We live in a biological era and have new studies every day to be transformed into a potential treatment for fatal diseases.Researchers are conducting thousands of clinical trials to evaluate the efficacy of the first ergonomic therapy. However, in addition to bringing the excitement of expanding the boundaries of life to human beings, innovation also brings discussions on high medical costs and drug fairness.
Generally speaking, the cost is borne by medical service providers and patients.However, heavy therapy such as gene therapy and CAR-T is still out of reach for most parts of the world.
Scientists in low -income countries such as India and Brazil are trying to reduce costs through many plans, such as developing local intellectual property rights, expanding the scale of local production, and finding biomarkers.But it turns out that there are still difficulties in supervision and production challenges.
India Car-T therapy
The development of local intellectual property (IP) is a key step in improving innovation therapy.
"The only way to reduce these high -end technical costs is to have this technology," said the founder and CEO Rahul Purwar of Mumbai IMMUNOACT.
CAR-T therapy research founded its own company.
In the past ten years, the ImmunoACT team has obtained three patents, namely the new version of the CAR carrier, a proprietary chronic virus gene delivery carrier, and the manufacturing process (these patents have been approved in India and are applying in the United States to applymiddle).
Purwar said that their goal is to have a full -chain intellectual property rights, both in order to reduce costs and to commercialize in other countries.In India, about 100,000 patients with malignant tumors of B-cells each year, the emergence of cheap CAR-T therapy will meet huge market demand.
The CAR-T cell therapy was developed at Mumbai, India Institute of Technology, and then split the establishment of the biotechnology company Immunoact.
Purwar attaches great importance to the importance of intellectual property.He said that most people in the Indian Pharmaceutical Industry are still paying attention to the production of introduction and generic drugs, but Immunoact has done something that is not easy but meaningful- "Innovation, developing Car-T local products, applying for patent patents, Promoting the entire clinical development and commercialization process. "
ImmunoAct recently completed ACTALYCABTAGENE
AUTOLEUCEL’s phase II clinical trial among 50 patients with B -cell malignant tumors was approved by the listing permit in October 2023.Since then, the company will continue to test in bone marrow tumors, gastric cancer and brain cancer, as well as tests such as heart disease, heart fibrosis and autoimmune diseases.At the same time, Purwar is closely paying close attention to the transformation of CAR-T and heterogeneous CAR-T mediated by CRISPR-CAS, because the latter can greatly reduce costs.
The low-cost CAR-T therapy has aroused interest in the world.Purwar claims that the cost of this therapy can eventually be reduced to about $ 50,000, and the current YESCARTA (Axicabtagene
The costs of Ciloleucel) and Kymriah (TisagenlecleUcel) were US $ 373,000 and $ 475,000, respectively.
Purwar said that the Indian pharmaceutical market has specificity. Even if the price is so low, 90%of Indian patients cannot be treated, because only a few patients have medical insurance, and most patients are at their own expense.But "At least there are already medicines that some people can afford," he said, "How the next challenge is to make more people afford it."
India is not the only country that develops local CAR-T cell therapy.Researchers at Mashron University in Thailand have developed an anti -CD19
CAR-T therapy, this therapy has been authorized to the headquarters in Bangkok’s startup Geenepeutic
BIO.It is said that the cost may be 80%lower than the existing treatment.Its clinical trials are underway, provided by the Thai Investment Commission, and are expected to be approved in Thailand at the end of 2024.
DEBOJYOTI, a scientist at the Institute of Genology and Integrated Biology, New Delhi Science and Industry Research Council (CSIR)
Chakraborty said cancer is the focus of Indian biotechnology. Such therapies have hopes to bring good investment returns.India is the country with the second highest incidence of cancer in the world, and there are also many rare patients.
Chakraborty uses Francisella (Francisella
Natural CAS9 isolated from Novicida) developed its own CRISPR-Cas gene therapy carrier to correct gene mutations that cause sickle cell disease and are currently undergoing preclinical research.
To push this therapy to the clinic, Chakraborty believes that there are two key requirements to meet: first, the Indian government’s funding (which was originally provided by the Indian Science and Industry Research Council, and was later provided by the Ministry of Treasures), the other was local production.Including the establishment of a GMP plant in CSIR.Fortunately, during the COVID-19 period, India produced vaccines for most parts of the world, and the number of GMP plants surged.These technologies are crucial to the preparation of clinical trials they are about to conduct.
Initially, the participation of the tribe department (MOTA) surprised Chakraborty.The agency usually does not fund medical research, but it is committed to the treatment of sickle cell disease, which is one of the biggest issues facing the tribal community.In addition to funds, the government’s participation also helped Chakraborty to establish contact with patients. These patients usually live in places far away from New Delhi, such as the dense forest in the central India.Chakraborty said, "the Indian government is working together to support this clinical trial."
The CRISPR-Cas gene therapy he led by his leadership is tested in the animal model. It is expected that the clinical partners of the Institute of Indian Medical Sciences will start recruiting patients from the tribal community in 2024 to promote a small-scale concept verification test.After that, he hoped to transfer technology to biotechnology companies, or continue to advance clinical practice with government funding, because "the government provides a large number of healthcare services for the poor."
He is also studying new technologies that can further reduce costs, including using lipid nanoparticles directly to bone marrow or genetic treatment through blood.This will avoid bone marrow ablation, in vitro editors or bone marrow transplantation, which greatly reduces costs.But this technology has not yet been confirmed.
In addition to the government’s role, patients have also become a strong supporter of gene therapy research.Chakraborty revealed that "India has very many rare disease patients, and they now suddenly see the opportunity for treatment." In some cases, they will crowdfund it for treatment.
Brazilian gene therapy
In St. Paul, Brazil, Ricardo Weinlich also shoulder a similar mission.
He is in non -profit -rich Albert Einstein Hospital (HOSPITAL Israelita Albert
Einstein leadership gene therapy project, the hospital is one of the top hospitals in Latin America (Pellers who died in 2022 received colon cancer treatment in the hospital).
Weinlich and colleagues have developed a patent plan that uses Crispr-Cas9 glands-related virus (AAV) carriers to replace defective sickle cell genes, which also uses in vitro.
He said Weinlich’s technology "is very close to other laboratory technology."However, independent intellectual property rights are vital to avoid the cost of avoiding high -priced patents and reducing gene therapy -Hemgenix (ETRANACOGENE
DezaParvovec) is a drug produced by CSL Behring to treat hemophilia. It is the most expensive drug in the world with a price of $ 3.5 million.
The Albert Einstein Education and Research Center, located in St. Paul, Brazil, has obtained duty -free qualifications from the government for the development of health technology.
Like India, Brazilian patients are also a powerful advocate that improves the fairness of gene therapy.
In a previous case, the judge had ordered the public health system Sistema particular
Saúde (SUS) provides Novarton’s Zolgensma (onasemnogene
AbeParvovec), each person’s cost is $ 1.7 million, which is an amazing number for Brazil’s public health system.
Weinlich believes that the Brazilian government needs to negotiate with gene therapy companies to reduce costs, rather than waiting for the court for mandatory treatment.
Weinlich is doing his best to reduce costs. Because preclinical research prospects are optimistic, he is currently expanding production scale, and clinical trials are about to begin.Chennai Investment
"The goal is not commercialization, but to formulate a solution that can explore in the public environment through a single health system, and provide this drug for our own people at a lower cost." Weinlich said that he and Albert LovePart of the clinical research funds of the Instan Israeli Hospital comes from the Duty -free plan provided by the Brazilian government for non -profit organizations, which supports the research of emerging health technology, including gene therapy.
The art of turning waste into treasure
The development of local intellectual property is not the only way to reduce costs.
Jennifer Adair believes that "what really affects the cost of gene therapy is consumables and reagents", she is the co -person in charge of the Caring Cross Global Gene therapy Plan, and the Fred of Seattle
Hutchinson Cancer Research Center gene therapy transformed Fleischauer family donation chairman.
Non -profit organization caring
CROSS mainly acquires intellectual property rights for the slow virus carrier abandoned by a pharmaceutical company and provides these vectors to low -income countries for clinical trials.Some of them have proven the curative effect in the past clinical trials, while others have to be tested.
Caring Cross has an important cooperative company -Vector Biomed, which also shoulders the "social mission" that reduces the cost of gene therapy.
Vector biomed by gene therapy pioneer BORO
Dropuli 创 was co -founded, and he was also the founder of Lentigen, the first gene therapy approved by another company, Kymriah). The main goal was to solve the problem of long -term backlog production of cells and gene therapy virus carriers.
In January 2023, Vector Biomed received a first round of financing of $ 15 million, and will also be with Caring with Caring
CROSS cooperates to treat the 10%production capacity for the treatment of the drugs of people who do not get enough services.Adair revealed, vector
Biomet is studying alternative envelopes, improving production processes, and improving other efficiency to reduce costs to reduce costs.
In Africa, CISSY
KITYO plans to use the vector that the pharmaceutical company has abandoned in Uganda to conduct clinical trials of gene therapy, first starting with sickle cell disease.She is with caring
Cross discussed that the latter has obtained these carriers from Blue Bird Biological Corporation and Novartis.
Localization can reduce many costs.For ionizing gene therapy (including CAR-T cells), patients’ cells are extracted and frozen, and then transported to concentrated facilities operated by companies provided, usually in Europe, the United States, or India.If patients happen to be far away in Brazil, India or Uganda, it will incur high extra costs.Made in bed manufacturing can change this situation.
In 2021, LENTIGEN, who was acquired by Miltenyi Biotec, Germany, Germany, was funded by two anti -CD19 anti -CD19s
CAR-T cells in Phase I in patients with B-cell malignant tumors.The difference between this experiment is that CAR-T cells are manufactured on the spot in Moscow and Cleveland.The relief rate of treatment is high, but the cost is greatly reduced.
The biotechnology startup IMMUNEEL has obtained CAR-T technology permit for its phase II clinical trial. The company is trying to reduce costs through the bedside.
The key requirement for instant manufacturing next to the bed is to establish GMP.Nelson, a hematological expert of Albert Einstein Hospital in Israel
Hamerschlak, the first CAR-T therapy approved by the Brazilian regulatory agency.Hamerschlak and his team use the anti-CD19 provided by Miltenyi-BIOTEC
CAR-T carrier and solution, but they use on-site production.
Low labor cost
The instant manufacturing next to the bed also uses one of the largest assets of low and medium -income countries: low labor costs.
In 2022, VIKRAM, Dean of Walol Christian Medicine, India
An analysis led by Mathews found that in India, it can produce real-time CAR-T cells at a price of $ 35,107-one-tenth of the price of Yescarta.
This analysis is part of the clinical trials of the phase I of the Academic Health Center. The clinic test of Miltenyi Biotec
The PRODIGY fully automatic closed system avoids the demand for industrial -grade clean rooms, because the maintenance costs of clean rooms are usually high.At present, Mathews has completed a phase I trial of nine patients, and his team has treated 20 cancer patients in Phase II trials.He hopes to be approved for listing in the next 18 months.
Mathews said that GMP is the key to clinical trials, and labor costs are the key to reducing costs."Although the per capita income may be much lower than Western countries, the purchasing power is actually very high. Therefore, the same money can take a long time." Weinlich said that the situation in Brazil was the same.
Hospitals can further reduce costs by using local reagents and consumables (from clinical medium and cytokines to plastic cell culture boards).At present, almost all of these reagents and consumables are produced in Europe, the United States or India, so the cost of low and medium -income countries is relatively high.
Mathews said that through the local replacement of reagents and consumables, we are quite confident. "In two to three years, we can reduce the cost of Indian CAR-T cell therapy to US $ 10,000 to 15,000."
However, he relies on Miltenyi
Biotec provides a CAR carrier for its clinical trials for free, which also brings uncertainty.He acknowledged that "if it is listed, I don’t know what price they will sell this carrier, if they are willing to sell."
No one suspects that the commercial company plays a key role in expanding the available aspects, but in order to reduce costs, Mathews believes that "you must keep industry in the right position", so the industrial production reagent, but they do not control the entire process.
Expand the scale of bed treatment
Expanding the scale of bed treatment is a challenge.At the Christian Medical College, Mathews can treat three cancer patients with a maximum of CAR-T cell therapy per month, which is only a small part of the need to treat.His vision is to allow patients to be treated in any hospital alliance across India, and each hospital will design CAR-T cells.He believes that "the scale will be forced to reduce costs in the industry."
In Immunoact, Purwar also has a similar "regional decentralization" vision, that is, several hospitals across the country set up GMP units for CAR-T cell therapy.但他警告说，完全分散的即时床旁治疗方法有可能使患者因质量控制不完善而受到伤害，“印度是一个非常大的国家……每家医院都有不同的门槛，不同"Standards".
Some people suspect that the real-time production of CAR-T or gene therapy is a feasible solution for small and medium-sized countries in Africa.
KITYO not only worried about cost (including huge preliminary costs and continuous maintenance costs of fully automatic closed systems), but also because manufacturer Miltenyi
BIOTEC requires the country’s third -party dealers to provide machines and repair it.
"They have placed one in South Africa," Adair said, "But so far, we have not used it in clinical trials." KITYO pointed out that mobile GMP facilities may be a solution for Africa. It has a standardized process and training.Vegetarian labor can provide in vitro genetic treatment in multiple African countries.
Kevin, the Fourth Industrial Revolution Center of the World Economic Forum
Doxzen believes that multi -purpose resources and redundancy are critical to maintain low cost. One of the main sources of potential funds is the PEPFAR of the US President AIDS Emergency Rescue Program.
Pepfar
In 2023, the budget was as high as $ 6.9 billion, and the lives of more than 25 million people had saved (although its funds are now threatened).Doxzen said that when Pepfar’s funds are used to build infrastructure for AIDS, these devices can also be used for the treatment of sickle cell disease.
Weinlich also agrees to the importance of multi -purpose resources to maintain low cost.In his genetic therapy, the AAV single -batch price of AAV for transporting the supply body DNA is $ 5 million.He believes, "If we establish a joint venture with other hospitals that can use the same method, we can share costs."
As far as sickle cell disease is concerned, the number of patients in Brazil, India or Africa is one more magnitude more than the United States or Europe, so it can pay much at a much lower price.The cost of certification and verification, including the cost of manufacturers dependent on its products, can also be shared between different locations of the same country.
Weinlich also, St. Jude Children’s Research
HOSPITAL) has established a cooperative relationship, and the hospital’s Akshay Sharma is developing a specialized genetic therapy based on fetal hemoglobin.
Sharma’s clinical trial started in the United States in 2023. If the results are positive, the organization will expand the test to a cooperative hospital in Brazil and India.Sharma has high requirements for partners, and they must have experience in bone marrow transplantation, cell therapy, blood bank and GMP equipment.He said he was negotiating with Weinlich in Brazil and Purwar in India.
After the clinical trials, St. Jude will conduct technical transfer to cooperative hospitals in Brazil and India."We hope these therapies can be used by where people need most," Sharma said.He believes that gene therapy is particularly needed for patients living in remote areas in India, and they can hardly obtain routine treatment of sickle cell disease.
"You can bring patients from their hometown to Mumbai’s third -level medical center," he saidNew Delhi Stock Exchange. "Let them stay there for three to six months, complete genetic treatment, and then send it back."
Improvement of biomarkers
Even special medicines are not effective for all patients.Revealing the mechanism of treatment of treatment can help patients who use the treatment for the right patient, and avoid expensive therapy on patients who are not answering.
A better biomarker can reduce the cost of immune examination point inhibitors, Kenneth
GOLLOB said that anti-PD-1 and anti-CTLA-4 therapy has been approved by Brazilian regulatory agency ANVISA as first-line therapy drugs for metastatic non-small cell lung cancer and advanced metastatic melanoma.
However, like CAR-T therapy, most patients cannot be treated through SUS.
Gollob and his team have proven that among patients with melanoma, those who express specific trending factor in the blood are more likely to react against PD-1 treatment.He predicts that if only patients expressing this biomarker are treated, the response rate of cancer patients will increase from 60-65%to more than 90%.
It is rejoicing that this biomarker can easily incorporate the test of leukemia’s standard flow cell diagnosis test, and most of the hospitals in Brazil have this test.He said, "They can be used in any medical clinic of any single health system."What he didn’t know was that the price of the immune checkpoint inhibitor can be provided by a unified health system, because there is no such inhibitor.
GOLLOB’s funds are from the British Pharmaceutical Company GSK, which is the company’s public -private partnership "Trust in
Part of the SCIENCE) provides matching funds by the St. Paulo State Research Foundation (FAPESP). According to the provisions of the donation, GSK has any commercial priority. Now, GOLLOB has determined the biomarkers (the research results have not been published), he has not yet been published). He has not yet been published).It is hoped that the clinical trials of anti-PD-1 immunotherapy in patients with different trend factor (ideal situation is drugs donated by pharmaceutical companies).
Weinlich is still using biomarkers to reduce costs and improve the efficiency of stem cell transformation, which is the key part of gene therapy solutions.He uses CD34 markers to separate patients’ bone marrow stem cells, but this is not the precise marker of long -term stem cells that has been successfully implanted.According to calculations, these stem cells account for 5%of the total number of CD34 cells.If he can find a better logo for long -term stem cells, then he can reduce the number of carriers required, and the cost can be reduced by up to 20 times.
Regulatory challenge to be solved
Only with the support of regulatory agencies, low -income countries can truly realize "the freedom of the therapy".
This discussion may be challenging because many regulators have almost no experience in genetic and cell therapy or bone marrow transplantation, and bone marrow transplantation is a key step in vitro gene therapy including CAR-T.
Mathews starts to resist CD19
When CAR-T cell therapy I test, the test is the first gene therapy test conducted by the Indian Academic Center.He said, "The approval of the regulatory authorities takes a long time because in India and other countries, the regulatory framework itself is still developing."Purwar also believes that in India, "the regulatory approach is very complicated."
Some reforms have been started.For example, Uganda approved the first organ transplantation bill in 2022. Prior to this, the East African country had not performed legal transplantation cases including bone marrow.
Although the Ugandan National Drug Administration has never approved genetic therapy tests, Kityo now has a legal framework for gene therapy clinical trials.Adair said, Caring
Cross’s global gene therapy plan is "carrying out a lot of training to help them understand genetic treatment."
She added that researchers conducted clinical trials of heavy drugs in Africa, India and Latin America were also benefiting the world.Especially in Africa, has unparalleled genetic diversity.She said, "Evaluating (a treatment method) in patients with the highest index with the highest genetic diversity (a treatment method) will be the most likely to obtain the most beneficial treatment for everyone."
References: 1. Johnson, B. Reducing the Costs of BlockBuster Gene
And cellspies in the global south. Nat Biotechnol 42, 8–12
(2024).
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