Final Operational Milestone #6

Osteoarthritis (OA) is the most common joint disorder in the United States, characterized by the progressive degeneration of articular cartilage, in part due to abnormal activation, differentiation, and death of articular chondrocytes, which are the primary cell type present in cartilage. The joints most often affected by OA are the hands, knees, hips, and spine, with symptoms of joint pain, stiffness, and movement limitations. Osteoarthritis may have a profound effect on the quality of life of patients, impacting both, physical function and psychological well-being.

Current treatment options for OA include pharmacological and nonpharmacological interventions focused primarily on reducing pain and improving physical function. Patients who do not have adequate pain relief or preservation of function may require surgical replacement of the hip, knee, or shoulder joint. There are no approved disease-modifying treatments that delay or prevent OA progression or joint destruction. Since the hallmark of OA is cartilage loss leading to joint destruction, a potential approach to treating OA is stimulation of chondrocyte regeneration from endogenous mesenchymal stem/progenitor cells in the cartilage. KA34 is a first-in-class, low molecular weight, experimental compound that promotes articular cartilage repair and is being explored as a potential treatment for OA of the knee.

With the support of CIRM through the CLIN2 award, a randomized, double-blind, placebo-controlled clinical study was conducted to assess the safety, tolerability, PK, and PD response of KA34 when administered via intra-articular (IA) injection to subjects with OA of the knee. The study consisted of 7 cohorts of subjects who were randomized to receive a 5 mL injection of KA34 or placebo in the affected knee which consisted of single ascending dose (SAD) and multiple ascending dose (MAD) arms. The study was conducted at 4 sites in the United States. 60 subjects were randomized in this study.

The overall conclusions of the Phase 1 clinical study were:

Treatment with 50, 100, 200, and 400 µg KA34 was safe and well-tolerated in the subject population. There were no dose-related trends for AEs noted in the SAD or MAD parts of the study. No subject was discontinued due to AEs and no subject died during the study.

Single-dose PK for the first dose in the MAD part (measured under similar conditions to the SAD part) was comparable to single-dose PK in the SAD part of the study at equal dose levels. The dose range studied (50 to 400 µg KA34) showed dose proportionality in the PK parameters that characterize systemic drug exposure.

In both the SAD and MAD parts the change-from-baseline results for PIIANP and CTX-II were variable in all groups. No dose-related or time-related trends or difference from placebo were noted in mean changes-from-baseline as a marker for collagen synthesis or degradation, respectively.

Treatment with 200 and 400 µg KA34 had a trend towards greater improvement in total WOMAC scores (a patient-reported outcome measure) compared with other doses studied as well as placebo, as shown by the change in WOMAC scores from Baseline to Day 8 with a single dose (SAD part) and Baseline to Day 180 with 4 weekly doses (MAD part). This trend was mostly contributed by change in physical function score.

Exploratory analysis to look for changes in the structure of the articular cartilage in the knee joint through WORMS scores were calculated from the low-resolution MRI performed on patients at Day 90 and Day 180 in the MAD phase of the study. The overall changes in the placebo group at Day 90 (0.56 ± 1.59) and Day 180 (0.33 ± 1.66) were very small and indicate minimal disease progression, thus not allowing meaningful KA34-related changes to be detected. Similarly, small changes were also observed in the subjects who received KA34, without consistent time or dose related patterns. Drug-related AEs were not observed in any of the WORMS scores.

Scripps Research will continue to perform additional analyses on the patient samples and MRI images as the team actively develops improved formulations, designs clinical plans and prepares for the next clinical study to support the development of KA34 for osteoarthritis.