Actimab-A

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 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.

1) Maiti et al. Outcomes of relapsed or refractory acute myeloid leukemia after front-line hypomethylating agent and venetoclax regimens 2) 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) 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. Graphic adapted from ASH abstract

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. To learn more about the CRADA or to submit a proposal please see NCI’s Announcement of Availability to Investigators of Actimab-A