Category: Biotech / Biosimilars

The next generation of oncology treatments will likely require a personalized approach wherein a patient’s own immune system will be harnessed to specifically tackle their unique cancer cells. Mark Shlomchik, M.D., Ph.D., co-founder and Chief Scientific Officer at BlueSphere Bio, discusses how the company’s new platform technologies enable the rapid development of effective personalized T cell receptor (TCR) T cell therapies for the treatment of solid tumors with Pharma’s Almanac Editor in Chief David Alvaro, Ph.D.

David Alvaro (DA): Can you explain what you see as the critical limitations of CAR-T cell therapy with respect to solid tumors and the advantages that a TCR approach presents?

Mark Shlomchik (MS): To me, the division is between targeting tumor-associated or tumor-enhanced invariant antigens versus neoantigens. CAR-T cell therapies are designed to bind to monomorphic antigens that are associated with a given class of tumor. The classical example is CD19, which is of course present on tumor cells, but also on normal B cells. Although there is a pathway to making off-the-shelf CAR-T cell therapies of this type — which is certainly viewed as being easier and cheaper — there are problems with this approach.

One of those problems is that these tumor targets may also be expressed elsewhere in the body, in normal tissues. I worry about on-target, off-tumor effects, which give rise to toxicities. This on-target, off-tumor effect has been seen in both CAR-T and TCR T cell therapies.

There is also the issue of autoimmunity in some patients. One case in point is CAR19-T cells, which destroy normal B cells. We live with that, because it is ultimately better to have that problem than to have leukemia or lymphoma. If an analogous problem occurred with, for example, epithelial cells, which are the source of many solid tumors, though, there would be a real issue.

Another problem with monomorphic antigens is escape. Because CAR-T therapies typically target just one antigen that may not be important to the cancer cell’s survival, especially in leukemias, the cancer cells are able to lose the CD19 (or other targeted) receptor. This can also happen with solid tumor CAR-T targets and is a real issue.

Finally, with CAR-T cell therapy, the antigen space is not very diverse because the antigens that can be targeted must be tumor-specific, on the surface of the tumor cell, and expressed at a high enough level to activate the CARs.

 With TCRs, it is possible to access a much broader and more diverse antigen space. The challenge with TCRs is HLA (human leukocyte antigen) restriction. Every TCR must be considered in the context of not only the target antigen but also the HLA alleles that the patient carries. 

DA: How does targeting neoantigens overcome those issues?

 

MS: I am really excited about this approach, because I believe that neoantigens are undoubtedly the Achilles heel of tumors. Tumors are comprised of cells that, in order for them to be malignant, must have a number of mutations. Even a tumor classified as having a relatively low number of mutations truly has quite a large number of mutations. Because of those mutations, tumor cells produce mutant proteins that are visible to the immune system. The immune system then recognizes these mutant proteins and will engage T cells specifically driven to target and kill those cells expressing the mutant proteins. Except for a limited list of driver mutations, which I think are very interesting and are a class of monomorphic but truly tumor-specific mutations that produce specific fusion proteins, peptides, or other unique biomolecules, many of the mutant proteins are going to be unique and idiosyncratic to the individual patient.  

Creating TCR T cell therapies to target those mutations offers several advantages. The most important is that there isn’t a risk of autoimmunity. Those T cells targeting the neoantigens will not kill the patient due to adverse effects, regardless of how “charged up” they are. They only target and kill the tumor. That makes TCRs a great approach in general. It does, however, mandate personalization, as off-the-shelf neoantigen therapies are difficult to develop, as most neoantigens are unique to a particular patient and tumor. To target recurrent neoantigens, there would need to be an extremely large data set available to understand specific clusters of shared neoantigens across patients. That is one reason I think that larger movers and players are not yet showing that much interest, given that this approach has yet to be proven. There are smaller companies focusing on this area though, such as Neon and Gritstone. They are largely looking at vaccine development and TIL (tumor-infiltrating lymphocyte) expansion.

DA: How is this approach applied to cancer vaccines?

MS: With vaccines, the goal is to get the patient’s own immune system to destroy tumor cells. It is a promising concept, because we know how the checkpoint blockade — which has efficacy in a lot of people — works. There have been many great publications from a number of labs demonstrating that what happens at the checkpoint blockade is the re-emergence or the expansion of neoantigens for specific T cells. We thus have some proven biology that these cells are there.

Unfortunately, not enough patients respond, and that’s probably because they don’t have enough of the right T cells, or their T cells are too exhausted. As a result, cancer vaccines today have limited success. Cancer is immunosuppressive, and patients receiving these therapies are generally older and have had chemotherapy and other treatments that tend to make them nonresponsive. In addition, the cells that you want to respond are stuck in the tumor microenvironment, which is unfriendly to T cell responses.

DA: You also mentioned TIL expansion — what is driving interest there?

MS: TIL expansion was pioneered by Steve Rosenberg and others and has led to the generation of some pretty significant companies like Iovance. The work done by these investigators and companies has provided excellent proof of principle, because they have shown that — at least in some patients, for some tumors — you can get T cells out of the tumor, expand them in vitro, administer them back to the patient, and achieve long-term remission. I think that really demonstrates the viability of the fundamental biology.

Unfortunately, TIL expansion as performed to date fails in a large percentage of patients. It’s not standardizable. I believe there have been issues with this in terms of defining what a product really is, because it is difficult to know exactly what is undergoing expansion. Furthermore, expanded cells for some people may work great, but for others may be exactly the wrong cells. There is also the challenge of needing a relatively large tumor biopsy with enough T cells in it to begin creating the therapy. That isn’t always available for a number of patients for various clinical reasons across the broad spectrum of potentially responsive tumors.

TIL expansion is a great idea, and there has been terrific proof of principle, but I think it is very difficult to implement as an adoptive cell therapy. However, I do think that it has potential for personalized therapy. What I love about it is that, instead of relying on the patient’s own immune system to be vaccinated, it involves boosting the patient’s immune system with T cells. I like to refer to is as pushing TCR therapy or pushing T cell therapy. In the end, even if the T cells are not the best, you can probably outnumber the cancer cells and get rid of minimal residual tumors — at least, that’s the theory.

DA: What can you tell me about the approach that BlueSphere Bio is taking to overcoming these issues?

MS: Instead of taking the T cells out, we wanted to capture the T cell receptors and use them to modify a patient’s own unexhausted primary T cells in a more CAR-T cell–like manufacturing process. In this way, we can leverage the progress that has been made — and continues to evolve — for adoptive cell therapy. The industry continues to make improvements to the manufacturing of cell therapy products; we still have a way to go, but I have little doubt that we’re going to get better at it and it’s going to become cheaper and faster.

The missing ingredient was getting the TCRs out, matching them to patients, and finding the important neoantigens. Until BlueSphere Bio introduced the TCXpress™ technology, I think most people felt it would be too expensive, too slow, and impossible to personalize. Our platform, however, makes it possible to do all of this a couple of orders of magnitude faster and more cheaply than previously thought possible.

Our technology allows us to take T cells out of a tumor and sort them. Because the process is so efficient and we aren’t growing the T cells, we only need a few thousand cells, which means that even a needle biopsy is sufficient. We take the TCRs out of the individual T cells and convert them into functional T cell receptors in a few days at a cost of less than four dollars per TCR. The process is ultra-small-scale and performed by a series of pipetting robots with minimal human intervention, which makes it robust and reliable. At the same time, we also sequence the tumor and perform RNA-Seq, because we are only interested in moving forward with TCRs that target antigens that we know are expressed within the tumor. This analysis of the tumor using modern genomic techniques is combined with well-established informatics tools to enable us to understand what the mutations are for a particular patient’s tumor and to predict which will be immunogenic.

Our second platform — NEOXpress™ — identifies the sequences that are different in the tumor from the sequences found in the patient’s normal T cells and that are predicted to be presented by their HLAs. A series of antigens is then created and placed into antigen-presenting cells that are then cross-screened against the TCRs derived from TCXpress™. As a result, in a period of a few weeks and without much hands-on work, we can identify the TCRs that are specific and matched to the neoantigens in the patient’s tumor.

DA: What would you say are the key differentiators of your approach at the clinical level?

MS: First of all, our approach provides multiple neoantigen hits for a single patient. Just like we wouldn’t treat cancer with a single chemotherapy agent because it is likely to escape (the problem I mentioned with monomorphic TCRs), with our approach at least three targets are identified per person, increasing the likelihood of preventing escape. I don’t have any illusions that we’re always going to cure everybody, because nothing works that way, but I think that by going after multiple targets you do have a better chance. Second, because we have identified the neoantigens, we can demonstrate for safety purposes that the TCRs for those neoantigens do not react with the native peptides found in the rest of the body.

With this approach, we create primary T cell products that are personalized for the patient. Given the data that has been gathered on TIL expansion at checkpoint blockades, we expect that this approach will be synergistic with checkpoint inhibitors. Such a therapy could also be given with a variety of the other amazing drugs people are developing to make the tumor microenvironment more amenable. I believe this is how we are going to cure cancer eventually — with a combination of personalized approaches. We are providing the missing link to make that accessible in a timely and cost-effective way.

DA: What challenges will you need to overcome to make this approach a reality? Are there any technological advances yet on the horizon that will be crucial to your success?

MS: I’m hoping that, as cell therapy advances, we will be able to manufacture products more cost-effectively and easily. We are still a few years away from deploying this personalized solid tumor therapy, but I think that developing nonviral editing approaches where you don’t have to expand the T cells as much will be beneficial to the success of this program. This approach allows the T cells to retain a lot more of their capabilities.

In general, there is also a lot of optimization that must take place to make the process faster, cheaper, and more efficient. To best develop this process, we are doing what we call “virtual patients,” where we practice on tumors. One question we must answer is how many T cells we really need to screen per patient. Literature estimates that T cells in a tumor that are neoantigen-reactive range from 1% to 20%. That means that we should screen maybe hundreds up to a thousand T cells for each person. That is one to four 384-well plates. That’s not that hard to do, but we might find that we don’t need to screen that many. I also think the informatics are still imperfect; the prediction algorithms can be improved. Experience will tell us that. As we practice more and more, we might get better at that.

Overall, I believe it is really an evolving process that will improve as we study it. I want to get to where it is efficient enough to introduce into real patients. Given what we have seen thus far, we believe that this approach is feasible, and so we will continue to develop it with the goal of achieving significant speed and cost optimizations.

DA: What about from a regulatory perspective? What potential hurdles do you see facing such novel and personalized therapies?

MS: With any new therapeutic approach, there is a need to introduce regulators to the concept. You have to think of cell therapies differently from pills. I think we have to take even another step and recognize that, if we really want to offer people with incurable lung cancer something that could cure them, we’re going to have to be more flexible about how we define the product. You simply can’t spend months validating such a personalized therapy, because the patient is likely to die during that time.

However, there is still a lot of opportunity to provide extensive information to regulators on the products that we will be developing, and I am optimistic that it will be sufficient. The T cells that we will be working with will have come from patients and therefore will not be foreign to them. We will also be able to show regulators that these T cells react with tumor-specific mutations but not with the patient’s own cells. That is a real advantage of our approach, because we can demonstrate safety.

That is another reason why I want to get away from viral delivery using lentiviral vectors. Viral vector delivery has been clearly demonstrated, but there are risks associated with it that can be avoided by using an easier, nonviral TCR knock-in approach. We have seen proof of principle for these approaches in the literature already, and at BlueSphere Bio we are working on optimizing the process.

In general, I believe that everyone understands that solid tumors are different and that personalized solutions are going to be required. The key will be to show the right amount of efficacy using the right approach with demonstrated safety. If that can be achieved — and we think it can be with our technology platforms — it will be a real breakthrough and will be welcomed by the regulators.

DA: Given the multiple technological aspects of your approach, it seems that collaborations with partners that possess different skillsets would be valuable. Do you have any notable partnerships in place?

MS: We are interested in partners who can offer something to help improve our process or the efficacy of our products. We would love to work with a company that has an effective nonviral TCR knock-in approach, for instance. That is one example of aspects on the manufacturing side where we would be excited to collaborate.

On the other hand, BlueSphere Bio has a great platform for very quickly and inexpensively finding many, many TCRs for various applications. Just in the last four months, we’ve produced TCRs for five different targets — four of them in the minor histocompatibility antigen space. Our ability to provide a panoply of TCRs for any target makes it possible to identify elite and different TCRs that are more sensitive and that have the right qualities. We are looking for somebody who wants to partner with us to access our platform. We in turn want to partner with companies that have a therapeutic hypothesis for which they require a TCR — not on a fee-for-service basis as a service provider, but as a true development partner working together to bring impactful new therapies to patients.

DA: Do you have any products in development that you would like to highlight?

MS: We have a first-generation product that is semi-off-the-shelf. It is designed to treat blood cancers in the context of allogeneic bone marrow transplant. It is an important product, because it is going to get BlueSphere Bio into the clinic by early next year with a product for which we have used our TCXpress™ platform. Instead of looking for neoantigens, however, the platform was used to find minor histocompatibility antigens, which are like neoantigens.

Usually, transplants involve donors who are HLA-matched (for example, siblings) with many allelic proteins. We are getting TCRs that target allelic proteins that we have selected because they are only expressed in the hematopoietic system. For this therapy, we engineer a TCR from donor T cells and reprogram them with a TCR specific for an allele that the patient expresses but the donor does not. These engineered T cells kill the host bone marrow and the leukemia because these cells are hematopoietically derived, but they do not touch skin or liver cells. As a result, the anti-leukemia product we are developing does not cause graft-versus-host disease and also allows the stem cell transplant to engraft. It is developed using minor antigens analogous to solid tumor neoantigens that segregate in the human population and are thus reusable from one patient to another.

Our first target is HA-1 and will cover 15–20% of bone marrow transplants. Our manufacturing process has been standardized — much like the process for CAR-T cell therapies, and we anticipate filing an Investigational New Drug (IND) application with the FDA by the end of this year.

DA: I’d love to close with your thoughts on how disruptive or transformative you think this approach to cancer therapy will ultimately be.

MS: Immune cells travel throughout the body. It is very likely that, in most adults, many cancers have been edited out by our immune systems. Part of the reason why humans today live as long as they do could be because our immune systems are pretty good at editing out nascent cancers, at least until they become somewhat senescent. The process is very natural. We also know from checkpoint inhibitor and TIL infusion therapies that these types of treatments can be very effective in certain patients.

There are 230,000 new cases of lung cancer every year in the United States alone. Only maybe 10% or 15% of them are going to get treated in a way that will result in a definitive cure, because lung cancer is typically caught very late and there is a high tumor mutation burden. That’s a lot of people still dying from this disease.

In my opinion, targeting neoantigens in a personalized way is the best way to fight solid tumors, and I think we really have found a great way to make that approach work. In the end, these personalized products should be nontoxic and relatively easy to manufacture. It is an autologous product, which is immunologically safe and sound. While I know that there is great interest in allogeneic products because of perceived ease of manufacture, there is risk in that approach of both rejection and even graft versus host disease. The biggest problem to practically producing autologous therapies is going to be how to scale up the process. That’s why we have to make it more efficient. At BlueSphere Bio, we are developing technology that will make it possible to personalize these therapies so that they will be effective for a large number of patients.

I truly believe that this personalized approach will become the mode of treatment in the future. The reason I founded BlueSphere Bio is because I realized that we could use this technology to develop therapies that meet a huge unmet need. BlueSphere Bio now has 55 employees and we’ve already raised $120 million. The reason I have put so much time and effort into the company is because I thought it could be really disruptive. Actually, transformative is the better word.

If we are successful like I anticipate, then between 5 and 10 years from now, the approach being developed by BlueSphere Bio will be an effective way to treat cancer. In 15 years, I think our approach will supplant chemotherapy in some settings, because using these systemic treatments comes with such high toxicity. At the end of the day, it needs to be the immune system that fights cancer, and because of that, therapies must be personalized.

Fab Biopharma was founded with a mission to address unmet needs in women’s health, focusing beyond reproductive health to conditions like Sjögren’s syndrome and lupus, which predominantly affect women and have historically been under-researched. Fab also prioritizes research that emphasizes female biology, utilizing female-derived cell lines and animal models to better understand disease mechanisms in women.  By leveraging bispecific receptors to target both T and B cells in autoimmune diseases and cutting-edge genetic and biomarker analysis, Fab aims to expedite development and reduce costs while creating effective treatments to address these unmet needs in women. In this Q&A, Chia Chia Sun and Gardiner Smith, two of Fab Biopharma’s founders, discuss the company’s vision and mission and the unique expertise the team brings to drive their novel approach, with Pharma’s Almanac Editor in Chief David Alvaro, Ph.D.

David Alvaro (DA): Could you each tell me a little about your professional journeys and how they led to the founding of Fab Biopharma?

Gardiner Smith (GS): My journey began with studying chemistry at the undergraduate level, but I transitioned into intellectual property and business transactions within large pharmaceutical and biotech companies. At first, it didn’t occur to me to question the strategic directions of the companies I worked for; I assumed our shared goal was to help get new medicines into the hands of patients. However, a growing entrepreneurial drive led me to reconsider both the direction and purpose of these companies and my own. Through experiences in biological drug development and women’s health, I had seen the unrealized value of empowering women, particularly through better biologic drugs. Many women suffer from untreated diseases, and I realized that the dominant male perspective — including my own — might inherently limit the understanding and focus on female-centric conditions. This realization gave me a new purpose: dedicating more resources to address these unmet needs, which eventually led to the founding of Fab.

Chia Chia Sun (CCS): I traveled an academic path — I hold a master’s degree in genetics, specializing in cancer, an MBA with a focus on corporate finance, and a Master’s of Science in bioethics, which was dual-programmed with my genetics studies. After entering the industry, I mostly worked with large pharma companies, spending significant time in commercial market research and management consulting. The turning point came when I founded Damiva, a topical women’s health company. This venture, coupled with our biopharma experiences, expanded my awareness of the vast unmet needs in women’s health and my commitment to the field. About 12 years ago, both Gardiner and I decided to dedicate our careers to this cause. During the COVID-19 pandemic, Gardiner developed a business plan for a biologics firm focused on women’s health beyond reproductive issues, which was the genesis of Fab.

That decision turned out to be not only necessary but particularly timely, as the NIH (National Institutes of Health) just released a new grants policy focusing on women’s health — the  first in its history — which aligns perfectly with our mission of pushing the boundaries of research through the lens of women’s health. The notice of special interest arises from Biden’s executive order proposing $12 billion for new research in women’s health.

Outside of reproductive health, the largest class of conditions that predominantly affect women are autoimmune diseases, so that became our focus. We prioritize diseases like Sjögren’s syndrome, because, despite its significant impact, there are currently no adequate therapeutic options, as well as lupus, due to both the need and our being the team that developed the first biologic lupus drug, Benlysta^®.

DA: Why have drug development efforts not adequately addressed Sjögren’s syndrome?

CCS: Sjögren’s is a complex disease to diagnose because it often presents with nonspecific symptoms, such as dryness of mucous membranes, which can easily be confused with more common symptoms of menopause. Since women are typically diagnosed in their 40s and 50s, though the disease likely begins in their 20s and 30s, this results in a significant diagnosis bias. This delayed diagnosis means that there’s a large portion of the patient population that remains unstudied and untreated, which has impeded the development of drugs against the disease.

DA: Once you had established that goal, how did you begin developing solutions?

CCS: As we began this work, I had the view that the industry already has plenty of technologies that could be redirected to address women’s diseases. We chose to pursue bispecific receptors, which are a new modality, but, like most inventions, they were built on earlier inventions — soluble single receptor fusion drugs and bispecific antibodies. We saw an opportunity to leverage those technologies and apply them uniquely to autoimmune diseases. In a similar manner, we decided that, rather than find novel drug targets, we would instead look at existing druggable targets where clinical data had already been generated and tackle them through this new approach. Finding smarter, more targeted applications of resources that have already been developed can really speed up development and reduce risks, which is especially critical for underrepresented diseases like Sjögren’s.

Another unique aspect of our mission is that our commitment to women extends beyond typical drug development; we are ensuring that our research and trials emphasize female biology, a factor that is too often overlooked in medical science. This involves prioritizing female animal models and incorporating female-derived cell lines in our disease-specific organoids. It’s about more than just meeting FDA requirements — it’s about redefining how we study and treat diseases that affect women, ensuring that our interventions are as relevant and effective as possible.

Many autoimmune diseases are primarily considered to be driven by T cells and later lead to B cell disease. Increasingly, we are realizing that autoimmune disease has both T and B cell components. Traditional approaches to drug development have focused on either targeting T cell disease to prevent B cell disease or to treat the B cell disease itself.

Sjögren’s involves both T and B cell components from the onset. The histopathology and genetics of Sjögren’s demonstrates an involvement of both types of cells very early — certainly by the time patients present with the disease — which suggests that targeting both cell types with the same drug could be more effective. Of the two best candidates currently in the clinic, one targets T cells and the other targets B cells. We believe that our approach leveraging bispecific technology will allow us to address both pathways in a single treatment, which we believe will enhance efficacy and has the potential for remission.

GS: Adding to that, our understanding of Sjögren’s and similar diseases like lupus, which we are also investigating, has evolved. Lupus is an incredibly heterogeneous disease, but we now know that, like Sjögren’s, it involves both T and B cells iteratively and early. Among many other accomplishments, our Chief Medical Officer, Bill Freimuth, M.D., developed the clinical endpoints for lupus that are still used today, which are based on a sophisticated organ domain analysis.  This methodology allows for detailed monitoring of disease impact on various organs, crucial for diseases as heterogenous as lupus and Sjögren’s. The variability in how the diseases present makes clinical trials particularly complex and challenging.

Our strategy using soluble bispecific receptors for both lupus and Sjögren’s aims to initiate therapy with this combined approach, potentially improving outcomes from the start, and has a lot of other advantages in terms of development speed, dosing, and pricing compared with establishing a combination therapy after approvals.

DA: For both of those diseases, do that heterogeneity, the delayed diagnosis, and other factors create challenges in clinical trials?

CCS: Clinical trials for diseases like Sjögren’s and lupus are notoriously challenging due to their heterogeneity. Bill’s work has been instrumental in defining clinical endpoints that reflect the multi-organ impact of these diseases. For Sjögren’s, adapting these rigorous criteria ensures that our trials are comprehensive and that our treatments address the disease effectively across various organ systems.

GS: Our strategy incorporates cutting-edge genetic and biomarker analysis to enhance the predictability of our phase II trials. By identifying and utilizing robust markers, we aim to better forecast the outcomes of pivotal phase III trials, which is crucial for efficiently directing our resources and efforts.

We have the key expertise in house, but we’re also collaborating with some of the leading rheumatologists in the country, who have many Sjögren’s and lupus patients and can not only provide us with access to critical patient samples but also deep insights into the biomarkers associated with these diseases. Our intellectual property around specific B cell biomarkers, used in conjunction with our bispecific receptors, positions us to pioneer effective therapies for Sjögren’s and lupus.

DA: Since you’re targeting both B and T cells simultaneously for both Sjögren’s and lupus, is it feasible that the same candidate bispecific receptor could treat both diseases?

GS: We’ve decided to use different receptor pair combinations for lupus and Sjögren’s for both risk reduction and commercial reasons. Additionally, we’re exploring separate therapeutic areas, like osteoimmunology and asthma, both of which disproportionately affect women compared with men. Our diverse approach allows us to minimize risk if a particular molecule shows a liability and to optimize both scientific and marketing strategies for different molecules. Our team, including the fourth founder, Reiner Gentz, who has authored many of the foundational  TNF family publications, focuses on diverse applications of our technologies, and it was his idea to develop bispecific receptors rather than bispecific antibodies, which was the original plan.

CCS: The name Fab was originally meant to stand for “female antibody,” but with that pivot it became “female autoimmune biologic,” which is more expansive.

GS: With antibodies, there are so many possibilities: traditional drug discovery methods like phage display or the use of transgenic mice generate millions of novel binding regions to screen and find your candidate. Soluble receptors are a different story. They’ve already evolved to bind a specific ligand. So, rather than starting with millions of combinations, we have one or two dozen to investigate. We can then generate diverse candidates by combining each B cell receptor with each T cell receptor.  This focused diversity means we’re not overwhelmed by volume and can rapidly screen and select the most promising candidates. This streamlined process allows us to advance from initial selection to lead compounds in just three to six months, which is very different from antibody discovery.

CCS: Although soluble receptors are relatively unexplored, Fab isn’t alone in seeing the value of soluble receptors for autoimmune diseases.  Vertex Pharmaceuticals recently acquired Alpine Immune Sciences for just shy of $5 billion, largely on the strength of Alpine’s lead asset, povetacicept, which is a soluble TACI receptor that’s a dual BAFF and APRIL antagonist. It’s currently in phase II trials for a small indication — IGA nephropathy — but they claim that it shows Humira-like universal properties. Alpine’s approach with povetacicept, specifically how they optimized the receptor for BAFF but not APRIL to avoid side effects, mirrors our strategy to not overly optimize receptors for the same reason. And povetacicept is a single receptor, not a bispecific like what we are developing.

DA: How generalizable do you view the strategy of simultaneously targeting B and T cells across autoimmune diseases and beyond?

CCS: The approach is highly generalizable. B and T cell activities are commonly linked, so managing both within a safe and effective therapeutic window is crucial. For now, our priority is diseases like Sjögren’s and lupus, which significantly affect glandular and organ systems, but we’re also exploring conditions like osteoimmunology and asthma, which may not traditionally be seen as autoimmune but have strong immunological components.

GS: It’s a nuanced approach. For instance, osteoporosis is often considered a metabolic condition rather than strictly autoimmune. Yet, there’s a clear immunological aspect to it. Similarly, while asthma is generally viewed as a pediatric condition, it is significantly more severe in women than in men, illustrating the gender-specific differences in disease manifestation and severity.

CCS: Because our soluble receptors bind extracellular cytokines and ligands and effector molecules rather than membrane-bound ones, they should be safer in autoimmune disease. That means that we can develop drugs for indications like asthma and osteoporosis where you need a robust safety profile because we are trying to only target one organ system: the lungs for asthma and bone for osteoporosis.

GS: When you bind cell membranes with bispecific drugs, there is the possibility that it results in bringing two cell types together, which can have consequences. By focusing on extracellular targets, we can fine-tune our approach to ‘gobble up’ excess harmful molecules without disrupting cell integrity.

DA: With that generalizability in mind, what is your current strategy for how to handle the multitude of therapeutic possibilities that this work presents?

GS: With Sjögren’s and lupus, we can conduct parallel development efficiently, because the screening assays, the organoid models for kidney and salivary glands, and so on overlap for the two diseases. That lets us pursue both programs and reduce costs significantly. For example, the animal model used for lupus, which was validated by our team during the development of Benlysta, is also applicable to Sjögren’s. This synergy enables us to push these programs forward swiftly, maintaining most activities in-house up to phase IIA or even into pivotal studies.

CCS: For conditions where the path to approval is less established, like Sjögren’s, or for diseases with rapid model readouts, like osteoporosis, our approach might be different.

GS: Osteoporosis is a good candidate for out-licensing, letting us focus resources on areas where we can make the most impact quickly. Similarly, for conditions like scleroderma and asthma, where there is already a substantial safety database, out-licensing becomes a practical option. Our approach is flexible; we’re prepared to out-license where it strategically makes sense to accelerate development and leverage external expertise.

Our immediate priority remains to advance our lead programs for lupus and Sjögren’s through to clinical stages. These programs form the backbone of our development strategy, but we remain agile, ready to pivot and adapt strategies for other indications based on emerging data and partnership opportunities.

DA: Can you tell us a bit more about your investment and funding strategy, particularly in the near term?

GS: Our progress to date in data accumulation, intellectual property, and operational planning has largely been powered by the initial investments from our four cofounders. This foundational funding has allowed us to establish a robust platform on which we can build further.

We have an important partnership with Wheeler Bio, a boutique CDMO with co-investment in the potential of our biologics. They contribute services and expertise in their facilities, which helps us manage costs and risks effectively. As we move forward, we plan to continue this partnership into the scale-up phase of our projects.

DA: You mentioned earlier that the company is not only focusing on diseases that affect women; you are also looking to rethink drug science from a female perspective.  Can you expand on what that will mean?

CCS: A change in perspective is essential across the entire pharma landscape. For example, while the gender gap in clinical trial recruitment has narrowed significantly in the last decade, there remains a critical need for further inclusivity.

One major point of differentiation is our focus on autoimmune diseases that disproportionately affect women. We prioritize diseases based on their prevalence among women compared with men. Moreover, our drug development process overall is driven from a female perspective and intensely focused on the female biology; we predominantly use female animal models to better understand disease mechanisms in women. 

GS: While it’s common to acknowledge sexual dimorphism in mammals, it’s rare to see it significantly influence pharmaceutical research. Our emphasis on these differences is not just academic; it’s practical and necessary for developing effective treatments.

CCS: We are finally getting some real insight into why autoimmune diseases in general are more prevalent in women than men. Some very recent work has indicated that the Xist complex — which is involved in X chromosome inactivation in women — may be directly involved in the development of autoimmune diseases.

Those results also point to some of the challenges in translating results from animal models to clinical trials. We know that, in female mice, somewhere between 3% and 7% of genes on the inactivated X chromosome are partially expressed, but in humans it’s more like 20–30%. Our models must adapt to reflect these differences accurately.

We are paying very close attention to the epidemiology of these autoimmune diseases. It’s not only gender: for example, Sjögren’s manifests very differently in Asians than in Caucasians, and Hispanics of both genders are overrepresented for lupus. By focusing on these biological nuances, we not only address gaps in current treatment options but also pave the way for more personalized and effective therapies. This approach isn’t just about being thorough; it’s about being right and making a meaningful impact where it’s most needed.

GS: Our goal is to achieve a balanced representation of women and men in our management and board. Once we secure additional funding, we’ll be better positioned to recruit and achieve this balance.

CCS: It’s about getting the balance right. This diversity encompasses mental, intellectual, emotional, communicative, observational, and data processing differences that are critical for innovatively addressing women’s health issues.

GS: This is vital because if we lack diverse perspectives, especially at the senior level, our approach to developing biologics for women’s diseases won’t be as effective. It’s about what we don’t know, and without a diverse team, we miss out on insights that could lead to breakthroughs.

CCS: To that end, we’re dedicating substantial research on drug science from the female perspective, including understanding more about mechanisms like Xist. The increasing body of literature supports this approach, and it’s exciting to see the field evolve.

When I speak on panels, I make it clear: we are not just another biotech company. We are actively developing and testing treatments specifically designed for women, and this mission is crucial. It’s about making our presence known and our voices heard in a space where such perspectives are often sidelined. And while our approach is innovative, it still adheres to established scientific and business protocols. We’re leveraging what’s known and proven, like the models used in developing Benlysta, and applying it to our work without reinventing the wheel every step of the way.

GS: It reminds me of a quote from Benjamin Franklin: “We get old too soon and wise too late.” In our case, we’re combining the youthful energy and passion of our team with a seasoned understanding of female biologics development. This combination is rare and key to our success.

Ensuring the safety, quality, and efficacy of biosimilars is essential to garnering confidence in these cost-saving medicines by both physicians and patients. A strong regulatory framework is thus essential to avoiding the introduction of poor-quality biosimilars that lack strong data supporting their similarity to the original (reference) product. At present, some countries around the world have long-established, mature, and robust regulatory pathways for biosimilar approval, while others have strong regulations in place but are not yet experienced in implementing or evaluating biosimilars.  Still other countries have guidelines that reference the regulations from these countries but only weak regulatory frameworks in place or none at all. Differences among the mature pathways further compound the challenges associated with launching biosimilar products into many markets. The added time and cost not only reduce patient access — they inhibit further innovation.  

The Critical Role of Biosimilar Approval Pathways

Small molecule medicines are created from chemicals with well-defined molecular structures. Although there are requirements, such as in vivo bioequivalence studies for these compounds, verifying whether a generic version has the correct active substance and similar behavior from the reference product that has already been tested and approved is much simpler than it is for biological products. In addition to understanding the kinetic behavior of generics, another major challenge in obtaining approval for small molecule generics is to ensure that no new potentially harmful impurities are introduced through the various routes of synthesis.  

In contrast, biologic drugs are complex and consist of multiple molecular entities. Producing recombinant proteins and antibodies using living cells leads to a heterogeneous product mixture, with slight variations in protein sequences and posttranslational modifications (such as added sugars, phosphates, or other moieties). This complexity means that biopharmaceuticals require a very complex and well-characterized manufacturing process to match molecules as closely as possible in order to retain therapeutic action. It is also important to note that even the inter-batch variability of an innovator product effectively presents the same difficulties — no two batches of innovator products are the same, only similar to one another.  

As mentioned, it is possible to develop and manufacture biosimilars, which are products that closely resemble the original biologic drug in terms of physicochemical properties, pharmacokinetics, safety, and efficacy. Regulatory approval pathways that mandate extensive characterization and demonstration of in vitro and in vivo performance, including relevant human clinical studies, are crucial. These pathways ensure that biosimilars introduced to the market exhibit sufficient similarity to their reference products, guaranteeing safety and efficacy for patients.  

Limited International Harmonization

One of the greatest challenges to the growth of the biosimilars market — and thus to greater access to safe, life-changing medicines worldwide — is the lack of standardized regulations for the development and approval of biosimilar products. While there are international guidelines that provide recommendations for high-quality and safe product development, such as the World Health Organization (WHO), the European Medicines Agency (EMA) and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, differences in regulatory implementation from country to country lengthen timelines, increase costs, and ultimately stifle innovation and limit patient access to medicines.¹  

The first biosimilar approval pathway was introduced in Europe in 2006, and this region continues to lead with the highest number of approvals. The United States did not establish its regulatory pathway until 2009. It took another six years before the first biosimilar was approved in the country, and the United States continues to lag behind Europe (53 approved biosimilars in the United States vs. 86 in Europe as of the end of June 2024).² Changes are occurring, though. A record eight biosimilars were approved by the U.S. Food and Drug Administration (FDA) in the first half of 2024, and the agency announced the Biosimilars Action Plan, which aims to streamline the development of biosimilars.  

However, significant differences remain in the approaches to biosimilars taken by the EMA and the FDA, making it difficult to achieve harmonization between the two agencies, despite the hard work that has been ongoing for more than six years. While both agencies require a thorough scientific assessment to determine the similarity of the biosimilar candidate to the originator product, once approved by EMA, biosimilars can be automatically substituted for branded drugs by physicians and pharmacists. In the United States, additional requirements (switching studies) must be met for biosimilars to be considered interchangeable with the originator drugs.³ Each state has also passed legislation regarding the interchangeability of biosimilars, with some forbidding it. The Biosimilar Red Tape Elimination Act, first introduced in the U.S. Senate in 2022 and again in 2023, seeks to harmonize U.S. regulations with those of the EMA regarding automatic interchangeability. No action has been taken on it to date.  

The World Health Organization (WHO) published initial guidelines on the evaluation of “biologically similar biotherapeutic products” in 2009. These recommendations were updated in 2022 and include renaming biosimilars as “biological products that are highly similar” to well-characterized reference products.⁴ There is notable variation in the terminology surrounding biosimilars in regulations passed by different countries. While the term “biosimilars” is used in the EU, United Kingdom, United States, China, and a handful of other countries, terms including “biosimilar products,” “similar biologics,” “similar biological medicinal products,” “follow-on biologics,” and “bioanalogues” have been employed by various regulatory bodies.¹  

Most countries have modeled their biosimilar regulations after those developed by the WHO, EMA, and/or FDA or recommend that any biosimilars submitted for approval have already received marketing authorization by the EU or U.S. agencies. However, discrepancies exist.¹ Both “comparability” and “similarity” are used when discussing the comparison of the properties of a biosimilar candidate and its reference products. Criteria that must be met to allow extrapolation of a biosimilar approval from an initial indication to others differ from country to country. As exemplified by EU and U.S. regulations, definitions and requirements for interchangeability also vary. Guidance regarding the selection of the reference product can be ambiguous, and some require the use of in-country products. Differences also exist with regard to application fees and patent protection.  

Regulatory Pathways in Mexico and Canada

Canada is considered to have a mature biosimilar approval pathway.⁵ In Canada, biosimilars are approved according to a science-based regulatory framework that requires the demonstration of comparative quality and performance, ensuring highly similar structure, function, efficiency, and safety to the reference product, including evidence of no clinical differences.⁶ Interchangeability is determined by individual provinces.  

In Mexico, biocomparables were first mentioned in drug regulations in 2011.⁷ The General Health Law Regulations of Mexico define biocomparables as being comparable to reference products regarding safety, quality, and efficacy. Initially, the Federal Commission for Protection against Sanitary Risk (COFEPRIS) granted some marketing authorizations to biolimbos, non-innovator biologics not supported with data demonstrating equivalent quality, safety, and efficacy. Currently, NOM-257-SSA1-2014 concerning biologics (NOM 257) requires that all biolimbos undergo the appropriate review process, but some biocomparables remain on the market that have not undergone specified evaluations. As of May 2021, Mexico accepts clinical data obtained in the country of origin for initial applications, but the renewal of a marketing authorization requires clinical data collected in Mexico. Biocomparables are approved for all indications of the reference product as appropriate, and extrapolation to other indications may be possible if scientifically justified.  

A Regulatory Certainty Strategy for the Pharmaceutical Sector: Biosimilars was proposed by the Mexican Ministry of Health in 2024 with the goal of promoting the development of biocomparable biologics. This will be achieved in part by establishing regulations aligned with international standards.^7,8 Regulations will be aligned with the ICH and the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) and the WHO guidelines on biosimilars, particularly with respect to bioequivalence and biocomparability studies. The requirement for Mexican clinical studies is also expected to be eliminated.  

Regulatory Landscape in Latin America

The regulatory landscape for biosimilars in Latin America is inconsistent. Argentina and Brazil are two countries that have taken significant steps toward establishing strong approval pathways — so much so that they are the only two full members of the ICH in Latin America. However, while the trend in the region is to improve regulatory standards, internationally recognized regulatory frameworks remain lacking in many other countries.⁹ As a result, non-comparables, biocopies, biomimics, and non-regulated biosimilars are marketed in the region.¹⁰ Regulations also vary notably from one country to another owing to cultural, economic, and regulatory outlooks.  

The Brazilian Health Regulatory Agency (ANVISA) published its initial biosimilar regulation in 2010, and by the end of 2021, had approved more than 40 biosimilar products.¹¹ In Argentina, the Administración Nacional de Medicamentos, Alimentos y Tecnología Médica (ANMAT) issued a draft guideline on “medicamentos biológicos” (the term biosimilars is not used but a specific guideline refers to biologics products with previous background) in 2008, which was based on the EMA guidelines.12   With respect to other Latin American countries,¹⁰ Chile has had Technical Guideline Number 170 in place since 2014, which outlines the approval process for biosimilars, requiring submission of both preclinical and clinical data. There have also been three possible approval routes for biocompetitors, biosimilars, or biogenerics in Colombia since 2014. Ecuador’s 2014 regulation on biosimilar approval was updated in 2019 to align with international guidelines. Guatemala’s 2019 regulation allows the extrapolation of biosimilars approved by FDA, EMA, and recommended by WHO. In Peru, according to a 2016 decree, biosimilar approval requires submission of comparative data according to ICH requirements, and extrapolation can be applied to biosimilars approved by the FDA and EMA and recommended by the WHO.  

Regulatory Framework in the Asia-Pacific Region

Within the Asia-Pacific region, the largest markets for biosimilars are China, India, and Japan. South Korea is also a leading player in biosimilar manufacturing and use. Japan was one of the earliest countries to establish a regulatory pathway for biosimilars, developing its guidelines in 2009, and continues to streamline the approval process.¹³ Both Japan and South Korea modeled their regulations after the EMA and FDA requirements.¹⁴  

China and India developed their own regulatory pathways.¹⁴ China issued guidelines in 2015 and approved its first biosimilar in 2019, although non-approved copy-biologics had already been available in the country for many years.¹⁵ The China National Medical Products Administration (NMPA) has been working overtime to align its approval pathway for biosimilars with international regulations, since China is now a full member of the ICH as well.^14,16  

India’s regulations continue to evolve. A guideline was issued in 2012 and revised in 2016 to include post-marketing study requirements, but the first “biosimilar” was approved in 2000 without any specific requirements.⁷ In addition to not being aligned with international regulations, the guidelines in India are not legal requirements. As a result, international companies have challenged Indian biosimilar makers on several occasions, particularly regarding the legitimacy of the reference products used for comparative clinical studies.¹⁸   Taiwan and Malaysia recently developed approval guidelines for biosimilars.¹⁴  

Regulatory Landscape in the Middle East and Africa

Only a few countries in the Middle East and Africa have somewhat mature and established biosimilar approval pathways. This inconsistency makes introducing biosimilar products into the region quite challenging.  

For instance, there are 54 countries on the African continent, and each has its own regulatory authority. Only South Africa has an established framework (first issues in 2014) for biosimilar approval.^19,20 Tunisia’s biosimilar regulations, issued in 2018, refer directly to EMA, WHO, and ICH guidelines. Algeria announced it was developing draft regulations on biosimilar approval in 2018, and while it is believed a draft exists, nothing has been shared with industry (as of the end of 2023).²¹  

Most countries in the Middle East have some level of guidance or regulations for biosimilar approvals. Saudi Arabia, Egypt, Lebanon, Jordan, Bahrain, and Iraq all have published guidelines.  

The Saudi guidelines and regulations for biosimilars are covered in the regular drug approval framework, heavily referencing U.S. FDA regulations while incorporating local/regional requirements contained in the Gulf Cooperation Council (GCC) Guideline on Biosimilars issued in 2016.²² A separate guidance document (Guideline on Biosimilar Products – Quality Considerations, current version 1.0) addresses requirements for demonstrating comparability.

Egypt’s current biosimilar regulation was published in September 2023,²¹ primarily referencing EMA regulations.²² Imported biosimilars must meet some different requirements, including being approved and marketed in the country of origin and from certain countries; otherwise, a site inspection for GMP compliance is required. Jordan’s biosimilar guidelines were adopted in 2015 and specifically reference EMA guidelines.  

Iraq has no specific biosimilar approval guidelines, but its general drug regulations refer heavily to the EMA.²¹ It is recommended that biosimilars have received approval in the EU, U.S., Canada, Japan, Switzerland, or Australia before registering them in the country. Lebanon issued guidance on the approval of similar biological medicinal products in 2016, following the WHO biosimilar guidelines. Bahrain issued a guideline for licensing biosimilar medicinal products in March 2023. Kuwait relies on the GCC guideline on Biosimilars from 2016. The United Arab Emirates currently has no biosimilar-specific regulations, but the UAE Ministry of Health and Prevention is developing guidance. In the meantime, imported products are required to meet U.S. FDA or EMA expectations for biosimilars.  

Conclusion

Biosimilars have the potential to reduce treatment costs and increase patient access to state-of-the-art medicines. However, the lack of standardized international regulatory pathways has led to reduced efforts by drug makers to market their biosimilar products globally. Meeting vastly varying regulatory requirements across different regions adds significant time and cost to biosimilar development.  

Standardization is needed in reference product sourcing and dossier preparation.⁵ In emerging markets, there is a significant need for additional clarification and details regarding requirements for clinical study design and the establishment of critical criteria. Differences in philosophies regarding the extrapolation of approvals for different indications and the interchangeability/switching/substitution of biosimilars further complicate compliance. The development of pediatric biosimilars is another area requiring attention.  

Global harmonization of biosimilar regulatory frameworks would afford many benefits to both manufacturers and patients.¹ Uniform regulatory reviews would allow the sharing of data between regulatory bodies in different countries, reducing the need for nearly duplicate testing and document preparation. Biosimilar products approved in one country could more quickly be introduced into other markets. The costs of launching biosimilars into multiple markets would also be much lower. Consequently, more biosimilars would be launched in countries around the world at reduced costs for patients, dramatically increasing access.  

Achieving global harmonization of biosimilar regulations is not an easy task. It will require extensive communication and collaboration between regulatory authorities and agreement on scientific requirements for demonstrating similarity, as well as alignment on approaches to extrapolation and interchangeability, areas that are currently highly contentious. Numerous legal and intellectual property issues will also need to be addressed.

The first step, according to the international organization Act4Biosimilars, is to help countries lacking strong regulatory pathways for biosimilars develop and implement them.²³ The initial focus is on Latin America and Africa, with the overall goal of increasing global biosimilar adoption from approximately 14% in 2022 by at least 30 percentage points across more than 30 countries. Countries will be encouraged to reference WHO guidelines for biosimilar approval to ensure the quality, safety, and efficacy of new products and to start working toward internationally aligned regulations.    

References

1.     Jarab, Anan S., Shrouq R Abu Heshmeh, and Ahmad Z. Al Meslamani. “Bridging the gap: The future of biosimilars regulations.” Hum. Vaccin. Immunother. 20: 2362450 (2024).

2.     “FDA approves record eight biosimilars in H1 2024; okays first interchangeable biosimilars for Eylea.” Radio Compass Blog. 27 Jun. 2024.

3.     Hornung, Jayne. “Navigating the U.S. Patchwork of Biosimilar Laws.” MMIT. 22 Jun. 2023.

4.     Kaitwasser, Jared. “New WHO Biosimilar Guidelines Aim to Streamline, Clarify Regulations.” Center on Health Equity & Access Spotlight. 8 Mar. 2023

5.     Rahalkar, Hasumati, Hacer Coskun Cetintas, and Sam Salek. “Quality, Non-clinical and Clinical Considerations for Biosimilar Monoclonal Antibody Development: EU, WHO, USA, Canada, and BRICS-TM Regulatory Guidelines.” Front. Pharmacol., Sec. Drugs Outcomes Research and Policies. 9 (2018).

6.     “Biosimilars and their Approval in Canada.” Canadian Association of Professionals in Regulatory Affairs. 24 Mar. 2022.

7.     Luna, Alejandro and Ingrid Ortiz. “Mexico: regulatory certainty for biosimilars on the horizon.” IAM. 2024.

8.     Smith, Jennie. “Latin America Roundup: Mexico unveils ambitious biosimilar strategy.”  RAPS. 20 Feb. 2024.

9.     “Latin America’s biosimilars market: regulatory, institutional, and technological aspects.” Generics and Biosimilars Initiative. 21 Nov. 2023.

10.   “Regulatory landscape for biosimilars in Latin America.” Generics and Biosimilars Initiative. 9 Sep. 2022.

11.  Cestari de Oliveira, Sílvia Helena, Marcos Castanheira Alegria, and Marco Antonio Stephano. “Brazilian Regulation of Biosimilar Products: What Is Important to Know.” BioPharm International. 35: 30–37 (2022).

12.  “Argentinian guidelines for similar biological medicines.” Generics and Biosimilars Initiative. 24 Jun. 2022.

13.  “Biosimilars Revolutionizing Healthcare in Asia Pacific: A Promising Future Ahead.” BioPharma APAC Insight Series. 23 Feb. 2023.

14.  Duttagupta, S et al. “Is Asia Ready for Biosimilars? a Review of the Regulatory Landscape for Biosimilars?” Health Care Use & Policy Studies – Regulation of Health Care Sector. 21: S56-S57 (2018).

15.  “Regulatory Pathways for Biosimilars: A Comparative Analysis.” Bioboston Consulting. 22 Jan. 2024.

16.  “Cell’s trends reviews journal published the regulatory differences of Henlius’ biosimilar for approval between Europe and China.” Henlius. 17 Mar. 2023. 

17.  Meher, Bikash R.  et al. “Biosimilars in India; Current Status and Future Perspectives.” J. Pharm. Bioallied Sci. 11: 12–15 (2019).

18.  Thakur, Dinesh and Prashant Reddy. “Pharmaceutical sector: Why India needs a regulatory pathway for biosimilar drugs.” Scroll. 7 Mar. 2024.

19.  Rathore, A. S. and A. Bhargava. “Regulatory considerations in biosimilars: Middle East and Africa regions.” Preparative Biochemistry & Biotechnology. 51: 731–737 (2021).

20.  Hegde, Madava and Shivani Hiremath. “Unlocking the Promising Opportunities of Biosimilars in the Middle East and Africa Market.” IQVIA. 1 Jun. 2023. 

21.  Singh, Guriqbal. “Mapping The Biosimilar Regulatory Landscape In The Middle East.” Bioprocess Online. 13 Dec. 2023.

22.  “Biosimilars in the MENA Region: Regulatory Landscape.” Biomapas. Accessed 1 Jul. 2024.

23.  Turner, Sally. “From Europe to Latin America: Driving access to affordable biosimilars.” Pharmaceutical-Technology. 9 Aug. 2023.

Biologic drugs have revolutionized the treatment landscape for many severe and chronic conditions, providing targeted therapies for diseases like rheumatoid arthritis, various forms of cancer, diabetes, and multiple sclerosis. These complex medicines, derived from living organisms, offer significant advantages over traditional pharmaceuticals, often delivering improved efficacy and fewer side effects. Despite their transformative potential, biologics are associated with high costs of development, production, and distribution. These financial barriers have resulted in limited accessibility, particularly in underserved markets across Africa, Latin America, and parts of Asia. Only a small fraction of the global population can readily access biologic treatments, leading to significant disparities in healthcare outcomes. Here, we explore the critical role of biosimilars in addressing these challenges by providing more affordable alternatives to high-cost biologics. By examining the strategic efforts of companies like Biosidus, we highlight how biosimilars are expanding global access to essential biotherapeutics, thereby contributing to a more equitable healthcare system.

The Current Landscape of Biologic Drugs

Unlike conventional pharmaceuticals, which are synthesized through chemical processes, biologics are derived from a variety of natural sources and require more sophisticated technologies for their production. Biologics have transformed the treatment landscape for many severe and chronic conditions, offering therapies for diseases that previously had limited or no treatment options. They are particularly crucial in the management of diseases such as rheumatoid arthritis, various forms of cancer, diabetes, and multiple sclerosis, among others. Their ability to target specific components of the immune system or disease pathways allows for more tailored treatments, often with improved efficacy and fewer side effects compared with traditional drugs.  

Despite their therapeutic potential, biologics come with significant challenges, primarily related to their high cost of development, production, and distribution. The complexity of their production processes, involving living organisms, necessitates sophisticated facilities, stringent regulatory compliance, and prolonged development periods. This complexity results in higher prices for the end products. For example, while the United States is one of only seven countries that collectively consume 85% of biologic drugs worldwide, only 2% of the U.S. population actually takes biologic drug products, and this small demographic accounts for 40% of the total costs of drugs in the country. The high cost of biologics places a considerable strain on healthcare systems, often leading to challenges in patient access to these critical treatments.  

Access to biologic drugs varies significantly across different regions of the world. While countries in North America, Western Europe, and parts of Asia have comparatively better access to these medications, there is a stark contrast in many parts of Africa, Latin America, and less developed regions in Asia. In total, only 16% of the global population has even theoretical ready access to biologics, with 5.5 billion people facing limited access, and 1 billion having no access at all, even to basic and essential biologic drugs like vaccines. This disparity is not just a reflection of economic differences but also varies with each country’s healthcare infrastructure and regulatory environment, affecting how quickly and efficiently biologic drugs can be made available to the populations that need them most. These disparities highlight the urgent need for more equitable distribution strategies and underscore the potential role of biosimilars as a means to broaden access to these crucial therapies globally. Biosimilars, by offering similar therapeutic benefits at a lower cost, represent a promising solution to the challenges posed by the high costs of original biologics and the resultant disparities in global access.  

What Are Biosimilars?

Biosimilars are officially approved versions of original “innovator” biologic drugs that have lost their patent protection, analogous to small molecule generic drugs. However, unlike generics, which are chemically synthesized and can be replicated exactly, biosimilars are derived from living organisms and can at best be similar, but not identical, to their reference biologics. This similarity is due to the natural variability and complex manufacturing processes of biologics — in a sense, even different batches from the same manufacturer are never identical. The development of biosimilars involves a rigorous process to demonstrate that they match their reference products in terms of purity, safety, and effectiveness, but at a reduced cost.  

The economic benefits of biosimilars are significant, primarily reflecting in their potential to reduce healthcare costs through competitive pricing. Biosimilars generally enter the market at a price 15% to 30% lower than that of the reference biologics. This cost-saving aspect is crucial, especially as biologics are among the most expensive treatments on the market today. The introduction of biosimilars has led to increased affordability of treatments in diseases like cancer and autoimmune disorders, thereby expanding access to vital medicines for more patients globally.  

Biosimilars must meet rigorous standards set by national or regional regulatory bodies, such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). These standards require extensive analytical, preclinical, and clinical data to ensure that biosimilars have no clinically meaningful differences from their reference products in terms of safety, purity, and potency. The regulatory pathway for biosimilars also includes detailed guidance on the design and conduct of clinical trials to establish comparability, thus ensuring that patients and healthcare providers can have confidence in the quality and efficacy of biosimilars just as they would with the original biologic drugs.  

Role of Biosimilars in Expanding Access

Biosimilars are pivotal in reshaping the global healthcare landscape by providing more affordable alternatives to high-cost biologic drugs, owing to the reduced production and development costs associated with biosimilars compared with their reference biologics. The introduction of biosimilars can substantially reduce costs, enabling healthcare systems to reallocate financial resources to broaden and enhance healthcare services, extending critical treatments to a larger patient base.  

The changing regulatory landscapes across various regions, including Europe and the United States, have facilitated a more straightforward pathway for the approval and market introduction of biosimilars. These regulatory enhancements are vital in reducing the barriers associated with bringing biosimilars to the market. Streamlined guidances and accelerated review processes ensure that biosimilars reach patients more swiftly, which is especially critical in times of healthcare budget constraints. Furthermore, emerging markets are beginning to adopt similar regulatory frameworks, which support local manufacturers in navigating the approval process more efficiently and foster a competitive marketplace that benefits healthcare systems and patients alike. As regulatory frameworks continue to evolve and manufacturers expand their expertise, the influence of biosimilars is set to increase, promising significant public health benefits worldwide.  

Strategic Expansion and Local Production

Biosidus, a pioneering biotechnology company based in Argentina, has been at the forefront of developing and manufacturing biosimilars for over four decades. With a strong foundation in research and development, Biosidus is committed to providing affordable and high-quality biotherapeutics to patients globally, particularly in underserved markets.  

Biosidus has adopted a strategic approach to expansion that focuses on penetrating new markets by establishing local production facilities. This strategy is not only aimed at enhancing market access but also at reducing logistical costs and overcoming barriers related to import restrictions. A prime example of this approach is the development of a new facility in Algeria. This facility is intended to handle the packaging initially and eventually move toward full production, where raw materials are shipped in, and final products are manufactured locally. This expansion strategy allows for a more robust presence in the market by directly addressing the needs of local populations and ensuring a steady supply of biosimilars.  

Local manufacturing offers numerous advantages, particularly in terms of meeting healthcare needs more effectively within specific regions. First, by producing drugs locally, companies can significantly reduce the costs associated with shipping finished products over long distances, which often includes expensive cold chain logistics given the sensitive nature of biologics and biosimilars. This reduction in cost is directly passed on to the healthcare system, making these vital drugs more affordable for local populations.  

Additionally, local production facilities can be tailored to meet the specific demands of the regional market in terms of drug types, quantities, and dosage forms, ensuring that supply aligns more closely with demand. This alignment helps prevent shortages and excesses, contributing to more stable healthcare provision. Local manufacturing also fosters closer relationships with local regulatory bodies, healthcare providers, and patients, leading to improved trust and acceptance of the biosimilar products.  

Moreover, establishing production facilities in target markets supports local economies by creating jobs and building local expertise in biotechnological manufacturing. This contribution to economic development can foster stronger relationships with local governments and communities, further solidifying the market presence of companies like Biosidus. 

By integrating these strategies, Biosidus aims to enhance its global footprint while supporting the sustainability and accessibility of healthcare in emerging and underserved markets. This approach not only advances Biosidus’ business objectives but also aligns with broader global health goals of increasing access to essential medicines.  

Overcoming Barriers in Emerging Markets

Emerging markets present unique opportunities for the expansion of biosimilars but also come with distinct challenges that need to be addressed to maximize these opportunities. Among these are regulatory hurdles and the necessity for comprehensive educational efforts.  

One of the primary challenges faced by biosimilar manufacturers in emerging markets is navigating the varied regulatory landscapes that exist across different countries. Each country may have its own set of standards and requirements for the approval of biosimilars, which can significantly differ from those in more developed markets like the United States or Europe. These differences can lead to complexities in the registration process, requiring manufacturers to tailor their regulatory strategies to each specific market. This often means conducting additional studies or adapting documentation to meet local guidelines, which can prolong the time to market and increase costs. Additionally, the lack of harmonization in regulatory standards can create unpredictability and increased risk for manufacturers attempting to launch products in multiple countries.  

Another significant barrier is the need for extensive education of both healthcare providers and patients about the benefits and safety of biosimilars. Misconceptions and lack of awareness about biosimilars can lead to hesitancy in adoption, even when they are available. Educating healthcare providers is crucial, as they directly influence treatment choices and can advocate for the use of biosimilars based on their understanding of the biosimilar’s efficacy and safety profile. Patient education is equally important to ensure acceptance and compliance with biosimilar therapies, particularly in regions where skepticism about generic drugs might extend to biosimilars.  

Biosidus has actively engaged in efforts to overcome these barriers through targeted educational and training programs. For instance, the company has implemented initiatives to train healthcare professionals in emerging markets, providing them with detailed information about biosimilars, including clinical data and real-world evidence that support their comparability to originator biologics. These training programs are designed to build confidence among prescribers and dispel any myths regarding biosimilars. Furthermore, Biosidus has participated in various forums and workshops that aim to educate regulatory bodies and help shape biosimilar policies in these markets. These efforts are part of a broader strategy to facilitate smoother regulatory approvals and foster a more favorable environment for biosimilars.  

By addressing these challenges through strategic regulatory navigation and comprehensive education campaigns, Biosidus aims to enhance the accessibility of affordable biologic treatments in emerging markets, ultimately improving patient outcomes in these regions. This approach not only benefits the healthcare systems by providing cost-effective alternatives but also supports Biosidus’ long-term commitment to global health improvement.  

Innovative Approaches

As the biosimilar industry continues to evolve, the horizon is marked by promising innovations and potential shifts that could redefine access to biotherapeutics globally. Emerging technologies and scientific advancements are poised to usher in a new era of treatment options that may significantly enhance patient outcomes and healthcare efficiency worldwide.

The biosimilar sector is beginning to explore beyond traditional monoclonal antibodies and is setting its sights on more complex biologics, such as multi-specific antibodies and advanced gene therapies. Multi-specific antibodies, which can bind to multiple targets, offer the potential for more effective disease intervention with fewer side effects compared with conventional monoclonal therapies. These sophisticated molecules can be designed to engage various pathways involved in complex diseases like cancer and autoimmune disorders, potentially offering more comprehensive treatment solutions.  

Gene therapies represent another frontier in biologic treatments, involving the modification or manipulation of genes to treat or prevent disease. While traditionally not categorized as biosimilars, the concepts of replicating or improving upon these therapies can be seen as an extension of the biosimilar philosophy to provide accessible, cost-effective alternatives to high-priced genetic treatments. As these technologies mature, they could pave the way for treating a range of genetic disorders that have been challenging to address with current therapies.  

Global Health Impact

The integration of these advanced biologics into the biosimilar paradigm could dramatically transform access to essential medicines globally, particularly in underserved markets. By reducing the costs associated with these cutting-edge treatments, biosimilars could make even complex therapies more accessible to populations that currently have limited access to even the most basic biologic treatments. This would not only broaden the scope of diseases that can be effectively treated but also enhance the overall quality of life for patients in low- and middle-income countries.  

For example, studies have shown that biosimilar erythropoietin (EPO) is as effective as its original counterpart in increasing hemoglobin levels and reducing the need for blood transfusions in patients with chronic kidney disease. This improvement in anemia management has significantly enhanced the quality of life for these patients, allowing them to lead more active and fulfilling lives.  

In the treatment of multiple sclerosis, biosimilar interferon-beta has been shown to reduce the frequency and severity of relapses, similar to the original biologic. Patients who previously could not afford the high cost of the original drug now have access to an effective treatment option, improving their long-term health outcomes.  

Cancer treatment is another area where biosimilars have made substantial contributions. Biosimilar versions of Trastuzumab, used in the treatment of HER2⁺ breast cancer, have provided a more affordable option without compromising efficacy. These outcomes are critical in regions where access to the original drug is limited due to cost constraints.

Furthermore, as regulatory frameworks adapt to accommodate these innovations, it could lead to more streamlined approval processes and quicker market entry, reducing the lag time between drug development and patient access. This would be critical in addressing global health emergencies more efficiently, such as in the case of pandemics or widespread health crises, where rapid deployment of effective treatments is essential.  

The future of biosimilars, infused with these innovations, holds the promise of not just mimicking existing therapies but enhancing them, potentially delivering solutions that are not only more affordable but also superior in efficacy and safety. As the landscape of biologics continues to evolve, the role of biosimilars will be crucial in shaping a more equitable global health system, ensuring that the next generation of biotechnological advancements remains within reach for all who need them.  

Conclusion

Biosimilars represent a transformative force in global healthcare, offering a cost-effective solution to the high prices associated with biologic drugs. By replicating the therapeutic benefits of original biologics, biosimilars make critical treatments more accessible, particularly in underserved regions. The strategic initiatives of companies like Biosidus underscore the potential of local production and educational efforts in overcoming regulatory and market barriers, further enhancing accessibility.  

As the biosimilar industry continues to evolve, the integration of advanced biologics promises to broaden the scope of treatable conditions and improve patient outcomes worldwide. These innovations hold the potential to not only mimic but also enhance existing therapies, ensuring that cutting-edge treatments reach those who need them most. Investing in biosimilars is not just a business opportunity but a crucial step towards achieving global health equity. By supporting the development and distribution of biosimilars, stakeholders can contribute to a more sustainable and inclusive healthcare system, ultimately improving the quality of life for millions of people around the world.