Nightstar Therapeutics Ltd. filed to raise about $86.2 million in an IPO to advance its gene therapy candidate, NSR-REP1, for choroideremia (CHM), due to enter phase III trials in the first half of next year.
It’s the most clinically advanced product for the indication worldwide, the London-based firm pointed out in SEC paperwork. But not the only product.
CHM, an inherited disorder, causes progressive vision loss and leads to complete blindness. It’s caused by mutations in the CHM gene, which encodes Rab escort protein-1, or REP1, known to play a key role in intracellular protein trafficking and in the elimination of waste products from retinal cells. Absence of functional REP1 leads to death of the retinal pigment epithelium cells and degeneration of the overlying retina, which contains the retinal photoreceptors required to convert light into visual signals.
Nightstar’s NSR-REP1 is composed of an adeno-associated virus (AAV) vector used to deliver a functional version of the CHM gene into the retinal pigment epithelium and photoreceptor cells, which means patients will express REP1, thereby slowing or stopping the progression of CHM and the decline in vision. “In some cases, we have seen substantial improvements in visual acuity after treatment with NSR-REP1, which we believe is due to its ability to rescue, or reverse the process of cell death in already compromised retinal cells,” the company said in its IPO prospectus.
And the benefit seems to last. After one year of follow-up, more than 90 percent of patients treated with NSR-REP1 either maintained or improved their visual acuity. Positive data from 32 patients treated in four investigator-sponsored trials, including five-year follow-up data from the first cohort of the first trial of the compound, formed the basis of the decision to try a phase III experiment, to be called the STAR trial.
The first-ever test of NSR-REP1 was an open-label, dose-escalation, single-eye phase I/II effort at the University of Oxford. In January 2014, the positive initial six-month proof-of-concept efficacy and safety data from the first cohort of six patients in the Oxford study was published in The Lancet. More data supporting the lasting effect after 42 months of follow-up in the first cohort were published in the New England Journal of Medicine in April 2016.
Generating particular excitement in the work done so far are the hyper-responders to NSR-REP1. Some patients have achieved gains in visual acuity of greater than 15 Early Treatment Diabetic Retinopathy Study letters on the commonly used eye chart. The treatment effect recorded for the five such hyper-responders treated with NSR-REP1 was observed as early as one month after treatment, and the benefit held from three months after treatment to at least five years, the longest evaluable follow-up time point available now.
In the projected STAR trial, the company aims to enroll about 140 CHM patients, randomizing them to one of three study arms: 56 patients in a high-dose drug treatment arm; 28 in a low-dose drug arm to provide additional masking; and 56 in an untreated, no-sham, parallel control arm. One-year follow-up results are expected in 2020. If the results confirm the efficacy seen so far, Nightstar plans to submit for marketing approval in the U.S. and Europe.
Underway already is a prospective, natural history observational study called NIGHT, in which 220 patients with CHM have signed up at multiple clinical sites in the U.S., Europe and Canada, as of the end of June. The NIGHT study is designed to yield evidence regarding the disease state and rate of progression in untreated CHM patients, while providing a benchmark against which to compare the effects of NSR-REP1. Patients for the STAR registrational trial will be recruited mainly from the NIGHT study as a way of speeding development along.
Competitor at earlier stage in CHM
Since Nightstar’s inception in May 2013, the company has chalked net losses of $13.6 million and $12.2 million for the years ended Dec. 31, 2015, and 2016, respectively, and $7.7 million for the six months ended June 30. “We have devoted substantially all of our efforts to research and development of our product candidates, including clinical development of our lead product candidate, NSR-REP1, as well as to building out our management team and infrastructure,” the company said, tallying $40 million as the total accumulated deficit.
The company’s leadership looks strong. CEO David Fellows came from Johnson & Johnson’s vision care franchise, where he led global marketing, new product and licensing activities. His curriculum vitae also includes a stint at Allergan plc, where he served primarily in the sales and marketing areas in a number of capacities, including regional president, corporate vice president and senior vice president in North America, Asia and Europe. Senthil Sundaram, chief financial officer, previously served in a variety of positions at Intercept Pharmaceuticals Inc., including most recently as its vice president and head of business development. Chief development officer Tuyen Ong hails from PTC Therapeutics Inc., where he was chief medical officer. Gregory Robinson, chief scientific officer of Nightstar, came from Agilis Biotherapeutics LLC, where he held the same role, and has worked in the licensing area for Shire plc.
Nightstar has competition in gene therapy for CHM, albeit clinically farther behind. Spark Therapeutics Inc., of Philadelphia, is working with SPK-7001 at the phase I/II stage, using a similar approach. While Nightstar’s program stems from co-founder (and board member) Robert MacLaren’s research at Oxford, the Spark program emerged from the lab of Jean Bennett at the University of Pennsylvania. Nightstar deploys the woodchuck hepatitis virus post-transcriptional regulatory element as a way to boost transgene expression, which could provide an edge in the clinic. (See BioWorld Today, Nov. 10, 2015.)
Jefferies analyst Michael Yee, in an Aug. 2 research report, pegged Spark’s odds of success with the CHM therapy, which is also known as SPK-CHM, at 25 percent to 45 percent. For Spark, the main investor attention is elsewhere. Yee reiterated his “buy” rating on the stock, saying the company “remains a top midcap idea based on multiple gene therapy programs advancing and supporting [a] strong gene therapy platform engine.” He predicted shares will move higher based on hemophilia data to come later this year, and its potential first U.S. approval in January 2018. During the company’s second-quarter earnings call, much was made of early data from the hemophilia A program, which turned up a steady and consistent rise in factor VIII activity levels in the first two patients tested in the phase I/II dose-escalation study testing SPK-8011. In May, Spark completed the rolling BLA for Luxturna (voretigene neparvovec), a one-time treatment for patients with vision loss due to biallelic RPE65 mutation-associated retinal disease. The BLA includes data from three clinical trials that enrolled 41 participants, including results from the first randomized, controlled phase III trial for a gene therapy for a genetic disease. (See BioWorld, Aug. 3, 2017.)
Nightstar plans to list on Nasdaq under the ticker “NITE.”