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Tag team against Usher syndrome
March 2018
by Mel J. Yeates  |  Email the author


COLUMBIA, Md. & LEIDEN, The Netherlands—Foundation Fighting Blindness and ProQR Therapeutics N.V. recently announced a partnership to develop QR-421a for Usher syndrome 2A. Under the agreement, Foundation Fighting Blindness will provide up to $7.5 million in funding to ProQR for the preclinical and clinical development of QR-421a. Usher syndrome is a devastating genetic disease in which patients first develop hearing loss and then progressive vision loss. Currently there is no treatment for the ophthalmic manifestation of Usher syndrome type 2A.
According to Smital Shah, chief financial officer of ProQR, “QR-421a is a first-in-class investigational RNA-based oligonucleotide designed to address the underlying cause of Usher syndrome 2A due to mutations in exon 13 of the USH2A gene. Mutations in this exon can cause loss of functional usherin protein. As a result of the loss of this protein, patients lose first their hearing and then sight by mid-adulthood, leading to numerous educational, workplace and life challenges. QR-421a is designed to repair the genetic defect in the RNA in the eye, such that it leads to the expression of a shortened but functional protein, thereby modifying the underlying disease, with the goal to either delay progression of vision loss or restore sight. QR-421a has also received orphan drug designation in the United States.”
ProQR in-licensed the technology underlying QR-421a from Radboud University Medical Center in the Netherlands, where it was invented by lead investigator Dr. Erwin van Wyck.
“FFB became aware of ProQR through the investigator FFB supported in the Netherlands, whose technology ProQR licensed,” notes Dr. Stephen Rose, Foundation Fighting Blindness’ chief research officer. “FFB initiated the research support that led to this technology. At ProQR, they have a very patient-centric approach to development and therefore work closely with patient organizations for the development of their programs.”
“FFB is a very important organization in that effort and has a very thorough assessment for selecting programs that they will collaborate on,” adds Shah. “Therefore ProQR is very pleased to be part of this collaboration with FFB to advance this therapy for Usher syndrome patients. 
“QR-421a has been selected as clinical candidate based on preclinical data. ProQR did significant preclinical validation in sophisticated models and is conducting IND-enabling studies of QR-421a. QR-421a is expected to start dosing patients in a Phase 1/2 trial around year-end 2018, with clinical data expected in 2019.”
“ProQR and FFB have built a strong relationship due to their common goal to make a difference in inherited retinal disorders, but this is the first formal collaboration,” state Rose and Shah. “ProQR and its work on QR-421a will be informed by the Foundation’s Clinical Research Institute’s natural history study of people with USH2A mutations. The study, being conducted at 20 sites worldwide, will monitor changes in vision and retinal structure of patients to better understand disease progression.”
Foundation Fighting Blindness’ Clinical Research Institute (FFB-CRI) has also launched a natural history study in 120 people with USH2A mutations. The study—known as RUSH2A (“R” stands for “rate of progression”)—was launched in 2017 and is being conducted at about 20 clinical sites around the world. RUSH2A investigators will use a variety of technologies to monitor changes in vision and retinal structure to document and analyze disease progression. Knowledge and data obtained from this trial are intended to provide a better understanding of how USH2A mutations affect the severity and progression of vision loss and help to inform the development of QR-421a.
Rose says, “We think our RUSH2A study results will be helpful for the simple reason that in order to determine if a treatment is effective, an endpoint that defines success in a clinical trial has to be determined. To do this, you have to know the clinical parameters of the disease onset and progression. The RUSH2A Natural History study will map the progression of Usher 2A retinal degeneration over time. Therefore, the clinical trial will be able to show if the treatment slows vision loss or even restores vision, as was seen in the RPE65/LCA2 clinical trial that led to the December 2017 FDA approval of Spark Therapeutics’ LUXTURNA gene therapy.”
QR-421a for Usher syndrome is the second program in ProQR’s growing ophthalmology pipeline scheduled to enter clinical trials. The lead program in the ophthalmology pipeline, QR-110, is currently in a Phase 1/2 safety and efficacy trial in adult and pediatric patients with Leber’s congenital amaurosis 10, due to the p.Cys998X mutation in the CEP290 gene.
“We are excited to team up with the Foundation Fighting Blindness to develop QR-421a for patients that suffer from Usher syndrome due to exon 13 mutations," said Daniel A. de Boer, CEO of ProQR. “Through this partnership with the Foundation we plan to gain access to important know-how to develop programs in retinal diseases. We expect that the additional funding will allow us to rapidly advance this novel therapy for this orphan disease with a severe unmet need.”
“The development of QR-421a is the culmination of years of FFB support for development of a treatment so affected individuals with the exon 13 mutation in the Usher 2A gene will not go blind,” Rose and Shah conclude. “Our shared goal is to get the QR-421a into a clinical trial as soon as possible so, if successful, the treatment becomes widely available to any patient who would benefit from it. This treatment has the potential to become another arrow in the growing quiver of potential treatments to prevent vision loss due to an inherited rare retinal degeneration.”
Code: E031803



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