By Anna Rose Welch, Director, Cell & Gene Collaborative
Celltrion’s subcutaneous version of biosimilar infliximab — Remsima SC — has turned many heads since its January 2020 EU launch. The intrigue has only continued to build following the recent announcement that Remsima SC was approved for five additional indications (ankylosing spondylitis, Crohn’s disease, ulcerative colitis, psoriatic arthritis, and psoriasis). Given Celltrion’s goals to launch even more value-added medicines known as “bioinnovatives” in the future, I wanted to learn more about the company’s thought process behind this long-term strategy. In this Q&A, HoUng Kim, Head of the Medical and Marketing Division at Celltrion Healthcare, shares the biggest market-related considerations and regulatory challenges facing a biosimilar company exploring both biosimilars and bioinnovatives.
Anna Rose Welch: Why did you choose to pursue a subcutaneous version of Remsima? Were there particular shifts or trends within the anti-TNF therapeutic class that made a subcutaneous product commercially valuable?
HoUng Kim: When we interviewed clinicians and thought leaders about the clinical use of anti-TNF-α agents, they highlighted that they are often used to treat patients with severe disease. They commented that infliximab has been used over the course of 20 years in clinical practice, however given the intravenous route of administration, it’s mostly used as an initial anti-TNF therapy rather than during the maintenance phase. As the frequency of administration and the cumulative costs of intravenous infusion can sometimes pose a burden to vulnerable patients, a subcutaneous formulation of infliximab could provide an alternative option.
Accordingly, Celltrion explored the development of a subcutaneous formulation of infliximab (Remsima SC) as part of extending the treatment longevity of infliximab – allowing for a rapid response with Remsima IV and maintaining the treatment regimen with Remsima SC, as the subcutaneous formulation can be self-administered by patients in the comfort of their own homes.
Anna Rose Welch: What have been the biggest regulatory and/or commercialization challenges you have faced in establishing your “bioinnovator” strategy for Remsima in the EU?
Kim: When biosimilars were first introduced, biosimilar manufacturers faced many challenges and difficulties without having clear guidelines and standards for biosimilars from regulatory agencies. The clarity of the biosimilar guidelines that existed varied and the regulatory pathways were diverse, with definitions for biosimilars significantly differing between countries and regions.
We hope to see a globally accepted, standardized regulatory guideline put in place to avoid any duplicated clinical trials that do not provide additional value. This would allow for greater, faster access of innovative treatments worldwide for patients that need them most.
In terms of regulation of bioinnovatives, the European Medicines Agency (EMA) provides an efficient regulatory track, but the pricing & reimbursement (P&R) processes differ on a country-by-country basis. If there were a common or uniform P&R process shared by EU member states in the future, we believe this would facilitate commercialization of these types of innovative products and would mean patients receive greater access to innovative treatments.
Welch: Are there any ongoing efforts to put such a framework in place?
Kim: There are some associations working on research to formulate efficient models or relevant suggestions as to what this process might look like. However, these are yet to be materialized. Given the different healthcare system structures and budget pressures across countries, a possible initial step could be a common Health Technologies Assessment to set up reimbursement guidelines.
Welch: What role do you see value-added medicines playing in healthcare systems in the future, especially as many healthcare systems increasingly prioritize cost-effective generic and biosimilar medicines to improve access and lower costs?
Kim: In the future, we believe the P&R process of value-added medicines will be based on the additional benefits that the medicines can bring, which is already starting to be recognized from a pharmacoeconomic point of view. In the case of Remsima SC, evidence shows that the treatment can contribute to minimizing spend by healthcare systems, by reducing infusion costs and delaying usage of more expensive 2nd line treatments.
Welch: What types of real-world evidence/data will be critical for manufacturers to collect and, most importantly, share with the necessary officials to build the framework for a P&R process?
Kim: We believe that some areas still need to be fortified. These include, 1) long-term clinical data for chronic diseases 2) switching data from other manufacturer’s products 3) additional clinical data for indications that are currently insufficient 4) pharmacoeconomic assessments reflecting each individual country’s situation, such as budget impact analysis, cost utilization/ effectiveness analysis, comparison of annual treatment cost between medications in the same or alternative category, and 5) reference pricing information on the list price (i.e. price in already launched countries). All these data need to be diligently delivered to necessary officials by the manufacturers.
Welch: Celltrion also has quite a few biosimilars in the oncology realm. What role do you anticipate biosimilars and bioinnovatives will play in oncology moving forward?
Kim: We see haemato-oncology drugs like Truxima and Herzuma as affordable backbone therapies to improve access to combination therapies for better clinical outcomes.
Combination regimens can improve patient outcomes, however, combining high-cost treatments can make the cost unsustainable. Payers are increasingly looking for new pricing models and ways to manage the budget impact of combination treatments. As such, the introduction of biosimilar rituximab to the rituximab, lenalidomide, and acalabrutinib (R2A) regimen may have the potential to reduce the overall cost of treatment. Data from a Phase II trial showed that a regimen of Truxima, lenalidomide, and acalabrutinib (R2A) was well tolerated in people with relapsed/refractory aggressive B-cell lymphoma.
Further, data from a phase Ib/II trial show a first-line triple combination therapy of pembrolizumab, Herzuma, and chemotherapy was effective in patients with HER2-positive advanced gastric cancer (AGC).
With the costs of oncology treatments often being so burdensome, the availability of biosimilar trastuzumab could reduce the overall cost by combining treatment with innovative new drugs and chemotherapy. High quality treatments at reduced overall treatment cost could result in a benefit to health systems worldwide.
Welch: Will a bioinnovative strategy be important for other biosimilar companies to consider for long-term success in the biosimilar market? Will there need to be any adjustments to existing biosimilar regulatory pathways to accommodate this innovation?
Kim: We anticipate that more and more companies will adopt bioinnovator strategies as biosimilar competition intensifies. We believe that biosimilar competition will be a driver for sustainable R&D investment in originator biologics. For instance, this could be done by replacing patent-expired assets with new products to offset the biosimilar challenge, or by creating headspace for innovation in drug budgets while expanding access to biologics overall.
There is currently no set regulatory framework or guideline for bioinnovatives today. The EMA allowed Celltrion to seek an expanded authorization for CT-P13 (Remsima) in its new formulation as a line extension, but in the U.S. context, the FDA has required that the company submit the product as a new drug.
According to the Director of the US FDA Center for Drug Evaluation and Research, in order to improve the efficiency of the review process, they may require separate regulatory pathways for biobetters.
Considering the internal voices of the FDA along with the evolution of biosimilar guidelines, which are currently similar between the EMA and the FDA, it is expected there will be a common standardized regulatory pathway in the near future.
Celltrion is committed to forming partnerships and collaborating with relevant authorities to support the development of regulatory frameworks for the introduction of biosimilars and bioinnovatives. We also plan to actively engage with payers, physicians, and patients to ensure they have access to unbiased scientific educational materials. Such frameworks will ensure that there is consistent and high-level public health protection that applies to biosimilars and bioinnovatives in the same way as with originator biologics.
Welch: What are one or two of the most important questions companies exploring biosimilar and value-added treatment development in the future will need to ask themselves to create a successful long-term strategy?
Kim: Companies exploring biosimilar and value-added treatment development need to consider the sustainability of the quality, supply, and business model. They need to be cost-competitive without undermining product and supply quality.
As for the long-term strategy, it is important to consider both the competitiveness of the cost structure as well as the value of the product on its own. To survive in a market with multiple competitors, the company needs to be cost competitive. But to be a leader in the market, cost competitiveness is not sufficient. A company needs to have a distinctive value or differentiating point incorporated into their products.
For example, in the infliximab market, several manufacturers are engaged in fierce price-competition. However, by providing additional clinical value through a different formulation, the product can be recognized as distinctive; therefore, a company can gain a better position from a sustainability point of view.
The value of biosimilars and bioinnovative products can also be fortified by appropriate data or additional augmented value. For example, Remsima generated clinical data to relieve concerns on extrapolation and switching even after regulatory approval. In addition, the novel subcutaneous formulation provides additional value clinically and offers a convenient alternative option for patients that, as mentioned earlier, also reduces infusion costs.