This article has been updated to reflect that Kura is based on San Diego and it expects to complete enrollment in KOMET-001 this year, not KOMET-007.
NEW YORK – Kura Oncology on Tuesday reported on the preliminary activity of its menin inhibitor ziftomenib in combination with chemotherapy in patients with NPM1-mutant and KMT2A-rearranged acute myeloid leukemia enrolled in the Phase I KOMET-007 trial.
Following the data disclosure Tuesday, Kura's stock price increased by around 12 percent and closed at $20.85 on the Nasdaq.
Ziftomenib is a small-molecule oral drug that inhibits the interaction between menin and the KMT2A protein. Rather than killing the cancer cells, as is the goal with anti-cancer agents, menin inhibitors lead stem cells to differentiate into normal adult cells. Kura is studying ziftomenib alone and in combination with other agents in multiple clinical trials.
In the KOMET-007 trial, Kura researchers are evaluating ziftomenib with AbbVie's BCL-2 inhibitor Venclexta (venetoclax) and azacitidine or with a standard cytarabine/anthracycline-based chemotherapy regimen in patients with NPM1-mutated or KMT2A-rearranged acute myeloid leukemia (AML). The trial has multiple cohorts in dose escalation and dose expansion phases, including patients with newly diagnosed, high-risk NPM1-mutated AML; newly diagnosed, high-risk KMT2A-rearranged AML; relapsed or refractory NPM1-mutated AML; and relapsed or refractory KMT2A-rearranged AML.
Patients in the newly diagnosed disease cohorts receive ziftomenib and seven days of cytarabine plus an anthracycline on the first three days. Patients in the relapsed/refractory cohorts receive ziftomenib, Venclexta, and azacitidine. In an interview, Kura CEO Troy Wilson said the use of the newer Venclexta regimen in the dose-escalation phase of the trial in the relapsed or refractory population was based on advice from the US Food and Drug Administration, and that if it proves safe, Kura will also test the ziftomenib-Venclexta-azacitidine combo as a frontline option.
Kura researchers are tracking toxicity, adverse events, and complete remission rates as primary endpoints in the trial, while secondary endpoints include the composite complete remission rate, measurable residual disease, median overall survival, and event-free survival.
The San Diego-based company reported data on Tuesday from the first 20 patients enrolled in KOMET-007 between July and November 2023, though they did not disclose the median follow-up time. Four of the patients have newly diagnosed, high-risk NPM1-mutated AML, one has newly diagnosed, high-risk KMT2A-rearranged AML, and 15 have relapsed or refractory NPM1-mutated or KMT2A-rearranged AML.
As of the Jan. 11 data cutoff, all five of the newly diagnosed patients treated with ziftomenib and cytarabine/anthracycline chemotherapy had achieved a complete remission. In a presentation to investors yesterday, Amer Zeidan, a hematologist at Yale Medicine and a KOMET-007 investigator, cautioned that the results are very early and include a small number of patients. Despite those caveats, he said the data were still "exciting."
"Remember those NPM1-mutated patients are not your standard young, fit patients who have no adverse cytogenetics," Zeidan said. Instead, he pointed out that the patients are older and high risk, and in that group, the rates of complete remission or complete remission with partial hematologic recovery have been reported in around a third of patients, as opposed to the 100 percent complete remission rate seen thus far in the trial cohort.
Among the 15 patients with relapsed or refractory disease on ziftomenib-Venclexta-azacitidine, the overall response rate was 53 percent. Nine of those patients had never received a menin inhibitor, and of those, five, or 56 percent, achieved a complete remission or complete remission with partial hematologic recovery. Four out of 10 patients, or 40 percent, of those who had previously received Venclexta responded to ziftomenib-Venclexta-azacitidine. Zeidan noted that the response rate for this group was "impressive" because typical rates of response to Venclexta-azacitidine in this setting range from zero to 20 percent.
Wedbush Securities analyst Robert Driscoll said in an interview that he was expecting these interim results on ziftomenib plus chemo to be positive after the earlier efficacy ziftomenib monotherapy had shown in patients with relapsed or refractory NPM1-mtuant AML in KOMET-001 Phase I/II trial. The composite complete remission rate was 40 percent in that study.
However, even more than efficacy, Driscoll said, investors had been eager to see the safety profile of ziftomenib in KOMET-007, particularly the rates of differentiation syndrome, a potentially fatal adverse reaction associated with menin inhibitors. Differentiation syndrome is characterized by fever, weight gain, shortness of breath, accumulation of fluid around the heart, low blood pressure, and kidney failure.
In KOMET-001, investigators saw grade 1 or 2 differentiation syndrome in 15 percent of patients and grade 3 differentiation syndrome in 5 percent. Prior to that, in November 2021, the FDA placed a partial clinical hold on KOMET-001 after a patient died from differentiation syndrome. The agency lifted that clinical hold in January 2022.
Amir Fathi, a hematologist at Massachusetts General Hospital and another KOMET-007 investigator, noted during the call with investors that differentiation syndrome tends to be milder and more manageable in patients with NPM1-mutated disease, while it occurs at a higher rate and is more severe in KMT2A-rearranged patients. Because it is an on-target adverse effect associated with the mechanism of menin inhibitors, Fathi said, "it would make sense that a way to potentially mitigate the effect of this drug in promoting differentiation syndrome in KMT2A-altered disease would be to combine it with conventional chemotherapy strategies to help bring down the leukemic cell population and decrease the burden of cells that are going into differentiation."
The early safety results from KOMET-007 seem promising for that strategy. Kura reported no differentiation syndrome events of any grade nor any dose-limiting toxicities, and the firm saw no evidence of QTc prolongation, drug-drug interactions, or additive myelosuppression.
Wilson emphasized that the early results do not necessarily suggest that differentiation syndrome will be eliminated completely with combination therapy. "Just to set everybody's expectations, we're thrilled that there were zero events of [differentiation syndrome]. Is that going to continue for all time? Likely, not," Wilson said. Because ziftomenib is a differentiating agent, Wilson expects that differentiation syndrome will likely occur in some patients at some point in the trial.
"What this update shows, as we've been saying since we reported our initial monotherapy data, is that the best way to mitigate [differentiation syndrome] is to give this drug in combination," he added.
Kura's goal with ziftomenib is to make it a market leader in menin-dependent leukemias across different drug combinations and lines of therapy. It expects to complete enrollment in the registration-directed KOMET-001 trial by the middle of 2024. "If all goes well," Wilson said Kura could be submitting a new drug application to the FDA for ziftomenib monotherapy by year-end or in early 2025.
Within the KOMET-001 trial, Kura plans to open sub-studies in other menin-dependent, non-NPM1-mutated and non-KMT2A-rearranged AML and in KMT2A-rearranged acute lymphoblastic leukemia. Wilson said the new AML cohorts will recruit patients who are neither NPM1-mutated nor KMT2A-rearranged, but who Kura believes could be sensitive to menin inhibitors based on other biomarkers that the firm hasn't publicly shared.
According to Wilson, patients with NPM1-mutated and KMT2A-rearranged AML and the third group of menin-sensitive patients defined by other biomarkers comprise about 50 percent of the relapsed or refractory AML patient population worldwide — a market he described as a "multiplayer, multibillion-dollar" opportunity.
Syndax Pharmaceuticals currently has a lead on Kura in the menin inhibitor space, since it has already submitted a new drug application seeking approval for revumenib as a treatment for KMT2A-rearranged advanced leukemia. The pivotal Phase II AUGMENT-101 trial supporting that application was terminated early after it met its primary endpoint during an interim analysis.
"We think the Kura data stacks up really well [against revumenib], especially on the side effect profile," Driscoll said. While he acknowledged that Syndax has an edge in KMT2A-rearranged disease, he said the two companies are "about neck and neck" in pursuing a broader indication for their agents.
Addressing the question of competition, Wilson said, "I hope more than one drug gets approved, because if you're a patient or a family member of a patient, you want to have multiple options and patients need choices."
In the coming year, Kura expects to complete enrollment in KOMET-001 and begin a new Phase I trial, dubbed KOMET-008. In the latter study, Kura will explore ziftomenib as a treatment for NPM1-mutated and KMT2A-rearranged relapsed or refractory AML in combination with Astellas Pharma's FLT3 inhibitor Xospata (gilteritinib) and FLAG-IDA (fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor) or low-dose cytarabine (LDAC) chemo.
In addition to leukemia, Kura is eyeing opportunities for ziftomenib in solid tumors and in a non-oncology indication. It plans to use a recent $150 million private placement to fund these new programs. Wilson said those funds will also support R&D activities for a cancer program targeting farnesyl transferase and allow the firm to build and advance its pipeline.