One Company's Mission to Save an Essential Radioimmunotherapy Treatment

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Unintended side effects often lead to transformational medical breakthroughs. The focus on negative symptoms, however, can blind people to potentially positive aspects of these side effects.

In 1919, a physician and captain in the US Army noticed that the prognosis of people exposed to mustard gas was dependent on how badly the poison had depleted their bone marrow and white blood cells. White blood cell depletion is a very dangerous situation.

Dangerous, that is, unless you have leukemia. If you have leukemia, your bone marrow produces immature white blood cells that neither mature nor die – they just replicate and overrun your body. Surviving leukemia requires a means of killing these immature white blood cells.

It took many years, but eventually scientists turned a chemical warfare agent into a positive treatment for people with blood cancers by making Mustargen from mustard gas. The chemotherapy era was born.

Sinking Ships

In 2002, the US FDA approved the radioimmunotherapy (RIT) treatment Zevalin for certain non-Hodgkin's lymphoma patients. The RIT Bexxar was approved a year later for similar indications. Both treatments were supported by very convincing efficacy data. But, there were downsides: RIT seriously depletes a patient's infection-fighting white blood cells. It does the same to red blood cells and platelets.

photo Also, RIT is administered in a hospital's nuclear medicine department. Many of the patients who would have benefited from RIT never received it because their doctors did not want to refer a patient out of their own care. Retaining patients and administering treatment in their own facilities appeals to a doctors' financial interest.

In 2012, just 75 patients received Bexxar. Despite widespread agreement that it worked, it was pulled from the market in February 2014. Zevalin has been passed from company to company like an infection. One could argue its days are numbered, too.  photo bexxar_logo2_zpsaf43833e.gif

Virtually every expert in the field will confirm the therapeutic benefits of RIT. It seems imperative that it be saved. Doctors show no interest in saving it. Pharmaceutical shareholders won't save it because doctors won't save it and it therefore won't generate any revenue. New marketing plans have repeatedly failed.

If a company were to save RIT, it would need to address two downsides: it would need to find a way to turn side effects from a liability to an opportunity, and it would have to find a way around those reluctant doctors who are concerned with their bottom line. From this perspective, saving RIT seems futile.

Saving RIT: Actinium Pharma and Iomab-B

Established in 2007, Actinium Pharmaceuticals specializes in cancer treatments. They and their collaborators are saving RIT from the dustbin of medical history by addressing the aforementioned downsides. How?

They have taken RIT's propensity for blood cell depletion and turned it from an unwanted side effect into a beneficial treatment target by applying RIT as a pre-bone marrow transplant therapy; the goal of the therapy is to deplete existing blood cells in the bone marrow.

Furthermore, they have found a way around reluctant physicians by incorporating RIT into the bone marrow transplant procedure. If a patient is undergoing a bone marrow transplant, they are already at a hospital and are being cared for by a multi-disciplinary team (oncologists, radiologists etc.) The nuclear medicine facility capable of administering RIT is already on-site.

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Actinium is nearing end-stage development of Iomab-B as a salvage therapy prior to a bone marrow transplantation. Iomab-B combines an anti-CD45 monoclonal antibody, Iomab, with the beta emitting radioisotope iodine 131 (I-131). In other words, it is radioimmunotherapy like Bexxar or Zevalin, except its antibody targets a different protein (CD45) on the cell surface than either Bexxar or Zevalin (CD20). Like Bexxar, Iomab-B uses iodine 131. Zevalin uses Yttrium-90.

However, Iomab-B is not a therapeutic regimen used to treat a patient with blood cancer. Creating another RIT simply so it could compete with one sunken ship and another sinking ship would make no sense.

The following is a brief look at what is involved in Iomab-B and how it can help people with otherwise untreatable blood disorders.

Bone Marrow Transplants

Bone marrow transplant and blood stem cell transplant are essentially the same thing: they are hematopoietic stem cell transplantations. In this procedure, a patient's immune system via their bone marrow is deliberately destroyed. Cells that can reconstitute healthy bone marrow function are then transplanted into the patient.

Worldwide, some 60,000 bone marrow transplants (BMT) were performed in 2010. According to Dr. John Pagel, MD, Ph.D of Fred Hutchinson Cancer Research Center, BMT is the fastest growing hospital procedure in the United States.

Undergoing a bone marrow transplant is similar to other organ transplants in many ways but very unlike them in one crucial way: receiving a kidney, or a heart, requires major surgery. Receiving bone marrow does not. By comparison the procedure is simple. Make no mistake though, BMTs are harsh endurance tests for patients and can be replete with life-threatening complications.

Furthermore, the history of BMT is not a smooth one. Pioneered in 1972, the procedure has proven to be an effective cure for many people with blood cancers and blood disorders. It may even offer hope for people who carry the HIV virus. But it has failed other patients. Notably, in the 1990s BMTs were hyped as breast cancer cures. This turned out to be wrong.

Salvage Therapy

Salvage therapy is the term given to the treatments a patient receives that prepare him or her for a bone marrow transplant. Currently this consists of radiation and high-dose chemotherapy with myeoablative intent (meaning the intent is to completely destroy the patient's existing immune system). It is called 'salvage' therapy because after you deliver it, the salvage operation to save the patient begins.

Actinium president and CEO Kaushik J. Dave pointed out to me the absence of any consensus among the medical community regarding which salvage chemotherapy regimen is the most effective, and in fact looking at the National Comprehensive Cancer Network's guidelines for treating adults with acute myeloid leukemia (AML) bears this out:

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This is in fact true across most if not all cancer subtypes. The choice of regimen typically comes down to one that is familiar to a patient's doctor, and one that is best suited for the patient. Evidence that supports the efficacy of an individual regimen comes in the form of peer-reviewed reports in medical journals.

While it may very well be that there is no one-size-fits-all salvage therapy, what is true is that there are currently no agents specifically approved by the FDA for salvage therapy. Iomab-B would be the first.

Radioimmunotherapy in a Nutshell

Imagine a commando rappelling down the side of a building. He stops at a specific window and cuts a hole in the glass. He throws his backpack through the hole and then drops to the street below. As he disappears into the night, his backpack explodes; the building, destroyed.

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Developing monoclonal antibodies [NCI / Linda Bartlett]

Conceptually speaking, that's how radioimmunotherapy works. An antibody (i.e. drug) is genetically engineered to seek out and attach itself to cells with a specific protein found on their surfaces. The antibody carries a tiny dose of radiation with it, and when it finds the right cells, it zaps them with radiation.

This type of therapy—brought to fruition in Bexxar and Zevalin—works by marrying the concept of targeted treatment with today's most potent cancer killer: alpha emitting radioisotopes.

Leukemia and Acute Myeloid Leukemia (AML)

We think of leukemia mostly as a cancer common in children. In fact, leukemia is the most commonly diagnosed childhood cancer. But the overwhelming majority of new diagnoses of leukemia occur in adults.

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Acute myeloid leukemia [NCI / Dr. Lance Liotta Laboratory]

Leukemia by the Numbers, from both the National Cancer Institute and the American Cancer Society

52,380
New cases of leukemia diagnosed annually in the United States (ten percent are under age 20)

24,090
Annual deaths from leukemia

66
Median age at diagnosis of leukemia

57.2
Five year survival rate of leukemia

18,860
New cases of AML (of all ages), or about 36 percent of all leukemia diagnoses

10,460
Annual deaths from AML, or about 43 percent of all deaths from leukemia.

The Near Future of Iomab-B

The principles behind Actinium know that the way to the heart of Dr. Richard Pazdur, Director of the Office of Oncology Drug Products at the FDA, is through meeting an unmet need, as opposed to treatments that might be improvements on existing treatments.

Iomab-B meets an unmet need. Specifically, patients over 55 with AML. These patients are almost never considered candidates for a bone marrow transplant, even when a BMT is the only remaining option, because the toxicity of salvage chemotherapy and radiation is simply too much for this population to bear. Yet, there are no other treatment options.

So Actinium is seeking market approval for Iomab-B as a salvage therapy, or bone marrow conditioning, prior to bone marrow transplant, in elderly patients with relapsed or refractory acute myeloid leukemia. Iomab-B has been administered to some 250 patients in Phase I and Phase II trials, which show that Iomab-B can successfully prepare these otherwise hopeless patients for a transplant.

In fact, it has shown a significant 1-year and 2-year survival benefit over currently available treatments. Specifically, as things are now the 2-year survival rate for this patient population is zero; with Iomab-B, it is 19 percent.

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They have met with the FDA and the Phase III trial design and primary endpoints have been established. This pivotal trial will recruit 150 patients and randomize them to receive physician's choice of existing salvage regimens, or Iomab-B.

Both Dave and Dragan Cicic, Actinium's COO and Chief Medical Officer, say they believe that Iomab-B can fundamentally improve the bone marrow transplant by replacing current salvage therapies with RIT, and that this is possible not just in elderly patients with AML, but also, down the road, across several indications, including Hodgkin's lymphoma, non-Hodgkin's lymphoma, and perhaps myeloma.

Current salvage chemotherapy regimens are so brutal that they exclude patients who might otherwise benefit from a bone marrow transplant. If Iomab-B can successfully remove this exclusionary aspect, and do it by turning up the downsides of a fast-fading but effective therapy, it will truly be transformational.

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