Exploring Novel Clinical Trial Designs for Gene-Based Therapies Proceedings of a Workshop (2020) / Chapter Skim
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4 Developing Endpoints for Gene Therapy Clinical Trials
4 Developing Endpoints for Gene Therapy Clinical Trials
Pages 41-54
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From page 41... ...
• Mechanistically agnostic endpoints reflective of common patho genic pathways may not be sufficient in gene therapy clinical trials. Due to the increased availability of genetic screening, early diagnosis, and advanced laboratory testing, there has been a shift toward using surrogate and clinical endpoints that reflect early disease manifestations.
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From page 42... ...
Lapteva also described some of the important concepts regarding endpoints and outcomes in clinical trials. Dwight Koeberl, a professor of pediatrics and molecular genetics and microbiology in the Department of Pediatrics at Duke University and the medical director of the Duke University Health System Biochemical Genetics Laboratory, discussed endpoints for clinical trials in Pompe disease; Albert Maguire, a professor of ophthalmology at the Hospital of the University of Pennsylvania and the Presbyterian Medical Center of Philadelphia, discussed clinical endpoints for a Phase 3 inherited retinal dystrophy gene therapy trial; and Julie Kanter, an associate professor of hematology and oncology at the University of Alabama at Birmingham School of Medicine, discussed her work determining optimal endpoints for gene therapy trials in sickle cell disease.
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From page 43... ...
In the traditional regulatory approval pathway, the endpoints used in the trials that are intended to demonstrate the product's evidence of effectiveness would be clinical endpoints that directly measure clinical benefit or surrogate endpoints that have been validated to predict clinical benefit.1 A second pathway, accelerated approval, has been around since the 1990s and is typically reserved for serious and, often, rare diseases for which there are no available treatments. Accelerated approval has been used in cases where the disease course may be prolonged and an extended period would be needed to observe clinical benefit.2 In order to make development feasible and also improve access to care for those who need it, accelerated approval allows for the use of surrogate endpoints that predict clinical benefit with reasonable likelihood, Lapteva said.
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From page 44... ...
In closing, Lapteva listed some points to consider in choosing endpoints for clinical trials with gene therapies: • The possibility of long-term or potentially irreversible effects of gene therapy treatments leaves little room for uncertainty about endpoint performance at the stage of study design and requires increased vigilance concerning the validity and accuracy of end point measurements during the study. • Endpoints reflective of common pathogenic pathways, but mecha nistically agnostic to the target disease or condition, may not be sufficiently sensitive in gene therapy clinical trials.
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From page 45... ...
The primary advantage of this liver-specific expression, Koeberl explained, is that it suppresses the production of antibodies against GAA, which can interfere with the current GAA enzyme replacement therapy.5 Other potential advantages of a gene therapy approach versus enzyme replacement therapy that have been identified from preclinical studies include sustained levels of GAA in blood, an increased uptake of GAA by muscle, a more complete correction of the enzymatic deficit, potentially decreased mortality, and a one-time dose of the gene therapy vector versus required injections of GAA every 1 to 2 weeks (Bond et al., 2019)
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From page 46... ...
Secondary endpoints include muscle function and pulmonary function tests, GAA activity and glycogen content in muscle biopsies, antibody formation, a urinary biomarker, and serum levels of GAA, the last of which Koeberl characterized as "very exploratory." Except for the last endpoint, each of the secondary endpoints was validated in the earlier clinical trial with clenbuterol, with two markers of muscle and pulmonary function suitable for using in a regulatory submission, he said (Koeberl et al., 2018)
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From page 47... ...
As one FDA reviewer put it, patients care about vision, not about their pupils, a sentiment with which Maguire agreed. At the time, he said, there was no recognized outcome measure considered clinically meaningful, except for one surrogate endpoint: three lines of improvement on an eye chart.
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From page 48... ...
DETERMINING OPTIMAL ENDPOINTS FOR GENE THERAPY IN SICKLE CELL DISEASE Developing endpoints for sickle cell disease has long been a challenge for the field and was recently the focus of a workshop hosted by the
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From page 49... ...
Stem cell transplants, as Courtney Fitzhugh described in her earlier presentation, can cure sickle cell disease and are particularly promising for children with matched related donors; the risk versus benefit for adults is improving as well, and early studies paint an optimistic picture for improved outcomes and quality of life (Aslam et al., 2018)
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From page 50... ...
"We cannot identify, when a person is born with sickle cell disease, if it will be severe, if they will have frequent pain crises and be in the hospital frequently, or even if the disease will not manifest itself until the individual is a young adult," Kanter said. There was hope that the presence of fetal hemoglobin might predict individuals who will have an easier disease course, but studies have found that many adults with persistent fetal hemoglobin have all of the same complications as those without persistent fetal hemoglobin, even though the disease appears 10 to 20 years later in those with persistent fetal hemoglobin.
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From page 51... ...
Developing more disease-specific endpoints will also be important, he added. When asked to comment on why she thinks there is no national registry for sickle cell disease patients, Kanter replied that it comes down to decentralized patient advocacy for this condition and a lack of funding.
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From page 52... ...
Developing and Validating Endpoints for Gene Therapies Will there be a time, a workshop participant asked, when the resolution of anemia in sickle cell disease will become an accepted endpoint, just as the resolution of hypertension is the endpoint for drugs designed to lower blood pressure instead of a reduction in the incidence of stroke? It will be important, Lapteva answered, to demonstrate how improving anemia correlates with reduced disease burden, such as by reducing hospitalization, improving respiratory function, and reducing fatigue.
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From page 53... ...
Sickle cell disease is somewhat different in that endpoints are a popular topic, Kanter said. In academia and in various organizations, the importance of endpoints needs to be realized in order to continue this type of research, she said.
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