ASH 2024 – Galapagos turns Car-T manufacturing on its head

Galapagos might be a Car-T latecomer, but it believes that the seven-day vein-to-vein time achieved in 92% of lymphoma patients, according to data just presented at ASH, makes its CD19-targeting project GLPG5101 unique. More importantly, it has spelled out the relevance of such a fast-manufactured cell therapy in the real world.

So far Novartis, Gracell (now part of AstraZeneca) and Bristol Myers Squibb, which have all toyed with fast manufacturing, have played up the benefits of getting cells back to patients quickly – a questionable claim when the biggest delay is between diagnosis and apheresis, not between apheresis and cell reinfusion. But Galapagos says short vein-to-vein time is key for localised manufacturing, which crucially doesn't involve cell freezing.

Cell freezing and thawing is necessary when using a central production facility, something done by all the current approved autologous Car-T players, where cells have to be flown from a treatment centre for manufacturing and expansion, before being flown back for reinfusion. Galapagos, however, has made much of a "decentralised" manufacturing system, and through a deal has started to put this in place.

Moreover, not needing to freeze cells could have safety advantages. Speaking to ApexOnco before ASH, John Mellors, Galapagos's head of cell and antibody therapy discovery, highlighted just one case of grade 3 CRS and one of grade 3 ICANS across the pooled phase 1 and 2 analysis in the latest dataset.

However, there were three deaths from intra-abdominal haemorrhage, respiratory distress and sepsis, according to the ASH presentation. The company put the respiratory distress fatality down to disease progression and respiratory infection, and noted that the sepsis death occurred over six months after infusion in a patient with hypogammaglobinaemia.

He said safety could be improved with GLPG5101 “because our cells aren’t frozen, they’re not ready to die or dying from a thawing process, so we don’t release dead cells as part of the product. When cells start dying alarm bells go off, including cytokine release, mobilisation of effector cells, macrophages, NK cells, T cells, B cells, and stromal cells.”

As for efficacy, the ASH data showed a 100% complete response rate among eight relapsed mantle cell lymphoma (MCL) patients treated in the phase 1/2 Atalanta-1 trial. However, across various haematological cancers, including DLBCL, the complete response rate was 83% (35 of 42 patients) – in line with conventional Car-T. “I think it’s close. Time will tell whether we have an advantage,” Mellors conceded.

You’re so vein

Mellors says fast turnaround is a unique selling point for Galapagos, which gained GLPG5101 through the 2022 double acquisition of CellPoint and AboundBio. The latest data represent a more typical Car-T setting than CLL, where a different Galapagos CD19 project, GLPG5102, yielded results at last year's ASH and will feature again this year in a poster presentation.

While other companies, including Novartis, aim to produce Car-T cells in as little as two days, doubt has been thrown on the relevance of fast manufacturing alone; in reality logistical issues mean that it can take patients weeks or months to receive therapy, an issue highlighted by the need to bridge many patients with chemotherapy in an ongoing study of Novartis's fast-manufactured rapcabtagene autoleucel.

“Fast manufacturing in a lab is one advance,” Mellors said. “But that doesn’t necessarily speed the vein-to-vein time. You can manufacture something fast, but ordering it and getting it delivered can take a long time.” As for the wait for booking a slot for treatment, the line for the apheresis machine at academic medical centres “is real”, Mellors said.

This elephant in the room was exposed at ASH 2022, when Novartis admitted that vein-to-vein time was “similar” between rapa-cel and the industry norm for standard, autologous Car-T therapies, implying two to six weeks. It's also notable that Novartis has discontinued two other fast-manufactured Car-T projects, while Bristol now uses a similar approach only in autoimmune disease.

For Galapagos, however, fast manufacturing is key to upending the way patients are treated with autologous Car-T cells. Rather than relying on a central manufacturing facility, the company wants patients to be treated quickly and locally, at one of many blood centres in a network it wants to establish through a collaboration signed in May with Blood Centers of America.

"To the best of our knowledge we are the only company actively establishing a scalable, decentralised manufacturing network," Galapagos told ApexOnco. "Our studies are the only ones specifically designed to deliver fresh, fit, stem-like, early memory cells within a median vein-to-vein time of seven days."

Accelerated approval plans

This is all well and good, but Galapagos has yet to dose any US patients in Atalanta-1, and only got an IND cleared for this trial in August; it plans to start enrolling US subjects by the end of 2024.

The hope is that Atalanta-1 will support accelerated FDA approval by 2028 in various underserved blood cancers, although Mellors wouldn’t say which ones. A recently revealed phase 3 trial is merely designed to generate long-term follow-up data.

The bigger use of DLBCL, where the likes of Gilead’s Yescarta and Bristol Myers Squibb’s Breyanzi are already approved, is likely to follow later, Mellors added. Making a mark here will depend on Galapagos showing that it is indeed differentiated.

It's clear that the company is late to the game, though Mellors contends: “The iPhone was the latecomer to the Blackberry. Better technology will supersede.”