Efficacy and Safety of the Melanocortin Agonist PL9643 in a … · 2021. 5. 7. · Palatin Technologies Inc. • Support Palatin Technologies Inc. • Acknowledgements Writing and

Efficacy and Safety of the Melanocortin Agonist PL9643 in a Phase 2 Study of Subjects With Dry Eye Disease

Presented at the Association for Research in Vision and Ophthalmology Virtual Annual MeetingMay 1–7, 2021 (Session Date and Time: May 1, 2021 from 3:15 PM to 4:45 PM EDT)

Kenneth Kenyon,1,2 George Ousler,2 Michael Watson,2 Gail Torkildsen,3

Patrick Vollmer,4 Eugene B. Mclaurin,5 David Evans,5 Jason Winters,6

John Dodd,6 Robert Jordan,6 Stephen T. Wills,6 Carl Spana6

1Tufts University School of Medicine and New England Eye Center, Boston, MA; 2Ora Inc, Andover, MA; 3Andover Eye Associates, Andover, MA; 4Core Inc, Shelby, NC; 5Total Eye Care, Memphis, TN; 6Palatin Technologies Inc, Cranbury, NJ

Disclosures

• Kenneth Kenyon was an independent contractor at Ora Inc throughout the duration of the study.• George Ousler and Michael Watson were employees of Ora Inc throughout the duration of the

study.• Gail Torkildsen received financial support from Mitotech, Kowa, Aldeyra, Topivert, Brim, Palatin,

Oyster Point, Allergan, Aerie, Aurinia, Regentree, Novaliq, Hanall, and Ora Inc. Patrick Vollmer has nothing to disclose.

• Eugene B. McLauren received financial support from Allergan, Aldeyra, Aurinia, HanAll, Mallinckrodt, Mitotech, Nicox, Novaliq, Orasis, Ocular Therapeutix, Palatin, RegenTree, Santen, and Topivert.

• David Evans received financial support from Alcon, Allergan, AxeroVision, Bausch & Lomb, Hovione, Kala, Novaliq, Novartis, Ocular Therapeutix, Vistakon.

• Jason Winters, John Dodd, Robert Jordan, Stephen T. Wills, and Carl Spana are employees of Palatin Technologies Inc.

• Support Palatin Technologies Inc.• Acknowledgements Writing and editorial assistance was provided by Miranda Tradewell for The

Curry Rockefeller Group, LLC, Tarrytown, NY, USA, which was funded by Palatin Technologies Inc.2

Background

• Dry eye disease• Multifactorial inflammatory and aqueous tear

deficient disorder affecting the cornea and conjunctiva1,2

• Characterized by ocular irritation and potential visual impairment1,2

• Existing dry eye therapies are often regarded as inadequate by many physicians and patients due to poor response, adverse effects (AEs), poor ocular tolerability, and prolonged interval preceding therapeutic activity3,4

3

1. DEWS Definition and Classification. The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5(2):75-92. 2. Bron AJ, et al. TFOS DEWS II pathophysiology report. Ocul Surf. 2017;15(3):438-510. 3. Mah F, et al. PERSIST: Physician's Evaluation of Restasis® Satisfaction in Second Trial of topical cyclosporine ophthalmic emulsion 0.05% for dry eye: a retrospective review. Clin Ophthalmol. 2012;6:1971-1976. 4. Tauber J, et al. Lifitegrast Ophthalmic Solution 5.0% versus Placebo for Treatment of Dry Eye Disease: Results of the Randomized Phase III OPUS-2 Study. Ophthalmology. 2015;122(12):2423-2431.

Presenter

Presentation Notes

This is a multifactorial inflammatory disease affecting multiple areas in the eye. Existing therapies are often inadequate due to poor efficacy, adverse effects, or poor tolerability. NEXT SLIDE

Background

• Melanocortins have a wide range of anti-inflammatory properties1-3

• Inhibition of leukocyte activation• Protection of tissues from the inflammatory

response

• Therefore, melanocortin agonists may represent a novel therapeutic avenue to treat inflammatory ocular diseases4,5

• PL9643, a melanocortin receptor pan-agonist (not active at MC2r), is currently being investigated for anti-inflammatory ocular indications, including dry eye disease

4

1. Manna SK et al. Alpha-melanocyte-stimulating hormone inhibits the nuclear transcription factor NF-kappa B activation induced by various inflammatory agentsJ Immunol. 1998;161:2873-2880. 2. Catania A, et al. Targeting melanocortin receptors as a novel strategy to control inflammation. Pharmacol Rev. 2004;56(1):1-29. 3. Perretti M, et al. Resolution Pharmacology: Opportunities for Therapeutic Innovation in Inflammation. Trends Pharmacol Sci. 2015;36(11):737-755. 4. Rossi S et al. Activation of Melanocortin Receptors MC1 and MC5 Attenuates Retinal Damage in Experimental Diabetic Retinopathy. Mediators Inflamm. 2016; 2016: 7368389. 5. Cai S et al. Α-Melanocyte-Stimulating Hormone Protects Early Diabetic Retina from Blood-Retinal Barrier Breakdown and Vascular Leakage via MC4R. Cell Physiol Biochem. 2018;45(2):505-522.

Presenter

Presentation Notes

Melanocortin agonists may provide a novel approach to treating the global affects of dry eye with an extremely favorable safety and tolerability profile. Melanocortins have a wide range of anti-inflammatory properties including inhibiting and protecting tissues from the inflammatory response. PL9643 is a melanocortin receptor pan-agonist that’s currently being studied for anti-inflammatory ocular indications, including dry eye disease and this is the topic of our discussion today. NEXT SLIDE

Objective

• This phase 2 study evaluated the efficacy and tolerability of PL9643 in adults with dry eye disease

5

Presenter

Presentation Notes

The objective of Palatin’s first exploratory study was to evaluate the efficacy and tolerability of PL9643 in dry eye disease. NEXT SLIDE

Study Design12-week Phase 2, multicenter, 1:1 randomized, double-masked, placebo-controlled study

6

Placebo run-inN=160

Week

CAE®

screeningCAE®

follow-upCAE®

confirmation/baseline

Screening–2

Randomization0 2 4 8

Primary analysis

12

Visit type

6 10

CAE®

follow-upCAE®

follow-upCAE®

follow-up

Placebo ophthalmic solution (vehicle) 3 times daily

1 µg/mL PL9643 ophthalmic solution 3 times daily

no study visit no study visit

• Inferior corneal fluorescein staining (sign)

• Ocular discomfort (symptom)

Co-primary endpoints (Week 12)

• Adults with mild, moderate, or severe dry eye disease

Study Subjects

Signs• Fluorescein staining• Lissamine green

staining• Tear film break-up time

Secondary endpoints (Week 2 and Week 12)

Symptoms• Burning• Dryness• Eye

discomfort

• Eye dryness• Foreign

body sensation

• Grittiness

• Itching• Ocular

discomfort• Stinging

CAE®, controlled adverse environment.

Presenter

Presentation Notes

This phase 2 exploratory study design consisted of a 12-week treatment period in approximately 160 subjects who were randomized to either PL9643 or placebo in a one-to-one fashion. They were dosed 3 times daily. The subjects included those with mild, moderate, or severe dry eye and they came into the clinic at 2, 4, 8, and 12 weeks post randomization. Although this was an exploratory study, the sponsor did designate as co-primary endpoints inferior corneal fluorescein staining and ocular discomfort in the event that if both were statistically significant this could have been considered a registrational study. The co-primary endpoints and the other many secondary endpoints were assessed to determine the best endpoints to move ahead into phase 3. NEXT SLIDE

Results: Co-Primary and Secondary Endpoints

• Co-primary endpoints of inferior corneal fluorescein staining (sign) and ocular discomfort (symptom) after 12 weeks• Overall ITT population of mild, moderate, or severe dry eye disease (N=160):

no significant difference• Subjects with moderate or severe disease (n=61): improvements in both

endpoints were observed (sign endpoint was significant)

• Several signs and symptoms secondary endpoints were significant

7

Presenter

Presentation Notes

The co-primary endpoints of the study included inferior corneal staining (as the sign) and ocular discomfort (as the symptom) assessed at 12 weeks and measured by the single question discomfort scale. The overall ITT population included subjects with mild, moderate, or severe dry eye disease and showed no significant difference in the endpoints between these groups. Subjects with moderate or severe disease showed improvements in both endpoints with the corneal fluorescein sign endpoint being significant. Overall, in the moderate to severe population good improvement was observed in symptoms at 2 weeks and signs at 12 weeks. NEXT SLIDE

Results: Baseline Demographics

• Baseline demographics of the moderate or severe subset were balanced across the groups• Median age was 69 years (range, 51–84) for the placebo group and 69.5

(range, 51–80) for the PL9643 group• 71% and 70% of subjects, respectively, were female

8

Presenter

Presentation Notes

Just for reference, as we move ahead and present more details of the data, the moderate to severe population had a median age of 69 years and approximately 70% of subjects were female. NEXT SLIDE

Differences between PL9643 and placebo (least squares mean change from baseline) in fluorescein staining in the subset of subjects with moderate or severe disease

• For subjects in the moderate or severe subgroup, significant improvement was observed for the PL9643 group compared with the placebo group for the primary endpoint of inferior corneal fluorescein staining (LS mean difference [SEM], –0.5 [0.2], P<0.05)

9

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

Total Sum(corneal +

conjunctival)

Total corneal(inferior +superior +

central)

Totalconjunctival(temporal +

nasal) Nasal Temporal Inferior Superior Central

Diffe

renc

e in

LS

Mea

n Ch

ange

Fr

om B

asel

ine

Week 2 Week 12

*

*P≤0.05

*

*

Presenter

Presentation Notes

The corneal staining in the moderate to severe population showed statistical significance at 12 weeks in total corneal staining, inferior corneal staining, and superior corneal staining. The efficacy shown in the different regions of the eye is encouraging. NEXT SLIDE

Differences between PL9643 and placebo (least squares mean change from baseline) in Lissamine™ green staining in the subset of subjects with moderate or severe disease

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

Total Sum(corneal +

conjunctival)

Total corneal(inferior +superior +

central)

Totalconjunctival(temporal +

nasal) Nasal Temporal Inferior Superior Central

Diffe

renc

e in

LS

Mea

n Ch

ange

Fr

om B

asel

ine

Week 2 Week 12

*

* *

*P≤0.05

10

Presenter

Presentation Notes

Keeping with the theme of efficacy in multiple regions of the eye, efficacy was observed in the conjunctiva using Lissamine green staining. The regions showing efficacy here are the total conjunctival score and the temporal region. It’s worth noting that the temporal region showed efficacy at 2 weeks in addition to 12 weeks. The global effect of PL9643 in different regions of the eye using different staining methods demonstrates the robustness of this data. NEXT SLIDE

-0.2

-0.18

-0.16

-0.14

-0.12

-0.1

-0.08

-0.06

-0.04

-0.02

0

Diff

eren

ce in

LS

Mea

n Sq

uare

Cha

nge

From

Ba

selin

e

Week 2 Week 12

Differences between PL9643 and placebo (least squares mean change from baseline) in conjunctival redness and tear film break-up time in the subset of subjects with moderate or severe disease

Conjunctival Redness Tear Film Break-up Time

11• Signs of conjunctival redness showed numeric improvements (as demonstrated by negative change from

baseline) and tear film break-up time showed significant improvement at 12 weeks

TFBUT, tear film break-up time.

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

Diff

eren

ce in

LS

Mea

n Sq

uare

Cha

nge

From

Ba

selin

e

Week 2 Week 12

*

*P≤0.05

Presenter

Presentation Notes

Further, when looking at the signs of conjunctival redness and tear film break-up time, we see improvement at 12 weeks including statistically significant improvement in tear film break-up time. So, we have observed efficacy across various sign assessments and in multiple regions of the eye. Let’s now look at how the subjects felt after PL9643 administration and let’s look at the symptom data. NEXT SLIDE

Co-Primary Endpoint (Single Question Scale): Differences between PL9643 and placebo (least squares mean change from baseline) in Ora Calibra® Ocular Discomfort Scale* scores in the subset of subjects with moderate or severe disease

• For ocular discomfort, PL9643 demonstrated numeric improvement over placebo as shown by negative change from baseline

12 *Measured on 0-4 scale.

Ora Calibra Ocular Discomfort Scale

-0.25

-0.2

-0.15

-0.1

-0.05

0

LS M

ean

Chan

ge F

rom

Bas

elin

e

Week 2 Week 12

Presenter

Presentation Notes

For the co-primary endpoint of ocular discomfort using the single question discomfort scale, subjects showed improvement over placebo at 2 weeks, but this didn’t result in a statistically significant change. NEXT SLIDE

Secondary Endpoint (5-Question Scale): Differences between PL9643 and placebo (least squares mean change from baseline) in the Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire† scores in the subset of subjects with moderate or severe disease

13 †Measured on 0-5 continuous scale.

• PL9643 demonstrated significant improvement in ocular discomfort over placebo at Week 2 (as shown by negative change from baseline)

-0.5

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

0.3

OcularDiscomfort Burning Dryness Grittiness Stinging

LS M

ean

Chan

ge F

rom

Bas

elin

e

Week 2 Week 12*P≤0.05

*

Presenter

Presentation Notes

When looking at the plethora of secondary endpoints of this exploratory study, we see consistent improvement at week 2 with PL9643 compared to placebo. Including the areas of burning, grittiness, stinging, and also statistically significant improvement at 2 weeks in the ocular discomfort question of the 5-question Ocular Discomfort and 4-Symptom Questionnaire. NEXT SLIDE

Differences between PL9643 and placebo (least squares mean change from baseline) in components of the visual analog scale* in the subset of subjects with moderate or severe disease

14*VAS was measured on 0-100

continuous scale.

• After 2 or 12 weeks, PL9643 demonstrated improvement over placebo (as shown by negative change from baseline) in ocular symptoms

-8

-6

-4

-2

0

2

4

Burning/stinging Itching

Foreignbody

sensationEye

discomfortEye

dryness Photophobia Pain

LS M

ean

Chan

ge F

rom

Bas

elin

e

Week 2 Week 12

Presenter

Presentation Notes

In the widely-used visual analogue scale, PL9643 demonstrated improvement over placebo at 2 weeks and 12 weeks for several endpoints including itching, foreign body sensation, eye discomfort, and eye dryness. NEXT SLIDE

Table 1. AEs by severity and relation to treatment

15

Event Mild Moderate Severe TotalPL9643 13 3 0 16

Non-ocular 12 3 0 15Not related 10 3 0 13Possibly related 1 0 0 1Unlikely related 1 0 0 1

Ocular 1 0 0 1Not related 1 0 0 1

Placebo 17 4 2 23Non-ocular 9 4 2 15

Not related 9 3 2 14Possibly related 0 1 0 1

Ocular 8 0 0 8Not related 4 0 0 4Possibly related 1 0 0 1Probably related 1 0 0 1Definitely related 2 0 0 2

Total 30 7 2 39

Safety

• No treatment-related serious AEs or ocular AEs were observed, and no subjects receiving PL9643 reported pain upon instillation of drops

• Fewer AEs occurred among subjects receiving PL9643 compared with placebo

Presenter

Presentation Notes

We’ve covered the global efficacy observed in signs and the consistent improvement observed in symptoms and in addition to efficacy PL9643 demonstrated a highly-favorable safety profile. NEXT SLIDE No treatment-related ocular AEs were observed versus 4 ocular adverse events with placebo and there was no pain upon instillation of PL9643 There were fewer AEs overall occurring among subjects receiving PL9643 compared with placebo NEXT SLIDE

Conclusions

• In subjects with moderate or severe dry eye disease, PL9643 ophthalmic solution led to benefits in signs and symptoms by the first evaluation at 2 weeks, which were maintained for the 12-week study duration

• PL9643 was well tolerated, with no treatment-related ocular AEs and a safety profile comparable to placebo

• These positive results across multiple signs and symptoms support the continued development of PL9643 as a novel therapeutic option for treating dry eye disease

16

Presenter

Presentation Notes

In this exploratory phase 2 study, subjects with moderate to severe dry eye disease treated with PL9643 showed improvement in signs and symptoms at 2 and 12 weeks. PL9643 was very well tolerated and these positive results support continue development of PL9643 as a possible novel therapeutic option for treating dry eye disease. If the efficacy and excellent safety profile continue through phase 3 development as a clinician, I can foresee this becoming a favorable treatment option for my dry eye patients. END

Documents

Efficacy and Safety of the Melanocortin Agonist PL9643 in a … · 2021. 5. 7. · Palatin Technologies Inc. • Support Palatin Technologies Inc. • Acknowledgements Writing and