ProQR Therapeutics, a Dutch biotech specializing in genetic medicines, expected results from a clinical trial of an experimental eye drug it's developing would be the last step before approaching regulators about an approval.
Instead, the drugmaker is attempting to figure out what went wrong after disclosing Friday its therapy failed to significantly improve patients' vision, a result that sent ProQR shares down by 75% Friday.
"We are shocked by this unexpected outcome," said ProQR CEO Daniel de Boer on a conference call with analysts. "The results we're sharing are hot off the press ... so it will take some time before we will be able to address all the questions that we have from this outcome."
Already, however, the findings raise doubts about the future of the therapy, called sepofarsen, which is ProQR's most advanced medicine and, until now, its nearest opportunity for an approved product. On the call, de Boer would not commit to running another trial of sepofarsen, but said "all options remain on the table" as the company further analyzes the data.
Sepofarsen is what's known as an antisense oligonucelotide, a type of RNA therapy that works by targeting the genetic messages cells use to translate DNA code into proteins. Antisense treatments have shown promise in a wide range of diseases, and several developed by other biotech companies are approved to treat rare muscular and liver conditions.
ProQR's aim is to use antisense therapies to treat inherited retinal disorders, many of which have no good treatment options and can be severely disabling.
With sepofarsen, ProQR is targeting a form of Leber congenital amaurosis, the most common genetic cause of blindness in children. Specifically, sepofarsen is for LCA Type 10, or LCA10, which is caused by mutations in a gene called CEP290.
Early study results in 11 adults and children with LCA10 caused by CEP290 mutations showed the drug might have helped improve their visual acuity, light sensitivity and ability to navigate an obstacle course. Several early volunteers had substantial changes in vision, including one who found himself able to see signs at the airport and and read print for the first time in years.
Those data raised expectations for ProQR's larger Phase 2/3 study, which recruited 36 participants older than 8 years of age who had lost the ability to read at least four lines on an eye chart but were still able to see hand motion in front of their eyes. Study volunteers were randomized to receive either a higher or lower dose of sepofarsen, or a sham injection as a comparison.
According to summary results disclosed Friday, treatment with ProQR's drug did not improve visual acuity over the sham injection after one year. All three groups — high dose, low dose and sham — had an average improvement of approximately one line on an eye chart.
"From our point of view, something like a one-line improvement is very much in keeping with what you would expect" in the sham group, said Aniz Girach, ProQR's chief medical officer, on Friday's call. "I think for us the most disappointing thing was the efficacy" in the sepofarsen groups.
There were also no differences between groups on additional measures like light sensitivity and mobility course navigation.
ProQR said sepofarsen treatment was "well tolerated," although investigators observed signs of retinal thinning and cataracts.
Behind sepofarsen, ProQR is testing antisense medicines for other retinal diseases like Usher syndrome and retinitis pigmentosa. Executives emphasized that the results for sepofarsen don't diminish their expectations for those programs.
"The science behind this is completely understood. It has approved therapies," said de Boer. "So we don't think it has anything to do with the underlying technology or platform. But we really need to invest the time to understand what happened here before we can draw any conclusions."
Not all may agree, however. Dae Gon Ha, an analyst at the investment bank Stifel, noted that results for sepofarsen could raise doubts about ProQR's pipeline prospects.
"We think today's readout calls into question [ProQR]'s antisense oligonucleotide approach in inherited eye diseases more broadly, or at least, necessitates caution when interpreting small Ph[ase] 1/2 outcomes," Ha wrote in a Feb. 11 note to clients.
ProQR's results may also have implications for Editas Medicine, another biotech working on a therapy for LCA10 that uses CRISPR gene editing. Early results last September from six participants treated with Editas' therapy showed some hopeful signs, but were inconsistent and difficult to draw definitive conclusions from.