- 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 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.
- 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.
Below is a detailed review of the Phase 1 results and key findings from Actinium's analysis of the data. Initiation of the Phase 2 trial represents yet another major catalyst for the shares. Interest in acute myeloid leukemia (AML) is high given Jazz Pharma's acquisition of Celator for $1.5 billion yesterday. Actinium, with two high-value AML candidates under development in Actimab-A and Iomab-B, looks very well-positioned.
Review Of Phase 1 Results
During the webinar, Dr. Joseph Jurcic, Director of Hematologic Malignancies and Professor of Clinical Medicine at Columbia University Medical Center and Study Chair reviewed the data from Phase 1. As a reminder, Phase 1 study (NCT01756677) is examining 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™ (cytarabine + daunorubicin liposome injection), 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). The data just presented 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 2.0 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 (CPXX) just got acquired by Jazz Pharma (JAZZ) for $1.5 billion, a return of 1700% on the stock since mid-March 2016.
A Mechanism for Action
Actinium and investigators in the Phase 1 trial explained these findings on the company's webinar, stating that a high peripheral blast burden may 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 (1), validating the company's 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.
Important Changes For Phase 2
Actinium plans to open enrollment for the Phase 2 portion of the trial in the coming months. 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 2.0 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 (LDC) 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 LDC 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 LDC unattractive to investigators. Now that Actimab-A has demonstrated efficacy in these patients, the required use of LDC 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 (2). 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 in the next few months and the company is guiding to initial data at ASH in December 2016. On the company's webinar, 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.
I've written pretty extensively on Actinium Pharma over the past few months. I think the recent success of Celator's VYXEOS™ is a big positive for Actinium's Phase 3 candidate, Iomab-B (read why here) and with similar response rates for Actimab-A, we could be looking at a similar re-valuation for the company in the next year. Mr. Seth confirmed that the Phase 3 SIERRA study with Iomab-B will start enrolling patients shortly. I think this starts the process of unlocking significant value in the shares and with Actimab-A now moving forward in a targeted, high-probability of success Phase 2 study, Actinium shares look very attractive at this level.
ATNM - Phase 3 For Iomab-B Should Unlock Significant Value At Actinium Pharma (LINK).
IMNP - Immune Presents Biomarker Data On Ceplene at AACR (LINK).
This article was written by Jason Napodano, CFA of BioNap, Inc.
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