Instead of looking at the year past, OIS Weekly is wrapping up 2017 by looking at the year ahead. Here’s a rundown of significant regulatory filings and actions along with trial readouts anticipated in 2018. This list is based on presentations made at OIS@AAO 2017, updates on Clinical Trials.gov, and company press releases and filings.
PDUFA Actions Set
First, here’s a rundown of Prescription Drug User Fee Act (PDUFA) dates set for the next year.
Spark Therapeutics may hold the most anticipated PDUFA date: January 12, 2018, for its Luxturna (voretigene neparvovec) gene therapy for treatment of biallelic RPE65 mutation-associated retinal dystrophy such as Leber congenital amaurosis and retinitis pigmentosa. In October, the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee unanimously recommended its approval. FDA approval would be the first for a gene therapy to treat a genetic disorder in the US.
Aerie Pharmaceuticals has a PDUFA date of February 28, 2018, for the glaucoma agent Rhopressa (netarsudil 0.02%). Rhopressa could be the first once-daily glaucoma drop. Netarsudil has been shown to inhibit both Rho kinase and the norepinephrine transporter, key mechanisms in elevating intraocular pressure (IOP).What makes Rhopressa novel are: it targets the trabecular meshwork; and it’s demonstrated efficacy in lowering episcleral venous pressure, which has been identified as a significant cause of elevated IOP.
Regeneron Pharmaceuticals received a PDUFA date of August 11, 2018, for 12-week dosing interval of Eylea (alibercept) for wet age-related macular degeneration (AMD) based on physician’s assessment. For wet AMD, the current recommended dose for Eylea is 2 mg bimonthly (eight weeks) following three initial monthly (every four weeks) injections. Eylea may also be dosed once per month. The supplemental Biologics License Application the FDA accepted for review is based on an analysis of two-year results from the pivotal VIEW 1 and VIEW 2 trials that showed 51% of study patients had their Eylea dosing interval extended to every 12 weeks at the beginning of the second year (week 52) of treatment, based on an evaluate-and-extend approach, and maintained the 12-week dosing interval and best-corrected visual acuity gains at two years without any new safety issues. Criteria for 12-week dosing include having no evidence of new or progressive wet AMD.
NDAs and INDs
A few New Drug Applications (NDAs) or Investigational New Drug (IND) filings are also on tap for 2018.
pSivida Corp. has in hand two successful pivotal Phase III studies of its Durasert implant for treatment of noninfectious uveitis, and plans to file an NDA in late December 2017 or early January 2018 for the indication. pSivida also expects to complete good laboratory practice safety and pharmacokinetic studies of a shorter-duration Durasert for posterior segment uveitis in Q4 2018.
Ocular Therapeutix plans to refile its NDA for the Dextensa intraocular insert for treatment of pain and inflammation after cataract surgery, president and CEO Anthony Mattessich said at OIS@AAO 2017. Ocular Therapeutix filed the NDA previously, but received a complete response letter (CRL) from the Food and Drug Administration in July 2017. Mattessich shared that the company has worked to address the issues the FDA pointed out in its CRL. The firm also expects to reach a couple of other important milestones in the same time frame in 2018, Mattessich noted: report topline efficacy results of its intracanalicular travoprost platform; and initiate a Phase I trial of intravitreal OTX-TKI (tyrosine kinase inhibitor).
ONL Therapeutics is using the $5 million in Series A funding it obtained in May 2017 to complete and file the IND for its lead candidate, ONL 1204, president and CEO John Freshley stated at OIS@AAO 2017. ONL 1204 is a small-molecule, first-in-class Fas inhibitor for treatment of retinal detachment, and has orphan drug designation. The company expects to file the IND in the first half of 2018, with plans to commence a Phase I/II dose escalation trial in the second half of 2018 and launch a Phase I/II dose-expansion trial in 2019, he said.
Clearside Biomedical expects in early 2018 topline Phase III data from the PEACHTREE trial of its proprietary CLS-TA platform for macular edema associated with uveitis, with an NDA filing expected later in the year. CLS-TA is Clearside’s proprietary suspension formulation of the corticosteroid triamcinolone acetonide for suprachoroidal administration. Clearside also anticipates in the first half of 2018 topline data of its Phase II trial of CLS-TA with or without Eylea for treatment of diabetic macular edema (DME).
Deeper in the pipeline, a host of companies are projecting readouts from important clinical trails in the next year.
Graybug Vision expects an initial readout of topline Phase Ia/IIb results of GB-102 for treatment of wet AMD in the first half of 2018. GB-102 is an injectable formulation of sunitinib, a tyrosine kinase inhibitor that blocks multiple VEGFR pathways. President/CEO Jeff Cleland, PhD, explained at OIS@AAO 2017 that the goal is to reduce treatments for wet AMD, DME, and retinal vein occlusion (RVO) to once or twice a year. The two-part ADAGIO trial is evaluating patients with wet AMD and already on anti-VEGF agents who are then switched over to treatment with GB-102 alone. The company expects a preliminary readout on safety and efficacy of the Phase I trial in Q4 2018, with Phase II topline safety and efficacy results due in 2020. In glaucoma, Graybug expects to initiate preclinical studies in Q1 2018 and file an IND and initiate a Phase I/II trial in Q1 2019, he said.
Ohr Pharmaceutical anticipates early in 2018 reporting of topline data from the Phase II/III MAKO study of topical squalamine lactate 0.2% to treat AMD. The trial compares the topical agent along with Lucentis (ranibizumab, Roche/Genentech) versus Lucentis alone. An early post hoc analysis reported that at 36 weeks those on squalamine-Lucentis gained on average 5.3 letters more than those on placebo-Lucentis.
Tyrogenex has in development another oral candidate for treatment of wet AMD, X-82 (vorolanib). A Phase II trial is due to report results in 2018. The trial completed enrollment in March 2017 and will evaluate treatment with one of three doses of X-82 or placebo after 52 weeks. The trial exceeded its enrollment target of 132 patients by 25 patients, senior VP and development director Daniel Salazar, PhD, reported last March.
Roche/Genentech’s RG7716 for treatment of neovascular AMD, the subject of the STAIRWAY trial, is due to complete data collection in June 2018. RG7716 is an anti-VEGF and anti-Ang-2 bispecific agent that uses CrossMab technology. The Phase II AVENUE study of RG7716 for wet AMD is also due for completion in January 2018 with final data collection slated for September. The BOULEVARD trial is also investigating RG7716 in patients with DME, with a study completion date estimated at May 2018.
Roche/Genentech is also working on a port to deliver Lucentis over a period of months, potentially reducing the burden of frequent injections. The ranibizumab port delivery system (RPDS) is placed beneath the conjunctiva, and physicians can refill it with a custom refill needle. The primary endpoint of the LADDER trial is time until a participant first requires an implant refill. Final data collection is estimated for September 2018. Genentech’s parent, Roche, acquired ForeSight Vision 4, which had been developing the port system, in January 2017, but Genentech and ForeSight Vision 4 had been collaborating on the RPDS since 2010.
Aura Biosciences is preparing to conduct a Phase IIa trial of its light-activated AU-011 therapy for treatment of ocular melanoma, CEO Elisabet de los Pinos, PhD, reported at OIS@AAO 2017. At the American Academy of Ophthalmology Retina Subspecialty Day, Carol Shields, MD, of Wills Eye Hospital in Philadelphia reported interim data from the Phase Ib/II trial that showed the drug candidate was well tolerated in the first six patients treated with AU-011 at three to six months post-treatment. Now Aura is preparing for a dose optimization study with plans to go into Phase III as early as 2018, Dr. de los Pinos said.
Allegro Ophthalmics is planning in 2018 a Phase III trial of its lead integrin peptide therapy candidate Luminate for treatment of DME, president Vicken Karageozian, MD, said at OIS@AAO 2017. The Phase IIb DEL MAR study showed that sequential therapy of Luminate with Avastin (bevacizumab, Roche/Genentech) was superior to Avastin alone and combination therapy of Avastin-Luminate, leading to a 7.1-letter gain in best corrected visual acuity at 20 weeks versus 6.7 letters and 1.4 letters, respectively. Allegro anticipates making major funding decisions before commencing the Phase III trial.
Upcoming Front-of-Eye Milestones
Kala Pharmaceuticals expects topline clinical data by year-end of Inveltys, otherwise known as KPI-121 0.25%, for first-line treatment of dry eye. Kala has already submitted an NDA for Inveltys for treatment of pain and inflammation after cataract surgery. Inveltys is a twice-a-day corticosteroid that utilizes Kala’s proprietary Mucus-Penetrating Particle (MPP) technology to enhance penetration into target tissues of the eye.
Shire expects to report in the first half of 2018 topline data from multiple international Phase III studies on 2,700 patients with viral and bacterial conjunctivitis treated with SHP640. SHP640 is a broad-spectrum antiseptic (povidone-iodine 0.6%), and anti-inflammatory steroid (dexamethasone 0.1%) combination under investigation for the treatment of adenoviral and bacterial conjunctivitis in adults and children. The treatment regimen being studied for SHP640 is one drop four times per day for seven days. Shire acquired SHP640 (formerly known as FST-100) through the acquisition of Foresight Biotherapeutics in August 2015.
Novaliq recently commenced a Phase IIb/III US clinical trial for its novel dry eye drug candidate CyclASol, which is anticipated to read out in Q3 2018. CyclASol is a preservative-free ophthalmic solution of cyclosporine A in EyeSol, Novaliq’s proprietary water-free technology. The ESSENCE IIb/III clinical trial is a randomized, double-masked, vehicle-controlled, multi-center trial, designed to evaluate the safety, efficacy, and tolerability of topical CyclASol for treatment of dry eye disease.