Cullinan Therapeutics’ T-cell engager, CLN-049, has been proven tolerable and safe in an early-stage study in relapsed or refractory acute myeloid leukaemia (r/r AML) and myelodysplastic syndrome (MDS).
In a Phase I study (NCT05143996), the FLT3-CD3 bispecific displayed a promising efficacy profile, triggering a complete response (CR) / complete remission with partial haematologic recovery (CRh) in 31% of the 16 evaluable patients at the highest target dose of 12µg/kg. The composite complete response (CRc) rate was 31%.
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The targeted therapy also demonstrated activity at a lower dose of ≥6µg/kg, triggering CR/CRh in eight out of 32 (25%) evaluable patients. Of these responders, 63% demonstrated a response to treatment of more than 16 weeks, and two additional patients were able to proceed to allogeneic haematopoietic stem cell transplant.
Among eight patients with TP53-mutated AML patients, who received high-dose CLN-049, 50% (four patients) achieved a CR/CRh response, with three achieving a CRh response and one achieving CR. TP53 mutations are commonly associated with poor outcomes in AML.
Revealed during an oral presentation at the 67th American Society of Hematology (ASH) Annual Meeting and Exposition, being held 6-9 December in Orlando, Florida, the data comes from 41 evaluable patients across seven study cohorts – all of whom had reached at least one on-treatment response assessment. AML patients had received a median of two prior therapies before joining the study.
According to a paper published last month ahead of the annual ASH meeting, as of a 9 June cut-off, 7.5% of the 40 evaluable patients discontinued treatment due to treatment-emergent adverse events (TEAEs), which occurred in 95% of patients.
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By GlobalDataIn a research note, Matthew Phipps, head of biotech equity research at investment bank William Blair, noted that CLN-049’s initial CR/CRh efficacy was similar to historical monotherapy benchmarks for targeted, mutation-specific assets, which have demonstrated CR rates between 20% and 30% in prior studies.
Phipps concluded: “Given CLN-049 can be used across a broader range of patients and has a tolerable safety profile with non-overlapping side effects, we believe it would be a strong combination partner with other approved regimens.”
William Blair currently forecasts that CLN-049 will reach a US sales peak of $640m in R/R AML, with approval anticipated in 2029.
Next steps for CLN-049
In conversation with Clinical Trials Arena, Cullinan’s CMO Jeffrey Jones said that the trial will investigate further dose escalation due to the drug’s favourable safety profile.
The biotech will initiate expansion in two parallel cohorts of patients, including one with p53-mutated disease. The first cohort will include both frontline and r/r AML patients, while another will cover just r/r patients.
In this study, Cullinan hopes to validate initial efficacy observations while determining the recommended Phase II dose to support CLN-049’s further development. According to Jones, the expansion phase of this study is set to complete by the end of 2026. After that, the company anticipates it will initiate a pivotal Phase II trial in 2027.
Cullinan is also looking to expand CLN-049’s role in the frontline setting alongside existing standard of care (SoC) treatment, as Jones noted that “improving the first treatment patients receive is very important”.
Though the US biotech is still considering combinations for this trial, Jones noted that targeted therapy Venclyxto (venetoclax) and chemotherapy agent azacitidine are “of great interest”.
A trial valuating potential combination therapies, Cullinan will commence a Phase I/II combination study in 2026.
Broadening the AML treatment landscape
AML has long been categorised as an aggressive disease, with around 30% of adults with the cancer surviving for five years after diagnosis.
While new targeted treatments have gained approval in AML, Jones noted that most of these therapies target a “narrow subset of patients” with specific mutations – including aberrations such as FLT3 kinase domain or IDH1 and 2 mutations.
This is not the case for CLN-049, which binds to the extracellular domain of FLT3, which Jones says can “open up broad treatment potential in AML” due to the high (80%) expression of the target protein on AML blasts.
By targeting an extracellular domain on FLT3, CLN-049 could also hold the potential to kill AML cells that have eluded immune detection through the protein.
