Molecular Partners AG presented encouraging clinical data from its ongoing Phase 1/2a trial of MP0533, a tetraspecific T-cell engager, in patients with relapsed/refractory acute myeloid leukemia (AML) at the 30th European Hematology Association Congress in Milan. The data demonstrate improved clinical responses with an optimized dosing strategy that extends therapeutic drug exposure.
Enhanced Response Rates with Accelerated Dosing
In cohort 8 of the ongoing study, three of eight evaluable patients (>30%) achieved clinical responses after the first treatment cycle. One patient achieved a complete response, while two patients achieved complete responses with partial hematologic recovery as their best overall response. Notably, one patient has maintained a response beyond 6 months at the time of data cutoff on April 14, 2025.
The improved outcomes in cohort 8 resulted from implementing an accelerated step-up dosing regimen that reached target doses by day 12, compared to day 15 in previous cohorts. This approach included a higher starting dose and an additional day of dosing, allowing patients to maintain exposure to MP0533 within the predicted therapeutic range for over 4 days during the first cycle.
Addressing Drug Exposure Limitations
The dosing optimization addressed a key challenge identified in earlier cohorts 1-7, where exposure to predicted therapeutic doses was limited to approximately 2 days in the first cycle, likely due to target-mediated drug disposition. Despite demonstrating initial blast reductions in roughly 30% of patients, this limited exposure resulted in fewer sustained responses.
Data from cohort 8 showed that 5 out of 8 patients displayed greater than 50% blast reduction, with patients maintaining longer therapeutic exposure through the accelerated dosing scheme. MP0533 demonstrated an acceptable safety profile with the adjusted target dose in cohort 8.
"I am encouraged by the number and level of responses observed in the most recent cohort and have started to include patients with the new 'dense administration' schedule aiming to establish the full potential of this product for our R/R AML patients," said Pierre Bories, MD, PhD, Principal Investigator at Institut Universitaire du Cancer Toulouse - Oncopole, France.
Future Development Strategy
Based on the encouraging antitumor activity observed in cohort 8, Molecular Partners has implemented further protocol amendments for cohort 9 and beyond. These modifications include additional acceleration of step-up dosing to reach therapeutically relevant doses faster, increased dosing frequency for higher cumulative MP0533 exposure, and introduction of anti-CD20 premedication to mitigate loss of exposure.
Cohort 9 is currently enrolling patients, with initial data from the amended dosing scheme expected in the second half of 2025. Future study cohorts will evaluate the combination of azacitidine/venetoclax with MP0533, potentially expanding treatment options for patients with relapsed/refractory AML.
Novel Therapeutic Approach
MP0533 is a tetraspecific designed ankyrin repeat protein (DARPin) that simultaneously targets CD33, CD123, CD70, and CD3. This multi-target approach represents Molecular Partners' strategy to address medical challenges that other drug modalities cannot readily address, leveraging the unique properties of DARPin therapeutics to engage T-cells against AML blasts expressing multiple surface antigens.
