Glaucoma drug Vyzulta receives approval

Nitric oxide makes the difference, proponents say.

By René Luthe, senior editor

Vyzulta (latanoprostene bunod ophthalmic solution 0.024%, Bausch + Lomb/Nicox SA) has received FDA approval for the treatment of glaucoma. This dual-action topical therapy – a prostaglandin analog with nitric oxide (NO) as one of its metabolites – is indicated for the reduction of IOP in patients with open-angle glaucoma or ocular hypertension. Angelo P. Tanna, MD, vice chairman, associate professor of ophthalmology, director of Glaucoma Service, Northwestern University Feinberg School of Medicine, Chicago, calls it “a new, highly effective option for medical therapy.”

This first-in-class monotherapy metabolizes into two moieties: latanoprost acid, which primarily works within the uveoscleral pathway to increase aqueous humor outflow; and butanediol mononitrate, which releases NO to increase outflow through the trabecular meshwork and Schlemm’s canal. It is administered once daily in the evening.

“The phase 2 dose-ranging study demonstrated that the FDA-approved formulation, latanoprostene bunod 0.024%, lowers IOP significantly more effectively than latanoprost 0.005%,” says Dr. Tanna, a consultant to B + L. “Other basic work demonstrates that this additional IOP lowering is driven by the nitric oxide-donating moiety of the new compound rather than by the higher concentration of latanoprost. The key mechanism by which nitric oxide is thought to lower IOP is by relaxing the cytoskeleton in cells in the trabecular meshwork and Schlemm’s canal. This in turn results in improved outflow facility of aqueous humor through the conventional pathway.”

Vyzulta’s efficacy and safety were demonstrated in two parallel-group phase 3 studies (Apollo and Lunar). These trials – randomized, at multiple sites, double-masked – involved 831 subjects with open-angle glaucoma or ocular hypertension. The primary objective was demonstration of mean IOP reduction over a three-month treatment period with Vyzulta to be noninferior to twice-daily timolol maleate ophthalmic solution 0.5%. A secondary objective was to show Vyzulta’s dosing superiority to timolol’s b.i.d. Vyzulta met the primary efficacy endpoint in both studies and demonstrated significantly greater IOP reduction than timolol 0.5% throughout the day at three months — delivering a reduction in mean diurnal IOP of 32% from baseline.

Most common ocular adverse reactions with incidence ≥2% are conjunctival hyperemia (6%), eye irritation (4%), eye pain (3%) and instillation site pain (2%), according to prescribing information.

B + L licensed this compound from Nicox in 2010; the FDA approval means B + L will pay Nicox $17.5 million. The new drug should be available by year’s end. OM

Microdosing eyedrops could end “hosing the eye”

Lower dosage keeps more medicine in tear lake, reduces chance of overdosing

By Robert Stoneback, associate editor

At AAO 2017, Tsontcho “Sean” Ianchulev, MD, MPH, questioned why the medical field is still using eyedropper technology that has not changed in 100 years. He presented data on the use of a new “microdosing” eyedropper technology that could end the complications associated with eyedrop overdosing.

REDUCED RISK OF SIDE EFFECTS

Dr. Ianchulev, professor of ophthalmology at the Icahn School of Medicine of Mount Sinai, shared results of the “piezo-ejection” microdose delivery system from a paper published online in October’s Therapeutic Delivery. This paper included clinical results of the EYE 102 Phase II study. The microdoser, created using some of the same technology as inkjet printers, was manufactured by Eyenovia, Inc. Dr. Ianchulev serves as Eyenovia’s CEO as well as director of Mount Sinai’s Ophthalmic Innovation Technology Program.

To validate the ocular microtherapeutic approach, Dr. Ianchulev’s research team used the mydriatic response to pharmacologic dilation measured by digital pupillometry as it provides one of the most sensitive, quantifiable and immediate pharmacodynamic markers of biologic effect.

In the study, 12 subjects had their pupils dilated with topical phenylephrine (PE); one eye had the medication administered by a 32-µl eyedropper (using a 2.5% or 10% PE formulation), while in the other it was delivered via 8-µl microdosing (using a 10% PE formulation). The study found that microdosing at 75% less total dose had comparable mydriatic effect to the eyedropper at 75 minutes and “significantly reduced” 20-minute plasma PE levels compared to the eyedropper (see chart below). Also, eye irritation was less common in microdosed eyes.

NOT “HOSING THE EYE”

Dr. Ianchulev compared the use of traditional eyedrop technology to “hosing the eye” — it delivers 30-50 µl volumes that far exceed the eye’s usual tear-fill volume (7 µl), more than 300% of what the eye can hold.

Patients lose about 80% to 90% of a drop because it falls out of the eye.In addition to the medical waste, this overdosing can lead to ocular toxicity, which results in conditions such as ocular discomfort, redness and hyperemia, Dr. Ianchulev says.

SMOOTH DELIVERY

The piezo-print handheld microdoser delivers its 7-µl microdose in 80 milliseconds. Other features include Bluetooth technology to allow the device to report to the clinic the number of times it has been used, which helps to determine whether the patient is compliant.

Dr. Ianchulev said he expects phase 3 clinical trials in glaucoma, dry eye, myopia and pharmacologic dilation to begin in the next year, with the first microtherapeutic programs delivering phase 3 results in 2019 for mydriasis, followed by dry eye, glaucoma and myopia.

Other trials for microdosing are in development as well, including ones for dilating drops, glaucoma, dry eye and myopia. OM