A Study Utilizing Patient-Reported and Radiographic Outcomes and Evaluating the Safety and Efficacy of Lorecivivint (SM04690) for the Treatment of Moderately to Severely Symptomatic Knee Osteoarthritis

Inclusion Criteria:

1. Males and females between 40 and 80 years of age, inclusive, in general good healthapart from their knee OA
2. Ambulatory (single assistive devices such as canes allowed if needed less than 50% ofthe time, subjects requiring a walker are excluded)
3. Diagnosis of femorotibial OA in the target knee by standard American College ofRheumatology (ACR) criteria at the Screening Visit (clinical AND radiographiccriteria); OA of the knee is not to be secondary to any rheumatologic conditions (e.g., rheumatoid arthritis)
4. mJSW by radiograph between 1.5 and 4 mm, inclusive, in the target knee within 12 weeksof the Screening Visit as assessed by independent central readers
5. Radiographic disease Stage 2 or 3 in the target knee within 12 weeks of the ScreeningVisit according to the Kellgren-Lawrence (KL) grading of knee OA as assessed byindependent central readers
6. Pain compatible with OA of the knee(s) for at least 26 weeks prior to the ScreeningVisit
7. Primary source of pain throughout the body is due to OA in the target knee
8. Body mass index (BMI) ≤ 40 kg/m2 at the Screening Visit
9. Widespread Pain Index (WPI) score of ≤ 4 and a Symptom Severity Question 2 (SSQ2)score of ≤ 2 at the Screening Visit and Day 1
10. Pain NRS scores recorded for the target knee on at least 4 out of the 7 daysimmediately preceding Day 1
11. Pain NRS scores recorded for the nontarget knee on at least 4 out of the 7 daysimmediately preceding Day 1
12. Daily OA knee pain diary average NRS intensity score ≥ 4 and ≤ 8 in the target knee onthe 11-point (0-10) NRS scale for the 7 days immediately preceding Day 1
13. Daily OA knee pain diary average NRS intensity score < 4 in the nontarget knee on the 11-point (0-10) NRS scale for the 7 days immediately preceding Day 1
14. WOMAC Pain of 20-40 (out of 50) for the target knee at baseline regardless of if thesubject is on symptomatic oral treatment (baseline questionnaire completed during thescreening period prior to randomization)
15. WOMAC Function of 68-136 (out of 170) for the target knee at baseline regardless of ifthe subject is on symptomatic oral treatment (baseline questionnaire completed duringthe screening period prior to randomization)
16. Willingness to use an electronic diary daily in the evening for the screening periodand 56-week study duration
17. Negative drug test for amphetamine, buprenorphine, cocaine, methadone, opiates,phencyclidine (PCP), propoxyphene, barbiturates, benzodiazepine, methaqualone, andtricyclic antidepressants, unless any of these drugs are allowed per protocol andprescribed by a physician to treat a specific condition
18. Subjects with depression or anxiety must be clinically stable for at least 12 weeksprior to the Screening Visit and, if on treatment for depression or anxiety, be on atleast 12 weeks of stable therapy
19. Full understanding of the requirements of the study and willingness to comply with allstudy visits and assessments
20. Subjects must have read and understood the informed consent form (ICF), and must havesigned and dated it prior to any study-related procedure being performed

Exclusion Criteria:

1. Pregnant women, breastfeeding woman, and women who are not post-menopausal (defined as 12 months with no menses without an alternative medical cause) or permanentlysurgically sterile (includes hysterectomy, bilateral salpingectomy, and bilateraloophorectomy), who have a positive or indeterminate pregnancy test result at theScreening Visit or Day 1
2. Women who are not post-menopausal or permanently surgically sterile who are sexuallyactive, and who are not willing to use birth control during the study period
3. Men who are sexually active and of reproductive potential, who have partners who arecapable of becoming pregnant, and who are not willing to use birth control during thestudy period
4. Significant malalignment of anatomical axis (medial angle formed by the femur andtibia) of the target knee (varus > 10°, valgus > 10°) by radiograph within 12 weeks ofthe Screening Visit as assessed by independent central readers
5. Partial or complete joint replacement in either knee
6. Currently requires use of a lower extremity prosthesis, and/or a structural knee brace (i.e., a knee brace that contains hardware)
7. Any surgery (e.g., arthroscopy) in either knee within 26 weeks prior to Day 1
8. Intra-articular (IA) injection into the target knee with a therapeutic aim including,but not limited to, hyaluronic acid, platelet-rich plasma (PRP),and stem celltherapies within 26 weeks prior to Day 1, or IA glucocorticoids within 12 weeks priorto Day 1
9. Effusion of the target knee clinically requiring aspiration within 12 weeks prior toDay 1
10. Use of electrotherapy, acupuncture, physical therapy, therapeutic ultrasound, and/orchiropractic treatments for knee OA within 4 weeks prior to Day 1
11. Any bone fracture(s) within 26 weeks prior to the Screening Visit
12. Previous treatment with SM04690
13. Subjects who have previously failed screening on this protocol and fail to meetrescreening criteria
14. Participation in a clinical research trial that included the receipt of aninvestigational product (IP) or any experimental therapeutic procedure within 26 weeksprior to the Screening Visit, or planned participation in any such trial
15. Treatment with systemic (oral, intramuscular, or intravenous) glucocorticoids ≥10 mgprednisone or the equivalent per day within 4 weeks prior to Day 1, or subjects on <10mg prednisone or the equivalent per day who have not maintained a stable regimen forat least 2 weeks prior to Day 1 in the opinion of the Investigator
16. Use of centrally acting analgesics within 12 weeks prior to Day 1
17. Use of anticonvulsants within 12 weeks prior to Day 1
18. Subjects requiring the use of opioids > 1x per week within 12 weeks prior to Day 1
19. Topical local anesthetic agents (gels, creams, or patches such as the Lidoderm patch)used for the treatment of knee OA within 7 days of Day 1
20. Planned surgery scheduled during the study period, not including non-surgical invasiveprocedures conducted for a diagnostic or therapeutic purpose scheduled during thestudy period
21. History of malignancy within the last 5 years, not including subjects with priorhistory of adequately treated in situ cervical cancer or basal or squamous cell skincancer
22. Clinically significant abnormal screening hematology values, blood chemistry values,or urinalysis values as determined by the Investigator
23. Any condition, that, in the opinion of the Investigator, constitutes a risk orcontraindication for participation in the study or that could interfere with the studyobjectives, conduct, or evaluation
24. Other conditions that, in the opinion of the Investigator, could affect study endpointassessments of either knee, including, but not limited to, peripheral neuropathy (e.g., diabetic neuropathy), symptomatic hip osteoarthritis, symptomatic degenerativedisc disease, and patellofemoral syndrome
25. Comorbid conditions that could affect study endpoint assessments of the target knee,including, but not limited to, rheumatoid arthritis, psoriatic arthritis, systemiclupus erythematosus, gout or pseudogout, and fibromyalgia
26. History of mania, bipolar disorder, psychotic disorder, schizophrenia, orschizoaffective disorder
27. Any known active infections, including urinary tract infection, upper respiratorytract infection, sinusitis, suspicion of IA infection, hepatitis B or hepatitis Cinfection, and/or infections that may compromise the immune system such as humanimmunodeficiency virus (HIV) at Day 1
28. Any chronic condition that has not been well controlled or subjects with a chroniccondition who have not maintained a stable therapeutic regimen of a prescriptiontherapy in the opinion of the Investigator.
29. Hemoglobin A1c (HbA1c) >9 at the Screening Visit
30. If using NSAIDs and/or acetaminophen, subjects who have not maintained a stableregimen in the opinion of the Investigator for at least 4 weeks prior to Day 1
31. Any contraindications for an IA injection in the target knee in the opinion of theInvestigator
32. Subjects who have a current or pending disability claim, workers' compensation, orlitigation(s) that may compromise response to treatment
33. Subjects who are immediate family members (spouse, parent, child, or sibling;biological or legally adopted) of personnel directly affiliated with the study at anyinvestigative site, or are directly affiliated with the study at any investigativesite
34. Subjects employed by Samumed, LLC, or any of its affiliates or development partners (that is, an employee, temporary contract worker, or designee) responsible for theconduct of the study, or who are immediate family members (spouse, parent, child, orsibling; biological or legally adopted) of said employees responsible for the conductof the study