The goal of this clinical trial is to learn if KBP-336 works to treat pain in osteoarthritis in individuals living with obesity. It will also learn about the effects on other parameters, such as quality of life and metabolism, as well as safety of KBP-336. The main questions it aims to answer are:

• Does KBP-336 lower knee pain from osteoarthritis in individuals with obesity
• Does KBP-336 lower bodyweight in the same population. Researchers will compare KBP-336 to a placebo (a look-alike substance that contains no drug) to see if KBP-336 works to pain and obesity

Participants will:

• Take KBP-336 or a placebo every week for 6 months
• Visit the clinic once every 2 weeks for checkups and tests
• Keep a diary of their symptoms and the amount of medication they use in addition to KBP-336

Inclusion Criteria:

1. The participant is able to read and understand the language and content of the study material 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 the participant) 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 method as graded by a central reader on a Fixed-Flexion X-ray obtained during screening, or on a recent (within 6 months) X-ray which fulfills the protocol specifications for reading
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 on physical examination, vital signs, ECG, and laboratory results in the opinion of the investigator.
8. Intolerance or insufficient pain relief with standard of care (e.g. physiotherapy, paracetamol, local or systemic NSAID, short term opioid use, injections of hyaluronic acid, or corticosteroids) for symptomatic OA in the index knee in the opinion 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, with the exception of low-dose aspirin for thromboprophylaxis), COX-2 inhibitors, Topical medication, 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 baseline visit, 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 medical history and laboratory results collected in screening

7. Participant-reported weight loss >5% of body weight within the last 6 months of the screening 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 illness known to be significantly associated with arthritis or joint pathology affecting any joint, including but not necessarily limited to endocrinopathies, inflammatory, or autoimmune disease with significant joint involvement (e.g., Rheumatoid Arthritis); Seronegative Spondyloarthropathies (e.g. Ankylosing Spondylitis, Psoriasis arthritis, Reactive arthritis)

10. Conditions significantly affecting joint and bone health, in the opinion of the Investigator should be excluded (including but not limited to atrophic or hypotrophic OA, subchondral insufficiency fracture, osteonecrosis, osteoporotic fractures, 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 the investigator.

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 trial participation that would require NSAID treatment, in the opinion of the investigator

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

15. Participation in any previous DACRA/amylin study

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

17. Intra-articular injection of corticosteroids within 3 months or hyaluronic acid within 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 6 months in target knee and 3 months into any other major joint).

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

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

20. Treatment with medication for obesity, including GLP-1 analogues, unless the dose of use 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 D supplementation and subsequent rescreening is allowed

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

23. Current malignancy or treatment for malignancy within the past five years, apart from resected basal cell carcinoma, squamous skin cell carcinoma, or resected cervical 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 opinion of the Investigator.

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

26. For women of childbearing potential:

    1. Pregnancy (i.e. positive serum pregnancy test at screening) or breastfeeding
    2. Failure to agree to practice a highly effective method of contraception (see Appendix 2), from enrolment up to at least 3 months after the study end

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

    1. Failure to agree to ensure that their female partners use a highly effective method of contraception (see Appendix 2) from enrolment up to at least 3 months after the study end
    2. Failure to agree not to donate sperm throughout the study and at least 3 months after the study end

28. Unsuitable for study participation for any reason in the opinion of the Investigator.