Podcasts

Key 2020-2021 updates to the Guide to Biosimilars litigation and Regulation in the US encompass antitrust litigation, preliminary injunctions, and a slowdown in litigation.

Not So Different: Goodwin Attorneys Discuss Updates to Biosimilars Litigation Guide

Tony Hagen is senior managing editor for The Center for Biosimilars

Articles

Minnesota legislators introduce what could possibly become the first law to curtail payers' rights to determine which biologics patients have access to.

Minnesota Moves to Override Payer Preferences on Biosimilars

Videos

Lalan Wilfong, MD, an expert on value-based care, explains how Texas Oncology worked with physicians and payers to make biosimilars available for patients.

ACCC Virtual: Dr Wilfong of Texas Oncology Discusses Biosimilar Integration

Here are the top 5 biosimilar articles for the week of March 1, 2021.

The Top 5 Biosimilar Articles for the Week of March 1

Investigators evaluated trial spending and reasons for biologics license application failures. 

Study: Biosimilar vs Originator Spending on Comparative Efficacy Trials

Fresenius Kabi, a Bad Homburg, Germany-based biopharmaceutical company with global operations, mapped out an ambitious biosimilar launch program as it released 

data that showed a 4% decline in net income ($2.2 billion) and 2% growth in sales ($44.0 billion) for 2020.

The company expressed confidence in its potential to make biosimilars an exceptional driver of income in the near future, although company executives described “unprecedented challenges” over the past year of the coronavirus disease 2019 (COVID-19) pandemic that affected performance.

“I am convinced these times will reward corporates who can draw resilience from their large critical infrastructure and well-proven business models,” said Stephan Sturm, CEO, in an investor presentation.

Fresenius has an adalimumab biosimilar that has been launched in 22 countries, most recently 

. In the second quarter of 2021, the product will be launched in Australia; and in the third quarter, Brazil. A US launch is planned in 2023.

The company said its biologics license application for a pegfilgrastim biosimilar was accepted by the FDA and European Medicines Association in May 2020. In those markets, the product is intended to launch in a prefilled syringe in the third quarter of 2021. In 2022, Fresenius hopes to launch a pegfilgrastim on-body injector, a device that has enabled the originator company, Amgen, to capture significant 

“Even though the prefilled syringe launch is important, the planned on-body device market entry is financially significantly more meaningful for us,” Sturm said.

The company has previously announced plans to bring a tocilizumab biosimilar to market, and the anticipated launch date is 2023 in the US and EU markets for subcutaneous and intravenous versions of this. The tocilizumab biosimilar would reference Actemra, for the treatment of rheumatoid arthritis. “The financially more meaningful market for us is the subcutaneous dosage form, since we are currently assuming to lead the competition here,” Sturm said.

Autoimmune biosimilars and an oncology biosimilar are slated for launch in 2024 and 2025, respectively, in the US and EU markets, although further description was not provided in the investor presentation.

Whereas biosimilars are an increasingly important part of Fresenius’ growth strategy, the company has a broad portfolio of therapeutic products in oncology, diabetes, critical care, liver and renal insufficiency, among others.

The Germany-based company with global operations plans to ramp up its biosimilars portfolio through 2025. 

Fresenius Kabi Maps Out Biosimilar Strategy

Frontline use of rituximab biosimilars plus chemotherapy in patients with follicular lymphoma (FL) is more costly than a regimen of obinutuzumab (Gazyva) plus chemotherapy, investigators reported, based on a decision-analytic modeling 

The study was conducted by assuming biosimilar rituximab agents were used in place of reference rituximab in the GALLIUM trial, which evaluated originator rituximab (Rituxan) vs obinutuzumab, both in conjunction with chemotherapy in the upfront setting. Rituximab is an older therapy, approved for first-line treatment of FL in 1997, and obinutuzumab was approved for advanced untreated FL in 2017.

provided evidence for longer progression-free survival (PFS) for patients with untreated, advanced FL who received the obinutuzumab regimen (G+chemo) vs the rituximab regimen, although grade 3-5 adverse events were more numerous with obinutuzumab. The 3-year PFS results from GALLIUM were 80.0% vs 73.3% for patients on G+chemo vs the rituximab regimen, respectively (HR 0.66; CI, 0.51-0.85; 

Investigators used GALLIUM as a model to evaluate potential savings and improvement in quality adjusted life years (QALY) for the rituximab biosimilars Truxima (Ra+chemo) and Ruxience (Rp+chemo). In the context of QALYs gained and cost savings that accrued from delayed disease progression, G+chemo proved to be the more cost-effective treatment, they said.

The model suggested that G+chemo would result in longer PFS and overall survival vs the rituximab biosimilar–based regimens 

. Although the overall cost of rituximab-biosimilar plus chemo options was less than for G+chemo, the incremental cost effectiveness ratio (ICER) for G+chemo was within commonly accepted thresholds for cost-effectiveness.

“Our results from the model indicate that G+chemo continues to offer good economic value, including improved patient outcomes, compared with R+chemo or equivalents based on rituximab biosimilars, and that value-based policy decisions should consider G+chemo as standard of care for patients with untreated FL,” the authors wrote.

A chief factor driving the cost-effectiveness outcome for G+chemo in GALLIUM was the “significant and clinically meaningful difference in PFS,” which the authors noted contributed to the additional QALYs deriving from use of this regimen.

Second, although the incremental costs of G+chemo vs Ra+chemo ($26,978) and Rp+chemo ($21,562) were higher, these differences were not high enough to undermine willingness to pay for the higher cost treatment, based on QALY thresholds. By contrast, in the original GALLIUM trial, the ICER for G+chemo vs the originator rituximab product plus chemo was $2300.

In addition, a cost savings of $7050 was attributed to the delay in disease progression afforded by G+chemo regimen.

Spencer SJ, Guzauskas GF, Felizzi F, et al. Cost-effectiveness of obinutuzumab versus rituximab biosimilars for previously untreated follicular lymphoma. 

. Published online February 17, 2021. doi:10.18553/jmcp.2021.20424.

Although a more costly medicine, obinutuzumab proved more cost-effective over the long run than rituximab biosimilars in follicular lymphoma.

Rituximab Biosimilar Regimen Fails Cost-Effectiveness Test in FL

Communicating the essentials of biosimilars to patients requires background knowledge and the right approach. These lower-cost agents have the potential to save money and improve access to care, but this can be of no avail if patients don’t get the information they need the way they want it.

Gary H. Lyman, MD, MPH, is an oncologist, hematologist, and public health researcher who has long been an advocate for biosimilars and, indeed, has developed guidelines in support of using these biologics for the treatment of cancer. In a recent interview, he shared his insights on conducting the patient-provider conversation about biosimilars and how physicians can prepare themselves to succeed with this encounter.

Lyman is co-director of the Hutchinson Institute for Cancer Outcomes Research in Seattle, Washington; a full member of the Division of Public Health Sciences at the Fred Hutchinson Cancer Research Center; and a professor of medicine and medical oncology at the University of Washington. 

CfB: What’s missing from the patient-physician biosimilar conversation, and what are the essentials of communicating a patient’s biosimilar options successfully?

 I’m speaking primarily from an oncology perspective, but I’ve been involved with biosimilars from day 1. It’s important to focus on education and convince patients and providers about the enhanced regulatory process for molecular characterization, both structurally and functionally, of these agents. It’s far more sophisticated than it was 20 years ago when the first biologics were approved based largely on clinical comparative trial data. The FDA, and I’m in support of this, feels that there is sufficient depth of clinical data for demonstrating efficacy and safety once you fully characterize the molecule and its structural [and] functional characteristics and critical quality parameters. There are now dozens of these that the FDA is using to classify these biosimilars as highly similar to the originators.

Biosimilars get approved with data on pharmacokinetics, pharmacodynamics, and immunogenicity, and these trials are often done in patients with disease, but also in healthy volunteers, because at least in the oncology space, problems may not be as apparent in an immunocompromised patient who has been on chemotherapy or radiation therapy. Clinical comparative data are used to fill in any gaps of remaining uncertainty about the safety and efficacy of these agents to demonstrate that they are essentially the same as the originator molecules.

When talking with the patient, the challenge is to communicate a lot of this comfort with the regulatory process and the integration of biosimilars into treatment guidelines. ASCO has recently published an updated guideline in early stage breast cancer and [human epidermal growth factor receptor 2]–positive breast cancer that basically said the 5 approved trastuzumab biosimilars in the United States can be used equally or alternatively to the originator [Herceptin] without any concern about loss of efficacy and safety.

We have all that, and I communicate that to patients, along with my personal comfort with these biosimilars. But patients have many different levels of background and education, and the challenge is to communicate this information in a simple, nontechnical fashion. Many doctors don’t understand some of the terms, such as 

. Even if the doctor has a science background, communicating biosimilar information to patients in any kind of depth is going to be a big challenge. We’ve encouraged professional organizations and health systems to develop targeted educational materials, such as pamphlets, that summarize these points in lay language.

It’s also important to make clear that no major safety issues have been raised with biosimilars. There has been no withdrawal of agents from the market. We really need to reassure patients that the experience to date tells us that these are safe and efficacious. 

I do tell patients that biosimilars are approved with less clinical data than was used to approve the original agents, but those reference products were approved years ago when our technology was not nearly as good. Even so, there could be rare or delayed adverse events that emerge that you did not see in the limited clinical data used for biosimilar approval. I tell the patient, even if it seems unrelated to your treatment, let us know. We need to know if you’re having any unexpected symptoms or signs or concerns as time goes along.

Of course, the FDA is doing a lot of postmarketing surveillance of these agents. Each biosimilar is given a random 4-letter suffix that is used to track the performance of these products very closely. For Herceptin and the 5 approved biosimilars, you want to know which was given to the patient who developed a rash or some adverse event, and you can do that by being able to go back to the specific name and label given the biosimilar. But it’s traceable, and with the data capture, through patient-reported/physician-reported adverse events to the FDA, and just patients telling their doctor about problems, we hope that anything that’s slipped through inadvertently can be tracked and quickly pinned down if it has anything to do with the drug patients have received. Communicating all of this to the patient in a nontechnical fashion is a challenge.

One other issue is that biosimilars are biologic substances that cannot be reproduced exactly like a generic, and that’s one of the starting points I take with patients in communication. Biosimilars are not produced like generics in a test tube in the laboratory They’re produced in living systems like the originator biologic, and small differences will inevitably occur. And over time, there can be what we call drift in the structure and functional nature of these molecules.

Any small change in manufacturing, in the components that go into manufacturing these agents, could potentially change the molecular structure of these, although mostly this will not impact  the functionality or the toxicity of these agents. You cannot assume that automatically, so the FDA mandates that changes in components or processes of the biosimilars and originator products be reported and evaluated to make sure no critical aspect of the molecule has been changed. I think everybody’s very much attuned to making sure that we track these molecules, these biologic substances, over time to make sure they’re the same as the original.

It’s very difficult in a 15-minute office visit to communicate this level of information, and even physicians are not necessarily always comfortable explaining this, so I think having this information in nontechnical language, written out, simple and short, and then allowing patients an opportunity to look it over and ask any questions that they come up with is a really critical part of our communication, rather than just throwing out a whole lot of jargon very quickly, which causes them to glaze over. They may not want to ask questions or they won’t know what to ask.

CfB: Do you find that the literature that you’re provided for this purpose is adequate, clear, and helps to ease patients’ concerns?

We’ve developed some of our own, locally, and I know ASCO has, and I’m sure other professional organizations have done so, and they use outside observers, generally patient advocates or patients themselves to review it and validate the information or the conveyance of the information. I do think that, at least in many instances, due diligence has been done to make sure it’s comprehensive and understandable. That’s not to say it can’t be better.

I know that the Biosimilars Council and other organizations have worked on this as well. I think we all have the same goal: to make sure that patients fully understand about biosimilars and that they’re partners in this effort to improve access and reduce costs, but also to make sure safety and efficacy are maintained with these complex molecules. The information is available, but like anything else, it probably can continue to be improved over time—in particular, making sure that patients get their questions answered.

CfB: How are patients reacting? Are they throwing up their hands and saying, “Look, I just want to go with a brand drug. It’s so much easier”?

It can be a problem. As I said, patients come in all shapes and sizes and backgrounds. It ranges between 2 extremes, one being they don’t want to know anything. “Just tell me what to do, doc. Tell me what to take and I’ll do it. I don’t want to know too much about it.” At the other end, I’ve had patients come in with a whole laundry list of questions because they were told they were going to get a new drug. They come in and say, “Oh, you know, I need to know all this stuff.” Most patients want to know or at least be told. You may have to quiz them or ask a couple of targeted questions to make sure they’re comprehending, or just to reinforce.

Most patients are in that middle ground. They’re going to trust you. The most common question I get is, “Would you give this to your wife or your mother?” and I’m generally able to say “Absolutely. These are perfectly safe and effective.” You can’t put that into the pamphlet, but for most patients, if they have any questions, they’re probably going to be of that nature rather than the technical ones. They do want to know they’re not being sold a bill of goods and being given a drug purely because it’s cheaper. I and my colleagues feel the same way. We don’t want to use biosimilars just because they’re less expensive.

CfB: Is there enough information out there to convince providers that biosimilars are safe and efficacious? Are you satisfied with the FDA’s decisions on biosimilars, outright?

I am satisfied with the process, and the sophistication of the preclinical work that’s done is just light-years ahead of where things were when we approved Herceptin, Rituxan, Avastin, and many other original drugs. It’s just night and day, so that really reassures me. But given all that, I still am a strong believer in postmarketing surveillance, and the FDA has taken some recommendations from us and others to use big data for that. They‘ve engaged with CancerLinQ, the ASCO big data system. They’re working with Flatiron and other commercial big data suppliers.

I don’t think we can ever assume that because a study of 300 patients didn’t show some rare, serious, long-term adverse event, that it wouldn’t emerge when you have tens or thousands of patients taking this—often patients with more comorbidities than were included in the pivotal trials. As much as I’m comfortable with the process and the need to use biosimilars the way we’ve embraced them, it’s important not to let our guard down, and I think that’s reassuring to patients as well, to be able to tell them there are continuing efforts to monitor these agents very closely. 

CfB: Should you be completely honest with patients and tell them whether they’re getting a biosimilar or an originator?

I think you should. If you’re changing a patient from what they were getting, it’s absolutely crucial, because if you don’t, a nurse will tell them, or they’ll know from the bag, the prescription label, or the color of the medication. Or they’ll get a bill that mentions the drug that they’re taking. Trust is gold when it comes to communicating with patients. Otherwise they won’t be confident in your care.

Even when you’re starting a patient off on a biosimilar, it’s still worth the effort to explain, along with a brochure that details the process. And you should tell them that they can call any time if they have more questions, because you’re very comfortable that the treatments they are getting are as good as anything available for their disease. With only rare exceptions, you should be open and honest and tell the patient what they’re getting. If it’s a biosimilar, you can tell them that without spending an hour doing it.

CfB: What can doctors do if they feel they need more preparation for the conversation with patients about biosimilars?

It’s 3 words: education, education, education. There are a lot of education materials out there, but it’s such a rapidly changing area. Many biosimilars have come along already, and we can expect more in 2021. Keeping up with that is not an easy task, just like all of medicine. We’re in a biologics revolution. Generally, with targeted small molecules or biologics, continuing education is just absolutely at the core of being an oncologist these days, and it’s true for biosimilars as well.

I’ve been privileged to chair an ASCO task force on biosimilars in educating oncologists on biosimilars, and we’re in the process of updating our original statement paper. I believe there’s a substantial segment of the professional community, including my oncology colleagues, who have not looked at the issue as deeply as I wish they had. And it’s understandable. The rate of change we are talking about here is not just biosimilars; it’s all of biologics itself—cancer, therapeutics, diagnostics, molecular testing, and so forth. I think we’re all kind of struggling with how do we attract that 50%, or maybe it’s even more, of oncologists who haven’t really dived in and fully educated themselves on biosimilars such that they can discuss them with comfort and reassurance to their patients.

Gary H. Lyman, MD, PhD, provides an expert overview on overcoming the challenges of discussing biosimilars with patients.  

Filling in the Blanks: The Patient-Provider Conversation About Biosimilars

Reference adalimumab (Humira), developed by AbbVie was approved by the FDA in December 2002 and quickly became a blockbuster drug used to treat 12 rheumatic and inflammatory conditions, including rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Biosimilar competition overseas has eroded much of AbbVie’s international market share. Humira’s patent thicket and settlements have shielded the drug from US market competition posed by biosimilars until 2023. Additionally, AbbVie developed and received approval for a high-concentration, citrate-free formulation, which has rapidly become the dominant form of adalimumab, posing an additional challenge to biosimilar competitors.

However, Celltrion Healthcare and Alvotech are positioning themselves to be the leaders in high-concentration, citrate-free adalimumab biosimilars, with Celltrion getting the greenlight Yuflyma in mid-February 2021 from the European Union to enter the market. With new versions of adalimumab on the horizon, what will this mean for the market and the biosimilars already marketed and in the US’ pipeline?

We sat down with Sarfaraz Niazi, PhD, an adjunct professor of biopharmaceutical sciences at the University of Illinois and the University of Houston, and founder of Karyo Biologics, Adello Biologics, and PharmSci, to discuss the implications for the adalimumab market and patients.

To learn more about Celltrion's EU approval, click 

To learn more about Alvotech’s high concentration adalimumab, click 

To learn more about high-concentration citrate-free adalimumab products, click 

We sat down with Sarfaraz Niazi, PhD, an adjunct professor and biosimilar industry expert, to discuss the potential impact high-concentration adalimumab products could have on the US market.

Not So Different: Sarfaraz Niazi, PhD Discusses Market Projections For High-Concentration Adalimumab Biosimilars

The Center for Biosimilars® (CfB): Hello, I'm Matthew Gavidia. Today on the MJH Life Sciences™ Medical World News, The Center for Biosimilars® is pleased to welcome Huiya Wu, JD, an expert with 20 years of intellectual property litigation experience based in Goodwin Procter's New York office, and Freddy Yip, PhD, PCLL, a molecular biologist and specialist in product licensing, [initial public offerings], and mergers and acquisitions who is based at Goodwin Procter's Hong Kong office. Great to have you both on.

Addressing regulatory and policy type topics, what's driving biosimilar growth in China and what role does the national reimbursement list play?

 We believe there are 4 major drivers for the biosimilar growth in China. The first driver is the understaffed medical needs in China. For example, China's oncology population is increasing at a faster pace than in the United States, but many patients in China still cannot afford the high costs of biologic treatments, which generally have superior efficacy. So, biosimilars with price advantage provide patients in China with affordable, effective treatment options. 

The second driver is the fact that many blockbuster biologics are coming off patent. The top 10 Global blockbuster biologics drugs in 2019 contributed to almost 30% of the total sales revenues of the overall biologics market, and many of them face loss of exclusivity over the following years. As of today, at least 5 out of the 10 best selling biologics no longer have patent protection. So, the expiration of patents and other IP [intellectual property] rights for the generated biologics opens up the opportunities for biosimilars to enter the market in China.

The third driver is the improved regulatory environment in China. So, China has been striving to establish clear regulatory pathways to ensure market access to qualified biosimilars. The biosimilar guidelines released in 2015 have set up the biosimilar development and registration regulatory framework in China. The regulations of R&D [research and development] and the regulatory pathway for biosimilars in China will continue to become increasingly clear and well defined, which will allow more biosimilars to quickly get into the market.

The last driver is the national reimbursement list. It makes expensive drugs more affordable. So, the list includes a list of therapies that are partially if not fully reimbursed for eligible patients in China. The list comprises 2 drug catalogs: List A and List B. Whereas List A generally includes low-priced and clinically necessary drugs that are fully reimbursed, List B consists of higher priced or new drugs, which generally requires a 10% to 30% copayment from the patients. Since 2017, a number of biologics have been added to the list. That includes rituximab [Rituxan], trastuzumab [Herceptin], and bevacizumab [Avastin]. As a result, the proportion of patients’ self-payment on those drugs decreased to approximately 10% to 30% of the previous figure. So, as more biologics are included in the international reimbursement list, the affordability of biologics it's expected to increase, which allows greater market access.

How does the Chinese government feel about protecting innovators' rights to recoup profits vs the public's right to affordable medicine?

 The new patent law will provide for patent term adjustment and patent time extension, which gives more time to innovators to record profits. It shows that the government is encouraging innovation. On the other hand, the introduction of the biosimilar guidelines in 2015 encourages more companies to bring biosimilars to the market as soon as the originator's patents have expired. So, it also shows the government commitment in allowing more affordable drugs to enter the markets.

Moreover, how might China's regulations affect the breadth of molecule types that enter the market?

 So, chemical drugs in China are still the largest segment in China's pharmaceutical markets. The reforms of the drug regulatory system since 2017 have benefited not only the biologics but also chemical drugs in general. That said, the chemical drug segment experienced significantly lower growth rates compared to that of the biologics, partly because of increasing R&D investment on biologics, increasing affordability of expensive biologics, which I’ve just mentioned, and also superior efficacy of biologics. And if we compare original biologics with biosimilars, the biosimilar market is expected to grow at even a higher rate than the biologics market. This is driven by the factors that we mentioned previously.

What does an originator company need to do to launch its product in China and can a biosimilar company launch even if an originator's product is not available in China?

 Since China has joined the ICH [International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use] in 2017, and started to accept data from overseas clinical trials, drug companies could leverage the clinical trial data obtained overseas and skip certain trials in China when they seek to apply for marketing authorization. For drugs that are on their priority lists, if there is no ethnic difference in the clinical study [trial enrollees represented Chinese ethnicity], the drug companies can even submit the clinical trial data obtained overseas and directly apply for a drug listing registration. So, the process is a lot easier nowadays for foreign companies to bring their drugs to China. 

A biosimilar company cannot use the biosimilar goods to launch a product if an originator’s product is not available in China because the NMPA [National Medical Products Administration] does not establish an innovative biologic approved by foreign regulatory authorities (for example, the FDA) as a reference drug. The reference drug must be approved in China by the NMPA at the time of the comparative clinical studies of the biosimilars.

Why has China worked so hard to upgrade its drug regulatory structure?

 In 2015, the Chinese government launched the "Made in China 2025" mega policy with the goal of elevating China's pace of innovation and quality of production. The mega policy cites both biopharma and medical technologies among the 10 strategic industries that will be the focus of continuing government support. So, these industries have been targeted specifically for domestic innovation and policies and initiatives are expected to receive further support from the government.

When it comes to biosimilars, the Chinese government seems to be putting a lot of pressure on itself. Can you discuss why?

 I believe there are 2 reasons. First of all, historically, the availability of overseas approved therapies in China has been limited. For example, out of 55 oncology drugs launched globally from 2012 to 2016, only 9 were available in China in 2017. So, the lack of available medications is particularly acute with advanced therapies, such as biologics and antibodies. That's 1 reason why the Chinese government was so eager to reform the regulatory system to accelerate the innovative drug approval process. 

The second reason is that China has been facing a rapid increase in health care expenses due to increasing prevalence of, for example, cancer and lung diseases, and also the extended average lifespan in China. So, China has been looking for solutions and taking a proactive approach to solving this problem, including developing alternatives to expensive branded drugs. So, generics and biosimilars offer attractive solutions.

And lastly, do either of you have any concluding thoughts on the China market for vice most?

 Yeah. So, for me, considering the introduction of the new biosimilar guidelines and the number of clinical trials of biosimilars that are being conducted in China, we expect that the China markets will continue to grow. In fact, it is expected that the size of the biosimilars markets 10 years [from now], will be at least 10 times bigger than that in 2020. However, we do expect that the market for first generation biosimilars will rapidly become crowded. So, the biosimilar companies will start to focus on lowering the manufacturing costs and develop more efficient distribution networks in order to maintain their profit margins. Huiya, what do you think?

 I agree with what you said, and in terms of our discussion of this proposed linkage system, it will be interesting to see what impact it has on this growth that you've described in the biosimilars market. Given some of the uncertainties with regard to what patents might be asserted, we don't know whether injunctions will come into play and potentially slow down the number and pace of biosimilars that come onto the market. We've seen some of the unintended consequences of the 1984 Hatch-Waxman Act that led to some fixes in the 2003 Medicaid Modernization Act. I don't know what some of the unintended consequences might be for this new patent linkage system. And in some ways, one of the big questions I have is are there enough incentives for biosimilars? I think the answer is yes, but it seems to me that some of the more innovative companies in China might be thinking about doing what's called "fast follow-ons" by making slight improvements and then making a straight biosimilar and trying to get a play for some of the benefits that innovative biologics would enjoy in China. So, I'm looking forward to seeing what happens.

To learn more, visit our website at centerforbiosimilars.com. I'm Matthew Gavidia. Thanks for joining us.

Huiya Wu, JD, and Freddy Yip, PhD, PCLL, attorneys at Goodwin Procter, discussed projections for the Chinese biosimilars market and the potential for foreign companies to get a share.

Goodwin Attorneys Discuss How Foreign Companies Can Break Into China’s Biosimilar Market

Fresenius Kabi has launched an adalimumab injectable biosimilar (Idacio) in Canada, the company said in a 

. The product, which marks Fresenius Kabi’s first North American biosimilar launch, is approved for all 12 indications of the reference product, Humira, in Canada.

Those indications are rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, adult and adolescent hidradenitis suppurativa, adult and pediatric Crohn disease, ulcerative colitis, adult noninfectious uveitis, and pediatric chronic noninfectious anterior uveitis. Health Canada issued approval for the biosimilar on October 30, 2020.

Fresenius Kabi’s global headquarters are in Bad Homburg, Germany, although it operates a Canada division that is managing this launch.

The Canada launch marks the second for an adalimumab biosimilar this week. Sandoz 

 Hyrimoz, also an injectable biosimilar, which is indicated for 9 of 12 indications of the originator product.

Idacio has been available in Europe since 2019, although in a low-concentration formulation that faces strong competition from other adalimumab biosimilars and a high-concentration version of adalimumab introduced by AbbVie, the originator company.

In its pipeline, Fresenius Kabi is developing a tocilizumab biosimilar, referencing Actemra, which is for the treatment of severe rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, and systemic juvenile idiopathic arthritis. The company also is developing a pegfilgrastim biosimilar, a supportive care product for the treatment of patients undergoing chemotherapy and vulnerable to infection.

Canada is considered an increasingly fertile territory for biosimilar distribution, given the country's embrace of these lower-cost medicines through the development of policies that give preference to biosimilar use. Earlier this month, Celltrion received Health Canada 

 for a subcutaneous infliximab biosimilar (Remsima) for the treatment of rheumatoid arthritis.

Also, in November, Alberta, the fourth largest province in Canada, reported early success with a 

. According to Graham Statt, assistant deputy minister of the Pharmaceutical and Supplementary Benefits Division for Alberta Health, 30% of patients receiving infliximab in Alberta had switched to a biosimilar since December 2019. And in general, the province had succeeded in switching 16% of patients from 7 costlier reference products. Alberta is aiming for biosimilar savings approaching $200 million over the next 4 years.

Fresenius Kabi steps into the Canadian market for adalimumab with Idacio.

Canada Sees Second Adalimumab Biosimilar Launch in a Week

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

Here are the top 5 biosimilar articles for the week of February 15, 2021.

Number 5: Lannett and HEC Pharm are developing an 

 on the heels of their insulin glargine codevelopment project.

Number 4: Biosimilars, supply chain adjustments, building trust, and international standardization were discussed during an 

 of government and industry experts as means to deliver innovation when it's needed, not after.

Number 3: Patients’ demographics and physiological characteristics influence whether they will accept a switch from an originator drug to a biosimilar, 

 an adalimumab injectable biosimilar, which is indicated for 9 of the 12 conditions of the originator product (Humira).

Number 1: Celltrion Healthcare has gained EU marketing authorization 

 high-concentration, citrate-free adalimumab biosimilar.

To read all of these articles and more, visit 

The Top 5 Biosimilar Articles for the Week of February 15

Increased availability of biosimilars for treatment of rheumatoid arthritis (RA) is expected to result in greater access for patients and earlier treatment in the disease cycle, leading to increased risk of immunosuppression and an increased risk of infection. Therefore, the authors of a review of available evidence argue, it is important to better understand the management of RA to mitigate the risk of overtreatment with tumor necrosis factor (TNF) inhibitors and immunosuppression.

“While the contemporary clinical treatment goal is to achieve remission, the ideal immunological treatment goal is to achieve an immune homeostasis, such that the immune system can respond dynamically and appropriately to the environment,” the authors wrote.

Based on their review of literature from the past 6 years, the authors concluded that it is important to consider comorbidities when making treatment decisions for patients with RA. Not just infection risk but also cardiovascular disease and cancer risks are increased in patients with RA. Both the immune dysfunction associated with RA and medications used to treat RA may affect risk of these conditions, they wrote.

The authorization of biologics targeting TNF more than 20 years ago dramatically improved treatment options, but the 

 limited access for many patients prior to the availability of less expensive biosimilars, the authors wrote. As treatment options expand, information on comorbidities could support the assessment of benefits and risks of each therapy.

The authors cited reports indicating the most common comorbidities in patients with RA are depression, asthma, cardiovascular events, solid-organ malignancies, and chronic obstructive pulmonary disease. They focused on cardiovascular disease (CVD), infections, and malignancies because these conditions “may lead to an increased risk of mortality” and “are also impacted by at least 1 of the therapeutic options currently available for the treatment of RA.”

The authors discussed studies that revealed elevated risks of heart failure, myocardial infarction, stroke, and coronary artery calcification and other conditions in patients with RA compared with control populations.

The elevated CVD risk associated with RA is thought to be due to a combination of traditional CVD risk factors, systemic inflammation associated with the RA disease process, and potentially adverse events from RA medications. The prevalence of CVD risk factors, such as smoking, hypertension, diabetes, hyperlipidemia, and obesity, is often higher among patients with RA compared with the general population, the authors noted, and current recommendations support CVD risk management as part of the overall clinical management of patients with RA.

According to the authors, the available evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) “should be used with caution” in patients with CVD or related risk factors, and the dose of glucocorticoids (GCs) should be minimized for prolonged use, as these treatments have been linked to increased risk of CVD in patients with RA.

On the other hand, they cited evidence suggesting inhibition of TNF offers risk reduction, as chronic inflammation can be a signal of the body’s attempt to control cardiovascular disease. Anti-TNF biologics used to treat RA include infliximab, adalimumab, and etanercept. Methotrexate also is associated with reduced risk of CVD in patients with RA.

Regarding newer drug classes, the interleukin-6 inhibitor tocilizumab has raised concerns over elevated lipid levels, although an increase in clinical risk has not been shown. The authors cited a small number of studies that have suggested tocilizumab or abatacept (which inhibits T-cell activation) may have cardiovascular advantages compared with anti-TNF biologics. This possible disconnect between lipids and cardiovascular risk “remains to be fully elucidated,” according to the authors.

Patients with RA are at increased risk of serious infections and infections overall. The authors discussed literature suggesting 3% to 8% of patients with RA experience infections, the most frequent being infections of the respiratory or urinary tracts, tuberculosis, and sepsis.

Like CVD, the increased infection risk in patients with RA is thought to be dependent on a number of factors, attributed to a combination of the immune dysregulation associated with RA, immunocompromising comorbidities, and immunosuppressive therapy. Additionally, they said, “there is evidence suggesting that the inflammatory processes underlying RA may also drive the development of infections,” as numerous studies have linked disease activity to risk of infection.

For GCs, the authors said, the “benefit-to-risk ratio of this treatment remains precarious,” as increasing susceptibility to serious infections and associated mortality associated with these drugs is “supported by numerous studies.”

For conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), such as methotrexate, the evidence suggests no increased risk for serious infection or serious infection-associated mortality, according to the authors.

Biologics overall are associated with an increased risk of infection compared with csDMARDs, and the association may be dose-dependent; however, the authors said, there is conflicting evidence. For example, the duration of biologic use in one study was associated with increased risk of serious infection, whereas another showed decreased risk of sepsis and lower mortality risk with biologics compared with csDMARDs.

Anti-TNF biologics in particular are associated with an increased risk of infection in patients with RA, the authors wrote, “although the magnitude of this risk is a topic of debate.” Whether any specific TNF inhibitor differs from another in serious infection risk remains unclear based on the authors’ review of the research. The authors said limited evidence suggests that patients treated with TNF inhibitors vs other biologics may have an increased risk of hospitalization due to infections compared with those treated with abatacept.

GC, csDMARD, and biologic therapies have been linked to reactivation of hepatitis B virus (HBV) infection. As such, there is a boxed warning regarding HBV reactivation in the prescribing information for rituximab, a monoclonal antibody targeting CD20 used to treat lymphoma and RA. The authors noted that medical organizations recommend screening for HBV prior to initiating immunosuppressive therapies or vaccinating patients with rheumatic diseases against HBV.

According to the authors’ review of literature, targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs), including recently introduced Janus kinase (JAK) inhibitors, as of yet “have an unclear association with infection risk.” Existing data suggest a link between JAK inhibitor use and herpes zoster (HZ) infection and “support the HZ vaccination of patients with RA, particularly if patients are to receive JAK inhibitors,” they wrote.

There are limited data regarding any increased risk of 

 outcomes associated with RA therapies; however, the authors discussed early studies suggesting a lower risk of hospitalization associated with TNF inhibitors and a greater risk associated with GCs compared with other treatments.

Patients with RA have increased risk of developing lymphoma. Although the relationship is not fully clear, the authors wrote there is “strong evidence that the inflammatory processes underlying RA may also drive the development of lymphoma.”

The authors noted there is “no compelling evidence” suggesting an association between the csDMARD methotrexate and an increased risk of lymphoma in patients with RA.

They discussed the black box warning issued by the FDA in 2009 for the risk of non-Hodgkin lymphoma associated with TNF inhibitors. This warning, according to the authors, was based on limited data, and newer data have called these earlier observations into question, as “a recent overview of systematic reviews and meta-analyses of malignancy risk with TNF inhibitors noted no increase in lymphoma risk in patients with RA.”

Patients with RA also appear to be at greater risk of nonmelanoma skin cancer compared with the general population. Anti-TNF therapy is associated in particular with squamous cell carcinoma, and “further studies are required to explore the factors that underlie this increase.” The authors advised that “regular skin examination is desirable for patients with RA treated with TNF inhibitors.”

Optimizing Benefit-to-Risk Ratio of Treatments

The authors concluded that ”dysregulated systemic inflammatory responses” are associated with the development of comorbidities in RA. Responsibly managing RA, they said, requires weighing the potential contribution of each treatment option with comorbidities and risks.

With TNF inhibitors in particular, the authors argued, the risks of overtreatment must be weighed against the potential cardiovascular benefits. This is especially important because access to biosimilars is expected to rapidly lead to wider use of these agents. Conversely, the improved access and lower costs associated with biosimilars could also lead to earlier initiation of treatment, which the authors suggested could improve control of systemic inflammation, leading to prevention of cardiovascular complications in patients with RA.

To mitigate the risk associated with overtreatment and immunosuppression, the authors advised that “for those patients achieving prolonged and sustained disease remission, step-down approaches may be appropriate.” They added that “a shared decision-making approach will be critical” to responsibly managing RA.

Taylor PC, Atzeni F, Balsa A, Gossec L, Müller-Ladner U, Pope J. The key comorbidities in patients with rheumatoid arthritis: a narrative review. 

. 2021;10(3):509. doi:10.3390/jcm10030509

Biosimilar availability will expand treatment of rheumatoid arthritis (RA) to more patients and earlier disease settings, so it's important to understand the potential complications. 

Study: Increasing Biosimilar Use in RA Requires Greater Disease Management Knowledge

The Center for Biosimilars® (CfB): Hello, I'm Matthew Gavidia. Today on the MJH Life Sciences™ Medical World News, The Center for Biosimilars® is pleased to welcome Huiya Wu, JD, an expert with 20 years of intellectual property litigation experience based in Goodwin Procter's New York office, and Freddy Yip, PhD, PCLL, a molecular biologist and specialist in product licensing, [initial public offerings], and mergers and acquisitions who is based at Goodwin Procter's Hong Kong office. Great to have you both on. 

CfB: Can you just introduce yourselves and tell us a little bit about your work?

Sure. My name is Huiya Wu. As you mentioned, I've been in this field for about 20 years specializing in both small molecule and also biologics litigations and also advising clients on this matter. Most of my clients are overseas so what I like to tell people I do is help clients launch products in the US market.

I am an associate in Goodwin Procter's Hong Kong office. I represent my clients in lots of licensing and cross-border US-China transactions. We represent lots of clients in many biologics and small molecule-related transactions.

CfB: Focusing first on marketing and distribution. Can you describe how biosimilars are distributed in China vs in the United States?

So, in China, drugs are mainly distributed via distributors. One thing I would like to point out is that in 2018, China launched the National Drug Centralized Procurement Pilot Scheme, with the aim to lower generic drug prices and encourage the consolidation of a fragmented system for procuring generic drugs in the country, starting with 11 major cities. Under this scheme, the government awards the tender for a generic drug to the lowest bidder, who will be guaranteed a sales volume of about 60% to 70% of the total market for a year, across 11 major cities, including Beijing and Shanghai. So, under this scheme, the originators will likely lose most drug tendering opportunities because of the price difference. This scheme is likely to accelerate the replacement of originator drugs with generics.

CfB: How does China handle the availability of multiple biosimilars for the same biologic?

So, I understand that in the United States, if a biologic is not on the formulary, it's not going to be approved [prescribed]. But in China, there's no such restriction. As long as a biosimilar meets all the regulatory requirements, it will be approved [prescribed].

CfB: Building on that, China already has 4 or 5 adalimumab biosimilars (approved). Are all of these marketed?

Well, at least 3 adalimumabs have been marketed. They [include] Henlius' adalimumab, Bio-Thera's adalimumab, and also Innovent Biologics’ adalimumab.

CfB: What about for etanercept [Enbrel]? Are there any differences here?

Well, a biosimilar etanercept was first launched in China in 2006. That's even before the NMPA [the National Medical Products Association], China's regulatory agency, released the biosimilars guidelines in 2015. But the biosimilar guidelines define what constitutes a biosimilar (ie, a drug that is similar in quality, safety and efficacy with the reference drug). So, biosimilar etanercepts fall within that definition and, accordingly, 3 preexisting etanercept biosimilars were developed in China. So, they actually already existed before there was a biosimilar regulatory pathway in China.

CfB: Can you describe the difficulties of entering China's biologics market for foreign companies?

From a business perspective, one of the difficulties is identifying an appropriate market entry model and the right partners. Effective entry strategy work should be geared around the company's overall strategic plan and commercial objectives, which are unique for each firm. For example, bigger [biopharmaceutical companies] may choose to acquire local companies with established infrastructures, supply chains, or commercial portfolios. Companies with novel drug therapies often choose to out-license their products, which requires a lower investment, but the companies will only have limited control over the products. Some [biopharmaceutical companies] choose the JV [joint venture] models, in which they will have slightly more control over the products, but in that case, the partner selection is critical. Further, some companies will prefer to invest directly either with internal capital or [private capital]. In any event, once a company identifies the appropriate market entry model, it needs to identify the right partners. So, they will have to consider their capabilities including R&D [research and development], expertise, product pipeline, clinical trial experience, and distribution network. This is what I believe to be one of the major difficulties.

An additional difficulty with entering the market is to try and figure out what this new proposed linkage system is about from an IP [intellectual property] standpoint. It brings a lot of wrinkles as to how litigations will play out, how settlements might play out and, of course, how all that will impact entry of products onto the market. So, it remains to be seen how all of the new legislation will be implemented and used.

CfB: And building on what you just said, transitioning to more legal content, how do patent exclusivities work for originator products in China?

The patent term now in China is 20 years. China's fourth amendment to the patent law, which will become effective from June 1, 2021, introduces the patent term adjustment [PTA] and also extension. So, for patent term adjustment, the amendment outlines that the term of a patent may be extended in order to compensate a patent proprietor for the time taken to review and approve a new drug for marketing in China. And the law will allow for the term of the patent directed to the new drug, which has received marketing approval in China, to be extended for up to 5 years, with the overall pattern term not exceeding 14 years from the date of the marketing authorization. For patent term extension [PTE], the amendment also outlines that for a patent that granted 4 years after its filing date and 3 years after the date of requesting substantive examination, the Chinese Patent Office will compensate the patent applicant for unreasonable delays in examination by adjusting the terms of the patent. In terms of data exclusivity, the latest patent law still doesn't involve data exclusivity.

I guess in comparison to the United States, I think the PTEs and PTAs are pretty similar. I think there are slight details in exactly when you have to apply and the deadlines for applying, but I think in terms of the policy and the length of times for the adjustments or extensions, they're comparable.

CfB: Is there a patent dance in China? And how do patent battles play out there compared with in the United States?

No, there isn't a patent dance in China. According to the draft amendment to the Chinese patent law, the agency will establish a listed drug patent information registration platform for patentees and drug manufacturers to register drug-related patent information in China. The listable patents included for biologics are sequence structure patents only. In the United States, the reference patent sponsor does not need to provide patent information to the patient. However, during the patent dance, it must disclose all the patents it may assert, and they include composition patents, methods of treatment patents, and also manufacturing process-related patterns.

Hopefully, we'll get a little bit of a leg up soon with the new rule about having the [patent disclosure] lists being published by the FDA. But it seems to me, Freddy, that China's going to have its own issues. I was very surprised to see, for example, that in terms of litigations with regard to both small molecules and biologics that there really is no notice to the originator [manufacturer]. That's a very big difference. Here, we have either the Orange Book for small molecules or we have the patent dance, and over there, the burden is all on the originator to pay attention.

CfB: How do biosimilar developers find out what patterns are likely to be an issue?

So, biosimilar developers need to monitor the original product's patents and track new applications or patents of the originators and other companies.

CfB: Can you describe the type of vigilance that originator companies need to exercise to protect their patents?

Yes. So, an originator company needs to watch the public listing of new biosimilar applications diligently. According to the draft amendments, the NMPA will publish the biosimilar drug application and a corresponding certification statement, and within 45 days after certification publication, a patentee or interested party can file a lawsuit. For biologics, the NMPA will not state the approval decision but will proceed with the approval process. So, if the litigation concludes favorably for the patentee before the generic approval has been made, the NMPA can still continue the approval process, but will indicate that such drug should not enter the market until the listed patent expires.

I think that's similar to the United States, where there's no stay for biosimilars litigation, but it's quite different in terms of the patent dance and it’s really a stick for the BLA [biologics license application] holder to assert everything they can possibly assert. So, I'm very curious to see how it's going to play out, because currently it's only the [sequence structure patents], which you mentioned, Freddy, and not listing for other patents that could be asserted. So, it'll be interesting to see kind of how other patents come into play as a result of the biologics patent linkage amendments.

CfB: And building on that, is it a level playing field for non-Chinese biosimilar companies looking to market their products in China?

Well, in terms of bringing biosimilars to the Chinese market, I'm not aware of any existing policies, laws, or regulations that particularly favor local companies over foreign companies. But given the US-China geopolitical tensions, it may change in the future.

It seems to me like with, certainly, language barriers and what you were saying earlier about market entry that local companies surely have a leg up in getting their products on the market and distributed. So, we'll see how that plays out, but it seems like there's a lot to learn if you're a foreign company getting into the China biosimilars market.

Huiya Wu, JD, and Freddy Yip, PhD, PCLL, attorneys at Goodwin Procter, discussed biologic drug patent laws in China and the US.

US vs China: Goodwin Attorneys Discuss Patent Hurdles and Adalimumab Marketing 

Coherus BioSciences reported that the FDA has 

 for review its biologics license application (BLA) for an adalimumab biosimilar (CHS-1420). The formulation concentration Coherus is seeking was not specified, although the market is swiftly moving away from lower-concentration forms of this agent.

In 2017, the Redwood City, California, company reported topline results from ongoing pharmacokinetic (PK) bioequivalence studies that compared CHS-1420 with a European-marketed version of the reference product (Humira). The company reported that the comparison was based on administration of a 40-mg dose in a group of 216 healthy patients, a trial that met all end points for clinical PK and pharmacodynamic biosimilarity.

By comparison in November, Icelandic company Alvotech indicated that the FDA had 

 its application for a 100-mg/mL dose biosimilar (AVT02). However, Alvotech’s supporting data for the application involved a phase 1 PK similarity study that employed a 40-mg single dose of Humira in healthy subjects and a phase 3 safety and efficacy study that employed an initial loading dose of 80 mg followed by 40 mg every 2 weeks.

In 2016, Coherus reported results from a phase 3 psoriasis study of CHS-1420 that were also positive, demonstrating biosimilarity in patients who achieved a 75% improvement in psoriasis area and severity index measures at week 12. Coherus said CHS-1420 and Humira were “similarly well tolerated with similar safety profiles.” This phase 3 study was intended to support a 351(k) BLA filing in 2017, although that filing was delayed; the company had hoped to achieve a filing by the end of 2020, according to its third-quarter 2020 

Coherus BioSciences filed a 351(k) biologics license application (BLA) for CHS-1420, an adalimumab biosimilar candidate. 