment of moderate to severe Crohn’s disease, UCB’s Cimzia (certolizumab pegol) patent expires in the US in 2024 (2021 in the UK). The product is PEGylated anti-TNF-alpha antibody (more precisely, a PEGylated Fab fragment).

In 2019, UCB received approval for use of Cimzia in nonradiographic axial spondyloarthritis. It was subsequently approved for the treatment of rheumatoid arthritis, plaque psoriasis, UC, adults with active psoriatic arthritis, and adults with active ankylosing spondylitis. It is not indicated for use in pediatric patients.

There seems to be little difference in efficacy or safety outcomes between certolizumab and adalimumab for the treatment of rheumatoid arthritis.

Eons ago (in 2017), only one prospective biosimilar manufacturer (Pfenex) had indicated certolizumab was part of its pipeline. Today, even that may not be the case. Pfenex is no longer playing in this space (and in fact, Ligand announced on August 10 that it would purchase Pfenex) , and a search for publicly available information reveals only one biosimilar in preclinical trials (from Xbrane). It is not yet known if Xbrane intends to market the product in the US (it announced an agreement with STADA in May 2019 for commercialization of the biosimilar in the EU and other countries). We may assume that Xbrane would likely partner with another company if it is to commercialize the drug in the US as well.  

For the first half of 2019, UCB reported US sales of Cimzia of approximately $560 million, with global sales of $915 million. This would put annual US sales at around $1.1 billion. By 2024, estimates put that figure closer to $2 billion in the US alone. Drug Patent Watch indicates that UCB has 85 patents associated with the agent.

Although the sales figures are rather modest next to behemoths in the autoimmune space like Humira and Enbrel, it should certainly have an appeal to biosimilar manufacturers. However, there is a curious lack of interest (publicly stated interest, anyway) for this reference product. Joshua Whitehall at Goodwin (publishers of Big Molecule Watch, which he edits) confirmed for us that currently no patent litigation is pending within the US involving Cimzia.

One thing we do know. The competition hasn’t scared anyone off. For now, Xbrane could have a rare, lucrative opportunity in the US market.

(Note: this article was updated on August 18th to include information on Celltrion’s CT-P43).

A Profile of a Lesser-Known Player in the Biosimilar Space: Alvotech

On occasion, we profile some biosimilar manufacturers about whom our readers may not be familiar. This generally refers to companies with products that are in earlier-stage research or those who simply have not been in the news as often as their colleagues. In this post, we highlight the European manufacturer Alvotech. The drug maker has its main headquarters and manufacturing facility in Reykjavik, Iceland, with other centers in Germany, Switzerland, and in the United States.

Established in 2013 by its current Chairman, Robert Wessman, Alvotech exists to develop and produce biosimilars. Mr. Wessman also founded the generic manufacturer Alvogen, which is based in New Jersey (and founded in 2009). Alvotech does not currently have any marketed proprietary agents. However, it does promote its contract biologic manufacturing capabilities.

Why you may be hearing more about this company: Alvotech has just signed a commercialization agreement with Teva for its entire pipeline of six biosimilars. The lead product seems to be a biosimilar of adalimumab (AVT-02), and this agent was the subject of 6 clinical trials. Alvotech’s website does not list the other biosimilars in its pipeline, and none of the others seem to be in early-stage clinical trials. The phase 1 and 3 trials of AVT-02 seem to be completed. The Alvotech/Teva partnership gives Teva a stake in a crowded adalimumab biosimilar field (seven adalimumab biosimilars already licensed by AbbVie to launch in 2023). We assume that Alvotech will also join the licensing queue with AbbVie in order to launch in 2023.

In other biosimilar news…Pfizer’s Inflectra® sales, though generally considered “anemic” in the US at only a 10% marketshare, have actually outearned EU sales of the drug. Ronny Gal, PhD, of Bernstein Research was quoted in FiercePharma, explaining that Inflectra holds 30% of the EU market but only earned second-quarter 2020 revenues of $116 million, because it sells at a much lower price than in the US. In comparison, second-quarter US sales were $158 million. To put this into some perspective, that means annualized sales of more than $500 million, which would more than cover its research and development costs, despite the poor market penetration.

Delving into Misleading or Disparaging Information on Biosimilars

The presence of misleading information on biosimilars, along with outright false statements, continues to pester the biosimilar industry. This situation repeats the marketing efforts of branded medications in the 1980s as it attempted to fight off the insurgence of generic drugs. And it is very important to note that there are still, 35 years later, people who do not fully accept that generics are expected to provide the same clinical efficacy and safety as the branded drug. No one really expects that only by 2050 will biosimilars be fully accepted. Yet, the longer misinformation exists, the more difficult it will be to gain full acceptance of biosimilars.

misleading biosimilar information

Recognizing the problem, the US Food and Drug Administration and the Federal Trade Commission announced a collaboration to combat false and misleading information about biosimilars.

Last week, Hillel P. Cohen, PhD, Executive Director of Scientific Affairs, Sandoz, and Dorothy McCabe, PhD, Executive Director, Specialty Medicine: Immunology, Biosimilars, and CNS, Boehringer Ingelheim, published an important article in BioDrugs that delves into the nuanced types of disparaging and misleading information as well as the context that may contribute to negative connotations of biosimilars. Yes, we just quoted Dr. Cohen on interchangeability in the past week, and have done so many times in the past. He happens to be one of the smartest and quotable experts in the biosimilar arena.

The article by Drs. Cohen and McCabe provided an opportunity to amplify the statements he made at the March 2020 conference announcing the FDA-FTC collaboration.

TOTALITY OF EVIDENCE: TOTALLY CONFUSING?

Unintentionally, the FDA may have contributed a bit to this lack of clarity. The agency has long emphasized analytical, structural, and physiochemical comparisons in the biosimilar review process, and its use of clinical studies only as a validation tool. It relies on the term “totality of evidence” to describe the basis for approval. However, for most people, this term does not describe the types of evidence or the veracity of the data being assessed. In an interview, Dr. Cohen said he actually feels differently: “I happen to think that totality of evidence is a good term. There are simple ways in which it can be explained such as meaning all evidence, not just clinical data. So, while it’s a bit of a challenge, I think totality of evidence is a term and concept that can be explained well.”

EUROPE’S PREVENTIVE TACTICS

Misleading information and false representations about biosimilars no doubt circulate. Some biosimilars such as Sandoz’ biosimilar filgrastim are doing well as the market leader in its category, but at present one class of marketed biosimilars—infliximab—has low marketshare. The rebates offered by Janssen Pharmaceuticals to protect Remicade®’s 85% share accounts for a large portion of this effect. Dr. Cohen cautioned, “We are not claiming in this article that biosimilar disparagement and misinformation is the sole or even primary reason for the slower than anticipated uptake of some biosimilars. We are saying it’s a contributing factor.

With the damage threatened by misleading information, we reflected back on the European experience. Did the European Medicines Agency foresee this to be a problem, and what steps did the organization take to address it? Dr. Cohen explained, that the Europeans took a different approach. “The European Medicines Agency and the European Commission together commissioned two major documents on what physicians should know and what patients should know.” He explained, “They pulled together the EMA, health authorities from individual countries, professional societies, manufacturers, and patient groups.

“It was a multiyear effort, and resulting basic education, background documents were issued maybe five or six years ago; they were actually just recently been updated,” he said. “Then it was the responsibility of each country individually and the professional societies in each country individually to take on biosimilar education. Biosimilar uptake in Europe varies widely from country to country.”

BREAKING DOWN MISINFORMATION

One real value of this article is that it analyzes the types of disparagement and misinformation by type of category:

  • Statements about biosimilar science or policy that are factually incorrect
  • Misleading information, where the information is correct but is provided out of context
  • Incomplete information, where only partial or a limited set of facts are provided
  • Creation of a false narrative, especially in scientific and medical literature, that provides a set of references to support incorrect conclusions
  • Negative framing of factual statements to create a negative perception

“Unless you understand what’s out there, you can’t begin to counter it,” Dr. Cohen said. “We’ve referred to ‘whisper campaigns’ and we have been talking in general terms about things being misunderstood or aren’t being explained well. From everything that we’ve seen in the past several years, it’s not really just one big category. There are different types and different things that are being said, from flat out incorrect statements (which is not the biggest piece) to negative framing of factual statements.”

He continued, “Negative framing is a very big issue and another one is false narratives. I mean, we’re still hearing people saying the issue of switching from reference biologics to biosimilars is unsettled. [The latest research from Barbieri and colleagues] reviews 178 switching studies and found no new safety or efficacy concerns, and some people still say, “Oh, still not enough.”

Even the language derived from the BPCIA, that use of a biosimilar will result in no “clinically meaningful difference” compared with the reference product contains elements of negative framing. Instead, FDA could frame the language in a positive sense, saying, “it gives you the same safety and effectiveness,” suggested Dr. Cohen. 

A MORE RAPID LEARNING CURVE

Returning to the question of when (and how) the general public will understand usefully the place of biosimilars, Dr. Cohen told us, “I would like to think that uptake and acceptance of biosimilar will be more rapid [than generics]. To some degree, if people think of biosimilars as ‘like generics’ but not quite the same, that will provide a decent level of understanding and maybe enable biosimilars to be accepted more quickly.”

Interchangeability, Switching, and What Happens Next

On July 24, 2020, we still await the first FDA-designated interchangeable biosimilar. This may not be a surprise: All of the biosimilars launched to date are administered in the physician’s office, hospital, or outpatient clinic. Without pharmacy distribution, there can be no automatic substitution, the prize at the end of this journey.

The last time we addressed interchangeability in earnest on this piece of Web real estate was more than 2 years ago. Then, in October 2018, we followed Boehringer Ingelheim’s quest for the elusive designation for Cyltezo®. The company’s phase 3 VOLTAIRE-X study was underway. The hope was that this pharmacokinetics and switching trial would check the remaining boxes for FDA.

Molly Burich, MS

In that article, we interviewed Molly Burich, MS, Boehringer’s Director of Public Policy. The listing on the government’s ClinicalTrials.gov website indicated a study completion date of July 2020. In preparing to write today’s post, a visit back to the VOLTAIRE-X page noted that the trial was actually completed in April 2019 after enrolling 259 patients. Unsure of whether there was an error, we reached out to Ms. Burich earlier this month, who confirmed that the study was indeed completed. “We’re in the process of submitting data for presentation,” she said in an Email. “We continue to have conversations with the FDA to confirm next steps for filing for the designation.”

Not reading very deeply into the response, it is clear that an official filing has not yet occurred. The purpose of this article is not to speculate on the content of those conversations between the FDA and Boehringer. The wait continues. There is really no rush, however: Cyltezo’s launch is not scheduled until July 2023, and no other manufacturer of an eligible biosimilar has publicly announced the intention to seek the interchangeability designation.

SWITCHING, INTERCHANGEABILITY, AND OFFICE-ADMINISTERED BIOLOGICS

For now, the problem boils down to whether a Part B or office-administered biosimilar product can be easily and safely switched for a reference product. Today, it is no longer a question of safety—ample evidence exists to support the use of biosimilars in place of originator drugs. This point was driven home and put to bed by Barbier and colleagues’ May 2020 review of 178 biosimilar switching studies. This analysis revealed virtually no adverse events or drop in efficacy amongst the trials.  

Hillel P. Cohen, PhD, Executive Director, Scientific Affairs, Sandoz, went one step further today, stating during an Academy of Managed Care Pharmacy webinar, “From a science standpoint, there is really no reason why one biosimilar cannot be switched for another.” He indicated that there were perhaps 3 peer-reviewed studies and 3 abstracts (regarding filgrastim, infliximab, and etanercept) studying this question.

Biosimilar Market Success
Hillel Cohen, PhD

One reason for the more limited evidence of biosimilar-to-biosimilar switching is the small number of drug categories with sufficient competition. This is growing, with the addition of multiple trastuzumab and bevacizumab biosimilars launching in the last 12 months. Biosimilar-to-biosimilar switches will likely be the more important topic henceforth, as individual payers begin to prefer one biosimilar to the reference product or another biosimilar. When people inevitably switch health plans over time, biosimilar preferences, as listed on the drug formulary, will change.

Without an interchangeability designation and a strict policy, biosimilar coverage policies are still being enacted. Some payers, like Kaiser Permanente, are demonstrating a clear preference for biosimilars over reference products. The extent to which these policies apply to treatment-naïve patients and established patients vary, but in Kaiser’s case anyway, the health plan expects all patients to be switched to the preferred biosimilar.

Without this type of commitment, biosimilar switches may more likely be driven by patient–physician conversations, particularly around out-of-pocket costs. As Dr. Cohen emphasized in his presentation, interchangeability is only a regulatory construct. “Physicians can prescribe whatever product they believe is appropriate for their patients.” If they believe that a biosimilar is interchangeable or “switchable” with a reference product, they don’t have to wait for the FDA to issue an interchangeability designation. They just have to believe that prescribing the biosimilar product (whether covered by the medical or the pharmacy benefit) is in everyone’s best interest.

Overall, there seems to be less physician resistance to biosimilars in the US than a few years ago. It is more a question of physician incentives to prescribe them (or patients to request their use). The ability to employ interchangeability is in the hands of physicians. The ability to mandate switching is in the hands of whoever makes the coverage decision.

Adalimumab Biosimilar Approval for Mylan and Fujifilm Kyowa Kirin

On July 6, the Food and Drug Administration approved partners Mylan/Fujifilm Kyowa Kirin Biologics’ biosimilar version of adalimumab for use in patients with autoimmune diseases. Officially dubbed Hulio® (adalimumab-fkjp), this 28th approved biosimilar will be first available for prescription in August 2023, based on the licensing deal Mylan signed previously, making it the fourth adalimumab biosimilar to launch.

Hulio approval

The drug was first approved in the European Union in October 2018, and has launched there. The FDA approval was partly based on the results of a phase 3 clinical trial in patients with rheumatoid arthritis, comparing Hulio with AbbVie’s reference product. The investigation found no meaningful differences in outcomes, safety profile, or immunogenicity between the agents.

According to the approved labeling, Hulio received approval for seven indications, including rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, ulcerative colitis, and plaque psoriasis.

Interestingly, Mylan had at one point its own adalimumab candidate, MYL-1401A, which was the subject of a phase 3 trial completed in 2017. Mylan signed its agreement with Fujifilm Kyowa Kirin in time to join the European launch of Hulio, and it focused its attention on getting the latter’s adalimumab version, designated FKB327, approved in the US.

In other biosimilar news…In a case that may mirror the internationally publicized retraction of COVID-19 papers relying on a healthcare database, the results of a study in Toxicology and Applied Pharmacology are being questioned. The study claimed a higher incidence of side effects for several biosimilars available in India compared with the reference product Neupogen®, but the study methods and reliance on a specific database have been criticized.