Ash 2022 – Adicet has a case of déjà vu

Just as at this year’s Asco, Adicet came into Ash under the weight of investor expectations about a small trial of its off-the-shelf gamma-delta Car-T project ADI-001. And, like at Asco, it will exit Ash desperately trying to convince the markets that the therapy is durable.

However, this time around investors might not be as forgiving. In a dataset that now includes 16 lymphoma subjects it is clear that relapses are a problem: across four dose levels an initial 75% response rate falls to 18% at six months. Pre-Ash jitters saw Adicet lose 13% on Friday, and another fall when the stock opens on Monday cannot be ruled out.

The company’s poster is being presented at Ash later today, but is understood to be no different to that seen in the abstract, which has a July 15 cutoff. Instead, the most up-to-date cut has just been put out by press release, relating to a December 5 cutoff – just a few days ago.

The latest swimmers plot shows a couple of important updates, including a fourth dose level (one billion cells) comprising six subjects, and one patient at dose level 3 given two lots of 300 million ADI-001 cells, at days one and seven, with just a single lymphodepletion.

However, the most salient feature is relapses – a problem that has taken the wind out of the allogeneic Car-T companies Allogene, Precision Biosciences, Crispr Therapeutics and Caribou.

All but two of the previously detailed nine subjects had relapsed by six months’ follow-up; this includes one patient who died of causes unrelated to treatment. Of the seven new subjects, five are in remission, though at very short follow-up.

ADI-001 targets CD20, and is the industry’s most advanced Car asset using gamma-delta (rather than the more common alpha-beta) T cells.

It is encouraging that all five CD19 Car-T relapsed lymphoma patients in this trial were put into complete remission, and that safety is clean, with no cytokine release or neurotoxicity at grade 3 or above. But the fact remains that just two patients have durable responses, and one of these has mantle cell lymphoma, a less aggressive disease than the diffuse large B-cell lymphoma that will be the focus for further trials.

Speaking to Evaluate Vantage under embargo yesterday, MD Anderson Cancer Center’s Dr Sattva Neelapu, the lead investigator, said that despite the relapses the six-month CR rate was comparable to an autologous anti-CD19 Car-T therapy.

Three patients got double ADI-001 doses, two of these while they were in complete response a few months later, with a second lymphodepletion. The third patient was treated differently, receiving a planned double ADI-001 dose at days one and seven to explore any potential benefit, Adicet’s chief executive, Chen Schor, told Vantage.

How this third patient, who is in CR at around three months, performs in the longer term will be important for gauging whether persistence can be improved. It is highly notable that this third patient was not lymphodepleted a second time – the need to undergo lymphodepletion again would likely hamper the potential to give any cell therapy multiple times.

No higher

Mr Schor also described the design of a pivotal study, due to start in the second quarter of 2023. This would target large B-cell lymphoma patients in whom Car-T therapy has failed.

However, despite the still clean safety profile at high ADI-001 doses, there is no plan to increase dosing further, perhaps because dose level 4 has not boosted initial responses. The pivotal dose has yet to be determined, said Mr Schor, but the protocol will likely allow double doses on days one and seven after a single lymphodepletion.

Though Adicet has shown enough to go into a bigger trial, as before it is asking investors to hold out for further results, but this time with more relapses. “We’re very happy with the CR rate ... and at dose level 4 we just need to wait for data to mature,” said Mr Schor. “Overall we think we’re on safe ground.”