Phase 3 enabling program for a small molecule in treatment resistant depression and major depressive disorder
Disease Team Therapy Development - Research
Clinical depression is a chronic, recurring psychiatric illness that, according to Datamonitor, afflicts more than 12.5 million adults in the U.S. It is a disabling condition that adversely affects the patient’s quality of life, eating and sleeping habits, and overall health. Currently, clinical depression is treated with various antidepressants but their use is associated with a number of significant limitations. First and foremost, antidepressants have many undesirable side effects, including sexual dysfunction, fatigue, and weight gain. Moreover, many patients only partially respond to antidepressant therapy while some do not respond at all. In this sub-set of patients who do not respond to antidepressants (treatment resistant depression or TRD), the treatment alternatives are limited. It is this group of TRD patients which our research primarily aims to benefit. The prevailing therapy for TRD is electroconvulsive therapy, or ECT, which involves a patient first being anesthetized and then having electric currents passed through the brain. Although deemed effective, ECT is known to cause memory loss and confusion in some patients. Through our research program with [Redacted] we seek orally available therapeutic alternative to ECT that is efficacious but without significant side effects. In addition, we believe that [Redacted] could be a novel treatment for patients with MDD devoid of the undesired side-effects of existing treatments. The potential effectiveness of our drug is premised on two recent discoveries in the field of neuroscience: that it is possible to create new neurons in the adult human brain, and that these new neurons are necessary for antidepressants to work. Our earlier research has shown, in a laboratory setting, that [Redacted} causes human stem cells to grow into new neurons. Additionally, [Redacted] yields positive results in animal depression models. Further, our [Redacted] Phase I trials to date reflect a promising safety profile in humans. Therefore, we believe that [Redacted] has the potential to be a new standard of care for the treatment of TRD and second-line therapy for MDD patients who do not respond adequately to current treatments or cannot tolerate their side effects.
Statement of Benefit to California:
Depression or major depressive disorder (MDD) is a major public health concern in terms of its prevalence and cost to society. It is associated with significant impairment and decreased productivity. It can lead to changes in immune and endocrine function, increasing susceptibility to physical disease. The proposed research will evaluate the efficacy of an oral medication, [Redacted], for the treatment of MDD with a primary emphasis on patients who are unresponsive to current therapies (treatment resistant or TRD). Current treatments for TRD are invasive, require inpatient care and are accompanied by undesirable side effects such as psychosis and short-term memory loss. The primary goal of the proposed research program with [Redacted] is to develop an efficacious and less costly therapy for TRD patients without the significant side effects. A secondary goal is to provide a therapeutic alternative for MDD patients who do not adequately respond to current therapies or who cannot tolerate their side effects. The realization of these goals will lead to significant health, social and economic benefits in California. The World Health Organization estimates that depression is the leading cause of disability worldwide. The symptoms of depression impair work, social interaction and personal functioning. Depression can lead to changes in health behaviors such as increased smoking, high-risk sexual activities and increased risk of sexually transmitted diseases, particularly among the young, with major economic consequences. In the most serious cases, it can lead to long-term, costly inpatient care. An NIMH-sponsored analysis (2009), found that patients diagnosed with depression incurred ~ $22,960 in annual health care costs, while those without depression incurred ~ $11,956 in costs. If the [Redacted] program achieves it goals, it has the potential to radically improve patient care and reduce the negative impact of depression on quality of life factors such as family life, interpersonal relationships, job retention and performance. It also has the potential to reduce the significant economic burden to the State resulting from the deleterious, long-term health consequences of depression. The Substance Abuse and Mental Health Services Administration estimates that in 2003 approximately 58% of all mental health care, which includes depression, were paid by publicly funded programs. An effective therapy may also reduce the indirect costs associated with depression such as disability benefit payments and loss of earnings and tax revenue associated with those earnings. Finally, this grant helps to foster the further development of a robust and sustainable life science community in [Redacted] by providing jobs and funding to support the research outlined. Over time, [Redacted] has the potential to generate significant revenue which will not only increase the tax base for California but will also allow for further investment in new technology.
This proposal is focused on the clinical development of a small molecule compound for treatment resistant depression (TRD). The compound was identified in a screen for drugs that promote the differentiation of human neural progenitor cells (NPCs) into new neurons. This compound is currently being tested for safety in a Phase I study in healthy volunteers and the applicant proposes to continue development in two Phase II, placebo-controlled clinical studies. The first would be a smaller, shorter, proof-of-concept study, which if successful, would lead to a larger, longer confirmatory trial. Significance and Impact - Clinical competitiveness is not adequately addressed. The applicant compares the candidate to electroconvulsive therapy and ketamine but there are multiple atypical antipsychotics labeled for TRD, additional therapies under development and numerous other psychotropics that have shown some degree of efficacy. - The application is technically responsive to the RFA because the therapeutic candidate was discovered in a screen of compounds that could enhance neurogenesis from human NPCs. However, reviewers noted that no evidence is provided that the compound’s effects are mediated by a neurogenic mechanism and that the proposed time course of action effectively rules out this possibility. - The Target Product Profile (TPP) is not clearly defined and does not include contraindications. In addition, reviewers noted that the clinical endpoint of a rating change on the HAM-D17 scale might not be the most appropriate and suggested using the MADRS or HAM-D24 scale. - A novel, well-tolerated oral treatment for TRD would have a substantial clinical impact, given the prevalence of this disease and its high cost. Project Rationale - The majority of the preclinical animal studies have been performed using the active metabolite of the proposed compound rather than the compound itself. The application would have been stronger if it contained more preclinical efficacy data with the proposed compound including a comparison against a panel of approved anti-depressants. - Inadequate data are provided to demonstrate safety of the therapeutic candidate relative to ketamine. These compounds share a similar mechanism of action, which raises concerns that the therapeutic candidate could share ketamine’s dissociative and psychotic effects. The applicant addresses this possibility but does not present data. Therapeutic Development Readiness - The therapeutic candidate is being tested for safety in healthy volunteers overseas. The applicant appears ready to hold a pre-IND meeting with FDA and to file an IND in late summer 2012. Feasibility of the Project Plan - The project timeline is very optimistic if not unrealistic. Patient recruitment is extremely difficult in this indication and the applicant does not provide justification for patient accrual expectations. - The proposed clinical studies do not include a maximum severity cutoff or exclusion for patients with psychotic symptoms, which would be expected for trials of this type. - The rationale was unclear for testing a single dose in the first proposed Phase II clinical trial followed by two doses in the second trial. Reviewers recommended that the applicant focus on a well-powered, multiple dose Phase IIa study and consider secondary biomarker endpoints that may indicate durability and mode of action. They also recommended that the applicant engage in end of study dialogue with the FDA prior to initiation of a Phase IIb trial. - No formal power calculation is provided or rationale stated to support the estimated number of patients proposed for the second Phase II trial. - There is no discussion of centralized patient ratings for the first Phase II trial. Reviewers noted that subjective scoring is an important issue in these types of trials and one of the reasons there is such a high failure rate. Principal Investigator (PI) and Development Team - There is insufficient clinical development and trial experience on the team. The chief medical officer is a consultant and the medical team is diffuse, with clinical responsibility spread across multiple individuals. Collaborations, Resources and Environment - The clinical development of this compound could be limited by intellectual property considerations. Reviewers noted that given the patent filing date and an estimated clinical development timeline, the compound could have a very short window of patent protection following FDA approval. - The outsourcing of preclinical studies and clinical trial monitoring is appropriate. Budget (Assessment of the budget was conducted separately from the overall scientific evaluation and points or concerns raised in this section did not contribute to the scientific score. This section highlights items that must be addressed should the application be approved for funding.) - The proposed budget for the preclinical studies appears high. The budget for phase 3 enabling studies was not discussed but would be out of scope.