Enliven Therapeutics Announces Positive Proof of Concept Data from Phase 1 Clinical Trial of ELVN-001 in Chronic Myeloid Leukemia

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Summation

  • ELVN is a clinical-stage precision oncology company focused on the discovery and development of next-generation small molecule kinase inhibitors, today announced positive proof of concept data from the Phase 1 clinical trial evaluating ELVN-001 in patients with chronic myeloid leukemia (CML) who are relapsed, refractory, or intolerant to available tyrosine kinase inhibitors (TKIs) (NCT05304377).
  • “We are excited to present the first look at the safety and clinical activity of ELVN-001, which we believe supports the potential for ELVN-001 to address the limitations of the available active-site TKIs,” said Helen Collins, M.
  • “Across a wide dose range, ELVN-001 demonstrated activity in a heavily pre-treated patient population that includes post-asciminibpatients, with a preliminary safety profile consistent with its highly selective design.

Enliven Therapeutics, Inc.: ELVN is a clinical-stage precision oncology company focused on the discovery and development of next-generation small molecule kinase inhibitors, today announced positive proof of concept data from the Phase 1 clinical trial evaluating ELVN-001 in patients with chronic myeloid leukemia (CML) who are relapsed, refractory, or intolerant to available tyrosine kinase inhibitors (TKIs) (NCT05304377).

ELVN-001

ELVN-001 is a potent, highly selective, potentially best-in-class small molecule kinase inhibitor designed to specifically target the BCR-ABL gene fusion, the oncogenic driver for patients with CML.

Significant advancements have been made over the past few decades for patients with CML, and the approved TKIs provide important treatment options for patients with CML. However, there arelimitations with the available therapies, including intolerance or resistance, that result in inadequate target coverage, the loss of molecular response and disease progression in many patients,” said presenting investigator Fabian Lang, M.D., from Goethe University Hospital. “Similar to our experience with previous successful Phase 1 trials in CML, ELVN-001 looks promising. The preliminary data support that ELVN-001 is a potent and highly selective BCR::ABL1 inhibitor that has activity in heavily pre-treated patients, including post-asciminib patients.

We are excited to present the first look at the safety and clinical activity of ELVN-001, which we believe supports the potential for ELVN-001 to address the limitations of the available active-site TKIs, said Helen Collins, M.D., Chief Medical Officer of Enliven. Across a wide dose range, ELVN-001 demonstrated activity in a heavily pre-treated patient population that includes post-asciminibpatients, with a preliminary safety profile consistent with its highly selective design. Not only did all evaluable patients have improved or stable BCR::ABL1 transcript levels, but, importantly, 89% of all patients enrolled remain on study. We believe the initial data demonstrate the potential clinical utility of ELVN-001 for all types of patients, including those that are earlier in the treatment paradigm.

Patient Demographics

As of the cutoff date, March 18, 2024, 27 patients had enrolled in the ongoing Phase 1 clinical trial across five dose levels of ELVN-001, ranging from 10mg once daily (QD) to 120mg QD. Of the enrolled patients, 16 were evaluable for molecular response by 12 weeks.
Patients enrolled were heavily pretreated:
o 70% of patients had 3 prior TKIs.
o 70% of patients had received prior ponatinib and/or prior asciminib.
o 67% of patients had discontinued their last prior TKI due to lack of efficacy.

Preliminary Efficacy

ELVN-001 achieved a cumulative major molecular response(MMR) rate of 44% (7/16) by 12 weeks and demonstrated responses in patients with prior exposure to asciminib and/orwho were TKIresistant:
o Among post-asciminib patients, ELVN-001 achieved a cumulative MMR rate of 44% (4/9) by 12 weeks.
o Among TKI-resistant patients, ELVN-001 achieved a cumulative MMR rate of 40% (4/10) by 12 weeks.
Among responseevaluable patients, all had improved or stable BCR::ABL1 transcript levels by 12 weeks.
These data compare favorably to precedent Phase 1 cumulative MMR rates for approved BCR::ABL1 TKIs, particularly given the shorter time frame for response assessment and a more heavily pre-treated patient population.

Preliminary Safety

ELVN-001 has been well tolerated, consistent with its selective kinase profile.
A maximum tolerated dose has not been identified, and there have been no dose reductions.
No ≥ Grade 3 non-hematologic treatment-related adverse events(TRAE) and no specific non-hematologic TRAE of any grade occurred in >11% of patients.
Hematologic adverse events observed are consistent with the approved BCR::ABL1 TKIs.

Pharmacokinetics (PK) & Target Coverage

ELVN-001’s PK profile supports once daily dosing with flexible administration requirements (no significant food effect and minimal risk of drug-drug interactions).
Importantly, given the strong correlation between target coverage and 1L efficacy for the approved BCR::ABL1 TKIs,
o ELVN-001, at doses equal to or greater than 40mg QD,achieved superior target coverage compared to 2ndGeneration, active-site TKIs.
o ELVN-001, at 80mg QD, achieved similar target coverage compared to asciminib.

“We are thrilled with ELVN-001’s initial Phase 1 data in heavily pre-treated patients with CML,” said Sam Kintz, Co-founder and Chief Executive Officer of Enliven. “We believe that with the data presented today, ELVN-001 has initially addressed each key area of our target product profile. Given our expectation that asciminib [Scemblix] will soon become an important standard of care in the earlyline CML setting, we hope to initially position ELVN-001 as the best-in-class active-site BCR::ABL1 TKI. We believe that ELVN-001’s initial cumulative MMR rate, including in post-asciminib patients, and its tolerability profile are supportive of this positioning. These data are supported by ELVN-001’s pharmacokinetic data, which showed superior target coverage at doses equal to or greater than 40mg QD compared to 1st and 2nd Generation TKIs. Finally, and most importantly, we recognize that this achievement is made possible by the patients, caregivers, and investigators who are participating in the ELVN-001 trial, and we offer them our sincere gratitude.”

Company Event with Investigators and Key Opinion Leaders(KOLs)

Enliven is hosting a company event with KOLs today at 8:00 AM ET. The event will feature leading CML investigators and hematology care experts, Michael Mauro, M.D., from Memorial Sloan Kettering Cancer Center, and Fabian Lang, M.D., from Goethe University Hospital, along with the management of Enliven Therapeutics. The discussion will cover details of ELVN-001’s Phase 1 initial proof of concept data, the evolving treatment paradigm in CML, and how ELVN-001 could fit into the CML landscape.

About the Phase 1 ELVN-001 Trial: The Phase 1 clinical trial of ELVN-001 is a dose escalation trial designed to evaluate the safety and tolerability, and determine the recommended dose for further clinical evaluation of, ELVN-001 in patients with CML with and without T315I mutations who are relapsed, refractory or intolerant to TKIs. The primary endpoint of the study is safety. Secondary endpoints include pharmacokinetics, MMR by central qPCR, duration of MMR, BCR::ABL1 transcript levels and complete hematologic response.

About ELVN-001: ELVN-001 is a potent, highly selective, small molecule kinase inhibitor designed to specifically target the BCR-ABL gene fusion, the oncogenic driver for patients with chronic myeloid leukemia. As a highly selective active site inhibitor, ELVN-001 has a mechanism of action that is complementary to allosteric BCR::ABL1 inhibitors, which may play an increasingly important role in the standard of care. ELVN-001 was also designed to have activity against the T315I mutation, the most common BCR::ABL1 mutation, which confers resistance to nearly all approved TKIs as well as activity against mutations known to confer resistance to allosteric BCR::ABL1inhibitors.

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