Prostate Cancer Landscape
Prostate cancer is a major public health problem affecting at least 2 million men in the United States and another 4 million in Europe. It is the second leading cause of cancer-related deaths among men in the United States behind lung cancer. The American Cancer Society estimates that in 2012 there will be over 241,000 new cases of prostate cancer diagnosed and more than 28,000 men will die from the disease. Globally, more than 900,000 new cases of prostate cancer were diagnosed in 2010 and more than 260,000 men died from the disease. According to the World Cancer Research Fund International it is predicted the number of new prostate cancer cases will almost double to 1.7 million by 2030.
Current diagnosis is typically through digital rectal exam and blood prostate specific antigen (PSA) testing. Since the introduction of serum PSA screening, prostate cancer incidence rates have increased dramatically as have the number of men being treated for the disease. However, elevated serum PSA levels do not always correlate with disease. An estimated 20% to 30% of men with prostate cancer have serum PSA levels within the reference range, resulting in false negatives; others have elevated serum PSA levels due to conditions other than prostate cancer (i.e., benign prostatic hyperplasia), resulting in false positives and unnecessary biopsies.
The management of the prostate cancer patient is challenging as there are numerous clinical factors and treatment options to consider in deciding on the optimal therapy for a given patient. Since men are living much longer with the disease due to early detection, clinical decision making will have long-term consequences. Accurately defining the extent of disease burden (amount and location) and aggressiveness of the disease at diagnosis and during disease progression are important factors in selecting the appropriate course of treatment. Rising PSA values in the setting of other non-definitive diagnostic information often occurs, causing patient management challenges or uncertainty. The ability to visualize the disease is increasingly important for informing therapeutic selection and treatment planning.
Visualizing the Disease
Monitoring metastatic prostate cancer disease progression and the success of interventions remains challenging. Current clinical imaging modalities commonly applied to the evaluation of patients with prostate cancer include: transrectal ultrasound (TRUS) for evaluating disease in the prostate and guiding biopsy of the prostate gland, computed tomography (CT) or magnetic resonance imaging (MRI) for evaluation of soft-tissue metastases and nuclear medicine bone scans for evaluation of metastatic spread to the skeleton. While each of these modalities has a role, these techniques have significant limitations due to the lack of specificity and, in some cases, sensitivity. TRUS is a standard imaging technique used primarily for biopsy guidance and brachytherapy seed placement. TRUS is unreliable in differentiating normal prostate gland from cancer tissue, resulting in biopsies not specifically targeted to areas most likely to be malignant. Cross-sectional imaging, such as CT or MRI, is used to evaluate the presence of soft-tissue metastases, particularly lymph node involvement. The presence of disease using cross-sectional imaging is based on size criteria. Such threshold criteria imply suspicion of an abnormal lymph node only, as the cellular make up of the lymph node cannot be determined using CT or MRI alone. As metastatic spread to lymph nodes is initially microscopic, the ability to detect early spread using cross sectional imaging is of little value. Bone scans are sensitive for bone metastasis but lack specificity, and changes in disease burden, especially regression, cannot be easily derived from bone scans due to the persistent metabolic activity of the bone in the case of inflammation and healing. In addition, previous bone injuries and arthritis are often detected on bone scans as false positives.
Imaging agents that will more accurately detect and stage prostate cancer, as well as monitor response to therapy, will enable improved disease management, resulting in improved patient outcome and reduced overall societal costs of the disease. A sensitive and specific means of imaging tumor burden throughout the body, in both soft tissue and bone, is the goal for Molecular Insight’s diagnostic product candidate 99mTc-trofolastat.
Treating the Disease
An estimated $2 billion is currently spent worldwide on surgical, radiation, drug therapy and minimally invasive treatments, with $1 billion of the spending in the United States alone. Definitive therapy (surgery or radiation) is highly effective, but if the tumor escapes the prostate gland, treatment options are limited. The current standard of care for the treatment of metastatic prostate cancer includes hormonal therapy followed by several chemotherapeutic agents. Relapse post androgen depravation therapy is inevitable and chemotherapeutic agents, such as docetaxel, have shown limited survival benefit. Recently, novel treatments including Abiraterone, Denosumab, MDV3100 and Alpharadin® have demonstrated efficacy of approximately 3-5 months prolongation of survival. Thus, patients continue to have a poor prognosis once they fail primary therapy and more effective treatments are still needed. 131I-MIP-1095 is Molecular Insight’s radiotherapeutic drug product currently under investigation for the treatment of metastatic prostate cancer.
Molecular Insight’s Approach
Molecular Insight’s approach to overcoming the limitations of current imaging modalities is to exploit specific disease-related molecular and biochemical changes at the cellular level that occur early in the disease process and as such present a means of detecting disease at the initial stage of its manifestation and throughout its progression, allowing for more rapid and effective intervention. Our radiopharmaceuticals that target prostate cancer specific molecular processes may make it is possible to visualize the presence of cancer with improved sensitivity and specificity.
Targeting by the radiopharmaceutical may be so significant and specific that a therapeutic radioactive element can be incorporated into the molecule to deliver radiation therapy precisely to the cancer wherever it may reside in the body. The selective accumulation of radiotherapeutic compounds in prostate cancer cells allows destruction of the tumor while sparing normal tissues of serious toxicity. Targeted radiotherapy for widespread disease permits a well understood, effective and successful therapy (radiation) to be used for the treatment of late-stage prostate cancer. Since the targeted radiotherapy is localized in the tumors and the mass of nonradioactive compound is very low, side effects may be less severe than conventional chemotherapy. In addition, this approach is pathway independent and as such may be complementary to and combined with other therapeutic approaches.
The Science of the Target
Prostate-specific membrane antigen (PSMA), also known as folate hydrolase I or glutamate carboxypeptidase II, is a member of a family of zinc-dependent exopeptidases. It is primarily expressed at low levels in normal human prostate epithelium, brain, kidney proximal tubules, and intestinal brush border membranes. Importantly, its expression is highly amplified in >95% of prostate cancer, including metastatic disease. A correlation of PSMA expression with PSA level, tumor stage, disease recurrence, and time to progression has been demonstrated. While the function of PSMA in prostate cancer is unclear, research has demonstrated a role in tumor invasiveness. Since PSMA is expressed by virtually all prostate cancers and its expression is further increased in poorly differentiated, metastatic and hormone-refractory carcinomas, it is a very attractive target for the development of radiopharmaceuticals for prostate cancer imaging and therapy.
PSMA was originally identified as the ligand of the monoclonal antibody 7E11-C5. The 111In-radiolabeled 7E11-C5, marketed as ProstaScint™ (Capromab Pendetide), has been approved by the FDA to diagnose prostate cancer metastasis and recurrence in newly-diagnosed patients with biopsy-proven prostate cancer that is thought to be clinically localized after standard diagnostic evaluation that are at high-risk for pelvic lymph node metastases. However, the intracellular ProstaScint targets the domain of PSMA and is not in widespread use because it detects mostly necrotic regions of prostate tumors and not viable cells. More recently, radiolabeled monoclonal antibodies have been developed that bind to the extracellular domain of PSMA. Radiolabeled antibodies must be administered several days prior to imaging.
While radiolabeled antibodies have validated PSMA as a molecular target for prostate cancer, radiolabeled antibodies in general have met with limited clinical success outside of lymphoma because of their long circulating plasma half-lives and low permeability in solid tumors, particularly in metastases to the bone. Lower molecular weight small molecules, with higher permeability in solid tumors, will likely have an advantage. In addition, small molecules will likely display improved pharmacokinetics in normal tissues as compared with intact immunoglobulins, making lesion detection more conspicuous.
Molecular Insight’s Compounds for the Detection and Treatment of Prostate Cancer
Molecular Insight is currently developing two small molecule inhibitors of PSMA: 99mTc-trofolastat is a 99mTc-labeled compound for imaging prostate cancer by SPECT (gamma camera), and MIP-1095 is a 131I-labeled compound for the treatment of metastatic prostate cancer.
In patients with metastatic prostate cancer, 99mTc-trofolastat, administered by intraveneous infusion, rapidly localizes to lesions in lymph nodes and bone on whole-body imaging as early as 1 hour post injection with the following results: SPECT/CT images demonstrate excellent lesion contrast target-to-background ratios; enlarged and sub-centimeter lymph nodes are clearly visualized as is the diseased prostate gland; good correlation is seen with bone scans in most subjects although, in general, more lesions are visualized with 99mTc-trofolastat than with bone scan.
An Investigational New Drug application for 99mTc-trofolastat was allowed in the second quarter of 2012. The Company initiated a multi-center international Phase 2 clinical trial in high risk prostate cancer patients undergoing prostatectomy in the third quarter 2012.
131I-MIP-1095 is also administered by intravenous infusion, circulates throughout the body, and binds to the extracellular domain of prostate specific membrane antigen (PSMA) and is subsequently internalized by the prostate cancer cells. In pre-clinical tumor models, 131I-MIP-1095 is retained within the prostate cancer cell, allowing the intense energy emitted by iodine-131 to be absorbed in the tumor cells causing targeted cell death of prostate cancer. The ability to specifically deliver radiation to prostate cancer cells anywhere in the body is a desirable advance, allowing this commonly used therapy of radiation to be applied to systemic disease.
Preclinical data on 131I-MIP-1095 have shown high tumor uptake and a favorable tumor-to-kidney discrimination yielding a lethal radiation dose to the tumor while minimizing normal tissue dose. In human prostate cancer mouse models, 131I-MIP-1095, administered in single or multiple dose schedules, significantly reduced tumor burden for a prolonged period of time and enhanced survival with no significant signs of toxicity.
Molecular Insight expects to file an Investigational New Drug application for 131I-MIP-1095 by the end of 2012. The Company also plans to initiate a clinical study in 2013 to determine the maximum tolerated dose and define dose limiting toxicities, and to examine the pharmacokinetics, normal organ distribution, radiation dosimetry, and excretion of 131I-MIP-1095.