On October 30, 2018 Actinium Pharmaceuticals, Inc. (NYSE American: ATNM) reported that the next stage of development for its CD33 ARC (Antibody Radiation Conjugate) Ac-225-Lintuzumab program, after successful completion of the Actimab-A phase 2 trial in Acute Myeloid Leukemia (AML), will incorporate two key initiatives; a pivotal trial pathway for its Actimab-MDS program for Myelodysplastic Syndromes (MDS), and also in two combination trials with Venetoclax for AML (Press release, Actinium Pharmaceuticals, OCT 30, 2018, View Source [SID1234530365]). Actinium’s development strategy for its CD33 program is being informed by: clinical data from 4 trials totaling over 100 patients including the recent Actimab-A Phase 2 trial in AML; positive interactions with the FDA regarding its Actimab-MDS trial; company research findings regarding potential synergy with Venetoclax; support from leading physicians; and attractiveness of the targeted indications given the unmet medical need and potential of its differentiated ARC modality in combination with chemotherapy.
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
Actinium highlighted the outcome of its successful discussions with the FDA for the Actimab-MDS program, which resulted in guidance for an accelerated pathway to a pivotal trial after a short dose finding Phase 1 portion. Actinium’s initial proposal to the FDA was to conduct a larger Phase 2 trial prior to a pivotal trial in patients with a TP53 mutation, however, the company was encouraged by the FDA to expand the trial to include all high-risk patients with poor or very poor and complex cytogenetics. The program will use the ARC Ac-225-lintuzumab for targeted conditioning in combination with a reduced intensity dose of fludarabine and melphalan prior to a BMT or Bone Marrow Transplant in patients with high-risk Myelodysplastic Syndrome (MDS).
Dr. Mark Berger, Actinium’s Chief Medical Officer said, "In our studies to date, we’ve seen that Ac-225 – Lintuzumab can achieve remissions with minimal extramedullary toxicities even in patients progressing to AML from MDS. Typically, high-risk MDS patients undergoing a BMT do poorly with standard conditioning resulting in poor outcomes. The goal of the Actimab-MDS program is to use our ARC AC-225 – Lintuzumab to target cells of the myeloid lineage including progenitor cells in combination with reduced intensity conditioning with the goal of achieving improved conditioning and BMT outcomes, as successful BMT is the only potentially curative treatment option for these patients. We are building on the data we already have from our CD33 program and we are excited to have a quicker pathway to a pivotal trial that targets a larger patient population than originally envisaged."
Actinium’s two combination trials with Venetoclax, a BCL-2 inhibitor that was jointly developed by AbbVie and Genentech, will leverage Actimab-A’s unique and differentiated mechanism of action to explore synergies between the two agents for patients with relapsed or refractory AML. Venetoclax is an approved drug for patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) and a supplemental New Drug Application (NDA) has been submitted to the FDA for patients newly diagnosed with AML. The first proposed study will evaluate Actimab-A in combination with Venetoclax and will be led by Dr. Gary Schiller, Director, Hematology/Stem Cell Transplantation at UCLA Medical center. The second study will evaluate Actimab-A in combination with Venetoclax and hypomethylating agents and will be conducted in collaboration with Dr. Hagop Kantarjian and Dr. Tapan Kadia of the MD Anderson Cancer Center. The company is pursuing these combination trials with Actimab-A and Venetoclax on the basis of internal preclinical studies which have demonstrated a synergistic effect between these two agents that is supported by a mechanistic rational. Specifically, patients with AML have high levels of MCL-1, a protein that mediates resistance to Venetoclax, which is known to be depleted by DNA damage caused by external radiation treatment. Preclinical studies have demonstrated that MCL-1 is effectively depleted by DNA damage caused by external radiation and Actinium believes that Actimab-A’s targeted radiation mechanism will therefore lead to a greater effect of Actimab-A plus Venetoclax, as demonstrated in the Company’s preclinical work.
Dr. Berger added, "Many therapeutic advances in oncology, and also in AML, have been the result of combination therapies. We are excited to be advancing our Actimab-A program in combination with Venetoclax, which has the potential to lead the next evolution of AML therapy, in collaboration with top thought leaders from leading medical institutions. As indicated by our collaborators during the CD33 Update webinar, while results with Venetoclax in patients with AML are encouraging, there remains a high unmet need for durable responses and curative outcomes. We believe Actimab-A can be used in combination with Venetoclax to improve patient outcomes, which is based on a strong scientific rationale supporting the combination as well as preclinical and clinical data. Our proposed trials with these combinations demonstrate the strong investigator interest we have seen for working with Ac-225 – Lintuzumab as an Antibody Radiation Conjugate is a new therapeutic modality for patients with radiation sensitive cancers such as AML, MDS and Multiple Myeloma that has the potential to improve their outcomes."
Sandesh Seth, Actinium’s Chairman and Chief Executive Officer said, "Having a clear and relatively quick pathway to a pivotal trial for Actimab-MDS materially strengthens our targeted conditioning pipeline. It also enhances our outlook for building a business focused on developing and launching multiple products for targeted conditioning prior to BMT or CAR-T that can improve both patient access and outcomes due to their superior safety and efficacy balance compared to non-targeted chemotherapy that is current standard of care. With the solid progress of the Iomab-B Phase 3 trial for BMT, the recent launch of the Iomab-ACT program for CAR-T and the solid impetus for a near-term Actimab-MDS pivotal trial, our pipeline prospects for targeted conditioning have never been better."
Mr. Seth added, "The Actimab-A trial which was recently closed has been a big success as it has provided the foundation for the near-pivotal Actimab-MDS program in an area where there is high unmet need, no competing development programs by other companies and a larger patient population than originally envisaged. Additionally, our combination trials with Venetoclax and Actimab-A are very exciting as we have the opportunity to validate our preclinical research showing superiority of the combination in two highly relevant clinical settings where the unmet medical need continues to be high. Based on these recent developments, our CD33 Program has evolved much beyond the narrow AML focused CD33 programs in the industry due to the versatility of our ARC technology. The ARC approach has allowed us to expand into other radiation sensitive diseases such as multiple myeloma and MDS, and into targeted conditioning using high doses of the ARC as well as therapeutic combinations at lower ARC doses which allow incorporation of targeted radiation as another modality to treat highly radiation sensitive cancers."
"In addition," said Mr. Seth, "from a strategic perspective, the Actimab-MDS targeted conditioning trial strengthens our go-it-alone outlook. However, the other CD33 program developments including combination trials increase its attractiveness to potential collaborators and are expected to provide our company with attractive optionality going forward, as the period between now and 2019 are expected to yield several valuable clinical milestones and data readouts. We look forward to providing updates as value in this program continues to build.".