Paving The Way For India's First Domestic CAR-T Approval

By Tyler Menichiello, contributing editor

Last October, India’s first domestic CAR-T cell therapy, NexCAR19, was commercially approved by their Central Drugs Standard Control Organization (CDSCO). Priced at roughly $50,000 USD, NexCAR19 marks a significant achievement not only for India, but for the CGT industry as a whole, given that the average cost of CAR-T therapies in most markets (e.g., the U.S. and Europe) can reach nearly $500,000.

The pioneer behind this historic CAR-T approval is Mumbai-based ImmunoACT. With NexCAR19 being the nation’s first homegrown CGT, ImmunoACT faced the unique challenge of not only developing a novel therapy but also setting a regulatory precedent for future CGTs. “We jokingly say that we had to make our own car and our own road,” says Shirish Arya, co-founder and director of ImmunoACT’s corporate strategy and business development. I recently had the pleasure of meeting with Arya and Karan Gera, ImmunoACT’s business development manager, to discuss the company’s journey to approval, as well as its plan to bring this affordable therapy to other low- and middle-income countries.

Building A Regulatory Framework From Scratch

India is the largest generics manufacturer in the world. As such, most of the country’s regulatory framework was historically built around evaluating generics — not novel therapies like CGTs. This made the development and approval process for NexCAR19 as much of a learning experience for ImmunoACT as it was for India’s regulators.

“So much of the regulatory framework is designed around showing equivalence in safety and efficacy,” Arya explains. “Gene-modified cell therapies present much more complexity from an evaluation perspective, so the challenge when we started with NexCAR19 was that it was so new. We had to work hard to educate regulators and other stakeholders about the work we were doing, its long-term impact on Indian healthcare, and addressing the patients’ unmet needs.”

NexCAR19’s clinical journey, from the start of its Phase 1 trial all the way to market authorization, took about 30 months. Product development, however — pioneered by Dr. Rahul Purwar from the Indian Institute of Technology Bombay’s bioscience and bioengineering department — took around 10 years. Gera says the company’s early R&D for NexCAR19 was done on a shoestring budget after raising only $18 million from two rounds of funding.

According to Arya, the goal was to ensure that all preclinical work and planned clinical studies were benchmarked with the “best-in-class” globally. “I think the knowledge sharing and getting the regulatory framework ready were the two biggest challenges to ensure we did this right,” he says.

India’s regulatory framework for gene therapy products has evolved over the last few years thanks in large part to collaboration among several agencies — namely, the Review Committee on Genetic Manipulation (RCGM) and the Indian Council for Medical Research (ICMR). “These different organizations provided scientific input on what the guidelines should be from their perspectives, which led to the CDSCO finalizing its guidance,” Gera says.

As many in the CGT industry know, a lot of the complexities surrounding personalized therapies are related to the supply chain. Unlike conventional off-the-shelf therapies — which are manufactured in mass and delivered to hospitals — CAR-T therapies involve collecting a patient’s cells, sending them to a manufacturing facility, and shipping the modified cells back to the hospital for infusion. “It took some time for stakeholders to fully understand the connection between the hospitals and the manufacturer,” Arya says. “Being a new therapy, it took a lot of education — of clinicians, hospital staff, logistics providers, and regulatory agencies at different levels — to comprehend this process and put the right checks and balances in place, both on the hospital side as well as the manufacturing side.” According to Gera, this understanding of commercial operations between the hospitals and ImmunoACT was explained in the process of queries and responses over the course of four to five months.

Achieving Affordability Through IP Ownership

Arya and Gera say the driving force behind ImmunoACT and NexCAR19 was the desire to make an affordable and accessible treatment for patients in India suffering from relapsed/refractory B-cell malignancies. While other CGT companies exist in the country, many are the result of collaborations with U.S., European, or Chinese companies. “We realized that, in the context of Indian economics and the Indian healthcare ecosystem, western solutions will not always suffice,” Arya says. “We realized that if the IP is not owned end-to-end and created from the ground up, we can’t effectively address India’s huge unmet need.”

“When you in-license IP (e.g., CAR constructs, vectors, etc.), especially from a country with a higher currency value, you generally have to pay high licensing fees, which can lead to very high prices,” Gera explains. Understanding this, ImmunoACT evolved its entire value chain in India. From the plasmid, to the vector, all the way to the final CAR construct, the company maintained ownership of its IP. “I think that’s the big deal in this and truly the vision of Dr. Rahul Purwar, who started work on this when it was still a very niche R&D area, even in the U.S.” Arya says. “Indigenous development has enabled us to bring the cost down significantly and create a drug which is accessible to a much wider possible range of intended patients.”

Another way ImmunoACT brought down the cost of NexCAR19 was by “humanizing” the CAR construct. According to Gera, this decreased both the severity and incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), the most common adverse events of CAR-T. “Lowering the cost of the drug also meant lowering the treatment-impact cost of the drug as much as possible,” he says. “By humanizing the CAR-T construct, we’ve seen a significant improvement in the safety profile and reduction in post-infusion medical complications, thereby reducing the treatment costs for the patients.”

Clinical Strategy

A critical part of NexCAR19’s success was ImmunoACT’s collaboration with Tata Memorial Hospital (TMH), India’s oldest specialized cancer research center, and one of the largest cancer treatment centers in Asia. According to Gera, TMH treats an incredibly diverse cancer patient population — both in Mumbai and in locations across India. “The sheer variety of demographic areas from which they see patients makes them extremely effervescent and action-taking clinicians,” he says. “They had done their due diligence. They knew what the previous clinical data on CAR-T was. They also knew that it was not going to translate one-for-one in this lower- and middle-income setting, where sometimes even diagnoses happen a lot later compared to high-income countries.”

ImmunoACT collaborated with TMH to design its clinical trials to be “as inclusive as possible.” Gera says an important consideration in the trial design was recognizing that immunological data in India (a tropical region) is very different compared to northern regions. “In the tropics, you’re going to have a lot more susceptibility to infections,” he explains. “This means that your T-cell and B-cell landscape is going to be a little different — so how do you identify and accommodate for that?” He says TMH was very proactive in addressing these challenges. “Its support was vital to the clinical success of this product.”

Scaling Up, Bringing NexCAR19 To International Markets

Following ImmunoACT’s successful approval of NexCAR19 in India, it is now focused on scaling up operations and increasing access to this new therapy. Arya says the company’s strategy is a two-pronged approach that involves expanding therapeutic access within India and partnering with similar companies in other emerging markets — specifically in low- and middle-income countries. “The question for us is, how do we work within India’s ecosystem — the private sector, the insurance sector, and the government sector — to make this widely accessible? How do we decentralize some of our manufacturing processes to the extent possible for a vast geography like India?”

In November, ImmunoACT began manufacturing operations in its 15,000 square-foot GMP facility, located on the outskirts of Mumbai in Rabale. “We’ve broken ground on another facility, which will be about eight times this size — about 50,000 square feet — in Navi Mumbai.” Gera says this second facility should be functional by the end of 2025 and should serve at least 10 times the number of patients per year.

According to Gera, the company’s strategy involves centralized vector manufacturing at these facilities, and decentralized CAR-T manufacturing in locations around India, closer to patients’ point of care. The aim in doing so is to improve patient access — and thus, patient outcomes — in India. As it stands, ImmunoACT has partnered with more than 30 of India's leading oncology hospitals and is hoping to continue doing so in the coming years. “Establishing this infrastructure is a challenge,” Gera says. “Getting hospitals on board and educating patients about the commercial aspects of this work is also a challenge, as this will easily rank as one of the most expensive commercially available therapies in India.” He says ImmunoACT is hoping to treat 400-500 patients with NexCAR19 in its first year and close to 2,000 patients in its second year.

In terms of expanding access to NexCAR19 outside of India’s borders, ImmunoACT is focusing on emerging markets where CAR-T therapy isn’t widely available. The company’s most immediate focus is on Mexico (where it has already been approved to run a Phase 1 trial), but it is also hoping to bring the therapy to countries in Eastern Europe, the Middle East, and Southeast Asia. “In these emerging markets, we may not always have to run a trial from scratch when considering a severely unmet need,” Gera says. “If regulators agree, we may have to reproduce safety data and focus on efficacy evaluations in these patients.”

In these emerging markets, ImmunoACT is searching for partners to either establish joint ventures or completely out-license the therapy. “In either case, what would happen is that we’d continue to manufacture the critical starting material — the lentiviral vector — and transfer the technology around our CAR-T manufacturing process so that it can be indigenized to those local countries and economies,” Gera explains. “By virtue of indigenization, you’d save a lot on logistics costs and improve patient outcomes.”

Where ImmunoACT had to build the metaphorical car and the road, it is hoping to take its approved therapy to countries with existing “gravel roads” — countries where CAR-T may be available, but with very limited access. “It’s not that these roads weren’t built,” Gera says, “it’s just that they’re very difficult to reach. We want to make sure they can be better traveled.”