Within reach: Bringing cell and gene therapies to under-resourced regions

There was a time when the price of cell and gene therapies was inconsequential. 

Just 20 years ago, the field was contending with clinical holds and federal inquiries, still trying to dig itself out from under the shadow cast by patient deaths in high profile trials. 

“…a federal drug advisory panel on Friday will discuss the death of a French child in one such experiment and why, after so many years of hope, the technology has been such a disappointment,” read the lead-in of a New York Times piece in March 2005.

Cell and gene therapies, however, have made quick work of proving their worth.

“It is unquestionable that they’ve added a significant value in terms of efficacy responses, progression-free survival, and even survival long-term. Some of these very early patients have had durable responses for 10 years,” says Dr. Jorge Cortes, director for the Georgia Cancer Center. “Cell and gene therapies are a very valuable tool that’s here to stay.”  

But today’s cell and gene therapies are making headlines for something other their curative potential: Nascent technologies and manual processes have driven manufacturing costs sky high, resulting in treatments that carry price tags in the hundreds of thousands to multiple millions. And yet, when viewed from the lens of progress, the field is fortunate to be having these broadscale discussions about price. 

“It’s a privilege to talk about pricing because it means you have a thing that you’ve priced,” said Janet Lambert, former CEO of the Alliance for Regenerative Medicine, during a 2023 Meeting on the Mesa panel about ethics.

However, the pace of progress doesn’t mean much to the patient who can’t get access to a treatment that could offer a life without debilitating pain or a last hope of survival. While the sector’s 50+ global approvals are a laudable milestone, regulatory nods haven’t ensured that treatments reach patients. Companies grappling with commercial viability have focused initial efforts on more established markets, leaving large pockets of patients, especially those in low- and middle-income countries (LMICs), critically underserved.

Acknowledging the high disease burden in LMICs as well as the limitations imposed on the CGT field by siloing treatments in wealthy regions, various stakeholders have stepped up to identify and chip away at access barriers.

 “Over the last couple of years there’s been a shift from market approval milestones to a focus on the next mile marker on this journey, which is delivering all of the essential elements of patient access,” says Phil Vanek, chief technology officer at Gamma Biosciences. Vanek also serves as chief commercialization officer for the International Society for Cell & Gene Therapy (ISCT) and is overseeing the ‘launch and patient access’ segment of the upcoming ISCT 2025 New Orleans program.

According to Vanek, ISCT has adjusted the tone of its conference sessions beyond that of achieving regulatory milestones to that of also delivering global patient access. And they aren’t alone. The American Society of Gene & Cell Therapy (ASGCT) has made universal access a strategic priority, developing a free global gene therapy training course in partnership with Tanzania’s Muhimbili University of Health and Allied Sciences. In 2020, an international alliance of stakeholders came together to form the Global Gene Therapy Initiative to stimulate greater inclusion of LMICs in the CGT development cycle. Charitable organizations such as the Gates Foundation have linked up with governments and private industry to fund therapeutic development in LMICs, while new nonprofits such as Caring Cross have launched with the specific mission of improving global affordability and accessibility of CGTs.

As multiple stakeholders come at the problem from different angles, sustainable global access pathways are beginning to align. From process efficiencies aimed at reining in costs to innovative manufacturing and go-to-market models, cell and gene therapies are charting a course towards future milestones. 

Better, faster, cheaper

Among the many distinctions a therapy can garner, being included on the ‘world’s most expensive drug,’ list is not a coveted accomplishment, but in recent years, several gene therapies have received that unfortunate notoriety. 

BioMarin’s hemophilia A gene therapy, Roctavian, approved in Europe in 2022 and the U.S. in 2023, carried list prices of approximately $1.5 million and $2.9 million, respectively. The therapy employs an adeno-associated virus (AAV) vector to deliver a functional copy of the factor VIII gene to the liver. It was heralded as groundbreaking for its potential to serve as a one-time treatment, eliminating the need for lifelong injections to replace the missing factor VIII. But the high-priced drug’s commercial launch into a competitive hemophilia market was clouded by reimbursement hurdles. Struggling with a slow uptake of the therapy, in August 2024, BioMarin shifted its business strategy to focus commercial operations for Roctavian on three markets in high-income countries — U.S., Germany and Italy — where the drug had managed to secure reimbursement. 

The drugmaker’s decision to halt efforts to expand the drug’s geographic reach came just months after the Brazilian health regulator had approved the treatment in Brazil, home to the fourth largest global population with hemophilia. At present, BioMarin’s Brazilian subsidiary, Biomarin Brasil Farmacêutica, does not list Roctavian as an available therapy.

For pharma companies, even narrowing efforts to solely the U.S. market does not always translate to commercial success. Despite boasting the largest CGT market, the U.S. is still wading through its own struggles with access, most of which are tied to a health care system that is not ready nor designed to reimburse therapies that have high front-loaded costs. While the U.S. explores different reimbursement models, including pay-over-time and outcomes-based options, such as the Center for Medicare and Medicaid Innovation’s CGT Access Model, those within the CGT industry are working to lower price tags of therapies by taking aim at cost-contributing factors.

“In the U.S., because products can cost $500,000, with some of the stem cell gene therapies in the multiple millions, that causes a problem in terms of reimbursement. That’s a lot of money for a payer to fork out — so reducing the cost is important,” says Boro Dropulic.

Dropulic, who currently serves as executive director and co-founder of the nonprofit organization, Caring Cross, has spent much of his extensive biotech career developing lentiviral vectors as delivery systems for gene therapy, including creating the vector that became the basis for Kymriah, the first FDA-approved gene therapy. His more recent work is focused on affordability, and through Caring Cross he is working on several programs to enable access to CAR-T therapies outside high-income countries, including a pilot project underway in Brazil. 

According to Dropulic, the materials necessary to create CGTs are major cost components; in particular, he points to vectors as the “big gorilla” in the room. Viral vector production processes are estimated to represent anywhere from 15% to 50% of the total cost of goods for gene-modified cell therapies. A few years back, the surge of clinical trials and FDA approvals for therapies reliant on AAV and lentiviral (LV) vectors drove up demand, triggering a scramble for CDMO capacity.

In 2023, Caring Cross spun out its own CDMO, Vector BioMed, with the aim of providing affordable GMP lentiviral vectors. 

“We had to create a company because we couldn’t rely on a third-party vector manufacturer to provide vectors for us at a reasonable cost. So we launched Vector BioMed, a contract manufacturing organization that makes GMP vectors at half the price of all of its competitors,” says Dropulic, who also serves as Vector BioMed’s CEO.

Vector BioMed’s manufacturing technology enables the CDMO to provide algorithm-optimized lentiviral vectors with improved function and titers, at scale. While Vector BioMed will sell custom vectors to private industry, as a public benefit corporation, it reserves a percentage of its manufacturing capacity and special pricing to serve lower-income countries, in line with Caring Cross’ mission. 

Other CDMOs, such as Charles River Laboratories (CRL), are also taking aim at vector costs. 

“The industry needs a cost-effective and expedited path to GMP. We have launched two platforms on the viral vector side, one for LV and one for AAV, offering a standardized approach for manufacturing vectors,” says Ramin Baghirzade, global head of commercial for gene therapy CDMO services at Charles River Laboratories.

CRL says its AAV vector platform can reduce developer’s timeline to GMP by 55%, and its LV vector platform can reduce timelines by up to 60%. To create further efficiencies, CRL also has focused on starting materials, such as the plasmids needed to create vectors, unveiling off-the-shelf plasmid products to streamline manufacturing and reduce waste. 

Numerous technology companies in the CGT space have also stepped up, offering various automated and/or standardized manufacturing platforms, including end-to-end fully closed systems, all with an eye on streamlining production. 

All told, these collective efforts towards innovation will reduce the cost of goods tenfold over the next ten years, predicted a World Economic Forum report on accelerating global access to gene therapies. But while these are steps in the right direction towards bringing therapies to LMICs, alone they are still not enough to get the job done. 

Time is money — and lives 

The manual and patient-specific nature of the manufacturing process, particularly for autologous cell therapies, is so cumbersome that it’s been postulated that even if a therapy were free, it wouldn’t always be possible to get it to patients in LMICs. The World Economic Forum report on global access agreed, concluding that even a “cost-effective cure will remain inaccessible if the correct infrastructure is not in place.” 

Autologous cell therapies — treatments made from a patient’s own cells — have the benefit of reducing the risk of immune rejection, but they also amplify the time and cost of manufacturing. The potential for allogeneic ‘off-the-shelf’ cell therapies to offer a less expensive, more scalable approach, which would expand patient access to treatments, has been a source of healthy debate within the industry. Nevertheless, at present, most FDA-approved cell-based therapies are autologous. 

“Autologous therapies are here to stay, and so those logistics are very important as part of the cost,” says Dropulic. “You’re taking patient cells, bringing them into a facility to process and then bringing them back to the patient. And that changes the logistical footprint and the economics dramatically.” 

The logistics are challenging even in higher income countries that have supporting infrastructure. Current delivery models for CAR-T cell therapies offer an average vein-to-vein time — the time from leukapheresis to patient infusion — of 3-6 weeks. Patients eligible for the seven FDA-approved CAR-T therapies, who are battling refractory or relapsed blood cancers, often cannot afford to wait. Given the long turnaround times and high treatment costs, it’s frequently estimated that only one-third of patients eligible for CAR-T therapies receive treatment.

“In the U.S., there is a lot of talk about how to reduce vein-to-vein time. Even in the developed world, this infrastructure is not always streamlined. But in low- and middle-income countries, it may not even be available, so the barriers are even higher,” says CRL’s Baghirzade.

One potential enabler that frequently comes up in the discussion of CGT access — for CAR-Ts in particular — is the idea of decentralizing manufacturing as a means of eliminating some of the logistics associated with the pharma industry’s go-to centralized model. 

Although it has yet to gain widespread acceptance among multinational pharma companies that prefer to maintain full control over supply chains, Belgium-based biotech Galapagos has recently made headlines for its efforts to change the paradigm. Through partnerships with known players such as Gilead, Adaptimmune and Catalent, Galapagos is advancing its pipeline, including its lead asset, a phase 1/2 CD19 CAR-T cell therapy, using an innovative decentralized manufacturing platform. The platform has the potential to offer greater speed and scalability, with the delivery of fresh, fit cells with a vein-to-vein time of seven days. Ultimately this should equate to better physician control and improved patient experience.

Decentralization has been described as a spectrum, and Caring Cross has heavily backed a type of decentralized model at end of continuum known as ‘point-of-care,’ whereby therapies would be manufactured near or at the clinical centers or hospitals where patients receive treatment. In LMICs, this model could leverage existing clinical centers experienced in hematopoietic stem cell transplantation/bone marrow transplant.  

By eliminating the need to cryopreserve cells and transport them to centralized facilities, the POC model could reduce vein-to-vein time and improve outcomes. POC still has significant hurdles to overcome, however. At present there is no FDA guidance outlining regulatory expectations for manufacturing CAR-T products under CGMP compliant conditions in a hospital/clinic setting, but regulatory bodies have signaled a willingness to consider such models. 

Quality control to ensure safe and consistent product is also a crucial consideration. Encouragingly, a study conducted at two clinical centers, one in Moscow, Russia  and one in Cleveland, Ohio, found that it is possible for POC manufacture of CAR-T cells to result in a consistent cell product and effective clinical outcomes.

In country, for country

To truly get costs to a manageable level, Dropulic believes manufacturing needs to be taken a step beyond the decentralized model.

“While we have to think about a more decentralized, hospital-based manufacturing footprint, the cost is not only the logistics. A big portion of the CGT cost is labor to make the materials,” says Dropulic. “There’s a very simple answer that the pharma industry doesn’t like to hear — tech transfer. If you transfer the technology and process knowledge outside high income countries, other countries can make these therapies more affordably.” 

On the cost front, Caring Cross’ efforts in Brazil have made a compelling case for tech transfer and POC manufacture in the CAR-T space. Last year, Caring Cross launched a collaboration with the Brazilian nonprofit organization Fiocruz, backed by the Brazilian Ministry of Health, to develop local manufacturing of CAR-T and stem cell gene therapies, with an initial focus on creating improved versions of the CAR-T therapies that are already being used in other countries to treat leukemia and lymphoma. To accomplish this, Caring Cross will fully transfer the technology for its CAR-T manufacturing process, as well as its lentiviral vector manufacturing process, to Fiocruz. Fiocruz will then act as a manufacturing hub and reference facility for Latin American clinical centers to implement POC manufacturing for CAR-T and other CGTs.

“Fiocruz will be able to make all the materials themselves locally and cost-effectively, so that they can produce the final product for a cost that’s a tenth of the amount in high income countries,” says Dropulic. 

With local production, the treatment, which will be available free of charge to the population, will cost the Brazilian public health system around $35,000 per dose. 

“And that’s the price point that this becomes sustainable and affordable for LMICs,” says Dropulic.

Brazil (an upper-middle income country per World Bank) has been at the forefront of CGT approvals, with the country’s health regulator, Agência Nacional de Vigilância Sanitária (ANVISA), green-lighting nine cell and gene therapies, four of which are CAR-T cell therapies made by multinational pharma companies (Novartis’ Kymriah, Kite/Gilead’s Yescarta and Tecartus, and Janssen’s Carvykti).

Importantly, Dropulic stresses that the Caring Cross model isn’t intended to compete with approved, reimbursable products.

Regulatory approval in Brazil does not guarantee access because drugs must then pass through the government’s cost assessor before being added to the country’s public health system, known as the Sistema Único de Saúde (SUS). This creates access barriers for the roughly 75% of Brazilians who rely solely on SUS.

Dropulic says the goal is to find “middle ground” and create a harmonization between commercialized products and locally made products, where hospitals could step in and make therapies in the instances where patients are not able to get access. “If a pharma company came to us today and wanted to partner, as long as we can produce products that are affordable and sustainable, we’re not biased in any way,” says Dropulic.

As a clinical investigator with a focus on new drug development, Dr. Cortes is hopeful that the field will see more pharma companies in high-income countries form partnerships to further development of cell and gene therapies in LMICs. Cortes also serves as the inaugural editor-in-chief of the American Society of Hematology’s newest peer-reviewed journal, Blood Global Hematology, which will specifically discuss reviewed research and health care delivery challenges in LMICs.

“I think pharma companies would do well in collaborating with the local organizations that are developing these therapies to make sure it’s done well and to help them expedite the process,” says Cortes. “And see it not as a competition, but rather as a service to help people everywhere. After all, that’s what you want — to improve the health of everybody. If you’re only interested in a subset of the world population, well then it’s a commercial enterprise, not a health approach.”

Recently, Philadelphia-based GEMMABio also announced a partnership with Fiocruz to bring gene therapy treatments to Brazil under the SUS. A key component of the deal will involve tech transfer, replicating GEMMABio’s manufacturing technologies and process so that the partners can collaborate on programs and production in Brazil. The agreement also allows Fiocruz to use GEMMABio’s tech with other sponsors and programs.

These types of international partnerships could also help stimulate local manufacturing.

“I wouldn’t be surprised that there’s an emergence of local drug companies in countries like Brazil and India that start making therapies for their local or regional markets, but at a cost that’s much lower than what we have in high-income countries,” says Dr. Cortes. 

This has been the case in India, where two domestic CD19 CAR-T products have received approval from the Indian Central Drugs Standard Control Organization. Most recently, India-based startup Immuneel Therapeutics unveiled its CAR-T cell therapy for the treatment of relapsed and refractory B-cell non-Hodgkin lymphoma. Immuneel had licensed the early-stage asset from the public university hospital Hospital Clínic de Barcelona and its supporting research center and then developed the therapy in India.

The progress in Brazil and India underscores the transformative potential of partnerships and local manufacturing to help make cell and gene therapies accessible and sustainable on a global level. 

Go-to-market together

For small biotechs in the CGT space, collaboration has always been integral to success, but partnerships have also proven key to accessibility even for the most well-resourced multinational companies.

Strategic partnerships can unlock access to CGTs in markets prior to the commercial approval and launch in the country, typically through expanded access programs (EAPs). In the U.S. and Europe, EAPs are a legislative mechanism that enables therapeutic use of an unauthorized intervention for patients outside a clinical trial. Sometimes called ‘compassionate use,’ ‘named patient sales’ or ‘managed access programs,’ these programs have formally been in place in the U.S. since the AIDS epidemic in 1987. In the CGT space, they have proven to be a valuable method of unlocking access in LMICs.

“In the cell and gene sector, a significant number of patients will find their way onto therapies through expanded access rather than through commercial means,” says Dan Piggott, managing director of the Access division at Uniphar.

Given the time it takes to secure reimbursement and mobilize commercial operations for CGTs in each specific market, EAPs can get treatments to patients sometimes years before they would potentially become available. 

Uniphar, which entered the health care market over 50 years ago as a supply chain operator, has leveraged its legacy capabilities to help pharma companies bring innovative medicines to global markets. The company forayed into the CGT space about seven years ago, and since then has been working with global ministries of health, legislators, regulators and even treatment sites to lay the groundwork for what Piggott calls the “very gray if not nonexistent regulation” needed to supply non-commercial CGTs in countries that have never received them before.

Uniphar’s efforts have paid off — the company has supplied CGTs into over 50 countries, including countries classified as LMICs, such as Vietnam, Uzbekistan, India, Bangladesh, Pakistan and Egypt. Uniphar has also seen growing interest in expanded access programs in the MENA, Asia-Pacific and Eastern Europe regions. 

One of the most well-known uses of expanded access is Novartis’ Zolgensma. In 2019, Zolgensma became the first FDA-approved gene therapy to treat children less than two years of age with spinal muscular atrophy — a leading genetic cause of infant mortality. The therapy’s initial list price was set at $2.1 million in the U.S.

Coinciding with the therapy’s U.S. approval, and while preparing to file for registration in other countries, Novartis partnered with Uniphar to make Zolgensma available for international markets as a part of its managed access program.

“With Zolgensma, patients in over 50 countries have been provided with access through an EA mechanism,” says Piggott. “So from a patient and family impact standpoint, you’ve got several hundred babies that I’d like to think are still alive today because they got access to therapy in markets which Novartis had not yet commercialized.”

Beyond the vital patient benefits provided by EAPs, the programs offer additional advantages to pharma companies. Novartis’ initial program was a paid access program. While this is not the norm for EAPs, in the CGT space, it is common. According to Tom Smith, Uniphar’s strategic director of cell and gene therapies, a “meaningful” amount of drug sales for CGTs come from EAPs.

“In cell and gene, we’re seeing an increase in the amount of expanded access that’s being provided on a charged-for basis relative to what we’d see in non-CGT assets,” says Smith. “For the one-time therapies, the commercial viability of a product could be compromised if access was provided on only a free-of-charge basis, therefore a charged for program is considered by many as a sustainable and equitable vehicle to patient access.”

FDA guidance  permits companies to “charge reasonable costs” for therapies provided to U.S. patients through expanded access programs. In LMICs, governments and charities often mobilize to help patients afford lifesaving therapies through the expanded access mechanism, with some setting up specific funds for this purpose. India, for example, established a National Policy for Rare Diseases in 2021 through which the government will offer one-time financial assistance to each individual suffering from a rare disease.

EAPs also offer drugmakers the opportunity to provide health care providers with early experience with their treatments, and the potential to gather real-world data to inform commercialization strategies or support reimbursement processes. The programs also can help build infrastructure for a more seamless transition post-marketing authorization, therefore speeding access once a therapy is commercially approved. 

“It’s really a key strategic component of how companies ultimately bring their product to the global market, LMICs or elsewhere. When it comes to patient benefit, companies not thinking about running an access program are missing a trick. They really are,” says Piggott.

Pushing boundaries

The world has doubted CGTs before, and the field has dug into the science, responding with safer, more efficacious and more durable treatments.

“We’ve proven that the industry can make them, we’ve proven that we can get them approved. Now, can we make them a modern medicine within the supply chain that actually makes them available for everybody?” says Gamma Biosciences’ Vanek.

Among experts in the field, the answer is a resounding ‘yes.’

While stakeholders in the sector may have competing interests, the end goal for all is getting treatments to patients. The cell and gene ecosystem has now put forth multiple models that, when used in harmony, can put global accessibility within reach.

“We can do this. We can solve these problems. It might just take a little bit of out-of-the-box thinking,” says Vanek.