Prenatal Somatic Cell Gene Therapies: Charting a Path Toward Clinical Applications (Proceedings of the CERSI-FDA Meeting).

We are living in a golden age of medicine in which the availability of prenatal diagnosis, fetal therapy, and gene therapy/editing make it theoretically possible to repair almost any defect in the genetic code. Furthermore, the ability to diagnose genetic disorders before birth and the presence of established surgical techniques enable these therapies to be delivered safely to the fetus. Prenatal therapies are generally used in the second or early third trimester for severe, life-threatening disorders for which there is a clear rationale for intervening before birth. While there has been promising work for prenatal gene therapy in preclinical models, the path to a clinical prenatal gene therapy approach is complex. We recently held a conference with the University of California, San Francisco-Stanford Center of Excellence in Regulatory Science and Innovation, researchers, patient advocates, regulatory (members of the Food and Drug Administration), and other stakeholders to review the scientific background and rationale for prenatal somatic cell gene therapy for severe monogenic diseases and initiate a dialogue toward a safe regulatory path for phase 1 clinical trials. This review represents a summary of the considerations and discussions from these conversations.

FDA/Arthritis Foundation osteoarthritis drug development workshop recap: Assessment of long-term benefit.

OBJECTIVE: To summarize proceedings of a workshop convened to discuss the current state of science in the disease of osteoarthritis (OA), identify the knowledge gaps, and examine the developmental and regulatory challenges in bringing these products to market. DESIGN: Summary of the one-day workshop held virtually on June 22nd, 2021. RESULTS: Speakers selected by the Planning Committee presented data on the current approach to assessment of OA therapies, biomarkers in OA drug development, and the assessment of disease progression and long-term benefit. CONCLUSIONS: Demonstrated by numerous failed clinical trials, OA is a challenging disease for which to develop therapeutics. The challenge is magnified by the slow time of onset of disease and the need for clinical trials of long duration and/or large sample size to demonstrate the effect of an intervention. The OA science community, including academia, pharmaceutical companies, regulatory agencies, and patient communities, must continue to develop and test better clinical endpoints that meaningfully reflect disease modification related to long-term patient benefit.

Clinical Development of Gene Therapies: The First Three Decades and Counting.

In the past three decades the field of gene therapy has made remarkable progress, surging from mere laboratory experiments to Food and Drug Administration (FDA)-approved products that bring significant reduction in disease burden to patients who previously had no therapeutic options for their serious conditions. Herein, we review the evolution of the gene therapy clinical research landscape and describe the gene therapy product development programs evaluated by the FDA in Investigational New Drug applications received in 1988-2019. We also discuss the clinical development programs of the first six oncolytic and gene therapy products approved in the United States.

Gene and Stem Cell Therapies for Fetal Care: A Review.

Importance: Gene and stem cell therapies have become viable therapeutic options for many postnatal disorders. For select conditions, prenatal application would provide improved outcomes. The fetal state allows for several theoretical advantages over postnatal therapy, including immune immaturity and cellular niche accessibility. Observations: Advances in prenatal diagnostic accuracy and surgical precision, as well as improvements in stem cell and gene therapy methods, have made prenatal gene and stem cell therapy realistic. Studies in mouse models and early human trials demonstrate the feasibility of these approaches. Additional efforts are under way to streamline fetal applications of stem cell and gene therapy while carefully considering best ethical practice and following established regulatory pathways. Conclusions and Relevance: Fetal stem cell and gene therapy bring important therapeutic opportunities for select disorders that present in the fetal and neonatal periods. While this field is in its infancy, these therapies are starting to be available clinically, and clinicians should be aware of their benefits and challenges.

Regenerative Medicine Therapies for Rare Diseases.

The field of regenerative medicine is growing rapidly with the introduction of new therapies that have the potential to treat and cure serious medical conditions, including rare diseases, for which there are no available treatments. In the United States, the development of novel medical products is regulated and guided by the Food and Drug Administration (FDA). As scientific and technological advances are discovered and adopted by the medical industrial enterprise, the FDA's implementation of policies that create a climate conducive to safe development and rapid availability of novel medical products is one of the pillars which support the Agency's mission of protecting and promoting the public health. With advancements in cell modifications and tissue engineering, innovative creation of biomaterials, adoption of three-dimensional bioprinting, and rapid development of human genome editing technologies, the need for Agency's work in ensuring that its science-based policies remain relevant and helpful in facilitating the availability of new treatments to the most vulnerable populations of patients becomes more pressing than ever before. In December 2016, Congress amended section 506 of the Food, Drug, and Cosmetic (FD&C) Act [21 U.S.C. 356] by adding a new section 506(g), which defines the categories of products considered to be regenerative medicine therapies. As further described by FDA [1], regenerative medicine therapies are considered to include cell therapies, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies, as well as gene therapies, including genetically modified cells that lead to a durable modification of cells or tissues. The development and approval of regenerative medicine therapies are regulated by FDA's Office of Tissues and Advanced Therapies (OTAT) in the Center for Biologics Evaluation and Research (CBER). In this review article, we present practical considerations for investigating regenerative medicine therapies intended for the treatment of rare diseases. The material presented may be useful to researchers who are undertaking the challenging task of finding and delivering new treatments for those in need.

Investigational New Drug applications: a 1-year pilot study on rates and reasons for clinical hold.

BACKGROUND: The Food and Drug Administration (FDA)'s Center for Drug Evaluation and Research (CDER) receives about 1500 initial Investigational New Drug applications (INDs) per year. In the first 30 days after initial IND submission, FDA conducts a review to determine whether the proposed investigation is safe to proceed, and if not, the IND may be placed on clinical hold. METHODS: A retrospective study of rates and reasons for clinical hold for all initial INDs submitted to CDER in fiscal year (FY) 2013 was performed. INDs were assessed for reasons that led to clinical hold, included chemistry, manufacturing and controls (CMC), animal toxicology or clinical issues. INDs were further categorized by commercial versus research sponsorship, and rare versus common disease indications. All INDs placed on hold were reassessed by whether they remained on hold within the first year following hold imposition. RESULTS: CDER received 1410 initial INDs in FY 2013, of which 125 (8.9%) were placed on hold during the first 30 days after initial submission. Of the INDs placed on hold, more than half became active within the first year after first imposition of hold. CMC reasons were most commonly cited, followed by clinical, then toxicology reasons. There were no substantive differences in rates and reasons for hold between INDs for rare or common disease indications, or between commercial or research INDs. CONCLUSIONS: The vast majority of initial INDs moved forward within 30 days after submission, and for those applications placed on hold, most became active within 1 year. The findings also suggest that many holds for new drug product programs can be avoided by following the available guidelines for investigational product development.

Anti-N-methyl-D-aspartate receptor antibodies, cognitive dysfunction, and depression in systemic lupus erythematosus.

OBJECTIVE: To assess the association of cognitive dysfunction and depression with serum antibodies to N-methyl-D-aspartate (NMDA) receptor (anti-NR2) and analyze clinical and neuroimaging correlates in patients with systemic lupus erythematosus (SLE). METHODS: Sixty patients underwent neurocognitive assessment, evaluation for depression with the Beck Depression Inventory II (BDI-II) and psychiatric interview (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria), brain magnetic resonance imaging, and proton magnetic resonance spectroscopy imaging (1H-MRSI). Cognition was assessed in 5 domains: memory, attention/executive, visuospatial, motor, and psychomotor, and adjusted to each individual's best level of prior cognitive functioning estimated from the reading subtest of the Wide Range Achievement Test-3 (WRAT-3). Serum anti-NR2 antibodies were measured by enzyme-linked immunosorbent assay using a pentapeptide from the human NMDA receptor. RESULTS: Cognitive dysfunction was found in 28 of 60 patients (mild in 8, moderate in 20) before adjustment for WRAT-3 and in 35 of 60 patients (mild in 15, moderate in 11, and severe in 9) after adjustment for WRAT-3. The changes were most pronounced in the memory and visuospatial domains. There was no significant association between anti-NR2 antibody levels and cognition. On 1H-MRSI, patients with moderate or severe cognitive dysfunction had significantly higher choline:creatine ratios in the dorsolateral prefrontal cortex and the white matter, compared with patients with mild or absent cognitive dysfunction. Anti-NR2 antibodies were significantly correlated with BDI scores; patients with BDI-II scores of > or =14 had higher serum levels of anti-NR2 antibodies (P = 0.005, 95% confidence interval 0.83, 4.31), and there was a trend toward higher anti-NR2 antibody levels among patients who fulfilled the DSM-IV criteria for major depression. CONCLUSION: Serum anti-NR2 antibodies are associated with depressive mood but not with cognitive dysfunction in SLE at a given time point. Larger longitudinal studies are needed to address the possible association between anti-NR2 antibodies and depression in SLE.

Use of computerized assessment to predict neuropsychological functioning and emotional distress in patients with systemic lupus erythematosus.

OBJECTIVE: Cognitive dysfunction and neuropsychiatric disturbance are common in systemic lupus erythematosus (SLE). This study addressed the ability of the Automated Neuropsychological Assessment Metrics (ANAM), a computerized cognitive testing battery consisting of cognitive subtests, a sleepiness rating scale, and a mood scale, to predict neuropsychological status in patients with SLE. METHODS: Sixty individuals with SLE and no overt neuropsychiatric symptoms were administered ANAM to determine its validity as a screening measure of cognitive dysfunction and emotional distress in SLE. RESULTS: Performance on ANAM was compared with results of a consecutively administered, 2-hour battery of traditional neuropsychological tests and the Beck Depression Inventory II (BDI-II). Individual ANAM cognitive test scores were significantly correlated with most neuropsychological tests, particularly those measuring psychomotor processing speed and executive functioning. Using logistic regression, ANAM cognitive subtests successfully predicted individuals with SLE who had probable versus no impairment after controlling for premorbid levels of cognitive ability. Sensitivity of group classification was 76.2% and specificity was 82.8%, with 80% correct classification overall. ANAM's ability to predict neuropsychological functioning remained even after controlling for subjective reports of depressed mood and current sleepiness. Further, the ANAM mood scale was significantly correlated with the BDI-II (r = 0.67, P < 0.001), indicating its potential future use as a screening tool for emotional distress. CONCLUSION: ANAM shows promise as a time- and cost-efficient tool for screening and monitoring cognitive and emotional functioning in SLE, and can indicate when a more thorough neuropsychological investigation is warranted.