Using a novel ocular injection platform to deliver drug to the suprachroidal space (SCS) at the back of the eye, Clearside Biomedical (NASDAQ:CLSD) is relentlessly pursuing treatments for blinding diseases with a late-stage pipeline for macular edema associated with uveitis and retinal vein occulusion and DME, as well as an early development program for wet AMD.
“Drug delivery to the SCS has the potential to offer more optimal therapy through high bioavailability, even and efficient distribution throughout the eye, and rapid onset, with a better side effect profile,” president and CEO, Daniel White, says in an interview with BioTuesdays.
“The objectives of our program are rapid vision gains, sustained better vision, fewer injections and an improved benefits-to-risk ratio consistent across all patients, using the SCS microinjection,” he adds.
Mr. White explains that the SCS consists of 17-square centimeters in the eye and represents a space lying between the sclera and the choroid. “We believe administration of ophthalmic therapeutic agents to the SCS enables access to posterior segment ocular tissue while limiting exposure, and potential side effects, to the anterior segment, and other areas of the eye,” he points out.
The suprachoroidal space is a region that can be accessed easily using the Clearside SCS microinjector platform, he adds, making treatment an in-office procedure.
Clearside’s pipeline in retinal diseases include CLS-1001 for the treatment of macular edema associated with non-infectious uveitis, an inflammation of the eye; CLS-1003 for the treatment of macular edema associated with retinal vein occulusion (RVO); CLS-1004 for diabetic macular edema (DME); and CLS-1002 for wet AMD, a leading cause of blindness in the elderly.
CLS-1001 consists of a suprachoroidal injection of Zuprata, Clearside’s proprietary, preservative-free formulation of the corticosteroid, triamcinolone acetonide, specifically designed to be administered through its microinjector. In the RVO program, Zuprata is being used with intravitreal Eylea, or aflibercept. And for DME, the company is using Zuprata alone or with Eylea.
In the CLS-1002 program, Clearside is developing a proprietary formulation of axitinib for the treatment of wet AMD by injection into the SCS.
Beyond its four key programs, Clearside also is in preclinical development with a number of collaborators in retinal vascular disease and gene therapy for orphan eye diseases.
Last month, Clearside launched a $36-million stock offering and granted underwriters an over-allotment option to sell an additional 600,000 shares at $9 each. Proceeds will be used for its clinical trial program with Zuprata and axitinib. Clearside also was added to the NASDAQ Biotechnology Index in mid-December.
Mr. White says a pivotal Phase 3 trial is underway treating uveitis patients, with data expected in the second half this year or early 2018 and a Phase 3 trial is being initiated with RVO patients. In addition, a Phase 1/2 study is underway in DME and the company expects to file an IND for the treatment of wet AMD in the first half this year.
“We estimate that there are nearly five million people in the U.S. diagnosed with non-infectious uveitis, RVO, DME and wet-AMD, which are the back-of-the-eye diseases we target,” he adds. Some 1,700 retinal specialists treat these patients. “Our intent is to establish a commercial infrastructure with an estimated sales force of 35-to-45 people to reach these specialists.”
Mr. White explains that administration of corticosteroids is the most common treatment for all symptoms of uveitis, including macular edema. There are some 350,000 uveitis patients in the U.S., of which 33%, or 115,000 people, have macular edema, a build-up of fluid in the macula, which causes the macula to swell and thicken, resulting in distorted vision.
In an earlier Phase 2 study in 22 uveitis patients with macular edema, Zuprata achieved a statistically significant reduction in retinal thickness as well as improvements in Best Corrected Visual Acuity (BCVA) on average 2 lines of improvement.
In addition, there were no serious adverse events related to treatment or discontinuation of the study as well as no steroid-related increase in intraocular pressure.
The ongoing six-month Phase 3 study in uveitis is expected to recruit 150 patients at 50 clinical sites, with 90 patients receiving Zuprata and 60 receiving a sham injection. The primary endpoint is superiority of BCVA from treatment.
According to Mr. White, macular edema is the most common cause of vision loss for patients following RVO and affects some 2.2 million people in the U.S. First line treatment is 10-to-12 annual anti-VEGF injections of Eylea, Lucentis and/or off-label Avastin.
Anti-VEGF drugs work by stopping a protein called vascular endothelial growth factor (VEGF) produced by cells in the retina and leading to new blood vessel growth, which is a major problem in a number of eye diseases.
“Our objective is to improve the current standard of treatment by improving and sustaining visual outcomes over anti-VEGF treatments alone in order to potentially reduce the number of injections,” Mr. White contends.
In an earlier Phase 2 study with 46 RVO subjects, a single injection of Zuprata in combination with Eylea versus Eylea alone resulted in a greater improvement of vision in the combination arm, sustained efficacy over the three-month trial and significantly fewer additional injections of Eylea.
“This is very important for the patient, caregiver and payer,” Mr. White says, noting that there were no serious adverse events in the study.
In the first half this year, Clearside intends to begin a pivotal Phase 3 study at 150 clinical sites, testing Zuprata in combination with Eylea versus Eylea alone, with 230 RVO patients in each arm. The primary outcome is superiority at month two and the trial design allows the company to submit data to the FDA after six months. Patients would be followed out to one year.
According to Mr. White, intravitreal anti-VEGF injections have a good track record treating DME but roughly half of subjects have persistent disease even after monthly injections. Ongoing monthly intravitreal anti-VEGF therapy often results in continued visual improvements.
Steroids like fluocinolone and dexamethasone also appear to have a reasonable track record providing efficacy in DME subjects, but adverse events, like development of cataracts in certain patients often appear to compromise visual gains seen within the first few months, he adds.
“We believe delivery to the SCS can reduce not only the frequency of intravitreal injections but also avoid the causes of cataracts and intraocular pressure,” Mr. White contends.
Clearside currently is enrolling patients in a six-month Phase 1/2 study to determine the benefit of a single suprachoroidal injection of Zuprata alone and in combination with Eylea. The primary endpoint is reduction in retinal thickness.
In addition to Zuprata for uveitis, RVO and DME, Clearside has developed a formulation of axitinib to be a potential once-or-twice yearly treatment for wet age-related macular degeneration. “We know of no other compound being developed for wet AMD with that long of a half life,” Mr. White suggests. Pfizer currently sells axitinib for oncology indications under the trade name, Inlyta.
Intravitreal anti-VEGF agents, such as Lucentis, Eylea and off-label Avastin are being administered about seven times a year to treat wet AMD, with 30% of patients gaining 15 or more letters of vision with monthly injections.
“The SCS injection of axitinib provides a single molecule with the potential of good potency to VEGF and platelet-derived growth factor receptors, as well as a known safety profile,” Mr. White contends. Clearside plans to file an IND this year for a Phase 1/2 study of axitinib in wet AMD.
“We see a world without blindness and are relentlessly pursuing transformative and precise solutions to restore and preserve vision,” he adds.