Advanced Therapies: what are they and what are the challenges of expanding this type of treatment in Brazil

Imagine a reality in which one treatment session is enough to cure a disease. Or finally find a cure for genetic, rare, and/or autoimmune diseases. Advanced therapies promise to help with all of this.

Thus, in recent years, Brazil has positioned itself to encourage the production of these treatments in the national territory and expand its access. This is because, in addition to offering patients longevity and quality of life, it would also be possible to reduce the costs of continuous treatments in the SUS (Unified Health System).

Thus, since 2020, the National Health Surveillance Agency (Anvisa) has emphasized this treatment modality. Currently, Brazil already has eight approved treatments by the agency.

Consequently, in 2023, movements in this segment began to heat up. Among the main ones, it should be noted that, in September 2023, the National Supplementary Health Agency (ANS) began discussions about the inclusion of these therapies in health plans, which could further expand the population's access to these cutting-edge treatments.

The advanced therapy market in Brazil is also attracting new investments. In February 2024, FAPESP and Embrapii allocated R$ 150 million to Embrapii Competence Centers. Of this amount, R$ 30 million is earmarked specifically for advanced therapy research.

As early as March, Fiocruz established a partnership with Caring Cross, an American non-profit organization, to promote the development of genetic treatments for cancer and rare diseases - including cell therapies CAR-T, focusing on leukemia, lymphoma and HIV/AIDS.

Another important event occurred in June, when the Chinese biopharmaceutical Sinovac announced an investment of 100 million dollars, in partnership with Fiocruz, for the development of new cell therapies - such as vaccines and monoclonal antibodies.

But after all, what are these therapies and why is access to them still limited?

Understanding Advanced Therapies

According to Anvisa, advanced therapies are “biological products obtained from human cells and tissues undergoing manufacturing processes. This category also includes recombinant nucleic acids, which are DNA or RNA molecules manipulated in the laboratory for the purpose of regulating, repairing, replacing, or modifying the expression of a gene.”

Within this, according to Sindusfarma, therapies are divided into three main categories:

1. Cell therapy — which involves the administration of whole cells, such as stem cells, CAR-T cells and NK cells.
2. Gene therapy — injection of genetic material (DNA or RNA) to induce, block, or replace a gene of interest. In this area, it is possible to produce treatments using technologies based on CRISPR, viral vectors, and oligonucleotides.
3. Tissue engineering — development of artificial tissues and organs for use in humans.

Despite the distinction between the fronts, it is not impossible for a treatment to end up using more than one of these approaches. But of all the possibilities that humanity has ever seen, the best known are the CAR-T and CRISPR treatments. Therefore, it is worth highlighting the mechanism of each one. See below.

CAR-T

The acronym “CAR” represents the term “chimeric antigen receptor” (chimeric antigen receptor in Portuguese). The letter “T”, on the other hand, refers to the T lymphocyte, a type of immune system cell that can recognize antigens existing on the cell surface of external or internal infectious agents and tumors, producing antibodies to combat such invaders. That is, it acts as a defense of the body.

Therefore, “a CAR-T cell is a T lymphocyte that has undergone genetic modification,” explains Suy Anne Rebouças, ophthalmologist, PhD in molecular biology and Portfolio Manager of the stock fund JGP Health Care.

To do this, “T cells are isolated From the patient through a procedure called leukapheresis, which collects the patient's defense cells. These T cells are then modified Out of the body to become more effective in fighting cancer,” says the expert.

Thus, “the patient's own immune cells are directed to specifically attack tumor cells,” adds the doctor.

Suy Anne also points out that the process does not involve the addition of genetic material, as happens in traditional gene therapies, but rather the use of viral vectors to modify T cells so that they express the CAR (chimeric antigen receptor), which binds directly to the antigen present in the tumor. “This process is carried out entirely outside the body, and then the modified cells are reintroduced into the patient, becoming a personalized army against cancer,” he reiterates.

CRISPR

In 2020, microbiologist Emmanuelle Charpentier and biochemist Jennifer Doudna won the Nobel Prize in Chemistry due to the discovery of the CRISPR/Cas9 technique, which allows editing the genetic code of living beings.

CRISPR technology is a genetic editing tool that allows DNA to be changed precisely and efficiently. The CRISPR system, originally found in bacteria, works as an “immune system” that protects bacteria from viruses, reminding them of invaders through fragments of viral DNA that are stored for future reference.

CRISPR uses three main components: a guide RNA sequence, a protein called Cas9, and the target DNA sequence itself that will be edited. The guide RNA serves as a kind of GPS, directing Cas9 to the exact point on the DNA where the editing will take place. Cas9, derived from bacteria Streptococcus, works like molecular scissors, cutting DNA in the designated region.

Suy Anne explains that this Cas9 protein, although it originally causes immune responses in the human body (since it comes from a bacteria that causes infections), is modified to be safer and more effective when used in treatments. Even with these changes, the body can still develop an immune response against Cas9, but this is carefully managed to prevent problems.

Once Cas9 makes the cut, DNA can be modified in a variety of ways: defective genes can be inserted, removed, or replaced. This technology is promising in treating genetic disorders, offering the chance to correct mutations directly in patients' DNA.

The current moment of advanced therapies

Advanced therapies began as alternatives to cancer treatments. However, “in recent years, we have seen an interesting movement of these technologies being transferred to other therapeutic areas,” says Francisca Peixoto, PhD in biomedicine and co-founder of LifeLink Ventures, an investment manager focused on initiatives of Life Sciences in Europe and the United States.

What explains this movement is the high competitiveness and pace of development of the oncology sector, which allowed them to arrive in 2024 with a significant number of approved therapies. For this reason, now the industry's focus has been directed to areas that still face large therapeutic gaps.

Among the examples, it is worth highlighting the use of cell therapies. Originally developed and approved for the treatment of some types of cancer, these therapies are now being tested for autoimmune diseases, such as sclerosis or lupus. In fact, “today there is a growing effort to adapt these treatments to inflammatory and autoimmune diseases, a huge market that currently lacks robust therapeutic options,” Peixoto points out.

Another case is the use of monoclonal antibodies which, after establishing itself in oncology, is beginning to be applied in other areas, to treat cases of pulmonary fibrosis and fibrosis in other organs.

In other words, a reflection of the industry's quest to adapt and reuse successful technologies in oncology for other health conditions with great medical need.

In addition to cell therapies, categories of therapies based on RNA (ribonucleic acid) are also emerging, a new approach that shows promising signs, given the greater potential for safety - compared to traditional genetic therapies that alter DNA. “By acting on RNA, which is transient, side effects can be more controlled, offering therapeutic flexibility, something that is not possible with the direct modification of the genetic code,” explains Francisca.

There is also a growing trend surrounding small molecules (Small Molecules) covalents, which permanently bind to their target, offering a more stable and lasting therapeutic response. While potential toxicity is still a challenge, these molecules have aroused great interest due to their prolonged power of action.

In addition, Brazil currently has eight advanced therapies approved by Anvisa. They are:

1. Luxturna — treatment for vision loss caused by inherited retinal dystrophies;
2. Zolgensma — gene therapy for Spinal Muscular Atrophy (SMA) in children up to two years old;
3. Carvykti — treatment of relapsed or refractory multiple myeloma;
4. Kymriah — treatment for non-Hodgkin lymphoma (NHL) and B-cell acute lymphoblastic leukemia (ALL);
5. Yescarta — treatment for large B cell lymphoma and follicular lymphoma;
6. Tecartus — treatment of mantle cell lymphoma in relapsed or refractory adults.
7. Roctavian — approved in Brazil in 2024, it is a therapy for adult patients with severe hemophilia A without a history of factor VIII inhibitors.
8. Upstaza — single gene replacement therapy indicated for patients aged 18 months or older with a clinical, molecular and genetically confirmed diagnosis of aromatic L-amino acid decarboxylase (AADC) deficiency with a severe phenotype.

Science and market challenges

On the other hand, we cannot think of advances without talking about the challenges. In this sense, we can point out some as the main ones: the tall costs, which interfere with the potential of scalability, in addition to scientific issues.

Costs

In general, producing advanced therapies is complex and expensive. “To develop a drug, it can take 10 to 15 years and spend up to 2 billion dollars,” explains Suy Anne Rebouças.

With such high costs, the concern is: how will pharmaceutical companies recover their investment if the treatment is administered only once?

“The cost of treatment is high, because we are talking from a new perspective: treating the root of the problem. A single-dose treatment for a serious illness - if proven to be effective persistently over the years - can generate significant savings for health systems in the long term. In Brazil, it's up to health plans and the government to decide how best to pay for these revolutionary treatments,” says Rebouças.

In this case, we are talking about the manufacturers of these treatments and how they need high prices to recover the investment invested. On the other hand, as Suy Anne asks, “what health plan can afford 2 million dollars for a single treatment? In the case of CRISPR, for example, there are treatments for sickle cell anemia worth around US$ 2.2 million (Casgevy) and US$ 3.1 million (Lyfgenia)”, exemplifies the doctor.

In this sense, from a marketing point of view, advanced therapies are attractive mainly because of the possibility of reducing costs. This is because several conditions require expensive treatments, with no prospect of cure, continuous and with a wide range of side effects. In other words, at the end of the day, the patient still does not enjoy the quality of life they deserve and the operators pay dearly for this result.

As an example, Fiocruz outlined the potential of advanced therapies for the SUS economy. See the image below:

However, paying for these treatments is more a matter of power, than of wanting. A fact that points out the dimension of this issue comes from the study carried out by QuantiSaúde, at the request of the National Union of Health Self-Management Institutions (UNIDAS). According to the analysis, the cost of a single dose of Zolgensma would exceed the annual bill of 7.83% of self-management affiliated with the entity, while others would see 20.87% of the yield reduced by half.

In addition, analyses by Abramge (Brazilian Association of Health Plans) indicate that 62% of the health plans, within one month, are unable to bill the price of these treatments. It should be noted that this data refers to smaller operators.

With that in mind, last year, Abramge pointed to the possibility of creating a specific fund to offer these treatments. Basically, the idea is to divide the risk and the budgetary impact. To this end, it is also studied whether the ideal would be a public fund or a private one. Among other suggestions, UNIDAS also considered establishing a “reinsurance”, to be contracted when there was a need to cover a case in the plans.

This issue has been explored in greater depth in this article from the Futuro da Saúde portal.

Finally, while some of these therapies will become more accessible as production capacity increases, others, due to their intrinsic complexity, will continue to be expensive. But, “RNA-based therapies, for example, have the potential to be cheaper than genetic therapies or therapies with monoclonal antibodies,” adds Francisca Peixoto.

Scientific obstacles

The scientific part of using genetic technologies, such as CRISPR, is also a challenge. That's because, “when we started using CRISPR, there was a lot of fear of unexpected mutations. This effect is called 'Off-Target', that is, to miss the target. When you use CRISPR on a complex human genome, you may end up cutting the DNA in the wrong part,” explains Suy Anne.

The good news is that, in five years of follow-up, CRISPR for hemoglobinopathies showed no off-target mutations or the development of new types of cancer.

Another concern is associated with CAR-T therapy. In November 2023, the American health agency FDA (Food and Drug Administration) announced that it was investigating cases of patients who developed a second cancer after treatment.

In an interview with the portal of NIH (National Institute of Health of the United States), doctor Stephanie Goff, a specialist in the development and testing of therapies with genetically modified T cells and a member of the NCI (National Cancer Institute, also in the USA), cites two studies on this issue.

While the larger investigation failed to find the direct relationship between treatment and the development of a second cancer, the other suggested that CAR-T therapies may have contributed to the phenomenon happening.

In general, the technologies of bioinformatics and artificial intelligence can help reduce those risks. However, the potential of these technologies has been limited by the lack of database sharing. “Even with these advances, research is still protected by companies, which limits data sharing and makes it difficult to develop faster and more effective solutions,” says Suy Anne.

In addition, replicate the efficacy of certain treatments in preclinical models is a challenge, since animal models do not always mimic disease progression in humans, making the transition to clinical trials risky.

The future of the market

Currently, it can be said that few brands are actually profiting from advanced therapies. In fact, the specialized portal GenNews suggests that only ten treatments are on that list.

As an example, it is worth considering the value obtained with Sale of treatments in 2023. See the list below:

1. Yescarta, from Kite, a Gilead company — US$ 1.498 billion;

2. Zolgensma, from Novartis — US$ 1.214 billion;

3. Kymriah, also from Novartis — US$ 508 million;

4. Carvykti, from Janssen Biotech (Johnson & Johnson) and Legend Biotech — US$ 500 million;

5. Abecma, by Bristol Myers Squibb and 2seventy bio — US$ 472 million;

6. Tecartus, from Kite, a Gilead company — US$ 370 million;

7. Breyanzi, from Bristol Myers Squibb — US$ 364 million;

8. Elevidys, from Sarepta Therapeutics — US$ 200.356 million;

9. MACI, from Vericel — US$ 164.8 million;

10. Luxturna, from Spark Therapeutics (Roche) — about US$ 51 million.

Although they are still a select group, things may change when new treatments receive approval in the United States and Europe. According to the Alliance for Regenerative Medicine, up to 17 new cell and gene therapies should be approved in these regions by 2024.

North America x Europe x South America

While the pace on other continents seems somewhat fast, here in South America enthusiasm is accompanied by caution.

One of the reasons for this difference in scenery lies in the difference in focus of each area. As Francisca Peixoto explains, “in the United States, for example, biotechnology startups are already born with a focus on the market and are designing scientific studies already thinking about attracting investors. In Europe, on the other hand, the focus tends to be on academic research, which may delay the validation and commercialization of products”.

In Latin America, specifically Brazil, “innovations are too difficult to pass the earliest stages, often with limited scientific validation, which makes it difficult to attract investors,” Francisca points out. However, the approval of the new clinical research law in Brazil, there are expectations of an increase in the number of clinical studies and in the development of advanced therapies in the coming years.

In addition, for the future, advanced therapies, such as those aimed at autoimmune and inflammatory diseases, are expected to gain more and more space, with new products approved in the coming years.

“Although these areas are complex, there is an expectation that these treatments will advance more rapidly compared to areas such as neurodegenerative diseases, where understanding of the biology of the disease is still limited,” concludes the co-founder of LifeLink Ventures.