Actinium Pharmaceuticals: Well Positioned For A Breakout 2017

Iomab-B development is initially focusing on the treatment of elderly patients with refractory / relapsing AML. These are patients that have failed the “7+3” induction phase of chemotherapy and cannot tolerate intensive or even reduced conditioning myeloablation. There is no treatment option for these patients today, resulting in an inverse correlation between age and expected survival (1). In fact, elderly patients that fall into this “poor risk” category achieve response rates to salvage chemotherapy below 20% and see long-term survival rates below 10% (2). Many are simply placed on palliative care.

Myeloconditioning / myeloablation before BMT is an incredibly complex and delicate balance between safety and efficacy (3). Failure to ablate enough cells can result in high relapse rates or increased risk of Graft vs. Host Disease (GvHD), whereas overly intense therapy causes increased risk of treatment-related mortality. Selective radiation of leukemia cells using radiolabeled monoclonal antibodies against antigens on marrow cells promise to improve results by targeting malignant cells and causing less systemic damage (4).
Iomab-B has several potential advantages over current BMT conditioning regiments. Firstly, Iomab-B significant shortens the induction and conditioning time ahead of transplantation, as Iomab-B is given for six days versus standard induction chemotherapy which averages between 28 and 42 days. Secondly, Iomab-B gets a higher percent of patients – 100% so far based on clinical data to date in over 300 patients vs. roughly 50% historically (5) – to BMT than standard conditioning. A BMT is the only curative therapy for AML, so the goal is to get patients to a BMT. Finally, Iomab-B has significantly fewer side effects and toxicities compared to standard chemotherapy.

These important advantages will hopefully result in Iomab-B extending overall survival in the Phase 3 SIERRA study. The data support this hypothesis. For example, data from the Phase 1/2 trial (NCT00008177) was compared to standard conditioning and chemotherapy (outcome analysis compiled by the MD Anderson Cancer Center) and published in Blood in 2009. In a subset of 18 elderly patients with poor cytogenetics, Iomab-B when added to FLU plus 2Gy TBI resulted in a 1-year overall survival of 33% compared to 3% for standard conditioning and high-intensity chemotherapy. After two years, 16% of the Iomab-B cohort was still alive compared to 0% for standard conditioning and chemotherapy (source: ATNM Aug 2016 Investor Presentation).

– Iomab-B Market Opportunity

The market opportunity with Iomab-B is significant. According to the U.S. National Cancer Institute (NCI), there were an estimated 20,800 new cases of AML in the U.S. in 2015. Another 20,000 new cases arise in Europe each year. There are no currently approved treatment options for elderly patients with relapsed or refractory AML, a patient population of approximately 12,000 individuals in the U.S. and EU each year, the majority of which cannot tolerate standard conditioning regimens that allow them to progress to a BMT.By offering a more effective and more tolerable solution to the 12,000 elderly relapsed / refractory AML patients in the U.S. and Europe, Actinium is sitting on a sizable market opportunity with Iomab-B. Standard conditioning regimens cost between $50,000 and $200,000 ahead of BMT. They can also take as long as 28 to 42 days and historically only work about 50% of the time. At $75,000 for a course of treatment over only six days, Iomab-B targets a $900 million opportunity.

Both Phase 1 and Phase 2 trials with Iomab-B have led to effective cures in patients with no options. Once commercialized, I believe it makes sense for Actinium to test Iomab-B earlier in the treatment paradigm for these elderly “high risk” patients, or even move Iomab-B clinical studies into new indications such as myelodysplastic syndrome, acute lymphoblastic leukemia, Hodgkin’s disease, and non-Hodgkin lymphoma. From a mechanistic standpoint, pursuing these follow-on indications holds merit and could open up potentially billions of dollars in additional revenue opportunity for the company or its commercial partner.

Actimab-A: Phase 2 To Start Shortly

On June 1, 2016, Actinium Pharmaceuticals (ATNM) provided an update to the ongoing Phase 1/2 clinical program with Actimab-A, the company’s most advanced alpha particle immunotherapy (APIT) program, for the treatment of acute myeloid leukemia (AML) in elderly patients. The company hosted a webinar and the key takeaways were:

– Actimab-A has demonstrated excellent safety and tolerability so far in two Phase 1 clinical trials.

– During analysis of the Phase 1 and previous studies stemming from the HuM195 conjugated alpha particles program, an interesting trend emerged where patients with low peripheral blast burden experienced the best clinical response.

– CR/CRi/CRp for the dose Actinium plans to move forward with into Phase 2 (2 x 2 μCi/kg) in patients with low peripheral blast burden was 50%, matching the impressive data from Celator’s VYXEOS™ at 48% reported in March 2016. As a reminder, Jazz acquired Celator for $1.5 billion in June 2016.

– Management plans to alter the protocol for the upcoming Phase 2 portion of the trial by pretreating patients with hydroxyurea to reduce peripheral blast count. This should increase the response rate for all patients treated with Actimab-A. Additionally, the required use of low-dose cytarabine has been removed by the FDA for the Phase 2 portion, which should greatly improve enrollment rates and interest among investigators.

– The Phase 2 trial is expected to begin in the next few months with initial data expected at ASH in December 2016.

– Background Info on Actimab-A & The Phase 1 Results

Actimab-A a next-generation monoclonal antibody linked to radioactive actinium-225 (Ac-225). Actimab-A consists of lintuzumab, a humanized monoclonal antibody that targets the myeloid progenitor cell protein CD33. CD33 is a transmembrane receptor leukocyte antigen primarily expressed on cancer cells of myeloid lineage, although it can also be found on some lymphoid cells. Lintuzumab was originally developed by Seattle Genetics with ties back to Memorial Sloan Kettering Cancer Center (MSKCC). Seattle Genetics attempted to develop lintuzumab as a treatment for AML and other myeloproliferative diseases, but a Phase 2b clinical trial failed to demonstrate an increase in overall survival and the program was discounted in 2010 (6).

The concept of Actimab-A holds significant scientific merit. Lintuzumab was proven to be safe and tolerable in the Seattle Genetics clinical work and CD33 is a commercially validated target. Pfizer’s Mylotarg® (gemtuzumab ozogamicin) was an anti-CD33 murine antibody conjugated to the chemotherapeutic agent, calicheamicin hydrazide. Mylotarg demonstrated success in mid-stage clinical trials (7), earning Pfizer accelerated approval from the U.S. FDA for the drug in 2000; however, safety concerns and lackluster post-approval trials ultimately led to the drug being withdrawn from the market in 2010 (8).

Lintuzumab by itself has proven to be ineffective; but, linked to the short-ranged (50-80 µm), high-energy (~100 keV/µm) alpha particle–emitting radioactive isotope Ac-225, Actimab-A should see a powerful increase in cancer cell-killing effect. Actimab-A is a next-generation product to Actinium’s previous lintuzumab-linked alpha particle emitter, Bismab-A. Bismab-A utilized bismuth-213 and demonstrated positive results in a Phase 1/2 clinical trial – complete response rates in the 30% range, superior to that of Mylotarg – but the drug was hampered by the short half-life of bismuth-213 (~45 minutes) and lacked commercial viability due to the high cost of goods and complex on-site preparation. Actinium-225 has a half-life of approximately 10 days and should offer significantly improved costs with centralized manufacturing.

A Phase 1 study (NCT01756677) examined Actimab-A as a first-line treatment for AML patients over the age of 60 who are not suitable for standard induction chemotherapy. This is most likely because these patients have an antecedent hematologic disorder, unfavorable cytogenetic or molecular abnormalities, and significant comorbidities that make standard induction intolerable to these patients. It’s important that investors understand the enrollment criteria for Actinium’s study because these are patients that would not qualify for Celator Pharma’s VYXEOS, which reported impressive data in AML patients earlier in the year.

The goal of the Phase 1 portion of the trial was to demonstrate safety and tolerability of Actimab-A in the target patient population, as well as identify any dose-limiting toxicities (DLT) and a maximum tolerated dose (MTD). The company reported previous data showing strong anti-leukemic effects and overall good tolerability at the American Society of Hematology (ASH) meeting in December 2015 (see my analysis). Updated data confirms the excellent safety and efficacy reported at ASH in December 2015 and highlights a key finding on a predictive response.

A total of 18 patients were enrolled in the Phase 1 trial. The median age was 77 years old (range: 68-87) and all patients had intermediate or higher risk. One-third had unfavorable cytogenetics. Despite a significantly challenging patient population to treat, the results were quite impressive. Complete response (CR) or complete response with partial hematologic recovery (CRp) incomplete marrow recovery (CRi) was observed in 28% of patients. However, when doses were escalated to greater than 1.5 μCi/kg, the CR/CRp/CRi rate increased to 33% (n=15).

Investigators observed no early mortality (before day 28) from Actimab-A treatment and there were only two hematological DLTs. There were no extramedullary DLTs and the MTD was not reached. Serious adverse events (SAEs) were in-line with expectations for this challenged patient population and investigators observed no discernible trends across all doses tested.

– An Interesting Trend Emerges

Upon review of the Phase 1 data, as well as the data from the three previous Phase 1 studies under the company’s HuM195 conjugated alpha particle program, which included two programs with older-generation Bismab-A, an interesting trend emerged. Although there seems to be no correlation between response to these drugs and things like age or cytogenetic factors, there is a strong correlation between response and peripheral blast count (PBc). In fact, all patients that demonstrated CR/CRp/CRi in the most recent Phase 1 study had low PBc at baseline.

When looking at only patients with low PBc on doses of Actimab-A of 2 x 2.0 μCi/Kg in the recent Phase 1 trial (n=4), the CR/CRp/CRi response rate was 50%. This is very encouraging! The CR/CRi data from the VYXEOS Phase 3 trial was 48%, and Celator Pharma got acquired by Jazz Pharma for $1.5 billion.

The reason why Actimab-A seems to work better in patients with low PBc can be explained by the fact that peripheral blasts act to soak-up or saturate lintuzumab prior to penetration into the bone marrow. These peripheral blasts congregate outside the bone marrow in spleen and liver, resulting in not enough drug making it into the target bone marrow. This phenomenon of peripheral consumption and CD33 saturation was observed with Mylotarg (gemtuzumab) in independent studies (9), validating this hypothesis.

The figure below shows the distribution of Actimab-A following the first dose, with an immediate build-up in the spleen and liver at Day 0, followed by penetration into the bone marrow days later. Again, this confirms the hypothesis on peripheral consumption and CD33 saturation is possible.

Actinium plans to open enrollment for the Phase 2 portion of the trial shortly. There are several important changes for the Phase 2 study that both increase the odds of success and speed the path to data. Firstly, the Phase 1 trial was conducted at five centers in the U.S.: Memorial Sloan Kettering, Fred Hutchinson, Johns Hopkins, Baylor Cancer Center, and the University of Pennsylvania. Actinium plans to double the number of centers for the Phase 2 portion. Also, since management has selected 2 x 2.0 μCi/kg as the proper dose for the Phase 2 study, there is no DSMB review after each dose escalation. Target enrollment of 47 patients can proceed at an uninterrupted pace.

However, two biggest changes for the upcoming Phase 2 study include the elimination of low-dose cytarabine (LDAC) as part of the treatment protocol and the use of hydroxyurea prior to infusion with Actimab-A to lower the peripheral blast count of test subjects. During the Phase 1 portion of the trial, the FDA mandated that Actinium co-administer LDAC as part of the treatment protocol, believing that it was unethical to enroll late-stage cancer patients without providing any standard of care. However, the majority of these patients has poor risk factors and unfavorable cytogenetics that made the use of LDAC unattractive to investigators. Now that Actimab-A has demonstrated efficacy in these patients, the required use of LDAC has been removed from the protocol. This was a major sticking point to enrollment during Phase 1 and should greatly enhance the attractiveness and speed of enrollment for Phase 2.

The use of hydroxyurea to reduce PBc prior to Actimab-A infusion is quite interesting. According to the Phase 1 data, 11 of the 18 patients had low PBc at baseline. That equates to 61%, a nice subset to target. However, hydroxyurea, a drug used quite commonly for the treatment of chronic myelogenous leukemia and other myeloproliferative diseases, is a first-line choice cytoreductive therapy (10). The drug has a good safety profile and is generally well-tolerated in leukemic patients. With the use of hydroxyurea, Actinium is hoping to both expand the pool of patients for the Phase 2 study and increase the odds of success by getting all patients to low peripheral blast burden prior to infusion with Actimab-A.

Patient enrollment is expected to begin shortly and the company is guiding to initial data at ASH in December 2016. On the company’s webinar in June 2016, Executive Chairman, Sandesh Seth, noted the Phase 2 trial would cost about $6 million and that the current cash balance was sufficient to fund operations for at least the next twelve months. Top-line data are expected during the second half of 2017. This is expected to be a major valuation inflection point for the company. Positive data, defined by a combined complete response rate above 50%, likely allows Actinium to move into a pivotol Phase 3 trial with Actimab-A late 2017 / early 2018.