Mikhail Samsonov, Chief Medical Officer at R-Pharm
In early February, R-Pharm registered two biosimilars — a pertuzumab biosimilar for breast cancer therapy and a cetuximab biosimilar for metastatic colorectal cancer and head and neck cancer treatment. Developing biosimilars is a costly endeavor, requiring more time, investment, and expertise, which is why only a few companies undertake the task. We spoke with R-Pharm’s Chief Medical Officer, Mikhail Samsonov, about the specifics of manufacturing and registering biosimilars, as well as the most promising developments.
How did R-Pharm come to the decision to focus on biosimilars?
We approached this area several times but finally focused on it when patents for a whole range of biological drugs began to expire. The pandemic became an additional accelerator: it showed how important it is to have our own biotechnological competencies and sustainable production. Today, we have formed a large portfolio of biosimilars — over 20 drugs in development. Four of them are already undergoing various phases of clinical trials, the rest are at earlier stages — at the level of creating and selecting cell lines — and some are already registered.
What criteria do you use to select a biopharmaceutical for production?
First and foremost, we focus on therapeutic areas with the greatest medical significance and need for biological drugs. The largest of these is oncology; the second area is autoimmune and autoinflammatory diseases. This is an area where R-Pharm has already accumulated substantial experience: our portfolio includes two proprietary innovative drugs and one project implemented in partnership with Dr. Reddy’s. The third group is neurology and pulmonology. There are fewer biological drugs in these areas so far, but they are of high interest from the standpoint of future development and unmet medical needs.
In terms of intellectual property, are the same rules applied here as for generics?
The rules in the field of intellectual property are comparable to those for generics. But in practice, developing biosimilars is significantly more complex and expensive. It requires more time, investment, and deep biotechnological expertise.
While generics have been localized in Russia for a long time, with a significant portion of pharmaceutical substances being purchased abroad, primarily from China, in the case of biosimilars, Russian companies essentially start development from scratch. It is necessary to design the molecule, create a proprietary cell line, refine the production process, and then move on to manufacturing the finished dosage form. On average, such a cycle takes 4-5 years.
Reproducing a chemical molecule is relatively simpler, whereas working with living cells requires a fundamentally different level of control and process stability.
Moreover, biosimilars are not always a simple copy of the originator. Over the 15-20 years since the first drug’s release, technologies advance significantly, and next-generation drugs can have more effective characteristics — for example, providing higher protein yield and, consequently, lower cost. Today, platform solutions are emerging that allow scaling production from a single master cell line while maintaining stable product quality.
Is it possible to improve a biopharmaceutical in this way and create your own original drug from it?
In some cases, yes, such an approach is possible — we’re talking about so-called next-in-class drugs, the next generation of solutions within an existing therapeutic class. But an interesting paradox arises when working with biosimilars: sometimes creating a new original drug turns out to be simpler than bringing a biosimilar to market. The reason is that when developing a biosimilar, a company is strictly constrained by the characteristics of the originator drug — it is necessary to reproduce its parameters as accurately as possible.
This creates certain difficulties for the developer. If a new drug turns out to be better than the originator in some characteristics, it is undoubtedly good for the patient. But from the standpoint of regulatory requirements, such a product ceases to be a biosimilar. In this case, a more extensive clinical program, greater investment, and a longer path to registration are required.
Are there specific features in inspecting biosimilar production?
Currently, all countries are moving more or less in the same direction. The level of data is high, regulatory agencies and experts have accumulated significant experience, so the main emphasis is on analytical data — the description of the production process. From a certain point, European and American regulators stopped requiring preclinical studies. The Russian regulator has also abandoned this. And the main trend is that the two major agencies — the FDA and EMA — no longer require Phase III clinical trials. If you show good pharmacokinetics in Phase I, analytical comparability of a large number of batches across a range of indicators, starting from protein structure and so on, then regulators no longer require Phase III clinical trials for biosimilars. This reduces time and enables broader patient access with guaranteed quality.
Is the unpredictable nature of living cell behavior the primary reason for such stringent production quality requirements?
It’s about the production culture, expertise at the plant, plus process modeling. There are parameters such as medium, temperature, volumes, oxygenation — these protocols are refined and must then be precisely reproduced. Instead of conducting 50 repetitive experiments in a wet lab, developers do 20 and then refine the parameters using a special model.
Reports suggest a strong international appetite for Russian biosimilars. What is your perspective on this?
There is the concept of stringent regulatory authorities (SRA). These are seven regulators, including those of the US, EU, Canada, Japan, and so on. If a drug is not registered by one of them, then in many countries the process is slow or registration is impossible. For instance, until recently, this was the case in Vietnam; now the Vietnamese have an interest in our drugs, but the process is still not easy.
There is talk now about global harmonization of rules, but differences exist — for example, between national pharmacopoeias. We register drugs in many places — in Vietnam, the Persian Gulf, Turkey, and other countries — and there are difficulties with pharmacopoeias everywhere; part of the CMC (Chemistry, Manufacturing, and Control) specification has to be rewritten. Foreign companies do the same when entering Russia. That is, harmonization is still incomplete. Perhaps after some time, conditions will be more comfortable for Russian companies; we will approach that moment with a huge body of knowledge.
The development of biosimilars isn’t pursued by all countries, would you agree?
Developing biosimilars requires serious infrastructure, modern technologies, and, most importantly, highly qualified personnel. Accumulated biotechnological expertise and a market of sufficient scale are necessary for such investments to make sense.
There are a number of players for whom this is a strategic direction. For example, South Korea — one of the largest producers here is Samsung. Singapore also holds strong positions: several major biotechnological productions operate in the country, supplying drugs both to Southeast Asian markets and to countries with stringent regulatory control. China is becoming the largest player, and India is also developing its biotechnological industry.
Beyond your company, who are the other key Russian players in the biosimilar space?
A whole range of companies are successfully working in this direction: R-Pharm, Generium, Biocad. Several young players have now appeared. Russia has been doing this for about 20 years, there is accumulated experience, but in terms of specialists, as the pandemic showed, there is still a shortage. For our part, we are actively investing in training and developing personnel for biotech.
Which biopharmaceuticals show the most promise for reproduction?
Speaking of drug reproduction, we have already mastered the technology of classical monoclonal antibodies. Now the focus is shifting to more complex and promising formats — primarily to conjugates or antibody-drug conjugates (ADCs). These are targeted drugs where a monoclonal antibody “delivers” a cytotoxic molecule to a tumor cell.
Historically, this direction began with trastuzumab, to which a cytostatic agent was attached, and today such drugs show high efficacy in treating a number of solid tumors. There are no biosimilars of such drugs yet, either in the world or in Russia. Developments are underway, including by Russian and Chinese companies, but no drug has been registered so far. This is understandable: conjugates combine several complex components at once — the antibody itself, the cytotoxic burden, and the linker that connects them. Separate regulatory and evidentiary requirements apply to each of them.
Simultaneously, the creation and implementation into practice of so-called bispecific and trispecific antibodies, where one molecule simultaneously interacts with two or three targets, is rapidly developing. These are even more structurally complex drugs and, accordingly, complex in terms of development and proving efficacy, but it is precisely in this direction that the interest of many market players is now focused.
What is the attitude of Russian doctors and patients towards biosimilars?
The attitude has noticeably changed in recent years. The pandemic became a turning point: both doctors and patients saw that Russian original developments can be effective and reliable. This trust continues to form due to real clinical experience. Educational programs supported by the Ministry of Industry and Trade and the Ministry of Health also play their role, but the decisive factor remains practice: a doctor who sees the result in a specific patient can then trust the product.
