CRISPR Therapeutics’ off-the-shelf CAR-T therapy has fallen short of the high bar set by investors, while still achieving a response in more than half of patients with B-cell cancers in the trial.
The prospect triggered responses in 58% of patients without causing grade 3 or higher cytokine release syndrome (CRS), but six-month durability compared unfavorably to rival drugs, sending shares in the biotech down just over 9% in pre-market trading.
The stock price slipped from above $100 to below $95 as investors digested the implications of data that suggest the therapy, CTX110, works but leaves unanswered questions about whether CRISPR can carve out a space in a highly competitive market.
For its part, CRISPR hailed the study as a success, pointing to response rates and durability that are in the same ballpark as autologous CD19 CAR-Ts and a potentially superior safety profile to make its case.
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“The fact that we have consistent expansion, and where we have all these cells expanded day eight, that gives you a window where it kills the cancer cells. Then the cells are gone about a month later or reach that limit of detection. [That] yields this beautiful balance between having the efficacy we're seeing, producing durable responses, yet minimizing the CRS,” CRISPR CEO Samarth Kulkarni, Ph.D., said on a conference call with investors to discuss the data.
Kulkarni’s comments are based on an analysis of 24 patients with relapsed or refractory B-cell CD19+ malignancies who had received at least two prior lines of therapy, excluding autologous CAR-T. First, the positives: CRISPR saw responses in 58% of patients—and complete responses in 38% of patients—who received a single dose of CTX110, suggesting the initial hit from the off-the-shelf drug is roughly comparable to that of autologous CAR-Ts.
More than half of the patients experienced CRS after receiving CTX110, but all the cases were grades 1 or 2. As previously disclosed, one patient died 52 days after infusion. The patient suffered from neurotoxicity after receiving treatment but no other patients have experienced similar events. Kulkarni said CTX110 has a “very differentiated safety profile.”
The positives were offset by doubts about durability. Observers have questioned whether off-the-shelf CAR-Ts can match the durability of autologous treatments since the first days of the field. Allogene Therapeutics countered those questions with a six-month complete response rate that fell in the 29% to 40% range set by the three approved autologous CAR-Ts, namely Bristol Myers Squibb’s Breyanzi, Gilead’s Yescarta and Novartis’ Kymriah.
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CRISPR reported a six-month complete response rate of 21%, although the small size of the data sets on CTX110 and Allogene’s off-the-shelf rival make it hard to draw firm conclusions. The safety profile of CTX110 could offer CRISPR a way to improve durability, with Kulkarni discussing the potential to give a second dose to “completely eliminate the cancer and increase the percentage of durable responses.”
That CTX110 fell within the range of other autologous and donor-derived CAR-T programs is fine, according to Chardan Research analysts, but efficacy "is not a home run." RBC Capital Markets analyst Luca Issi called the data "underwhelming" and "directionally inferior" to Allogene's candidate on durability.
"CTX110 appears to have activity, but does not clearly separate from allogeneic peers," Chardan said in a note.
Armed with the data, CRISPR plans to expand its study into a potentially registrational trial in the first quarter of 2022. The timeline raises the prospect of CRISPR seeking to give CTX110 to more patients at a time when Allogene is unable to enroll participants because of a safety concern that may or may not have implications for the wider off-the-shelf CAR-T space.
CRISPR will pursue a consolidated dosing strategy for the registrational trial, which will see doses administered in one larger amount rather than smaller individual doses. Instead of waiting for the disease to progress, CRISPR will hit patients with a larger dose at the one month point, when the tumors are already reduced. This is a strategy that Allogene has employed as well, according to RBC's Issi.
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"The allo CAR-T conversation is shifting from persistence to re-dosing and consolidation as a potential path to response durability," Chardan wrote.
Lawrence Klein, Ph.D., chief operating officer at CRISPR, listed multiple differences between CTX110 and Allogene’s off-the-shelf candidates that may be relevant to the risk of chromosomal abnormalities, explaining that the gene-editing technologies “have different profiles in terms of their efficiency of editing, their off-target profiles and their propensity to cause changes to chromosomes.” With CRISPR also using a different vector to insert the CAR construct and a different lymphodepletion regimen, the biotech is holding its course.
“At the moment, we're not changing anything we're doing with CTX110 because we don't expect to see something like that with our trials,” Klein said.
Editor's note: This story was updated at 9:21 a.m. ET on Oct. 13, 2021, to add analyst commentary.