Clinical researchers from the US, Canada and the Netherlands, have reported a study to recommend clinical trial designs and outcomes for XLRP (X-linked retinitis pigmentosa). The study has been funded by the charity Foundation Fighting Blindness, Columbia, MD, USA and a public company, 4D Molecular Therapeutics, listed on the NASDAQ and based in Emeryville, CA. The recommendations include genetic screening, clinical trial inclusion criteria, the importance of conducting natural history studies early in clinical development, and the merits and drawbacks for measuring treatment outcomes. The recommendations should provide a valuable road-map to support patients and clinicians and should provide open-access data outcomes aimed to under-pin the decisions for marketing approvals by regulators.
X-linked retinitis pigmentosa (XLRP) is an incurable genetic disease that causes blindness in males affecting approximately one in 15,000 people. The disease is caused by pathogenic variants in two genes, retinitis pigmentosa guanosine triphosphatase regulator (RPGR) and RP2, accounting for approximately 70% and 20% of cases. Over 300 mutations occur in the RPGR gene, most of which in the open reading frame exon (ORF15), causing an abnormally short protein that is expressed in the connecting cilium of photoreceptors, and is an important component of all ciliated cells in the body. Mutations in the RPGR gene can be associated with a rod-cone or cone-rod dystrophy phenotype. The most common presentation is as a rod-cone dystrophy. It is one of the most severe forms of RP with nyctalopia in most affected males before 10 years of age and progression to legal blindness by the third to fourth decade. The disorder is initially identified with difficulties in scotopic visual function, where there is a predominant loss of rod photoreceptors. Simultaneously, peripheral vision deteriorates, resulting in visual field constriction on perimetry findings. The majority of cases present with a rod-cone dystrophy-type disease progression, where central visual acuity is initially less impaired than the peripheral field loss. The fovea is ultimately affected in all cases during the late stages of the disease by subsequent cone photoreceptor degeneration.
Considerations for designing XLRP RPGR gene therapy clinical trials has recommended a brief selection of the report’s experts’ evaluation, including:
- trials should provide expert genetic review boards available in order to help determine inclusion and exclusion criteria based on genetic mutations;
- trials should collect as much information as possible about the pathogenic mutations as part of standard genetic work-up in anticipation that technology will be available in the near future, allowing to better correlate XLRP genotype and phenotype.
- clinical trials should include only male participants and/or have separate trials or cohorts for affected female individuals.
- while a 2-year phase III clinical trial may be sufficient, a longer duration (3–4 years) may be required to demonstrate treatment efficacy for an RPGR-targeted therapy for XLRP;
- given that visual acuity (VA) can be preserved until later in progression, VA is of limited use as an XLRP gene therapy clinical trial outcome measure; regardless, this will be required by the regulators as a safety measure.
- as an outcome measure, full field ERG is only relevant for pediatric or adolescent clinical trials, and multifocal ERG should not be used due to low signal-to-noise ratio in XLRP;
- other research may be applied using OCT findings, such as EZ changes and photoreceptor OS volume, to measure outcomes in XLRP gene therapy clinical trials, which could allow for shorter trial durations.
- improvements on treatment in function (e.g. microperimetry or static perimetry) and changes in structure (e.g. OCT) could be a useful compound end point in phase III trials because of its potential to show the benefit of therapy even if the primary end point is not met;
- natural histories may be valuable for additional biomarkers that indicate fast versus slow progression, which could be used to select and stratify participants;
- finally, it would be useful for the field if such data is made accessible in an open clinical trial data repository or via a publication.
These recommendations may now provide a useful yardstick for the assessment of current designs and outcomes for both current and future trials for XLRP clinical studies.