Efficacy and Safety of KBP-336 in Obese Individuals with Osteoarthritis

Inclusion Criteria:

1. The participant is able to read and understand the language and content of the studymaterial and provide written Informed Consent.

2. Willing and able to comply with study requirements and instructions

3. A diagnosis of OA of the target knee based on American College of Rheumatology (ACR)clinical and radiographic criteria(31), with OA symptoms (as reported by theparticipant) that have been present for at least 3 months prior to screening

4. Radiological OA grade 2 or 3 of the target knee, using the Kellgren-Lawrence methodas graded by a central reader on a Fixed-Flexion X-ray obtained during screening, oron a recent (within 6 months) X-ray which fulfills the protocol specifications forreading

5. Age ≥ 45 years of either sex

6. Body Mass Index (BMI) ≥ 30 kg/m2

7. Good health, defined as no significantly relevant medical history or findings onphysical examination, vital signs, ECG, and laboratory results in the opinion of theinvestigator.

8. Intolerance or insufficient pain relief with standard of care (e.g. physiotherapy,paracetamol, local or systemic NSAID, short term opioid use, injections ofhyaluronic acid, or corticosteroids) for symptomatic OA in the index knee in theopinion of the investigator.

9. WOMAC pain subscale score in target knee at screening AND baseline ≥20 (0-50 scale)

10. Willing to withdraw from any pain medication including, but not limited to, Opioids (including semisynthetic opioids), Non-Steroidal Anti-inflammatories (NSAIDs, withthe exception of low-dose aspirin for thromboprophylaxis), COX-2 inhibitors, Topicalmedication, and Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs e.g.Duloxetine) and only use the allowed Rescue Medications from baseline to Visit 13/ET (maximum 4000 mg paracetamol per day)

Exclusion Criteria:

1. Partial or complete joint replacement of either knee

2. Target knee surgery or arthroscopy within 1 year prior to screening

3. Diagnosis of OA resulting from trauma within the last 5 years

4. Pain of the contralateral knee exceeding that of the target knee at the baselinevisit, as measured by the WOMAC pain subscale

5. Planned major surgery within the next 6 months

6. Uncontrolled thyroid disease in the opinion of the Investigator based on medicalhistory and laboratory results collected in screening

7. Participant-reported weight loss >5% of body weight within the last 6 months of thescreening visit

8. Bariatric surgery within the last 12 months of the screening visit

9. Current comorbid condition, other than OA, affecting target knee or systemic illnessknown to be significantly associated with arthritis or joint pathology affecting anyjoint, including but not necessarily limited to endocrinopathies, inflammatory, orautoimmune disease with significant joint involvement (e.g., Rheumatoid Arthritis);Seronegative Spondyloarthropathies (e.g. Ankylosing Spondylitis, Psoriasisarthritis, Reactive arthritis)

10. Conditions significantly affecting joint and bone health, in the opinion of theInvestigator should be excluded (including but not limited to atrophic orhypotrophic OA, subchondral insufficiency fracture, osteonecrosis, osteoporoticfractures, excessive malalignment of the knee or severe chondrocalcinosis)

11. Active comorbid condition other than OA (e.g radicular back pain, bursitis,tendinitis) significantly affecting target knee pain reporting in the opinion of theinvestigator.

12. A Patient Health Questionnaire-9 (PHQ-9) score of ≥ 15 at screening

13. History of gout, or pseudogout, with high likelihood of flare up during trialparticipation that would require NSAID treatment, in the opinion of the investigator

14. Hip dislocation and congenital hip dysplasia with degenerative joint disease shouldbe excluded.

15. Participation in any previous DACRA/amylin study

16. History or presence of clinically significant neurological disease or psychiatricdisorder in the opinion of the investigator

17. Intra-articular injection of corticosteroids within 3 months or hyaluronic acidwithin 6 months of screening in the target knee or into any other major joint within 30 days prior to screening (for extended-release corticosteroid injections: within 6months in target knee and 3 months into any other major joint).

18. Systemic corticosteroid treatment for the treatment of musculoskeletal conditions ofmore than 14 days during the past 6 months prior to screening.

19. Any pharmacological or non-pharmacological treatment primarily targeting OA startedor changed during the 4 weeks prior to randomization or likely to be changed duringthe duration of the study

20. Treatment with medication for obesity, including GLP-1 analogues, unless the dose ofuse has been stable for at least six months prior to screening

21. Vitamin D deficiency defined as blood 25-OH D3 concentration ≤25 nmol/L. Vitamin Dsupplementation and subsequent rescreening is allowed

22. Presence or history of clinically significant allergies, including relevant drughypersensitivity or allergy

23. Current malignancy or treatment for malignancy within the past five years, apartfrom resected basal cell carcinoma, squamous skin cell carcinoma, or resectedcervical atypia or carcinoma in situ, unless affecting the target knee area.

24. History of alcohol or drug abuse within 5 years prior to screening, in the opinionof the Investigator.

25. Use of an investigational drug within 90 days prior to screening

26. For women of childbearing potential:

27. Pregnancy (i.e. positive serum pregnancy test at screening) or breastfeeding

28. Failure to agree to practice a highly effective method of contraception (seeAppendix 2), from enrolment up to at least 3 months after the study end

29. For sexually active men with a female partner of childbearing potential:

30. Failure to agree to ensure that their female partners use a highly effectivemethod of contraception (see Appendix 2) from enrolment up to at least 3 monthsafter the study end

31. Failure to agree not to donate sperm throughout the study and at least 3 monthsafter the study end

32. Unsuitable for study participation for any reason in the opinion of theInvestigator.