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Thursday, January 7, 2016

Actinium's Place Among The CAR-T Hype and Radiopharma Busts

Shares of Actinium Pharmaceuticals (ATNM) have moved significantly higher over the past month as investors are starting to come to grips with the potential for the company's two pipeline products, Iomab-B and Actimab-A, both under investigation for the treatment of acute myeloid leukemia (AML). Iomab-B and Actimab-A are specific anti-cancer monoclonal antibodies (mAb) conjugated to alpha emitting radioisotopes. Both product candidates are based on patented technology co-developed with Memorial Sloan Kettering Cancer Center (MSKCC) for combining the targeted precision of monoclonal antibodies (mAb) and a proprietary alpha particle immunotherapy (APIT) platform. It was just recently announced that MSKCC owns 5.7 million shares of Actinium stock, approximately 13.6% of the basic shares outstanding.

Actinium has been cleared by the U.S. FDA to proceed with a Phase 3 pivotal clinical trial with Iomab-B, a myeloconditioning/myeloablative agent for refractory/relapsing AML patients ahead of hematopoietic stem cell transplantation (HSCT). Beyond r/r AML, Iomab-B has potential in a number of other hematological malignancies, including Myelodysplastic Syndrome (MDS), Acute Lymphoblastic Leukemia (ALL), Hodgkin’s Disease, and Non-Hodgkin Lymphoma (NHL). Some of these indications are the core focus for companies developing chimeric antigen receptor modified T cell (CAR-T) therapies. For the purposes of this article, I will discuss how Actinium's pipeline fits in within an investor and investigator community so acutely interested in CAR-T, and how the company's radio-pharma platform improves over first-generation radio-pharma drugs that were largely commercial failures.

Brief Background

Investor excitement over CAR-T stocks exploded in 2015. Juno Therapeutics (JUNO), what many argue as the best pure-play CAR-T biopharmaceutical company, went public in late 2014 and saw its market capitalization soar to $6.8 billion by late spring 2015. Kite Pharma Inc. (KITE), another major player in chimeric antigen receptor and T cell receptor (TCR) technology, boasted a market cap of $3.8 billion in November 2015 before the recent market sell-off. In contrast, Actinium's market cap is only $120 million, and investors are constantly asking me, "Where does Actinium fit in among all the enthusiasm for CAR-T?"

In short, CAR-T is the process of retraining the body's own immune system to find and attack cancerous cells. T-lymphocytes (T cells), which play a central role in the body's adaptive immune system, are genetically engineered (transfected) through the use of a virus to express a receptor for certain antigens, such as CD19 or CD20, found on both healthy and malignant B cells. Once returned to the patient, these engineered T cells actively find and kill B cells, malignant or healthy, in an effort to eliminate leukemia or lymphoma from the body. 

CAR-T - Encouraging Data, But Not Without Challenges

Initial results with CAR-T cells have been very encouraging. For example, Juno Therapeutics just recently presented data from mid-stage clinical studies with JCAR014, a CD19-specific CAR T cell, in patients with NHL and CLL demonstrating impressive response rates in a relapsed/refractory population. Juno is also seeing initial signs of success with JCAR014 and JCAR015 in patients with r/r Acute Lymphoblastic Leukemia (ALL). 

However, investors need to keep in mind, CAR-T is an aggressive therapy and not ideally suited for all patients. There are clearly challenges, and the U.S. FDA has expressed concern over the potential adverse events associated with CAR-T. Independent work shows CAR-T is associated with significant potential risk; thus, current investigational use is limited to the relapsed/refractory population.

I do not want to come across as someone bearish on CAR-T. I think these therapies hold significant promise for B cell leukemia and lymphoma patients with limited options. However, I do believe there are significant challenges ahead for these investigational products, including potential manufacturing and logistical issues. The valuation for stocks like JUNO and KITE is grounds for a separate article, but for a bearish take, investors can read an article on Seeking-Alpha written by someone called "Intrepid Investor" (link). 

Not All Leukemias Are The Same

I think the most important thing that investors need to understand with respect to CAR-T and how it competes with drugs like Iomab-B and Actimab-A is that, as of right now, these two strategies are fairly distinctive. CD19 expression is restricted to B cells and possible follicular dendritic cells, and antibodies against CD19 inhibit the growth of tumor cells. CD19 is expressed on the surface of most B cell malignancies; however, it is not expressed on pluripotent hematopoietic stem cells (HSCs).

 

This is important because HSCs give rise to common myeloid or common lymphoid progenitor cells that go on to form the specialized cells found in human blood, including monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, dendritic cells, megakaryocytes, platelets, granular lymphocytes, T lymphocytes, and B lymphocytes.


Malignancies that occur in immature myeloid progenitor cells are called Acute Myeloid Leukemias (AML), whereas malignancies that occur in immature lymphoid progenitor cells are called Acute Lymphoblastic Leukemias (ALL). Acute leukemias are rapid growth (quick onset) diseases. Chronic Myeloid Leukemia (CML) and Chronic Lymphoblastic Leukemia (CLL) are cancers that occur later in the maturation and differentiation process and tend to be slower growing diseases.

To date, the success of CAR-T has been mainly associated with malignancies developing from lymphoid cell lineage based on targeting CD19, CD20, or CD22. To date, CAR-T has "struggled to travel beyond" ALL. While the potential for targeting antigens specific to myeloid cell lineage or even antigens found on solid tumors certainly exists, there are specific issues that must be overcome when targeting malignancies of myeloid progenitor cells that are navigable when targeting lymphoid progenitor cells. To understand the primary difference, one must have a grasp of the differences between the innate and adaptive immune system.

CAR-T & Your Immune System

The innate immune system comprises the cells and mechanisms that defend the host from infection by other organisms. The cells of the innate system recognize and respond to pathogens in a generic way; but, unlike the adaptive immune system (which is found only in vertebrates), it does not confer long-lasting or protective immunity to the host. The innate immune system is made up of specialized chemical mediators called cytokines and mechanisms called complement cascades, but the backbone of the entire process are the granulocytes (eosinophils, basophils, and neutrophils) that make up the bulk of the white blood cells found in the body. These cells, which stem from myeloid progenitor cells, provide immediate defense against infection. 

The adaptive immune system is the body's immunological memory and consists of T and B lymphocytes that play a role in humoral immune response and cell-mediated immune response. In the simplest terms, you are born with your innate immune system while you develop your adaptive immune system over time.

The process of administering engineered CAR-T cells leads to the body actively killing all B cells, healthy and malignant, in an effort to wipe out the underlying B cell cancers (ALL, CLL, or NHL). This effectively destroys a major component of the adaptive immune system, which physicians often navigate by administering intravenous immunoglobulin (IVIg). With CAR-T, the innate immune system is left unharmed because the targeted antigens are not found on cells of myeloid lineage. 

The major issue with developing CAR-T for malignancies of myeloid progenitor cells is that the innate immune system would be destroyed, leading to profound neutropenia and dire health consequences even if the AML is eradicated because the patient would have virtually no ability to defend against even the simplest invading pathogen. The only logical path for CAR-T in AML is to target antigens overexpressed only on myeloid malignancies compared with normal cells or unique to the malignant myeloid clone. Several such antigens have been identified, but the vast majority are internal proteins that are processed and then presented as peptides by the cells’ human leukocyte antigens (Doubrovinza E, et al, 2012). Such peptides can usually be recognized only by the native T-cell receptor, not by an antibody-derived CAR (Brenner, 2015).

If CAR-T products are successfully developed to target antigens on myeloid progenitor cells, healthy or malignant, follow-on therapy of complete myeloablation and hematopoietic stem cell transplant (HSCT) would then be necessary to eliminate the CAR-T cells and "reset" the immune system back to normal. This brings the patient full circle back to drugs like Iomab-B or Actimab-A, which seek to accomplish the same process, without the CAR-T step.

Iomab-B & Actimab-A

So as investors can see, there are major hurdles to CAR-T therapy for the treatment of AML or CML. At the Friday Satellite Symposium at the 57th annual meeting of the American Society of Hematology (ASH) meeting last month, leading AML researchers discussed the current and future emerging therapeutics to treat AML. CAR-T was only briefly mentioned whereas drugs like Actimab-A attracted significantly more discussion. In short, CAR-T is not really the competition for Actinium. In fact, at this stage, there is very little competition for Actinium because r/r AML patients have no options beyond standard cytarabine + daunorubicin/idarubicin "7+3" chemotherapy. 

Actinium's Iomab-B, invented by researchers at the Fred Hutchinson Cancer Research Center (FHCRC), is a combination monoclonal antibody that targets a lymphocyte common antigen, CD45, and radioactive iodine-131. CD45 plays a crucial role in the function of hematopoietic cell activation and differentiation. By specifically targeting CD45, a cell surface antigen widely expressed on hematopoietic (myeloid and lymphoid) cells, but not other tissues, Iomab-B can effectively offer target-specific ablation as a conditioning regimen prior to bone marrow transplantation (BMT) with the potential for improved efficacy and safety/tolerability. And, because CD45 is expressed on both normal and leukemic cells, it can be used to target marrow in both remission and relapsed patients.

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. These elderly patients fall into the "poor risk" category where salvage chemotherapy offers response rates below 20% and long-term survival rates below 10% (Mangan J., et al., 2011). Many are simply placed on palliative care.

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.

Actinium Pharma - Radiopharma 2.0

The second most common question investors tend to ask about Actinium after the "CAR-T competition" one is, "Given the failures of two high-profile radiopharma drugs in the past, is the company headed down the same doomed path?" The answer to this question is, I don't think so...

In June 2003, GlaxoSmithKline gained approval for Bexxar®, a combination of the murine IgG anti-CD20 monoclonal antibody tositumomab conjugated to radioactive Iodine-131. Recall from above, CD20 is an antigen found on the surface of both healthy and malignant B cells. Bexxar® was initially approved for treatment of rituximab-refractory, low-grade NHL. The label was expanded eighteen months later to include relapsed/refractory follicular lymphoma. 

There were several reasons why Bexxar® failed. Firstly, the drug had to be administered by a nuclear medicine physician. This meant that practicing oncologists could not administer the drug at their local infusion center along with chemotherapy. Instead, patients had to be referred to nuclear medicine pharmacy or a radiation oncologist who could handle the drug. This meant lost revenues and patient follow-up by the original treating oncologist. Oncologists do not like to lose patients because patients pay bills. And speaking of bills, Bexxar® was rather expensive at the time and many hospitals were finding push-back from Medicare on the price. Lack of enthusiasm for treating physicians or the hospitals they sometimes begrudgingly referred patients to played a major role in the slow uptake of the drug, as did logistical and manufacturing issues. 

However, the end game for Bexxar® came in 2011 when the drug failed to demonstrate a clinical benefit over CHOP chemotherapy plus Rituxan® (rituximab) in patients with newly diagnosed follicular NHL. Oncologists no longer had any motivation to send their patients off to the nuclear medicine facility, exposing them to additional side effects, given this new data that showed adding Bexxar® offered no benefit to what the oncologist could accomplish with CHOP+R in house.

Another failed radiopharma drug, Zevalin®, a combination of the murine IgG anti-CD20 monoclonal antibody ibritumomab conjugated to radioactive Yttrium-90, is traveling a similar path. Zevalin® has been bounced around over the past decade, from Biogen to Cell Therapeutics, to currently at Spectrum Pharmaceutical. The drug is used in combination with rituximab in patients with both newly diagnosed and low-grade or follicular relapsed B cell NHL. The issues that keep Zevalin® at minuscule sales levels ($4.8 million in the third quarter ending September 30, 2015) are the same issues that slowed uptake of Bexxar®.

I do not see the issues that held back Bexxar® and that continue to plague Zevalin® as relevant to Actinium's Iomab-B. Iomab-B is a myeloconditioning/myeloablative agent for patients preparing to undergo hematopoietic stem cell transplant (HSCT). These are not patients that can be treated with alternative measures by the oncologist at an infusion center. These are patients already referred for reduced intensive conditioning, which includes total body irradiation (TBI) and potentially the use of busulfan, cyclophosphamide, and/or fludarabine. Iomab-B is designed to be a safer alternative to TBI+FLU/BU/CY in elderly patients that simply cannot handle standard myeloablation, but still strong enough to wipe-out all leukemia cells and prevent graft-vs-host-disease.

Actinium management is keenly aware of the issues with Bexxar® and Zevalin® and has made changes to the development plan for Actimab-A to improve the market potential for the drug. For example, Actinium-225 has a half-life of approximately 10 days. The longer half-life allows for centralized manufacturing and direct shipping of the product to the treating physician. It also offers improved costs of goods, which should yield a higher profit margin. The poor economics of Zevalin® is something none of the companies that sold or currently sell the product can figure out. And unlike both Bexxar® and Zevalin®, there is no direct competition in elderly r/r AML patients with poor cytogenetics. As noted above, these patients are often just put on palliative care. Actimab-A offers new hope for patients with currently no options on the table.

Conclusion

There is little doubt that CAR-T holds significant promise for the treatment of B cell malignancies, with a primary focus on ALL and NHL. Actinium is currently focusing on the treatment of AML, with an emphasis on relapsed/refractory patients with little to no options on the table. These are distinct diseases and the CAR-T players have major hurdles to overcome before aggressively targeting AML patients makes sense. As such, I do not see CAR-T limiting the market potential for Iomab-B at all. In fact, I think the drug could be a blockbuster once approved. My current forecast is for peak sales of $900 million in the U.S.

For Actimab-A, the recent Phase 1 data presented at ASH (see my analysis here) suggests a place for the drug in elderly patients with poor cytogenetics and limited options on the table. Additionally, management is keenly aware of the issues that hampered Bexxar® and Zevalin®, and I think the company's "Radiopharma 2.0" strategy makes sense. I peg the peak sales potential for Actimab-A at $250 million in the U.S. 

Related: Actinium Pharmaceuticals: An Impressive Platform Targeting Leukemia (LINK)

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  5. Jul. 7, 2016-- Juno Therapeutics, Inc. (NASDAQ:JUNO), a biopharmaceutical company focused on re-engaging the body’s immune system to revolutionize the treatment of cancer, today announced that it has received notice from the U.S. Food and Drug Administration (FDA) that a clinical hold has been placed on the Phase II clinical trial of JCAR015 in adult patients with relapsed or refractory B cell acute lymphoblastic leukemia (r/r ALL), known as the “ROCKET” trial. The clinical hold was initiated after two patient deaths last week, which followed the recent addition of fludarabine to the pre-conditioning regimen.

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