Nearly 14 months after Palatin Technologies, Inc. reported a pivotal phase 3 trial failed to meet its primary endpoints in evaluating PL9643 for the treatment of dry eye disease (DED), the company has released new findings supporting a more promising outlook.
Let’s start with Palatin and its pipeline.
The New Jersey-headquartered biopharmaceutical company is developing a pipeline of therapeutics targeting inflammation and autoimmune conditions (with one commercially available product so far).
Among these target indications: DED and retinal disease (still in the preclinical stage).
- And the science behind these therapeutics: Utilizes the melanocortin receptor (MCr) system.
Give me the rundown on this science.
Palatin’s investigational medications are based on molecules that regulate MCr system activity.
About the melanocortin system: This is comprised of five MCr receptors that play key roles in regulating the body’s management of inflammation, immune response, metabolism, steroid hormone production, and sexual function.
- And with this regulation: Palatin noted the receptors can have “medically significant pharmacological effects.”
So how are these receptors regulated?
This is where the company’s therapeutic pipeline gets involved, with each candidate designed to activate endogenous melanocortin pathways, reverse damaging inflammation, and allow time for the affected tissues to heal.
- Notably: All of this is done without the need to suppress the immune system (and the potential adverse side effects that come with that).
Interesting … and how does this impact the eye?
To start: As prior research has noted, tissues and immune cells located in the eye are known to express MCrs—and, as a result, these receptors are instrumental in maintaining ocular tissue integrity and immune homeostasis.
With this in mind: MCrs are considered “high tractable” (easy) targets for melanocortin agonists to prevent and reverse inflammation in the eye for ocular disease patients.
Got it. Now talk about this advanced therapeutic you mentioned.
That would be PL9643, formulated as a topical treatment.
Its clinical journey thus far: The formulation is currently undergoing clinical investigation in the MELODY program, which includes the phase 3 MELODY-1 trial and two other studies.
What the data has shown: A mixed review for PL9643, with both positive and lackluster performance data across phase 2 and 3 evaluations.
Give me a quick debrief.
Backtrack to 2020: In a phase 2 study, PL9643 demonstrated statistically significant improvement for multiple signs and symptoms of DED among patients with a mild-to-moderate diagnosis of the disease—as well as an excellent ocular tolerability.
- However: The 12-week data found that the study failed to meet its primary endpoint and did not achieve statistical significance in the overall patient population.
And more recently?
That brings us to this pivotal phase 3 MELODY-1 trial—our study of interest—in which the company’s reporting of topline data included both good and bad outcomes for PL9643.
- The good: The formulation demonstrated clinically meaningful and statistically significant data for ocular pain and other system endpoints over the placebo solution.
- The bad: While PL9643 for both ocular pain and secondary endpoints demonstrated “positive treatment effects over placebo in the intent-to-treat (ITT) population,” it did not reach statistical significance.
See our coverage on this, reported in March 2024.
Let’s get a more detailed refresher on this study.
- The design: multicenter, double-masked, randomized, vehicle-controlled study (NCT05201170)
- The participants: 575 patients (aged 18+; 60% > aged 60)
- Criteria: Those who initially underwent a 14-day study run-in period, in which they received a vehicle ophthalmic solution bilaterally, three times a day (TID)
- The setup: After the 14-day run-in period, patients were randomized 1:1 to receive either PL9643 or vehicle (bilaterally and TID)
- The treatment period: 12 weeks
As for outcome measures, the primary endpoints (measured at baseline and or through Week 12) included:
- Inferior corneal fluorescein staining
- Ocular pain
- Conjunctival sum lissamine green staining
Alrighty, now what’s the latest report?
In general: Updated results from responder analyses of the safety and efficacy study highlighted PL9643’s DED potential by “achieving statistically significant complete system resolution” across all three of its symptom endpoints.
- The company emphasized that this level of improvement has not been seen “with any currently approved DED therapies.”
Let’s get some specifics. How was this calculated?
Per Palatin: A responder analysis evaluated the percentage of patients who achieved complete symptom clearing (resolution) across 13 pre-specified symptom endpoints (including secondary and other).
Also: The overall symptom burden (from a patient’s perspective; referred to as the Symptom Composite Score [SCS]) was quantified based on seven Visual Analog Scale (VAS) symptom ratings.
- Using these ratings, investigators determined overall symptom improvement.
And the numbers?
Starting with symptom clearing at 12 weeks:
- This was achieved by a statistically higher percentage of PL9643-treated patients versus placebo-treated (p < 0.05) in six of the 13 symptom endpoints.
For early and sustained symptom resolution:
- At 2 weeks, PL9643-treated patients’ SCC demonstrated statistically significant symptom clearing—which continued to improve through 12 weeks (with no signs of plateau)
- An increasing number of clearing symptoms reached this point from Week 4 through 12
- Comparatively: Placebo-treated patients’ improvement was minimal and plateaued quickly
Nice! So what’s the significance of this data for potential regulatory approval?
As noted in the FDA’s approval guidance for dry eye therapeutics: Responder analyses can be used to demonstrate symptom improvement.
Specifically: Clinical data is required to show a “statistically significant difference in the proportion of patients achieving complete symptom resolution (complete clearing of a symptom).”
- Important to note: PL9643 has officially met this criterion.
This sounds promising … and a pivot from that last reporting. So what’s next?
There’re still two more phase 3 studies in the MELODY clinical program for PL9643 to undergo:
- MELODY-2 (not yet listed on Clinical Trials)
- MELODY-3 (not yet listed on Clinical Trials)
What we know so far: Both trials will evaluate sign and symptom endpoints, with patient enrollment expected to begin later this year (pending Palatin’s ability to secure a collaboration and funding).
And how close is the company to securing a partnership?
President and CEO Carl Spana, PhD, shared that Palatin is “actively progressing discussions” with potential collaboration partners.
While no specific companies were mentioned, he added that the plan is to finalize a deal in H2 2025.
Lastly, what’s the potential for this eye drop?
With this latest data supporting PL9643’s ability to achieve statistically significant complete symptom resolution across multiple symptom endpoints—as well as its rapid, sustained efficacy and promising safety and tolerability profile—Dr. Spana noted it as a “major breakthrough that could transform [DED] treatment.”