Trial Outcomes & Findings for Multiple Dose Safety and Efficacy of LKA651 in Patients With Diabetic Macular Edema (NCT NCT03927690)

Last Updated: 2024-06-20

Results Overview

An AE is any untoward medical occurrence (e.g., any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a patient or clinical investigation patient. The severity of the AEs (mild, moderate, severe) was based on the Common Terminology Criteria for Adverse Events (CTCAE). Number of participants in each category is reported in the table. A participant who falls multiple times in one category is counted only once.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

91 participants

Primary outcome timeframe

Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).

Results posted on

2024-06-20

Participant Flow

The study population consisted of male and female patients with DME, who were 18 to 85 years of age at screening, and who were either treatment naive or experienced i.e. had been treated with anti VEGF therapy \> 90 days before baseline.

Participant milestones

Participant milestones
Measure	LKA651 LKA651 5 mg Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	LKA651 + Lucentis LKA651 1 mg + Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	Lucentis Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase
Overall Study STARTED	28	30	33
Overall Study COMPLETED	21	27	31
Overall Study NOT COMPLETED	7	3	2

Reasons for withdrawal

Reasons for withdrawal
Measure	LKA651 LKA651 5 mg Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	LKA651 + Lucentis LKA651 1 mg + Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	Lucentis Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase
Overall Study Withdrawal by Subject	3	1	1
Overall Study Adverse Event	1	0	0
Overall Study Death	1	0	0
Overall Study Lost to Follow-up	2	2	1

Baseline Characteristics

Multiple Dose Safety and Efficacy of LKA651 in Patients With Diabetic Macular Edema

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	LKA651 n=28 Participants LKA651 5 mg Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	LKA651 + Lucentis n=30 Participants LKA651 1 mg + Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	Lucentis n=33 Participants Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	Total n=91 Participants Total of all reporting groups
Age, Continuous	61.6 Years STANDARD_DEVIATION 8.58 • n=5 Participants	63.8 Years STANDARD_DEVIATION 8.18 • n=7 Participants	61.2 Years STANDARD_DEVIATION 9.02 • n=5 Participants	62.2 Years STANDARD_DEVIATION 8.60 • n=4 Participants
Sex: Female, Male Female	9 Participants n=5 Participants	13 Participants n=7 Participants	10 Participants n=5 Participants	32 Participants n=4 Participants
Sex: Female, Male Male	19 Participants n=5 Participants	17 Participants n=7 Participants	23 Participants n=5 Participants	59 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	3 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	3 Participants n=4 Participants
Race (NIH/OMB) White	23 Participants n=5 Participants	27 Participants n=7 Participants	32 Participants n=5 Participants	82 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants

PRIMARY outcome

Timeframe: Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).

Population: Safety Set

Outcome measures

Outcome measures
Measure	LKA651 n=28 Participants LKA651 5 mg Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	LKA651 + Lucentis n=30 Participants LKA651 1 mg + Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	Lucentis n=33 Participants Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase
Number of Participants With Adverse Events AEs, Patients with AEs	20 Participants	16 Participants	19 Participants
Number of Participants With Adverse Events AEs of mild intensity	16 Participants	15 Participants	19 Participants
Number of Participants With Adverse Events AEs of moderate intensity	8 Participants	6 Participants	3 Participants
Number of Participants With Adverse Events AEs of severe intensity	4 Participants	2 Participants	1 Participants
Number of Participants With Adverse Events Study drug-related AEs	2 Participants	1 Participants	2 Participants
Number of Participants With Adverse Events Serious AEs	3 Participants	4 Participants	1 Participants
Number of Participants With Adverse Events AEs leading to discontinuation of study treatment	1 Participants	0 Participants	0 Participants
Number of Participants With Adverse Events Study-drug related AEs leading to discontinuation of study treatment	1 Participants	0 Participants	0 Participants
Number of Participants With Adverse Events Non-serious AEs	20 Participants	16 Participants	19 Participants

PRIMARY outcome

Population: Safety Set

An AE is any untoward medical occurrence (e.g., any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a patient or clinical investigation patient.

Outcome measures

Outcome measures
Measure	LKA651 n=28 Participants LKA651 5 mg Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	LKA651 + Lucentis n=30 Participants LKA651 1 mg + Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	Lucentis n=33 Participants Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase
Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye Vitreoretinal traction syndrome	0 Participants	0 Participants	1 Participants
Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye Patients with at least one ocular AE in study eye	11 Participants	7 Participants	9 Participants
Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye Conjunctival haemorrhage	1 Participants	4 Participants	2 Participants
Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye Diabetic retinal oedema	2 Participants	1 Participants	2 Participants
Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye Diabetic retinopathy	1 Participants	1 Participants	1 Participants
Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye Visual acuity reduced	3 Participants	0 Participants	0 Participants
Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye Vitreous haemorrhage	1 Participants	0 Participants	2 Participants
Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye Dry eye	0 Participants	1 Participants	1 Participants
Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye Macular oedema	2 Participants	0 Participants	0 Participants
Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye Ocular hypertension	2 Participants	0 Participants	0 Participants
Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye Abnormal sensation in eye	0 Participants	0 Participants	1 Participants
Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye Anterior chamber flare	0 Participants	1 Participants	0 Participants
Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye Corneal erosion	1 Participants	0 Participants	0 Participants
Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye Cystoid macular oedema	1 Participants	0 Participants	0 Participants
Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye Dacryostenosis acquired	1 Participants	0 Participants	0 Participants
Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye Eye pain	1 Participants	0 Participants	0 Participants
Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye Eyelids pruritus	0 Participants	0 Participants	1 Participants
Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye Lenticular opacities	0 Participants	0 Participants	1 Participants
Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye Punctate keratitis	0 Participants	1 Participants	0 Participants
Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye Retinal cyst	1 Participants	0 Participants	0 Participants
Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye Retinal detachment	1 Participants	0 Participants	0 Participants
Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye Retinal exudates	1 Participants	0 Participants	0 Participants
Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye Retinal haemorrhage	1 Participants	0 Participants	0 Participants

PRIMARY outcome

Population: Safety Set

An AE is any untoward medical occurrence (e.g., any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a patient or clinical investigation patient.

Outcome measures

Outcome measures
Measure	LKA651 n=28 Participants LKA651 5 mg Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	LKA651 + Lucentis n=30 Participants LKA651 1 mg + Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	Lucentis n=33 Participants Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase
Number of Participants With Non-ocular Adverse Events (>=2%)	16 Participants	15 Participants	14 Participants

PRIMARY outcome

Timeframe: Screening, and Day 85

Population: Safety analysis set

Intraocular pressure was measured per the study site's regular practice.

Outcome measures

Outcome measures
Measure	LKA651 n=28 Participants LKA651 5 mg Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	LKA651 + Lucentis n=30 Participants LKA651 1 mg + Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	Lucentis n=33 Participants Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase
Intraocular Pressure (IOP) in Study Eye Screening	15.1 mmHg Standard Deviation 3.20	14.9 mmHg Standard Deviation 3.44	15.5 mmHg Standard Deviation 2.88
Intraocular Pressure (IOP) in Study Eye Day 85	15.5 mmHg Standard Deviation 3.56	15.6 mmHg Standard Deviation 3.67	15.2 mmHg Standard Deviation 3.79

PRIMARY outcome

Timeframe: Days 2, 8, 15, 29, 43, 57, and 85

Population: Pharmacodynamic analysis set - Participants with a valid measure and without a protocol deviation that would have an impact on the outcome measure.

BCVA was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Visual function of the study eye was assessed using the ETDRS protocol. BCVA in study eye was analyzed with a mixed model for repeated measures. The model included treatment, visit, and the treatment by visit interaction as independent variables. An unstructured residual covariance structure was used. Baseline BCVA value and treatment naïve and treatment experienced variable were used as covariates. Min and max possible scores are 0-100 respectively. A higher score represents better visual functioning.

Outcome measures

Outcome measures
Measure	LKA651 n=25 Participants LKA651 5 mg Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	LKA651 + Lucentis n=28 Participants LKA651 1 mg + Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	Lucentis n=32 Participants Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase
Best Corrected Visual Acuity (BCVA) by Early Treatment Diabetic Retinopathy Study (ETDRS) Visual Acuity Charts in Study Eye Day 29	65.5 Scores on a scale Interval 62.6 to 68.4	68.2 Scores on a scale Interval 65.3 to 71.0	68.5 Scores on a scale Interval 65.9 to 71.1
Best Corrected Visual Acuity (BCVA) by Early Treatment Diabetic Retinopathy Study (ETDRS) Visual Acuity Charts in Study Eye Day 43	67.8 Scores on a scale Interval 64.4 to 71.1	70.4 Scores on a scale Interval 67.6 to 73.3	69.1 Scores on a scale Interval 66.2 to 71.9
Best Corrected Visual Acuity (BCVA) by Early Treatment Diabetic Retinopathy Study (ETDRS) Visual Acuity Charts in Study Eye Day 57	67.6 Scores on a scale Interval 64.7 to 70.5	71.5 Scores on a scale Interval 68.6 to 74.4	70.0 Scores on a scale Interval 67.4 to 72.6
Best Corrected Visual Acuity (BCVA) by Early Treatment Diabetic Retinopathy Study (ETDRS) Visual Acuity Charts in Study Eye Day 85	67.8 Scores on a scale Interval 64.8 to 70.9	72.5 Scores on a scale Interval 69.5 to 75.4	70.5 Scores on a scale Interval 67.8 to 73.2
Best Corrected Visual Acuity (BCVA) by Early Treatment Diabetic Retinopathy Study (ETDRS) Visual Acuity Charts in Study Eye Day 2	61.5 Scores on a scale Interval 58.6 to 64.4	64.4 Scores on a scale Interval 62.3 to 66.6	64.1 Scores on a scale Interval 61.8 to 66.5
Best Corrected Visual Acuity (BCVA) by Early Treatment Diabetic Retinopathy Study (ETDRS) Visual Acuity Charts in Study Eye Day 8	65.2 Scores on a scale Interval 61.7 to 68.7	68.6 Scores on a scale Interval 66.1 to 71.2	66.2 Scores on a scale Interval 63.4 to 69.0
Best Corrected Visual Acuity (BCVA) by Early Treatment Diabetic Retinopathy Study (ETDRS) Visual Acuity Charts in Study Eye Day 15	65.9 Scores on a scale Interval 62.4 to 69.4	68.6 Scores on a scale Interval 65.8 to 71.4	68.4 Scores on a scale Interval 65.4 to 71.3

PRIMARY outcome

Timeframe: Week 12 (Day 85)

Population: Safety analysis set - Participants in the safety analysis set with a valid measurement for the outcome measure.

Macular thickness was measured by spectral domain optical coherence tomography (SD-OCT).

Outcome measures

Outcome measures
Measure	LKA651 n=24 Participants LKA651 5 mg Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	LKA651 + Lucentis n=28 Participants LKA651 1 mg + Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	Lucentis n=31 Participants Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase
Inner Macular Thickness (Inferior)	503.06 micrometer Standard Deviation 137.235	400.82 micrometer Standard Deviation 53.180	390.48 micrometer Standard Deviation 48.097

PRIMARY outcome

Timeframe: Week 12 (Day 85)

Population: Safety analysis set - Participants in the safety analysis set with a valid measurement for the outcome measure.

Macular thickness was measured by spectral domain optical coherence tomography (SD-OCT).

Outcome measures

Outcome measures
Measure	LKA651 n=24 Participants LKA651 5 mg Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	LKA651 + Lucentis n=28 Participants LKA651 1 mg + Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	Lucentis n=31 Participants Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase
Inner Macular Thickness (Temporal)	505.27 micrometer Standard Deviation 141.410	414.64 micrometer Standard Deviation 67.032	404.93 micrometer Standard Deviation 56.099

PRIMARY outcome

Timeframe: Week 12 (Day 85)

Population: Safety analysis set - Participants in the safety analysis set with a valid measurement for the outcome measure.

Macular thickness was measured by spectral domain optical coherence tomography (SD-OCT).

Outcome measures

Outcome measures
Measure	LKA651 n=23 Participants LKA651 5 mg Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	LKA651 + Lucentis n=28 Participants LKA651 1 mg + Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	Lucentis n=31 Participants Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase
Outer Macular Thickness (Inferior)	388.66 micrometer Standard Deviation 88.128	349.39 micrometer Standard Deviation 44.538	342.88 micrometer Standard Deviation 50.612

PRIMARY outcome

Timeframe: Week 12 (Day 85)

Population: Safety analysis set - Participants in the safety analysis set with a valid measurement for the outcome measure.

Macular thickness was measured by spectral domain optical coherence tomography (SD-OCT).

Outcome measures

Outcome measures
Measure	LKA651 n=23 Participants LKA651 5 mg Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	LKA651 + Lucentis n=28 Participants LKA651 1 mg + Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	Lucentis n=31 Participants Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase
Outer Macular Thickness (Temporal)	404.60 micrometer Standard Deviation 103.616	371.83 micrometer Standard Deviation 70.124	352.24 micrometer Standard Deviation 56.793

PRIMARY outcome

Timeframe: Days 29, 57, 85, End of Study (Up to Day 140)

Population: Pharmacodynamic analysis set - Participants with a valid measure and without a protocol deviation that would have an impact on the outcome measure.

Foveal avascular zone was assessed by fluorescein angiography (FA).

Outcome measures

Outcome measures
Measure	LKA651 n=21 Participants LKA651 5 mg Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	LKA651 + Lucentis n=25 Participants LKA651 1 mg + Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	Lucentis n=30 Participants Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase
Number of Participants Without Changes in Foveal Avascular Zone as Measured by Fluorescein Angiography (FA) in Study Eye Day 29 - NO CHANGE	3 Participants	16 Participants	11 Participants
Number of Participants Without Changes in Foveal Avascular Zone as Measured by Fluorescein Angiography (FA) in Study Eye Day 57 - NO CHANGE	3 Participants	16 Participants	7 Participants
Number of Participants Without Changes in Foveal Avascular Zone as Measured by Fluorescein Angiography (FA) in Study Eye Day 85 - NO CHANGE	21 Participants	25 Participants	29 Participants
Number of Participants Without Changes in Foveal Avascular Zone as Measured by Fluorescein Angiography (FA) in Study Eye End of Study (Up to Day 140) - NO CHANGE	17 Participants	22 Participants	30 Participants
Number of Participants Without Changes in Foveal Avascular Zone as Measured by Fluorescein Angiography (FA) in Study Eye End of Study (Up to Day 140) - CANNOT GRADE	—	1 Participants	—

PRIMARY outcome

Timeframe: Days 8, 15, 29, 43, 57, 85

Population: Pharmacodynamic analysis set - Participants with a valid measure and without a protocol deviation that would have an impact on the outcome measure.

Central subfield thickness was measured by spectral domain optical coherence tomography (SD-OCT). Central subfield retinal thickness was analyzed with a mixed model for repeated measures. The model included treatment, visit, and the treatment by visit interaction as independent variables. An unstructured residual covariance structure was used. Log-transformed baseline central subfield retinal thickness and treatment naïve and treatment experienced variable were used as covariates. Results were back-transformed to show results as a ratio to baseline.

Outcome measures

Outcome measures
Measure	LKA651 n=25 Participants LKA651 5 mg Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	LKA651 + Lucentis n=28 Participants LKA651 1 mg + Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	Lucentis n=32 Participants Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase
Mixed Model Repeated Measures Analysis of Ratio to Baseline in Central Subfield Retinal Thickness (CSFT) in the Study Eye Day 8	0.99 ratio Interval 0.92 to 1.07	0.83 ratio Interval 0.78 to 0.88	0.83 ratio Interval 0.78 to 0.88
Mixed Model Repeated Measures Analysis of Ratio to Baseline in Central Subfield Retinal Thickness (CSFT) in the Study Eye Day 15	0.97 ratio Interval 0.9 to 1.05	0.83 ratio Interval 0.78 to 0.88	0.80 ratio Interval 0.76 to 0.86
Mixed Model Repeated Measures Analysis of Ratio to Baseline in Central Subfield Retinal Thickness (CSFT) in the Study Eye Day 29	1.00 ratio Interval 0.94 to 1.05	0.80 ratio Interval 0.76 to 0.85	0.82 ratio Interval 0.78 to 0.86
Mixed Model Repeated Measures Analysis of Ratio to Baseline in Central Subfield Retinal Thickness (CSFT) in the Study Eye Day 85	0.97 ratio Interval 0.91 to 1.05	0.75 ratio Interval 0.7 to 0.8	0.78 ratio Interval 0.73 to 0.83
Mixed Model Repeated Measures Analysis of Ratio to Baseline in Central Subfield Retinal Thickness (CSFT) in the Study Eye Day 43	1.04 ratio Interval 0.97 to 1.13	0.76 ratio Interval 0.71 to 0.81	0.79 ratio Interval 0.74 to 0.84
Mixed Model Repeated Measures Analysis of Ratio to Baseline in Central Subfield Retinal Thickness (CSFT) in the Study Eye Day 57	0.95 ratio Interval 0.89 to 1.0	0.75 ratio Interval 0.7 to 0.8	0.80 ratio Interval 0.76 to 0.84

SECONDARY outcome

Timeframe: Week 12 (Day 85) up to Day 140

Population: Pharmacodynamic analysis set - Participants with a valid measure and without a protocol deviation that would have an impact on the outcome measure.

Outcome measures

Outcome measures
Measure	LKA651 n=25 Participants LKA651 5 mg Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	LKA651 + Lucentis n=29 Participants LKA651 1 mg + Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	Lucentis n=32 Participants Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase
Number of Participants Who Needed Retreatment With Anti-VEGF in Study Eye After Week 12	16 Participants	16 Participants	21 Participants

SECONDARY outcome

Timeframe: Week 12 (Day 85) up to Day 140

Population: Pharmacodynamic analysis set - Participants with a valid measure and without a protocol deviation that would have an impact on the outcome measure.

Time to retreatment with anti VEGF (as determined by the investigator) after Week 12 during the additional 12 week extension phase (that was up to 16 weeks after the last dose) was examined with a Kaplan Meier plot.

Outcome measures

Outcome measures
Measure	LKA651 n=25 Participants LKA651 5 mg Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	LKA651 + Lucentis n=29 Participants LKA651 1 mg + Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	Lucentis n=32 Participants Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase
Time to Retreatment in Study Eye With Anti-VEGF After Week 12	55.0 Days after Day 85 (Week 12) Interval 17.0 to Not estimable due to insufficient number of participants with events.	34.0 Days after Day 85 (Week 12) Interval 12.0 to Not estimable due to insufficient number of participants with events.	31.0 Days after Day 85 (Week 12) Interval 9.0 to 109.0

SECONDARY outcome

Timeframe: Day 1 (0, 0.5 and 4 hrs post dose), Day 2, Day 8, Day 15, Day 29 (0, 0.5 and 4 hrs post dose), Day 43, Day 57 (0, 0.5 and 4 hrs post dose), Day 85

Population: Pharmacokinetic analysis set. Concentrations below the Lower Limit of Quantification (LLOQ) are reported as zero.

PK parameters were determined using non-compartmental methods using the most recent version of WinNonlin Phoenix (Version 8.2). Concentrations below the lower limit of quantification (LLOQ) were treated as 1/2 LLOQ in summary statistics.

Outcome measures

Outcome measures
Measure	LKA651 n=23 Participants LKA651 5 mg Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	LKA651 + Lucentis n=28 Participants LKA651 1 mg + Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	Lucentis Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase
Summary Statistics of Pharmacokinetics - Serum Concentrations of LKA651 Day 57 - 0.5 hrs post dos	0.00 ng/mL	0.00 ng/mL Standard Deviation 0.00	—
Summary Statistics of Pharmacokinetics - Serum Concentrations of LKA651 Day 1 - 0 hrs	0.00 ng/mL Standard Deviation 0.00	0.00 ng/mL Standard Deviation 0.00	—
Summary Statistics of Pharmacokinetics - Serum Concentrations of LKA651 Day 1 - 0.5 hrs post dose	0.00 ng/mL	0.00 ng/mL Standard Deviation 0.00	—
Summary Statistics of Pharmacokinetics - Serum Concentrations of LKA651 Day 1 - 4 hrs post dose	114 ng/mL Standard Deviation 211	4.43 ng/mL Standard Deviation 17.1	—
Summary Statistics of Pharmacokinetics - Serum Concentrations of LKA651 Day 2	36.3 ng/mL Standard Deviation 29.2	8.13 ng/mL Standard Deviation 21.6	—
Summary Statistics of Pharmacokinetics - Serum Concentrations of LKA651 Day 8	16.2 ng/mL Standard Deviation 27.5	2.08 ng/mL Standard Deviation 8.06	—
Summary Statistics of Pharmacokinetics - Serum Concentrations of LKA651 Day 15	7.24 ng/mL Standard Deviation 16.2	0.00 ng/mL Standard Deviation 0.00	—
Summary Statistics of Pharmacokinetics - Serum Concentrations of LKA651 Day 29 - 0 hrs	0.00 ng/mL Standard Deviation 0.00	0.00 ng/mL Standard Deviation 0.00	—
Summary Statistics of Pharmacokinetics - Serum Concentrations of LKA651 Day 29 - 0.5 hrs post dose	0.00 ng/mL	0.00 ng/mL Standard Deviation 0.00	—
Summary Statistics of Pharmacokinetics - Serum Concentrations of LKA651 Day 29 - 4 hrs post dose	—	7.60 ng/mL Standard Deviation 18.6	—
Summary Statistics of Pharmacokinetics - Serum Concentrations of LKA651 Day 43	0.00 ng/mL	0.00 ng/mL Standard Deviation 0.00	—
Summary Statistics of Pharmacokinetics - Serum Concentrations of LKA651 Day 57 - 0 hrs	0.00 ng/mL Standard Deviation 0.00	0.00 ng/mL Standard Deviation 0.00	—
Summary Statistics of Pharmacokinetics - Serum Concentrations of LKA651 Day 57 - 4 hrs post dose	—	0.00 ng/mL Standard Deviation 0.00	—
Summary Statistics of Pharmacokinetics - Serum Concentrations of LKA651 Day 85	0.00 ng/mL Standard Deviation 0.00	0.00 ng/mL Standard Deviation 0.00	—

SECONDARY outcome

Timeframe: Day 1 - 4 hrs post dose, Day 2, Day 8, Day 15, Day 29 - 4 hrs post dose, Day 43, Day 57 - 4 hrs post dose, Day 85

Population: Pharmacokinetic analysis set. PK parameters could not be derived due to the limited number of LKA651 concentrations above the lower limit of quantification.

Area under the curve over the dosing interval 0 to 28 days.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1 - 4 hrs post dose, Day 2, Day 8, Day 15, Day 29 - 4 hrs post dose, Day 43, Day 57 - 4 hrs post dose, Day 85

Population: Pharmacokinetic analysis set. PK parameters could not be derived due to the limited number of Lucentis concentrations above the lower limit of quantification.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1 - 4 hrs post dose, Day 2, Day 8, Day 15, Day 29 - 4 hrs post dose, Day 43, Day 57 - 4 hrs post dose, Day 85

Population: Pharmacokinetic analysis set. PK parameters could not be derived due to the limited number of Lucentis concentrations above the lower limit of quantification.

Area under the curve over the dosing interval 0 to 28 days.

Outcome measures

Outcome data not reported

POST_HOC outcome

Timeframe: On-treatment - up to 12 weeks; Post-treatment - greater than 30 days after last treatment, until study completion, up to approximately 168 days

Population: Safety Set

On-treatment deaths are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days). Post-treatment deaths are reported for the timeframe of greater than 30 days after last treatment, until study completion, up to approximately 168 days. All deaths refer to the sum of on-treatment and post-treatment deaths.

Outcome measures

Outcome measures
Measure	LKA651 n=28 Participants LKA651 5 mg Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	LKA651 + Lucentis n=30 Participants LKA651 1 mg + Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	Lucentis n=33 Participants Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase
All Collected Deaths On-Treatment Deaths	0 Participants	0 Participants	0 Participants
All Collected Deaths Post-Treatment Deaths	1 Participants	0 Participants	0 Participants
All Collected Deaths All Deaths	1 Participants	0 Participants	0 Participants

Adverse Events

LKA651

Serious events: 3 serious events

Other events: 20 other events

Deaths: 1 deaths

LKA651 + Lucentis

Serious events: 4 serious events

Other events: 16 other events

Deaths: 0 deaths

Lucentis

Serious events: 1 serious events

Other events: 19 other events

Deaths: 0 deaths

Total

Serious events: 8 serious events

Other events: 55 other events

Deaths: 1 deaths

Serious adverse events

Serious adverse events
Measure	LKA651 n=28 participants at risk LKA651 5 mg Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	LKA651 + Lucentis n=30 participants at risk LKA651 1 mg + Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	Lucentis n=33 participants at risk Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase	Total n=91 participants at risk Total
Cardiac disorders Angina unstable	0.00% 0/28 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	3.3% 1/30 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	0.00% 0/33 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	1.1% 1/91 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).
Eye disorders Retinal detachment	3.6% 1/28 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	0.00% 0/30 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	0.00% 0/33 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	1.1% 1/91 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).
Gastrointestinal disorders Cyclic vomiting syndrome	0.00% 0/28 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	3.3% 1/30 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	0.00% 0/33 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	1.1% 1/91 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).
Gastrointestinal disorders Varices oesophageal	0.00% 0/28 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	3.3% 1/30 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	0.00% 0/33 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	1.1% 1/91 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).
Infections and infestations COVID-19	0.00% 0/28 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	0.00% 0/30 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	3.0% 1/33 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	1.1% 1/91 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).
Infections and infestations COVID-19 pneumonia	3.6% 1/28 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	0.00% 0/30 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	0.00% 0/33 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	1.1% 1/91 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).
Infections and infestations Pneumonia	0.00% 0/28 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	0.00% 0/30 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	3.0% 1/33 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	1.1% 1/91 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).
Metabolism and nutrition disorders Dehydration	0.00% 0/28 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	3.3% 1/30 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	0.00% 0/33 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	1.1% 1/91 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bone cancer metastatic	0.00% 0/28 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	3.3% 1/30 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	0.00% 0/33 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	1.1% 1/91 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer metastatic	0.00% 0/28 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	3.3% 1/30 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	0.00% 0/33 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	1.1% 1/91 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).
Nervous system disorders Haemorrhagic stroke	3.6% 1/28 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	0.00% 0/30 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	0.00% 0/33 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	1.1% 1/91 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).
Psychiatric disorders Confusional state	0.00% 0/28 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	3.3% 1/30 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	0.00% 0/33 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).	1.1% 1/91 • Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: + 1 862 778 8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER