ASH Abstract Confirms Positive Outlook For Actinium's Actimab-A

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Last week, the American Society of Hematology (ASH) released abstracts for the upcoming 58th Annual Meeting & Exposition to be held December 3-6, 2016 in San Diego, CA. Included as part of the release was abstract #4050 from Actinium Pharmaceuticals, Inc. (NYSEMKT: ATNM). The abstract hi.ghlights the company's Phase 1 clinical results with Actimab-A for the treatment of Acute Myeloid Leukemia (AML). Below is a review of that abstract and a quick comparison to an abstract by Seattle Genetics and its similar CD33 targeting candidate.

The Actimab-A Story

At ASH, Actinium Pharma will present a detailed analysis of the company's recently completed Phase 1 clinical trial with Actimab-A. Recall, Actimab-A is the CD33 targeting monoclonal antibody, lintuzumab, linked to the short-ranged (50-80 µm), high-energy (~100 keV/µm) α particle-emitting isotope, Actinium-225.  CD33 is a cell surface antigen expressed in approximately 90% of AML, representing a promising target of therapy regardless of genetic or mutational heterogeneity.

The concept of Actimab-A holds significant scientific merit. We know CD33 is a validated target by the approval of gemtuzumab at Pfizer and the advancement of vadastuximab into Phase 3 trials at Seattle Genetics. Lintuzumab by itself has proven to be ineffective; but, linked to the radioactive isotope Ac-225, Actimab-A should see a powerful increase in cancer cell-killing effect.

The necessity for Actimab-A is significant. Elderly patients with previously untreated AML are often not candidates for standard induction therapy (i.e. continuous infusion cytarabine for 7 days and an anthracycline for 3 days "7+3") due to antecedent hematologic disorder, poor-risk cytogenetic or molecular features, and significant comorbidities such as patients with congestive heart failure, coronary artery disease, ischemia, and hypertension). Anthracycline has been associated with significant cardiotoxicity. Actimab-A represents an effective way to induce remission without the risk of major treatment-related adverse events. Previous Phase 1 data (Jurcic et al., 2011) in a relapsed / refractory AML population show a single infusion to be safe at doses ≤ 3 µCi/kg.

The market opportunity is significant. Approximately two-thirds of the AML population is over the age of 60 years old and half of these patients are not eligible for the current standard of care due to anthracycline toxicities with contaminant medications, comorbidities, and/or physician expectations on the patient's ability to tolerate 7+3 induction. In December 2014, Actimab-A was granted Orphan Drug status by the U.S. FDA. I estimate the patient population in the U.S. is approximately 6,500 individuals. The opportunity in Europe is another 7,500. Assuming a cost of approximately $65,000 per treatment in the U.S. and Japan and $42,500 in the EU (management guidance), the peak opportunity is easily $750 million. With 33% market share, Actimab-A looks to have sales in the $250 million range.

The trial was done well. Actinium enrolled 18 patients (median age: 77 years, with a range between 68 and 87). Enrollment took place at Baylor University Medical Center, Columbia University Medical Center, Fred Hutchinson Cancer Research Center, John's Hopkins School of Medicine, Memorial Sloan Kettering Cancer Center, and the University of Pennsylvania Medical School.

Twelve (67%) patients had prior myelodysplastic syndrome (MDS), for which 10 (83%) received treatment with hypomethylating agents (n=9) or allogeneic hematopoietic cell transplantation (n=1). One patient (6%) had chronic myeloid leukemia in molecular remission prior to developing AML. Eleven patients (61%) had intermediate-risk and 7 (39%) had poor-risk factors designed by the NCCN criteria.

Four doses were tested, 0.5 (n=3), 1 (n=6), 1.5 (n=3), or 2 (n=6) μCi/kg/fraction. Although two patients experienced dose-limiting toxicities (grade 4 thrombocytopenia with marrow aplasia for > 6 weeks following therapy), one each in the 1 and 2 µCi/kg cohorts, investigators felt that the maximum tolerated dose (MTD) was not reached. The 30- and 60-day mortality rates were 0% and 17%, respectively. Importantly, Actinium will move forward with the 2 µCi/kg dose for the recently initiated Phase 2 trial.

The data look very good. Eleven of 14 patients (79%) evaluated after Cycle 1 had bone marrow blast reductions (mean reduction, 66%; range, 19-100%). Objective responses (2 CR, 1 CRp, 2 CRi) were seen in five of the 18 patients (28%), but only at doses ≥ 1 µCi/kg (Table 1). At the 2 µCi/kg dose, the CR rate was 50%. All responses occurred after one cycle of therapy, in contrast to historical data with LDAC alone, where the median time to response was three cycles. Median progression-free survival (PFS) for all patients was 2.7 months (range, 1.0-31.8+ months). Median overall survival (OS) was 5.6 months (range, 1.6-32+ months). Median response duration was 5.6 months (range, 4.9-32+ months).

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