Actinium Pharmaceuticals, Inc. (ATNM)

ATNM TECHNOLOGY PLATFORM

ATNM’s Alpha Particle Immunotherapy (APIT) platform is a highly potent and selective form of targeted radiotherapy.  It is based on attaching powerful alpha emitting radioisotopes Actinium 225 or Bismuth 213 to monoclonal antibodies (mAbs) which are large molecules capable of binding specifically to cancer cells.  By virtue of carrying alpha emitters, mAbs bring them directly to cancer cells where alpha emitters can selectively kill the targeted cell.  Figure below presents a schematic of a drug based on the Company’s APIT technology.

APIT based drug construct and its components

The power of alpha emitters is best understood when compared to beta emitters, an alternative form of radioisotope used in cancer drugs.  The killing power of a radioactive particle is directly proportional to its energy and inversely proportional to its range.  Alpha particle carries the most energy but travels the shortest path, while beta particle has less energy but goes farther in the body.

Comparison between α and β irradiation’s effect
on cancer cells and healthy tissues

Being 100 times more powerful than beta particles, alpha therapy is effective in cancers that are not sensitive to beta irradiation.  Prime examples are the past and current clinical trials in AML.  APIT has demonstrated extremely high cancer cell kill levels even though AML is not considered particularly radiosensitive and radiotherapy is not used in treating the disease.  Based on these inherent isotope traits, the Company and Dr. David Scheinberg, Chairman of the Molecular Pharmacology and Chemistry Program at Memorial Sloan Kettering Cancer Center (MSKCC), ATNM’s key scientific collaborator, developed alpha particles as an ideal payload for targeted cancer radiotherapy.  While their potency is 100-fold higher than beta’s and cytotoxins’ significantly increases the killing power of alpha particle drugs against targeted tumor cells, their extremely short range limits any damage inflicted on healthy tissues.

In addition to its potency and range of emission, there are other key considerations for evaluating the suitability of particular radioisotopes for medical use.  Among them are half-life of the isotope, which is an indication of the period over which it remains radioactive, and its pharmacokinetics, i.e. its distribution in the body and its eventual elimination from it.  For these reasons, Actinium 225 (Ac-225) and the isotope derived from it, Bismuth 213 (Bi-213), were selected as lynchpins of the Company’s technology.  Both isotopes have relatively short half-lives and favorable and controllable pharmacokinetics.  However, for efficacy, logistics and cost reasons ATNM has decided to focus its efforts on Actinium 225 which has a 10 day half life versus Bismuth-213’s half life of 46 minutes.

Actinium Pharmaceuticals Drug Development Status

1. HSCT stands for Hematopoietic Stem Cell Transplantation, a procedure in which cells capable of reconstituting normal bone marrow function are transplanted to a patient.
   ATNM has decided to discontinue development of Bismab-A at this time for supply, logistics and cost reasons. Actimab-A is the second generation drug of Bismab-A.
   Properties of Actinium 225 are uniquely suited for Antiangiogenesis and API is considering options for further development in that area.
   Antiangiogenesis therapies starve cancerous tumors by choking off blood supply to them.

Phase I Trial with single dose of Actimab-A

In collaboration with Memorial Sloan Kettering Cancer Center (MSKCC) we are conducting a first-in-man Phase I dose escalation trial to determine the safety, pharmacology, and biological activity of Actimab-A in Acute Myeloid Leukemia (AML).  Eighteen patients (median age, 64 yrs; range, 45–80 yrs) with relapsed/refractory AML were treated to date.  Patients received a single infusion of Actimab-A at doses of 0.5, 1, 2, 3, or 4 µCi/kg (µCi –microCurie; total dose, 23–390 µCi).  No acute toxicities were seen.  Dose limiting toxicity (DLT) was suppression of the entire bone marrow lasting over 35 days and consequent death due to sepsis.  It occurred in one patient treated with 3 µCi/kg and in both patients receiving 4 µCi/kg.  Toxicities outside of the target organ (bone marrow) were limited to transient grade 2/3 liver function abnormalities.  With follow-up from 1–24 months (median, 2 months), no evidence of damage to kidneys due to radiation was seen.  Peripheral blood blasts (leukemia cells) were eliminated in 10 of 16 evaluable patients who received a full treatment dose.  Bone marrow blast reductions of over 33% were seen in 10 of 15 evaluable patients at 4 weeks, including 3 patients with 5 percent or fewer blasts.  Actimab-A is tolerable at doses less than 4 µCi/kg and has antileukemic activity.

Acute Myeloid Leukemia is characterized by very high numbers of immature cancerous white blood cells of certain kind that are similar to normal young blood cells and all immature white blood cells are called blasts.  It is not normal for a person to have any blasts circulating in peripheral blood (peripheral blasts) and to have more than 5 percent of blasts in the bone marrow.

Phase I/II AML Trial with two consecutive fractionated doses of Actimab-A

After receiving clearance from the FDA the Company started Phase I/II multi-center AML trial with fractionated doses of Actimab-A.  ATNM has concluded contracts with and provided training to 6 participating trial centers (Baylor University Medical Center, MSKCC, Johns Hopkins Medicine, University of Pennsylvania Health System, Fred Hutchinson Cancer Center and University of MD Andersen Cancer Center).  The Phase I (dose escalating) portion of the trial is ongoing. The Company estimates that it will take approximately 3-6 months to complete the Phase I portion of the trial and an additional 1- 1.5 years to complete the Phase II portion of the trial.  For the proposed Phase I/II study, patients are eligible if they have previously untreated newly diagnosed acute myeloid leukemia according to World Health Organization criteria, are age 60 years or older, and are unfit for or decline intensive chemotherapy, or are 70 years or older with newly diagnosed AML.  This target population has had better outcomes than relapsed and refractory patients who have been most of the patients in ATNM’s previous trials.

Maximum enrollment in the Phase I portion of the trial is 21 patients in dose escalating cohorts of 3 patients each with the goal of determining the maximum tolerated dose (MTD) for Actimab-A.  There is a six week interval between dose levels.  Once MTD has been determined, it will be used as the dose level for the Phase II portion of the trial which will enroll up to 53 patients.  There are 4 planned dose levels in the Phase I portion of the trial.

Iomab-B for Hematopoietic Stem Cells Transplantation:

Iomab-B (BC8-I-131 construct) has already been successfully used as a myeloconditioning/myeloablative agent in over 250 patients with incurable blood cancers. In both Phase I and Phase II trials Iomab-B has led to effective cures in patients with no options left. The only potentially curative treatment option for those patients is bone marrow transplantation (BMT), also known as a hematopoietic stem cell transplant (HSCT), but vast majority of patients over the age of 50 are either ineligible for myeloablative conditioning due to concomitant conditions or have a high burden and/or very resistant disease that makes reduced dose conditioning futile.

BC8-I-131 has demonstrated ability to successfully prepare such patients for bone marrow transplants when no other treatment was indicated. ATNM intends to develop Iomab-B through a regulatory approval via a pivotal registration trial in AML refractory/relapsing patients. That would allow for a relatively quick path to the market and provide a potentially curative treatment to patients who currently have little or no chance of achieving even a temporary remission, let alone a cure.

The targeting part of the Iomab-B construct is a monoclonal antibody that targets CD45, an antigen widely expressed on hematopoietic cells but not other tissues. Due to this broad expression, Iomab-B has demonstrated utility in other groups of patients and other indications as well, including Myelodysplastic Syndrome, Acute Lymphoblastic Leukemia, Hodgkin’s Disease and Non-Hodgkin Lymphoma. These are follow-on indications which could be pursued simultaneously or delayed, for cash conservation, and financed from commercial revenues.

The company is already preparing a program for replacing iodine 131 with Actinium 225 to create a second generation drug that would enable a significant expansion of use, described below as Actimab-B, Iomab-B was invented by researchers at the Fred Hutchinson Cancer Research Center (FHCRC), ATNM’s key collaborator on this program from whom ATNM obtained rights for all the commercial uses. FHCRC played a pivotal role in developing the entire field of bone marrow transplantation and the lead Hutchinson researcher, Dr. E. Donnall Thomas received the 1990 Nobel Prize in physiology/medicine for work in this area.