A Study Evaluating the Safety, Pharmacokinetics, and Pharmacodynamics of KA34 in Subjects With Knee Osteoarthritis

This is a randomized, double-blind, placebo-controlled study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of KA34 when administered via intra-articular injection to subjects with osteoarthritis of the knee. OA patients are randomized to receive either placebo or KA34 active drug in the range of 50-400 ug by intra-articular injection. The first portion of the study is with single ascending doses, the second portion of the study is with multiple ascending doses.

• KA34 (Drug), also known as KA-34: 50 µg - 400 µg intra-articular injection (single or multiple doses)
• Placebo (Drug): 50 µg - 400 µg intra-articular injection (single or multiple doses)

Primary outcomes

• SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) [Day 1 up to Day 29]: TEAEs were collected from time of first administration of IP (Day 1) until 28 days after the last administration of IP. The severity of TEAEs was classified by the investigator as mild, moderate or severe and graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The investigator also assessed relatedness of TEAEs. The number of subjects who experienced any TEAEs, serious TEAEs (SAE), related TEAEs and TEAEs with CTCAE Grade ≥ 3 are presented.
• MAD Part: Number of Subjects Who Experienced TEAEs [Day 1 up to Day 180]: TEAEs were collected from time of first administration of IP (Day 1) until 30 days after the last administration of IP. The severity of TEAEs was classified by the investigator as mild, moderate or severe and graded using the CTCAE version 5.0. The investigator also assessed relatedness of TEAEs. The number of subjects who experienced any TEAEs, SAEs, related TEAEs and TEAEs with CTCAE Grade ≥ 3 are presented.

Secondary outcomes

• SAD Part: Mean Change From Baseline in Hemoglobin at Day 8 [Baseline and Day 8]: The mean changes from baseline at Day 8 in hemoglobin levels for subjects in the SAD part of the study are presented.
• MAD Part: Mean Change From Baseline in Hemoglobin at Day 180 [Baseline and Day 180]: The mean changes from baseline at Day 180 in hemoglobin levels for subjects in the MAD part of the study are presented.
• SAD Part: Mean Change From Baseline in Hematocrit at Day 8 [Baseline and Day 8]: The mean changes from baseline at Day 8 in hematocrit levels for subjects in the SAD part of the study are presented.
• MAD Part: Mean Change From Baseline in Hematocrit at Day 180 [Baseline and Day 180]: The mean changes from baseline at Day 180 in hematocrit levels for subjects in the MAD part of the study are presented.
• SAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 8 [Baseline and Day 8]: The mean changes from baseline at Day 8 in total bilirubin and creatinine for subjects in the SAD part of the study are presented.
• MAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 180 [Baseline and Day 180]: The mean changes from baseline at Day 180 in total bilirubin and creatinine for subjects in the MAD part of the study are presented.
• SAD Part: Mean Change From Baseline in Liver Enzymes at Day 8 [Baseline and Day 8]: The mean changes from baseline at Day 8 in the following liver enzyme levels are presented for subjects in the SAD part of the study: alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST).
• MAD Part: Mean Change From Baseline in Liver Enzymes at Day 180 [Baseline and Day 180]: The mean changes from baseline at Day 180 in the following liver enzyme levels are presented for subjects in the MAD part of the study: ALP, ALT and AST.
• SAD Part: Mean Change From Baseline in Systolic and Diastolic Blood Pressure at Day 8 [Baseline and Day 8]: The mean changes from baseline at Day 8 in systolic blood pressure (SBP) and diastolic blood pressure (DBP) for subjects in the SAD part of the study are presented.
• MAD Part: Mean Change From Baseline in SBP and DBP at Day 180 [Baseline and Day 180]: The mean changes from baseline at Day 180 in SBP and DBP for subjects in the MAD part of the study are presented.
• SAD Part: Mean Change From Baseline in the QTcF Interval at Day 8 [Baseline and Day 8]: The mean changes from baseline at Day 8 in the electrocardiogram (ECG) parameter QTcF interval for subjects in the SAD part of the study are presented.
• MAD Part: Mean Change From Baseline in the QTcF Interval at Day 180 [Baseline and Day 180]: The mean changes from baseline at Day 180 in the ECG parameter QTcF interval for subjects in the MAD part of the study are presented.
• SAD Part: Number of Subjects With Injection Site TEAEs [Baseline up to Day 29]: Physical examinations were conducted by a physician or another medically-qualified individual and findings were noted at the injection site during the study. The number of subjects with injection site TEAEs, including the following, are presented: Injection site erythema, Injection site hypersensitivity, Injection site inflammation, Injection site joint discomfort, Injection site joint inflammation, Injection site joint pain, Injection site joint swelling, Injection site nodule, Injection site pain and Injection site swelling.
• MAD Part: Number of Subjects With Injection Site TEAEs [Baseline up to Day 180]: Physical examinations were conducted by a physician or another medically-qualified individual and findings were noted at the injection site during the study. The number of subjects with injection site TEAEs, including the following, are presented: Injection site erythema, Injection site hypersensitivity, Injection site inflammation, Injection site joint discomfort, Injection site joint inflammation, Injection site joint pain, Injection site joint swelling, Injection site nodule, Injection site pain and Injection site swelling.
• SAD Part: Mean Maximum Plasma Concentration (Cmax) [Pre-dose up to 4 hours post-dose on Day 1]: All Pharmacokinetic (PK) samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. Cmax values were obtained directly from the observed concentration versus time data, and the geometric mean Cmax values for subjects who received KA34 in the SAD part of the study are presented.
• MAD Part: Mean Cmax [Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29]: All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. Cmax values were obtained directly from the observed concentration versus time data, and the geometric mean Cmax values for subjects who received KA34 in the MAD part of the study are presented.
• SAD Part: Median Time to Maximum Observed Plasma Concentration (Tmax) [Pre-dose up to 4 hours post-dose on Day 1]: All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. Tmax was obtained directly from the observed concentration versus time data and the median Tmax values for subjects who received KA34 in the SAD part of the study are presented.
• MAD Part: Median Tmax [Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29]: All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. Tmax was obtained directly from the observed concentration versus time data and the median Tmax values for subjects who received KA34 in the MAD part of the study are presented.
• SAD Part: Mean Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-t]) [Pre-dose up to 4 hours post-dose on Day 1]: All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. AUC(0-t) was calculated by linear up/log down trapezoidal summation, and the mean AUC(0-t) values for subjects who received KA34 in the SAD part of the study are presented.
• MAD Part: Mean AUC(0-t) [Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29]: All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. AUC(0-t) was calculated by linear up/log down trapezoidal summation, and the mean AUC(0-t) values for subjects who received KA34 in the MAD part of the study are presented.
• SAD Part: Mean Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinite Time (AUC[0-inf]) [Pre-dose up to 4 hours post-dose on Day 1]: All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. AUC(0-inf) was calculated by linear up/log down trapezoidal summation and extrapolated to infinity by the addition of the last quantifiable concentration (Clast) divided by the elimation rate constant (λz), i.e. AUC(0-t) + Clast/λz. The mean AUC(0-inf) values for subjects who received KA34 in the SAD part of the study are presented.
• MAD Part: Mean AUC(0-inf) [Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29]: All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. AUC(0-inf) was calculated by linear up/log down trapezoidal summation and extrapolated to infinity by the addition of the last quantifiable concentration (Clast) divided by the elimation rate constant (λz), i.e. AUC(0-t) + Clast/λz. The mean AUC(0-inf) values are presented for subjects who received KA34 in the MAD part of the study.
• SAD Part: Mean Apparent Terminal Half-life (t1/2) [Pre-dose up to 4 hours post-dose on Day 1]: All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. t1/2 was determined as the natural log of λz, i.e. as ln2/λz. Mean t1/2 values for subjects who received KA34 in the SAD part of the study are presented.
• MAD Part: Mean t1/2 [Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29]: All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. t1/2 was determined as the natural log of λz, i.e. as ln2/λz. Mean t1/2 values for subjects who received KA34 in the MAD part of the study are presented.
• SAD Part: Mean Apparent Clearance (CL/F) [Pre-dose up to 4 hours post-dose on Day 1]: All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. The CL/F after extravascular dosing was calculated as dose divided by AUC(0-inf), and is presented for subjects who received KA34 in the SAD part of the study.
• MAD Part: Mean CL/F [Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29]: All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. The CL/F after extravascular dosing was calculated as dose divided by AUC(0-inf), and is presented for subjects who received KA34 in the MAD part of the study.
• SAD Part: Mean Apparent Volume of Distribution (Vz/F) [Pre-dose up to 4 hours post-dose on Day 1]: The Vz/F was calculated as dose divided by (λz*AUC\[0-inf\]), and the mean Vz/F values for subjects who received KA34 in the SAD part of the study are presented.
• MAD Part: Mean Vz/F [Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29]: The Vz/F was calculated as dose divided by (λz*AUC\[0-inf\]), and the mean Vz/F values for subjects who received KA34 in the MAD part of the study are presented.

Sex: All, ages: 40 Years to 75 Years

Inclusion Criteria:

* Diagnosis of localized osteoarthritis of the knee
* Males willing to use contraception and females who are no longer able to bear children

Exclusion Criteria:

* Body Mass Index (BMI) > 40
* Grade 0, 3 or 4 osteoarthritis on the Kellgren and Lawrence classification system
* Injury to the knee or other joint within the last 12 months
* Receipt of any investigational product or experimental therapeutic procedure within the last 12 weeks

Participant flow

Outcome results

• SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) (Primary), Count of participants, Participants: Placebo (SAD) 1; Cohort 1: KA34 50 µg (SAD) 2; Cohort 2: KA34 100 µg (SAD) 1; Cohort 3: KA34 200 µg (SAD) 4; Cohort 4: KA34 400 µg (SAD) 1
• MAD Part: Number of Subjects Who Experienced TEAEs (Primary), Count of participants, Participants: Placebo (MAD) 7; Cohort 5: KA34 100 µg (MAD) 3; Cohort 6: KA34 200 µg (MAD) 6; Cohort 7: KA34 400 µg (MAD) 5
• SAD Part: Mean Change From Baseline in Hemoglobin at Day 8 (Secondary), Mean, grams/deciliter (g/dL): Placebo (SAD) -0.12 +/- 0.58; Cohort 1: KA34 50 µg (SAD) 0.77 +/- 2.12; Cohort 2: KA34 100 µg (SAD) -0.07 +/- 0.81; Cohort 3: KA34 200 µg (SAD) 0.08 +/- 0.48; Cohort 4: KA34 400 µg (SAD) -0.32 +/- 0.50
• MAD Part: Mean Change From Baseline in Hemoglobin at Day 180 (Secondary), Mean, g/dL: Placebo (MAD) 0.36 +/- 1.21; Cohort 5: KA34 100 µg (MAD) -0.60 +/- 1.01; Cohort 6: KA34 200 µg (MAD) -0.48 +/- 1.29; Cohort 7: KA34 400 µg (MAD) -0.07 +/- 0.19
• SAD Part: Mean Change From Baseline in Hematocrit at Day 8 (Secondary), Mean, volume % of red blood cells (RBCs): Placebo (SAD) -0.20 +/- 1.61; Cohort 1: KA34 50 µg (SAD) 2.40 +/- 6.67; Cohort 2: KA34 100 µg (SAD) -0.37 +/- 2.70; Cohort 3: KA34 200 µg (SAD) 0.12 +/- 1.33; Cohort 4: KA34 400 µg (SAD) -0.97 +/- 1.58
• MAD Part: Mean Change From Baseline in Hematocrit at Day 180 (Secondary), Mean, volume % of RBCs: Placebo (MAD) 42.68 +/- 4.59; Cohort 5: KA34 100 µg (MAD) 41.33 +/- 4.77; Cohort 6: KA34 200 µg (MAD) 42.12 +/- 2.02; Cohort 7: KA34 400 µg (MAD) 44.54 +/- 2.35
• SAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 8 (Secondary), Mean, milligrams/dL (mg/dL): Placebo (SAD) 0.023 +/- 0.416; Cohort 1: KA34 50 µg (SAD) 0.053 +/- 0.137; Cohort 2: KA34 100 µg (SAD) -0.033 +/- 0.058; Cohort 3: KA34 200 µg (SAD) 0.100 +/- 0.179; Cohort 4: KA34 400 µg (SAD) 0.037 +/- 0.102
• MAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 180 (Secondary), Mean, mg/dL: Placebo (MAD) 0.067 +/- 0.100; Cohort 5: KA34 100 µg (MAD) -0.051 +/- 0.153; Cohort 6: KA34 200 µg (MAD) -0.017 +/- 0.112; Cohort 7: KA34 400 µg (MAD) -0.043 +/- 0.264
• SAD Part: Mean Change From Baseline in Liver Enzymes at Day 8 (Secondary), Mean, Units/Liter (U/L): Placebo (SAD) 0.0 +/- 3.8; Cohort 1: KA34 50 µg (SAD) -7.7 +/- 14.2; Cohort 2: KA34 100 µg (SAD) 3.7 +/- 7.0; Cohort 3: KA34 200 µg (SAD) 0.0 +/- 4.5; Cohort 4: KA34 400 µg (SAD) 4.0 +/- 11.7
• MAD Part: Mean Change From Baseline in Liver Enzymes at Day 180 (Secondary), Mean, U/L: Placebo (MAD) -3.4 +/- 8.8; Cohort 5: KA34 100 µg (MAD) -0.2 +/- 11.6; Cohort 6: KA34 200 µg (MAD) -10.2 +/- 13.8; Cohort 7: KA34 400 µg (MAD) 1.1 +/- 7.6
• SAD Part: Mean Change From Baseline in Systolic and Diastolic Blood Pressure at Day 8 (Secondary), Mean, millimeters mercury (mmHg): Placebo (SAD) -7.3 +/- 18.2; Cohort 1: KA34 50 µg (SAD) 6.0 +/- 12.2; Cohort 2: KA34 100 µg (SAD) -11.3 +/- 6.7; Cohort 3: KA34 200 µg (SAD) 7.8 +/- 10.9; Cohort 4: KA34 400 µg (SAD) 3.7 +/- 8.8
• MAD Part: Mean Change From Baseline in SBP and DBP at Day 180 (Secondary), Mean, mmHg: Placebo (MAD) 7.7 +/- 13.3; Cohort 5: KA34 100 µg (MAD) 8.9 +/- 8.5; Cohort 6: KA34 200 µg (MAD) -2.1 +/- 15.3; Cohort 7: KA34 400 µg (MAD) -0.3 +/- 20.4
• SAD Part: Mean Change From Baseline in the QTcF Interval at Day 8 (Secondary), Mean, milliseconds (msec): Placebo (SAD) 2.3 +/- 14.3; Cohort 1: KA34 50 µg (SAD) 11.7 +/- 6.8; Cohort 2: KA34 100 µg (SAD) -3.7 +/- 14.8; Cohort 3: KA34 200 µg (SAD) -10.7 +/- 25.3; Cohort 4: KA34 400 µg (SAD) 3.5 +/- 32.4
• MAD Part: Mean Change From Baseline in the QTcF Interval at Day 180 (Secondary), Mean, msec: Placebo (MAD) 3.9 +/- 13.5; Cohort 5: KA34 100 µg (MAD) 1.9 +/- 10.1; Cohort 6: KA34 200 µg (MAD) -3.6 +/- 14.7; Cohort 7: KA34 400 µg (MAD) 3.4 +/- 24.0
• SAD Part: Number of Subjects With Injection Site TEAEs (Secondary), Count of participants, Participants: Placebo (SAD) 0; Cohort 1: KA34 50 µg (SAD) 0; Cohort 2: KA34 100 µg (SAD) 0; Cohort 3: KA34 200 µg (SAD) 1; Cohort 4: KA34 400 µg (SAD) 0
• MAD Part: Number of Subjects With Injection Site TEAEs (Secondary), Count of participants, Participants: Placebo (MAD) 0; Cohort 5: KA34 100 µg (MAD) 0; Cohort 6: KA34 200 µg (MAD) 0; Cohort 7: KA34 400 µg (MAD) 0
• SAD Part: Mean Maximum Plasma Concentration (Cmax) (Secondary), Geometric mean, nanograms/milliliter (ng/mL): Cohort 1: KA34 50 µg (SAD) 0.8528 +/- 43.6; Cohort 2: KA34 100 µg (SAD) 2.757 +/- 29.9; Cohort 3: KA34 200 µg (SAD) 5.732 +/- 18.7; Cohort 4: KA34 400 µg (SAD) 9.435 +/- 41.4
• MAD Part: Mean Cmax (Secondary), Geometric mean, ng/mL: Cohort 5: KA34 100 µg (MAD) 2.536 +/- 33.7; Cohort 6: KA34 200 µg (MAD) 4.807 +/- 26.7; Cohort 7: KA34 400 µg (MAD) 10.67 +/- 40.3
• SAD Part: Median Time to Maximum Observed Plasma Concentration (Tmax) (Secondary), Median, hours (h): Cohort 1: KA34 50 µg (SAD) 0.25 (0.25 to 0.52); Cohort 2: KA34 100 µg (SAD) 0.50 (0.50 to 0.53); Cohort 3: KA34 200 µg (SAD) 0.38 (0.22 to 0.53); Cohort 4: KA34 400 µg (SAD) 0.30 (0.25 to 1.03)
• MAD Part: Median Tmax (Secondary), Median, h: Cohort 5: KA34 100 µg (MAD) 0.50 (0.23 to 0.55); Cohort 6: KA34 200 µg (MAD) 0.30 (0.25 to 0.50); Cohort 7: KA34 400 µg (MAD) 0.50 (0.28 to 1.00)
• 10 more outcome measures not shown.

Adverse events

Time frame: TEAEs were collected from time of first administration of IP (Day 1) up to 30 days after the last administration of IP (approximately 1 month for the SAD cohorts and approximately 6 months for the MAD cohorts).

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2020-04-02)
• Statistical Analysis Plan (PDF, 2020-05-15)

• Martin Lotz, MD, Study director, Calibr, a division of Scripps Research