Becoming ‘biologic-like’: CAR-T makers on quest to scale drugs’ production

Let’s take things back to the summer of 2017.

At that time, Pascal Touchon joined Novartis to take over all commercial activities surrounding a first-of-it kind, cell-based gene therapy for cancer. 

By then, the chimeric antigen receptor (CAR)-T treatment had achieved some renown, thanks in part to a young girl named Emily Whitehead.

Whitehead’s leukemia had gone into remission after she took the one-time treatment, Kymriah, years prior. It was known for its complex manufacturing process, individually made starting from her own white blood cells. That presented unique challenges. 

“At the time at Novartis, one key challenge was, ‘How do you build capacity fast enough to respond to the demand of patients?’” recalled Touchon, who’s now CEO of CAR-T company Atara Biotherapeutics. 

Kymriah (tisagenlecleucel) went on to secure Food and Drug Administration approval on August 30, 2017, for B-cell acute lymphoblastic leukemia (ALL), and a year later for a common type of lymphoma. 

“It’s nearly seven years after that first CAR-T approval and [capacity to meet demand] is still an issue,” said Touchon. 

Indeed, five more of these custom-made CAR T-cell therapies have since reached market, in indications ranging from multiple myeloma — Johnson & Johnson’s/Legend Biotech’s Carvykti and Bristol Myers Squibb’s Abecma — to various types of lymphoma — Kite Gilead’s Yescarta and Tecartus as well as BMS’ Breyanzi — and ALL (Tecartus).

All face the capacity challenge in some way. 

However, CAR-T drugmakers are poised to alleviate some of these bottlenecks, either through tweaks to production and logistics, or through the transition from first generation to next-gen therapies, whose manufacturing more closely resembles a typical biotech process. 

Both could propel the field commercially and, possibly, lead to changes in marketing.

A big upswing

Last year was a tough one for CAR T-cell therapies. 

A FDA review in November culminated in a class-wide boxed warning requirement on the risk of secondary blood cancers. It spanned all approved drugs in the class of autologous CAR-Ts, sans Tecartus and followed the agency’s unofficial acknowledgement of a probable causal link.

Still, the category is poised for an upswing. 

For one, CAR-T capacity is improving. Take Gilead, whose current capacity is about 10,000 CAR-T therapies per year. That’s set to grow to more than 24,000 a year by 2026, the company announced at its recent Kite Cell Therapy Day, according to recap from J.P. Morgan. 

“We constantly monitor demand and build capacity out in front of that,” noted Chris McDonald, SVP and global head of manufacturing at Gilead subsidiary Kite, which makes Tecartus and Yescarta.

In January, Kite said it had received approval for a process that shaves 48 hours off the Yescarta turnaround time in the U.S., from 16 days down to 14. According to McDonald, it took the company more than two years to secure the greenlight after one of its scientists discovered the procedural change in Kite’s lab.

“Even with an industry-best turnaround time, we have patients cancel because their disease progresses while they’re waiting for treatment,” said McDonald. “These are really sick patients, and every day counts. So reducing it by two days will be very impactful.”

Turnaround times — typically measured from leukapheresis, when a patient’s T cells are collected, to product release — ranges from two weeks in Yescarta’s case to six weeks for J&J/Legend’s Carvykti. 

“There is a physical constraint, because cells need time to grow,” explained Gilad Langer, industry practice lead at Tulip Interfaces, which makes technology to run drug manufacturing plants. “There is processing time, splitting out DNA and also how you take the white blood cell and tune it to attack the specific cancer.”

All of which impacts the supply chain. 

“It’s hard to balance supply and demand,” Langer said. “These CAR-T processes can involve hundreds of process steps, every one of which is life and death.”

The time, complexity and the number of parameters that need to be controlled for during the bespoke manufacturing process cost a lot of money, as approved products run about $400,000.

Two approaches

There have been two approaches to addressing the problems of cost and time with CAR-Ts. One involves speeding up the autologous process through automation and other manufacturing improvements. 

Largely through manufacturing enhancements, the cost of goods sold (CoGS) of engineered cell therapies is set to fall, from between $120,000 to $300,000 per dose today to below $100,000 in the next few years, according to an investor note from Leerink Partners that was published earlier this month.

Gilead, for instance, plans to reduce costs by 25% and is aiming for a “biologics-like gross margin” of about 80% for its CAR-T business in the U.S. by 2030, J.P. Morgan analyst Chris Schott wrote in an investor note. 

Additionally, Breyanzi’s CoGS in the U.S. will fall from an estimated $200,000 to $360,000 per dose in 2023 to approximately $80,000 by 2030, according to the Leerink team.

A lower CoGS should increase the profitability of these companies and may lead to more competitive pricing. However, the main issue faced by the half-dozen makers of autologous CAR-T drugs — speed of therapy — will, to a large extent, continue to be an issue. 

The problem comes down to their make-to-order approach. One batch treats only one patient. Compare this to the typical supply chain for a small-molecule drug or monoclonal antibody. Once the manufacturer has the raw materials, they can make inventory of the product and have it available when the patient needs it. 

“In [the CAR-T] environment…you’re not waiting for raw material,” said Langer. “The supply chain starts with the patient and ends with the patient, all in the custody of the manufacturer (other than some logistics companies needed to move the product around).”

The second way of reducing cost and time in this category has been through the allogeneic approach. The idea involves collecting immune cells from healthy donors or stem cells and transforming them to be able to create an “off-the-shelf” CAR-T — i.e., a product that’s available ahead of patient need.

Tab-cel, the first allogeneic T-cell drug approved in the world, is on the market in Europe for EBV-positive post transplant lympho-proliferative disease (EBV+ PTLD) and is sold there by Atara’s partner, Pierre Fabre. Atara plans to file Tab-cel’s biologic license application (BLA) this year and hopes to receive FDA approval by next year.

The promise of alloCAR-Ts 

Without treatment, about half of EBV+ PTLD patients die in a few weeks or months, the rest within two years, per Touchon. In trials, 86% of those treated with Tab-cel have survived to two years, so the product is transformative and well-tolerated. 

It’s also able to be manufactured at scale, which translates to 20% lower CoGS and to having inventory on-hand. Atara, Touchon reported, is running an experiment involving delivery of Tab-cel within three days to any site in the U.S. and just a couple more days to Europe, Australia and Canada. 

That promise is one reason, Touchon added, he left the autologous field to join Atara, which is moving from EBV T-cells to developing an allogeneic CAR T-cell therapy. 

“I truly believe allogeneic cell therapy is the best way to change the scope and impact of cell therapy to be more like what is a traditional biologic,” he said. 

Atara is just one of multiple companies pursuing activity in allogeneic CAR-Ts. Between second-generation CAR-Ts inching closer to the U.S. market and the autologous companies phasing in advanced manufacturing, higher levels of capacity should be possible to meet the increasing demand. 

Both approaches could radically alter accessibility to CAR-T therapies for patients, physicians and health systems. 

CAR-Ts are also expected to move into earlier lines of therapy and new disease states. Leerink forecasts the cell and gene therapy market, already in oncology and emerging in autoimmune diseases, growing to $38.1 billion over the next several years.

‘Marketing’ the manufacturing function

While manufacturing will become more of a strategic asset, whether it becomes a marketable attribute — or simply a talking point during earnings calls — remains to be seen. Will pharma begin to “market” the manufacturing function?

Moving forward, elements like higher manufacturing capacity, turnaround time and cost will surely become more of a competitive advantage for CAR-T drugmakers, sources say. 

In addition, to the extent next-gen companies can reduce patient burden and turnaround time, they’re going to have differentiation. Autologous CAR-T drugs require a pre-conditioning regimen which itself can lead to dangerous side effects.

“If your physician says, ‘Do you want to be treated tomorrow or in six weeks?’ If you have a rapidly progressing disease, you want to be treated tomorrow,” noted Touchon. “So speed will be a key differentiating factor.”