KPI-121, Kala Pharmaceuticals Inc.'s topical nanoparticle formulation of loteprednol etabonate (Lotemax, Bausch & Lomb), emerged with flying colors from a phase III study evaluating the lead program for the treatment of inflammation and pain following cataract surgery.

The ophthalmic suspension uses Kala's mucus-penetrating particle (MPP) technology to enhance penetration in target eye tissue. The randomized, double-blind, vehicle-controlled, parallel-group multicenter phase III trial enrolled 380 patients to evaluate two dosing regimens of KPI-121 compared to vehicle. Patients were randomized to 0.25 percent KPI-121 four times daily, 1 percent KPI-121 twice daily or the corresponding vehicles, administered for two weeks.

At day eight, statistically significant differences favoring KPI-121 were achieved in both the KPI-121 1 percent (p = 0.0024) and 0.25 percent (p < 0.0001) arms for the primary endpoint of complete resolution of inflammation. Complete resolution of ocular pain by day eight, a co-primary endpoint, also was achieved for both treatment arms (p = 0.0019 and p = 0.0003, respectively).

The company said treatment was generally well tolerated, with no significant treatment-related safety findings. Kala hopes to replicate those findings in a second phase III that it expects to use as a registration study, according to Charlie McDermott, interim president and chief business officer.

KPI-121 also achieved statistical significance for the primary endpoint of bulbar conjunctival hyperemia in a first-in-human phase II study in dry eye disease. The randomized, double-blind, parallel-group, multicenter trial compared 0.25 percent KPI-121 to vehicle, each dosed four times a day for 28 days, in 150 patients. Those treated with KPI-121 achieved statistical significance at day 29 (p = 0.0387). KPI-121 did not achieve statistical significance for the primary symptom endpoint of ocular discomfort but showed trends toward improvement, particularly in patients with more severe baseline ocular discomfort.

Kala said the candidate was generally well tolerated, with no significant treatment-related safety findings. The only treatment-emergent adverse event reported in greater than 3 percent of patients was instillation site pain, reported in 6.9 percent of patients treated with KPI-121 compared to 3.8 percent of patients treated with vehicle.

The data encouraged Waltham, Mass.-based Kala to stay the course in dry eye, as well, McDermott said.

"The fact that we hit an assigned endpoint in our dry eye trial on the first try, with this many patients, is fairly unique," he told BioWorld Today. "We're very pleased."

Kala's MPPs are designed to penetrate the mucosal barrier and lay down a coat of drug on the mucosal surface, resulting in improved efficacy.

"The technology allows us to get drug into the target compartments of the eyes more effectively than other approaches," McDermott said. "We've done a lot of work preclinically and using in vivo models to inform our trials, and the data have held up quite nicely with our lead molecule."

Thanks to the early success of that approach, the trajectory for Kala – co-founded by Massachusetts Institute of Technology professor and serial entrepreneur Robert Langer, who sits on the company's board – has been nothing short of astounding, McDermott maintained. When he joined the firm in mid-2013, the clinical strategy for KPI-121 was still on a whiteboard.

"In less than 18 months, we have a completely positive phase III readout in postoperative inflammation with all dose groups against all endpoints and a positive phase II trial in dry eye disease – the first time we put our MPP technology into man," he observed.

In fact, Kala "sat" on the KPI-121 data for several months while mulling over the next steps in its strategic plan, McDermott said, adding, "Now, we're off and running."

'NOT THAT CONCERNED' ABOUT FINANCING

In the coming months, management plans to meet with investigators and share updates at ophthalmology conferences while preparing for commercial-scale manufacturing of its MPP technology.

As the company undertakes design work for the registrational phase III of KPI-121 in post-cataract surgery, "we're also doing a lot of the long-term work on the CMC side to make sure we have a robust drug product with two years of stability for the indication," McDermott said. The company has a timetable in mind "but we're not prepared to discuss that publicly," he added.

"Patients for surgery are widely available, it's a couple weeks of therapy, it's a very clear pathway and there's a lot of precedence," McDermott said. "We're pretty confident we have that in hand."

Tailoring the design for the next set of phase II trials in dry eye will take a little more time, but Kala is determined to proceed. The company is drilling into the data to identify a subset of patients with the best prospects to show improvement not only in redness and inflammation of the eye but also in symptomatic discomfort. The goal is to identify the optimal dose and regimen to hit all of the endpoints, then replicate the findings in a phase III program and file for approval.

The company likely will stick with the 0.25 percent dosage, "but we're probably going to explore other doses and formulations, as well," McDermott said.

Kala plans to pursue a 505(b)(2) filing for KPI-121 in the surgical indication but will file a conventional new drug application in dry eye. The business strategy is to take the drug to market on its own in both indications, at least in the U.S.

"But we have lots of good relationships with the larger commercial-stage strategic players in the space," McDermott pointed out.

The company's clinical progress this year owes to a $22.5 million series B round that it closed a year ago, adding Abbvie Biotech Ventures Inc. and Ysios Capital as lead investors to a syndicate that already included Crown Venture Fund, Lux Capital, Polaris Partners and Third Rock Ventures. To date, the company has raised approximately $45.2 million. (See BioWorld Today, April 24, 2014.)

Kala is looking at the usual options for its next financing move.

"Our current investors are very supportive," McDermott said. "We're really not that concerned about the next round of financing. We're focusing on what makes the most sense for the trials that will get us to approval as quickly as possible in both indications."

Although the public markets have been relatively kind to biotech, "we're also aware they can fluctuate dramatically, especially in the biotech space," he added. "Most likely, we'll be doing a private round first."

Nanotech-based drug formulations are going through the same iterations as other drug delivery technologies, McDermott observed and, in his view, "these will be worked out empirically, on a case-by-case basis, matching the right drug with the right technology and the right delivery approach that makes the most sense in a particular patient population."

The MPP platform checks all of those boxes in eye care, he said.

"One of the biggest problems in developing topical ophthalmic products is making shelf-stable, robust formulations that can exist in an aqueous environment and also be comfortable on the eye" – practical but important considerations that most people take for granted, according to McDermott. MPP meets those requirements.

In addition, "we don't have any novel excipients that require special testing, and we don't do any covalent modifications of our products," he said. "That allows us to take advantage of quicker regulatory pathways."

Kala has other technologies that fall under the MPP umbrella for indications beyond ophthalmology, McDermott added, "but that is a very long-term plan."