Azedra is being developed as a treatment for pheochromocytoma/paraganglioma in adults and neuroblastoma in children. Pheochromocytomas are rare tumors that are usually found within one or both adrenal glands, but may arise in other extra-adrenal sites. Some of these tumors are found to be malignant at the time or immediately after the primary tumor is discovered, others are found to have malignant or recurrent disease at a much later stage. Although the five-year survival rate is less than 50%, the prognosis is variable; approximately 50% may have an indolent form of the disease while the other 50% of patients have rapidly progressive disease and die within one to three years after diagnosis. For malignant pheochromocytoma, radiation therapy may offer short-term symptomatic relief but does not cure the patient. Chemotherapy trials have failed to produce cures or significant remissions.
Neuroblastoma is a neuroendocrine malignancy affecting children. It develops in approximately 1 per 7,000 live births, is the most common extra-cranial solid tumor in children, and is extremely rare beyond childhood. The median age at diagnosis is 22 months and most cases are diagnosed prior to four years of age. Neuroblastoma originates in the nervous system. About two-thirds of cases arise in the abdomen (near the adrenal glands). Most patients have metastases at diagnosis, with metastatic sites including lymph nodes, bone, bone marrow, liver, and skin. Treatment of high-risk neuroblastoma includes surgery, chemotherapy, and radiation; however, there are no standard therapies for high-risk patients if they relapse or fail to respond to such treatment.
Azedra is Molecular Insight’s lead molecular radiotherapeutic product candidate under development for the systemic treatment of metastatic neuroendocrine cancers such as pheochromocytoma and neuroblastoma. Azedra consists of the iobenguane molecule radiolabeled with iodine-131 using the Company’s Ultratrace technology platform. Ultratrace is Molecular Insight’s proprietary solid-phase chemistry technique that avoids large quantities of cold (non-radioactive) iobenguane being included in the final formulation of the product. The lack of cold iobenguane provides two significant benefits: greater tumor uptake and reduced pharmacological toxicity or side effects, such as hypertension, nausea or vomiting, during the infusion.
Azedra’s anti-cancer activity is due to its ability to selectively deliver lethal radiation to cancer cells. After an intravenous injection, Azedra circulates throughout the body and selectively localizes in distant metastatic tumors because of its ability to bind to the norepinephrine transporter. The lack of cold contaminants (cold iobenguane) results in enhanced tumor uptake of Azedra. In vivo imaging and therapy studies in rodents confirm that tumor uptake of Azedra is at least twice as high and tumor kill is dramatically enhanced.
Diagram: Ultratrace Removes Unnecessary Cold Contaminants to Deliver Uniquely Ultrapure Radiotherapeutics
The Market Opportunity
Neuroendocrine tumors originate from cells that play a role in both the endocrine and nervous systems. They can occur anywhere in body, including the head and neck, adrenal gland, intestinal tract and in the spinal ganglia that support the peripheral nervous system. Approximately 80,000 people are diagnosed with neuroendorcine tumors.
Diagram: Azedra Dramatically Improved Tumor Kill. At each dose level, Azedra outperforms 1-131 MIBG in a pre-clinical study conducted in xenograft mice.
Clinical Development Plan
Pheochromocytoma
Two trials in adult patients have been completed. The first was a Phase 1 study (IB-11) of the pharmacokinetics and safety of Azedra in 11 patients. The aim of this study was to determine the metabolism, excretion, and radiation dosimetry in patients with pheochromocytoma and carcinoid tumors. The data from this study was used to plan the initial therapeutic evaluation of Azedra. The second trial (IB-12) was a Phase 1/2 study to determine the maximal tolerated dose of Azedra in patients with pheochromocytoma. This study provided data on safety and toxicity of Azedra as well as preliminary data on efficacy. The IB-12 study also established the dose the Company would use in its planned pivotal efficacy study. The preliminary results of the IB-12 study were presented at both American Society of Clinical Oncology and Society of Nuclear Medicine national meetings in 2008.
In 2009, Molecular Insight received a Special Protocol Assessment (SPA) letter stating that the U.S. Food and Drug Administration (FDA) has reached agreement with the Company regarding the design of the pivotal Phase 2 trial for registration of Azedra. (In 2006, Azedra was granted Fast Track designation and Orphan Drug status by FDA).
Molecular Insight's pivotal Phase 2 trial for Azedra (IB-12B) will be a single-arm clinical trial conducted in 58 adults (evaluable) with pheochromocytoma with an expected enrollment of about 75, The primary endpoint of the study will be clinical benefit as measured by at least a 50% reduction of the patients' anti-hypertension medications. Secondary endpoints include measurement of complete elimination or regression of tumors and improvement in quality of life, especially as a result of pain reduction. This trial has begun at centers in North America and ultimately will include sites in Western Europe.
Neuroblastoma
Molecular Insight has begun a Phase 2a study (IB-13) in approximately 12 to 15 patients. This trial is designed to define maximum tolerated dose and provide data on safety and toxicity, as well as efficacy. The Company has begun planning a Phase 2b pivotal efficacy study (IB-N-201). The primary endpoints for that study are tumor response. Biomarker response and progression-free survival (PFS) are secondary endpoints.