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Wednesday, December 9, 2015

Actinium Presents Strong Data on Actimab-A at Annual ASH Meeting

Actinium Pharmaceuticals (NYSEMKT: ATNM) had a very successful showing at the American Society of Hematology (ASH) annual meeting held over the past few days in Orlando, FL. The highlight of the event for the company was a poster presentation of Phase 1 clinical data with Actimab-A, the company's CD33 targeting alpha particle immunotherapy for the treatment of acute myeloid leukemia (AML). Below is a quick background on Actimab-A and a summary of the poster data presented at ASH.

Quick Background On Actimab-A

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. 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 (source).

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 (Hamann PR, et al., 2001), 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FDA for the drug in 2000; however, safety concerns and lackluster post-approval trials ultimately led to the drug being withdrawn from the market in 2010 (source).

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.

Phase 1 Data At ASH

Actinium Pharma is currently in a multi-center Phase 1/2 clinical trial (NCT01756677) with 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 antecedent hematologic disorder, unfavorable cytogenetic or molecular abnormalities, and significant comorbidities that likely makes standard induction intolerable to these patients. The trial is being conducted at five centers in the U.S., Memorial Sloan Kettering, Fred Hutchinson, Johns Hopkins, Baylor Cancer Center, and the University of Pennsylvania.

The goal of the Phase 1 part of this study is to find the highest tolerable dose of Actimab-A that can be given with cytarabine, a commonly used anti-cancer drug, to patients with AML. At ASH, Actinium presented data from fourteen patients treated to date (median age: 77 years). Actimab-A was given at 0.5 (n=3), 1 (n=6), 1.5 (n=3), or 2 (n=2) μCi/kg/fraction. Up to four cycles of low-dose cytarabine were administered. Dose-limiting toxicities were seen in one patient at 1 µCi/kg/fraction who had grade 4 thrombocytopenia with marrow aplasia for more than 6 weeks following therapy. Hematologic toxicities included grade 4 neutropenia (n=4) and thrombocytopenia (n=6). Grade 3/4 non-hematologic toxicities included febrile neutropenia (n=7), pneumonia (n=4), bacteremia (n=1), cellulitis (n=1), transient creatinine increase (n=1), hypokalemia (n=1), rectal hemorrhage (n=1), and generalized weakness (n=2).

Eight of 11 patients (73%) evaluated after one cycle had bone marrow blast reductions (mean reduction, 72%; range, 34-100%). Seven (64%) had blast reductions of at least 50%.

Objective responses (1 CR, 1 CRp, 2 CRi) were seen in four of the 14 patients (29%) after one cycle of therapy. Responses were seen only at doses ≥ 1 µCi/kg/fraction (4 of 11 patients, 36%). Median progression-free survival (PFS) was 2.7 months (range, 1.7-16.9 months). Median overall survival (OS) was 5.5 months (range, 2.2-24 months).


Data at ASH demonstrates the clear anti-leukemia effect of Actimab-A in elderly patients with AML not eligible for standard induction therapy. Based on previous and newly-presented data, Actimab-A is tolerable and effective at 1-2 μCi/kg/fraction, and can be safely combined with low-dose cytarabine to produce remission in older patients with untreated AML. The company is continuing with the dose escalation Phase 1 part of the study designed to define the maximum tolerated dose. Once complete, Actinium will enroll additional patients in the Phase 2 portion of the trial, which is designed to determine the response rate, progression-free survival, and overall survival in this difficult to treat population. The trial is designed to enroll a total of 72 patients in total.

I believe the target market for Actimab-A is meaningful. 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 overlapping toxicities with contaminant medications, existing co-morbidities, and/or physician expectations on the patient's ability to tolerate standard "7+3" induction. Complete remission to low-dose cytarabine is typically only seen in ~20%  of patients (Burnett AK, et al., 2007), and Phase 1 data presented at ASH looks superior to this standard.

In December 2014, Actimab-A was granted Orphan Drug status by the U.S. FDA (see release). 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 for Actimab-A is easily $750 million. With 33% market share, Actimab-A looks to have sales in the $250 million range.

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  1. ATNM has been running cohort 4 since March. The first patient was dosed in April. In 9 months ATNM managed to enroll only 1 more patient in cohort 4. Why?

    2. On July 29 ATNM claimed:
    "We are in the process of activating more centers to facilitate patient enrollment. Baylor’s Charles A. Sammons Cancer Center, one of the largest oncology centers in the nation, treating over 55,000 cancer patients every year, and other top US cancer centers including the Memorial Sloan Kettering Cancer Center, the MD Anderson Cancer Center, the Fred Hutchinson Cancer Research Center, Johns Hopkins Medicine and the University of Pennsylvania Health System are among the clinical trial sites that support the ongoing enrollment in our Phase 1/2 study."

    From these 6 trial sites with potentially 200-400000 cancer patients, ATNM could come up with only 2 AML patients for cohort 4? Why?

    1. Will have an answer for you shortly. I reached out to management but have not heard back from them.

    2. Thanks Jason. Also ask them this: Until last year ATNM did not have many enrollment sites for phase 1/2 study, and yet managed to complete cohorts 1,2,3 within a year or so. And now with 6+ largest oncology centers in the nation, ATNM is stuck on cohort 4, which should have been done and dusted by Q3. Why?

      Remind them that ATNM is not a private company. Making intentionally false statements/guidance under the cloak of forward looking statements is a corporate crime. By the way, on July 28 I was hours away from filing lawsuit against management for misleading guidances, when they requested me that if I can wait until July 29 they would issue a PR on the status on phase 1/2. Remind them that as well.

  2. Hi Jason, any info from ATNM management on cohort4 fiasco?

    1. I just emailed them again. I my thoughts on the subject but I'm waiting to hear if their official word is similar to what I'm thinking. Sorry it's taking so long, but I assure you I'm working on an answer.

    2. Cool. By the way, what are your thoughts on the Laidlaw - Relmada Therapeutics lawsuit? Do you see Laidlaw will try to takeover ATNM? Sandesh Seth is the chairman of both biotechs.

  3. So I took a hard look at the enrollment inclusion and exclusion criteria and I think I understand why the pace of enrollment in the P1 portion has been so slow.

    Firstly, patient that enroll in the trial must be "newly diagnosed" and "previously untreated" for AML. The most commonly used chemotherapy regimen for AML is cytarabine, given continuously for seven days through an intravenous line, and an anthracycline drug, such as daunorubicin or idarubicin, also given in a single IV dose for the first three days of treatment. This is sometimes known as the "7+3" regimen. The patients for this trial above must not have previously tried 7+3 or any radiation therapy for their AML.

    To qualify for ATNM's P1 trial, the doctor or physician must be "unwilling" to receive 7+3. In many elderly patients, which is the target market for Actimab-A, 7+3 is intolerable, mainly because drugs like daunorubicin or idarubicin are cardio-toxic and the majority of patients over the age of 60 tend to have some sort of underlying cardiovascular issue unrelated to the AML. So there is a market for Actimab-A, but if you look at the inclusion criteria it also says thing like:
    - poor risk-prognostic factors
    - have significant co-morbidities
    However, the patients must have adequate renal function and hepatic function. They also cannot have an infection, any other form of active cancer, psychiatric disorder (so that rules out anyone with Parkinson's or Alzheimer's), or significant cardiac disease.

    So it is a VERY narrow population for this P1 portion. For example, the ideal patient for Actimab-A - someone who is not willing to take 7+3 - will very likely have hepatic or renal decline and cardiovascular disease. Again, as note above, it is the cardiovascular disease that keeps more patients off daunorubicin or idarubicin.

    So the enrollment criteria is a little counter-intuitive. Actinium is looking for patients too sick to go on standard, but not sick enough that the Doc feels as though they cannot tolerate an investigational drug - especially in light of the fact that the Phase 1 portion is a dose-defining trial, with the primary goal of finding the maximum tolerated dose.

    So the longer the P1 trial goes on, the more likely that patients enrolled later in the Phase 1 portion will be receiving higher and higher doses, looking for that maximum tolerated dose, and Docs probably feel as though they are not going to guinea-pig their sick patients - that might fully qualify - given that the alternative is either just pushing 7+3 or risking potential treatment-related mortality.

    It's a catch-22, of sorts when you are doing a Phase 1 trial, looking for a maximum tolerated dose in a very defined, previously untreated patient population. That's why enrollment has slowed to a crawl. The maximum tolerated dose is likely 2 uCi and Docs are now waiting for the Phase 2 portion.

    I think enrollment picks up once the Phase 2 portion starts because the "guinea-pig" issue goes away, and now Docs can feel as though they have a real alternative to 7+3 with cytarabine and Actimab-A.

    That's my thinking.
    I have not confirmed this is management, but will continue to reach out to them and try to verify what I'm saying here. If they come up with an alternative, or I'm just completely off-base, I'll edit this post.

    Hope this is helpful!

    Thanks for reading and thank for your patience with my response.


  4. Good stuff. Hope the company contacts you as well. By the way, you say "Actinium is looking for patients too sick to go on standard, but not sick enough". Although I understand this was just a dose-finding phase, but will ATNM be able to enroll " really sick" patients in future phases? If so, would the efficacy signal likely get poorer than what we have currently? In the phase-1 cohorts 3-4, CR rate was quite low. Had the patients been sicker, the results would worsen? I am not an expert, but just wondering. Keep us posted.

    Off topic: AMBS CEO says Turing Pharma contacted them for MANF in June. It didn't pan out but sounds very promising for MANF. Let us know if you can get more details as regards what indication was discussed etc..