INVELTYS features Kala’s new drug delivery technology.

The frequent dosing of postoperative cataract drops presents a well-documented problem for patients. Ocular corticosteroids are critical to postoperative care, as they control inflammation and pain resulting from trauma caused during surgery; the agents are needed to achieve a rapid recovery and to promote healing.

Compliance, however, is always a concern. Patients’ adherence, or lack thereof, to surgeons’ prescribed steroid regimens is a key factor to a given procedure’s success, impacting patient satisfaction and the surgical experience.

NEW DELIVERY TECHNOLOGY

INVELTYS (loteprednol etabonate ophthalmic suspension) 1% utilizes Kala Pharmaceuticals’ proprietary AMPPLIFY Mucus-Penetrating Particle (MPP) drug delivery technology, designed to deliver higher drug concentrations to ocular tissue. The technology utilizes selectively-sized nanoparticles (200-400 nm) with noncovalent proprietary coatings. According to the company, these two key attributes were designed to help the drug particles penetrate through mucus barriers and significantly increase drug delivery to target tissues.

A 2014 preclinical study published in Ophthalmology and Therapy showed that INVELTYS with AMPPLIFY technology was capable of delivering 3.75 times as much loteprednol etabonate to aqueous humor compared to a traditional loteprednol suspension. The company chose loteprednol etabonate as its lead molecule because it is a C-20 ester steroid with a high affinity to the glucocorticoid receptor and is rapidly metabolized to inactive metabolites; this may be responsible for loteprednol’s reduced side effects relative to other glucocorticoids.

THE FIRST LINK IN THE CHAIN

“INVELTYS embraces the smart steroid legend of loteprednol etabonate with a meticulously formulated vehicle,” says John D. Sheppard, MD, president of Virginia Eye Consultants, Norfolk, Va. “Selectively sized nanoparticles utilizing a slippery polymeric, noncovalent surface coating allow loteprednol to penetrate through mucus pores guarding the ocular surface tissues and thus defy mucin’s tenacious grasp on the drug. Payload is delivered so efficiently that approved [b.i.d.] dosing for postsurgical inflammation control has finally become reality.” Dr. Sheppard was a study investigators for INVELTYS.

Approval of the agent was based on the results of two multicenter, randomized, double-masked clinical trials. In each, INVELTYS showed statistical significance with twice-daily dosing for the primary efficacy endpoints of complete resolution of ocular inflammation by slit-lamp biomicroscopy and complete resolution of subject-rated ocular pain. The study included participants who had routine cataract surgery with grade 2 or higher anterior chamber cells (≥6 cells) on postoperative day one. In the two trials, a total of 386 patients were assigned to INVELTYS treatment vs. 325 receiving placebo (vehicle); each group was dosed twice-daily for two weeks. Statistical significance for both primary endpoints was achieved in both trials.

Analysis published in December in Clinical Ophthalmology of the combined data from the two trials showed that significantly more subjects treated with INVELTYS (KPI-121 1.0%) vs. vehicle, achieved primary efficacy endpoints of complete resolution of ocular inflammation and complete resolution of subject-rated ocular pain at days eight and 15, with no rescue medication before day 15 (P ≤ .0001 for both). The investigators noted that the study agent was found to be safe and well tolerated in both trials, with adverse events reported more frequently with vehicle.

“INVELTYS approval is welcome news for the eye-care community, as it provides a clear advancement in the treatment for inflammation and pain following ocular surgery,” says Terry Kim, MD, an author of the combined analysis. “Having access to a [twice-daily] corticosteroid in a novel nanoparticle formulation with proven safety and efficacy will make a positive impact on the management of my postoperative patients.” Dr. Kim is professor of ophthalmology and chief, cornea and external disease division, Duke University Eye Center.

MORE AMPPLIFY TO COME

Another product candidate utilizing AMPPLIFY drug delivery technology is Kala’s KPI-121 0.25% (loteprednol ophthalmic suspension) for dry eye disease (DED). The company has submitted a new drug application (NDA) to the FDA seeking the indication of “temporary relief of signs and symptoms of dry eye disease.” The NDA includes data from three dry eye clinical trials of approximately 2,000 DED patients as the backbone of the filing (see page 20). This includes positive data from one Phase 2 and two Phase 3 efficacy and safety trials called STRIDE 1 and STRIDE 2 (or Short Term Relief In Dry Eye). Kala is also currently conducting a third Phase 3 trial (STRIDE 3) based on a recommendation from the FDA. The topline results readouts are scheduled for Q4 2019.

NEXT-GEN DROP

The interest around novel drug delivery technologies is high.

With MPP technology, Kala Pharmaceuticals has demonstrated that drugs can reach high concentration in ocular tissue. The company believes this could enable enhanced efficacy at equal or lower doses, as well as at fewer dosing intervals for better convenience and compliance. OM