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Actimab-A: CD33 Targeting Radiotherapeutic for Patients with Relapsed/Refractory AML

Mutation agnostic/resistant mechanism with combination backbone therapy potential in highly radiosensitive, mutation rich AML

Actimab-A now available via our Cooperative Research and Development Agreement with the National Cancer Institute

Actimab-A Molecule

Actimab-A is our second most advanced product candidate that we are focused on developing in combination with other regimens to exploit mechanistic synergies with the objective of establishing it as a backbone therapy. The intent is to leverage Actimab-A’s mutation-agnostic, resistant mechanism of action to develop an AML backbone therapy in combination with other treatment modalities in this mutation rich disease.

Actimab-A is being studied in a Phase 1/2 combination trial with the salvage regimen CLAG-M in patients with r/r AML fit for intensive therapy and in a Phase 1/2 combination trial with Venetoclax, a targeted therapy, in patients with r/r AML who are both fit and unfit for intensive therapy.

In collaboration with the Medical College of Wisconsin, the Actimab-A + CLAG-M Phase 1 trial was conducted in high-risk, r/r AML patients with a median age of 63 who had failed two or more lines of therapy, had adverse cytogenetics (i.e., 67% had adverse cytogenetics with 52% having a TP53 mutation associated with very poor outcomes) or failed Venetoclax, and consequently have dismal survival ranging from approximately two to six months. The scientific rational is to use CLAG-M, a powerful chemotherapy regimen routinely used to treat patients with r/r AML, and then use Actimab-A for its precision targeting ability that produces double-strand-DNA breaks that lead to cancer cell death to clear out residual disease.

Phase 1 results from the Actimab-A CLAG-M trial were presented in an oral presentation at the ASH Annual Meeting on December 10, 2022. Despite this difficult-to-treat population, the results demonstrate its high potential to treat this r/r AML population. We reported that the trial showed an Overall Response Rate (“ORR”) of 67% across all dose cohorts including subtherapeutic doses of Actimab-A, an 83% ORR and 75% MRD negativity rate at the recommended Phase 2 dose. We also reported a 12-month median OS among all patients, a 1-year OS of 53% and 2-year OS of 32%, which are as much as double what can be expected with available therapies. Patients received a median of two lines of prior therapy and 57% received prior treatment with Venetoclax, a BCL-2 inhibitor. This patient population has dismal survival outcomes and outside of this novel combination clinical trial, would not be treated with CLAG-M. To provide additional context, the median OS in patients who relapse post Venetoclax is less than 3 months and the median OS in patients who relapse with a TP53 mutation is less than 2 months. These results are highly encouraging and show that the high rates of responses and MRD negativity are translating to a meaningful survival benefit.

Chart showing survival rates

Table showing survival rates64% of eligible patients proceed to transplant. Median survival of transplanted patients 24 months.

1) Abedin et al. Lintuzumab-Ac225 with Combination with Intensive Chemotherapy Yields High Response Rate and MRD Negativity in R/R AML with Adverse Features. ASH Abstract # 65 ASH 2022 CR= CR, CRi and MLFS.
2) Abedin et al. Sequential Salvage Chemotherapy and Lintuzumab-Ac225 in Relapsed/Refractory AML Results in Deep Responses and Prolonged Survival in Adverse Risk AML and in AML Patients that Received Prior Venetoclax Therapy. SOHO 2023. Interim data analysis. Final results pending datasbase lock and final analysis. Graphic adapted from SOHO presentation.
3) Maiti et al. Outcomes of relapsed or refractory acute myeloid leukemia after front-line hypomethylating agent and venetoclax regimens
4) Zucenka, A., et al. Outcomes of relapsed or refractory acute myeloid leukemia patients failing venetoclax-based salvage therapies. Eur J Haematol. 2020; 106: 105– 1133)

We are also conducting a Phase 1/2 multi-center trial combining Actimab-A + Venetoclax in both fit and unfit patients 18 years and older with r/r AML led by UCLA Medical Center. On December 10, 2022, data from our Actimab-A + Venetoclax combination trial was presented at the ASH Annual Meeting. We have demonstrated preclinically that combinations of Actimab-A and Venetoclax have mechanistic synergies. Overexpression of MCL-1, an anti-apoptotic protein, is associated with resistance to Venetoclax in AML. Actimab-A kills tumors cells with DNA double-strand breaks and downregulates MCL-1, which can (re-) sensitize AML cells or reduce tumor resistance to Venetoclax. The Actimab-A + Venetoclax combination has been well tolerated with responses, including a CR and a partial response in early dose escalation cohorts. In our ongoing clinical trial, we are exploring the optimal dose of Actimab-A, as well as the dosing regimen of the combination. We expect to present proof of concept of this study in 2023.

Actimab-A is now available through our Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute, who will collaborate with Actinium in the development of Actimab-A for patients with AML and other hematologic malignancies through NCI’s Cancer Therapy Evaluation Program. Under the CRADA, Actimab-A will be available to approximately 2,000 clinical trial sites in NCI’s Experimental Clinical Trial Network includes ECOG, SWOG and Alliance.

Actimab-A Combos