ASH 2023 | LP-168: a novel next-generation BTK inhibitor with dual activity in CLL

So we performed a Phase I clinical trial of a novel BTK inhibitor called LP-168. And this is actually a very selective, potent BTK inhibitor with a dual mechanism of action. In the presence of wild-type BTK at position C481 the drug can bind covalently, so it binds similar to ibrutinib, acalabrutinib, and zanubrutinib. However, if C481 is mutated, the drug can bind reversibly like drugs like pirtobrutinib and nemtabrutinib too. So it has the potential to work both in CLL with wild-type as well as with mutant BTK with two different mechanisms of action. Also, really interestingly, in the preclinical setting, it appears to have efficacy in the setting of T474 mutations, which are one of the resistance mechanisms to the non-covalent BTK inhibitors.

So in this study, we enrolled 45 patients in the dose-limiting toxicity evaluable cohort. And this was across B-cell malignancies, 37 of those patients had CLL or SLL, and it was a very heavily treated high-risk group of patients as you might expect in the Phase I setting. The safety data for all of the DLT evaluable patients looks very promising. Because it is such a selective BTK inhibitor, as expected, we don’t see high rates of grade 3 or 4 toxicity. I think neutropenia is really the only hematologic toxicity that we’ve seen in high amounts, and most of the adverse events of special interest with BTK inhibitors like atrial fibrillation, no atrial fibrillation has been observed so far. Bruising and bleeding was seen mostly in low rates. There was one patient who had an intracranial hemorrhage, which looked to be in the setting of a fall, so it’s hard to say how much that was related to the drug.

So within the group of patients that were evaluable for efficacy, the response rate was a little bit over 70%, when looking at patients who received at least 200mg daily dose. The drug was investigated at doses from 100mg daily, up to 300mg daily and there did look to be some increased efficacy at the 200 or above doses. However, patients were allowed to have interpatient dose-escalation, and we did also see some responses when patients converted to a higher dose level. When looking at different patient subgroups, the overall response rate was pretty similar when looking at patients who had received a BCL2 inhibitor versus those that hadn’t, those with TP53 alterations as well. The follow-up data is not super mature for all of the patients, but we have a median follow-up right now of 14 cycles, and most of the patients still remain on therapy and doing well. There are some who are even approaching two years of treatment and still in remission. So definitely early clinical data, but it looks very promising