A Study Evaluating the Safety, Tolerability and Efficacy of Two Injections of 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 health

2. Ambulatory

3. Diagnosis of femorotibial OA in the target knee by standard American College of
Rheumatology (ACR) criteria at Screening Visit 1 (clinical AND radiographic criteria);
OA of the knee is not to be secondary to any rheumatologic conditions (e.g.,
rheumatoid arthritis)

4. Pain compatible with OA of the knee(s) for at least 26 weeks prior to Screening Visit
1

5. Primary source of pain throughout the body is due to OA in the target knee

6. Daily OA knee pain diary average NRS intensity score ≥ 4 and ≤ 8 in the target knee on
the 11-point (0-10) NRS scale for the 7 days immediately preceding Day 1

7. Pain NRS scores recorded for the target knee on at least 4 out of the 7 days
immediately preceding Day 1

8. Daily OA knee pain diary average NRS intensity score < 4 in the non-target knee on the
11-point (0-10) NRS scale for the 7 days immediately preceding Day 1

9. Pain NRS scores recorded for the non-target knee on at least 4 out of the 7 days
immediately preceding Day 1

10. WOMAC pain subscore of 20-40 (out of 50) and WOMAC physical function subscore of
68-136 (out of 170) for the target knee at baseline, regardless of if the subject is
on symptomatic oral treatment (baseline questionnaire completed during the screening
period prior to randomization)

11. Widespread Pain Index (WPI) score of ≤ 4 and a Symptom Severity Question 2 (SSQ2)
score of ≤ 2 at Screening Visit 1

12. Willingness to use an electronic diary on a daily basis in the evening for the
screening period and 52-week study duration

13. Negative drug test for amphetamine, methamphetamine, buprenorphine, cocaine,
methadone, opiates, phencyclidine (PCP), propoxyphene, barbiturates, benzodiazepine,
methaqualone, and tricyclic antidepressants, except if any such drugs are clinically
indicated and allowed by the protocol, at Screening Visit 1.

14. Subjects with depression or anxiety must be clinically stable for 12 weeks prior to
Screening Visit 1 in the opinion of the Investigator and, if on treatment for
depression or anxiety, be on 12 weeks of stable therapy

15. Full understanding of the requirements of the study and willingness to comply with all
study visits and assessments

16. Subjects must have read and understood the Informed Consent Form (ICF), and must have
signed it prior to any study-related procedure being performed

17. Subject's Screening Visit 1 visit must occur while enrollment into the study is open

Exclusion Criteria:

1. Women who are pregnant, lactating, or have a positive or indeterminate pregnancy
result at Screening Visit 2 or Day 1

2. Women who are not post-menopausal (defined as 12 months with no menses without an
alternative medical cause) or permanently surgically sterile (includes hysterectomy,
bilateral salpingectomy, and bilateral oophorectomy, but NOT tubal ligation), who are
sexually active, and who are not willing to use birth control during the study period

3. Males who are sexually active and have a partner who is capable of becoming pregnant,
neither of whom have had surgery to become sterilized or who are not using birth
control

4. Body mass index (BMI) > 35

5. Partial or complete joint replacement in either knee

6. Currently requires:

1. regular use (in the opinion of the Investigator) of ambulatory assistive devices
(e.g., wheelchair, parallel bars, walker, canes, or crutches), or

2. use of a lower extremity prosthesis, and/or a structural knee brace (i.e., a knee
brace that contains hardware)

7. Radiographic disease Stage 0, 1, or 4 in the target knee at Screening Visit 1
according to the Kellgren-Lawrence grading of knee OA as assessed by independent
central readers

8. Previous enrollment in a Samumed clinical trial investigating SM04690

9. Any surgery (e.g., arthroscopy) in either knee within 26 weeks prior to Screening
Visit 1

10. Any bone fracture(s) within 26 weeks prior to Screening Visit 1

11. Any surgery scheduled during the study period. Non-surgical invasive procedures
conducted for a diagnostic or therapeutic purpose scheduled during the study period
are not prohibited.

12. Significant and clinically evident misalignment of either knee that would impact
subject function, as determined by the Investigator

13. History of malignancy within the last 5 years; however, subjects with prior history of
in situ basal or squamous cell skin cancer are eligible if completely excised.
Subjects with other malignancies are eligible if they have been continuously disease
free for at least 5 years prior to Screening Visit 1

14. Clinically significant abnormal screening hematology values, blood chemistry values,
or urinalysis values as determined by the Investigator

15. Any condition, including laboratory findings not included in the Screening Visit 2
laboratory tests and findings in the medical history or in the pre-study assessments,
that, in the opinion of the Investigator, constitutes a risk or contraindication for
participation in the study or that could interfere with the study objectives, conduct,
or evaluation

16. Comorbid conditions that could affect study endpoint assessments of the target knee,
including, but not limited to, rheumatoid arthritis, psoriatic arthritis, systemic
lupus erythematosus, gout or pseudogout, and fibromyalgia

17. Other conditions that, in the opinion of the Investigator, could affect study endpoint
assessments of either knee, including, but not limited to, peripheral neuropathy
(e.g., diabetic neuropathy), symptomatic hip osteoarthritis, symptomatic degenerative
disc disease, and patellofemoral syndrome

18. Any diagnosed psychiatric condition that includes, but is not limited to, a history of
mania, bipolar disorder, psychotic disorder, schizophrenia, schizoaffective disorder,
major depressive disorder, or generalized anxiety disorder

19. Participation in a clinical research trial that included the receipt of an
investigational product or any experimental therapeutic procedure, or an observational
research trial related to osteoarthritis within 8 weeks prior to Screening Visit 1, or
planned participation in any such trial; the last date of participation in the trial,
not the last date of receipt of investigational product, must be at least 8 weeks
prior to Screening Visit 1

20. Treatment of the target knee with intra-articular glucocorticoids (e.g.,
methylprednisolone) within 12 weeks prior to Screening Visit 1

21. Any intra-articular injection into the target knee with a therapeutic aim including,
but not limited to, viscosupplementation (e.g., hyaluronic acid), platelet-rich plasma
(PRP), and stem cell therapies within 24 weeks prior to Screening Visit 1; treatment
of the target knee with intra-articular glucocorticoids greater than 12 weeks prior to
Screening Visit 1 is allowed

22. Treatment with systemic glucocorticoids greater than 10 mg prednisone or the
equivalent per day within 4 weeks prior to Screening Visit 1

23. Effusion of the target knee clinically requiring aspiration within 12 weeks prior to
Screening Visit 1

24. Use of electrotherapy, acupuncture, and/or chiropractic treatments for knee OA within
4 weeks prior to Screening Visit 1

25. Any known active infections, including urinary tract infection, upper respiratory
tract infection, sinusitis, suspicion of intra-articular infection, hepatitis B or
hepatitis C infection, and/or infections that may compromise the immune system such as
human immunodeficiency virus (HIV) at Day 1

26. Subjects requiring the chronic use (i.e., regular and consistent use for ≥ 12 weeks)
of centrally acting analgesics (e.g., duloxetine) within 12 weeks prior to Screening
Visit 1

27. Subjects requiring the chronic use (i.e., regular and consistent use for ≥ 12 weeks)
of anticonvulsants (not listed in the study protocol) within 12 weeks prior to
Screening Visit 1, unless used for seizure or migraine prophylaxis

28. Subjects requiring the usage of opioids >1x per week within 12 weeks prior to
Screening Visit 1

29. Topical local anesthetic agents (gels, creams, or patches such as the Lidoderm patch)
used for the treatment of knee OA within 7 days of Screening Visit 1

30. Any chronic condition that has not been well controlled or subjects with a chronic
condition who have not maintained a stable therapeutic regimen of a prescription
therapy in the opinion of the Investigator. In addition, subjects with an HbA1c >9 at
Screening Visit 2 will be excluded.

31. If on NSAIDs for the treatment of OA pain, subjects who have not maintained a stable
regimen in the opinion of the Investigator at Screening Visit 1

32. Any contraindications for performing DXA scans of the hips or spine including but not
limited to:

1. pins, screws, or any surgical implant, either on the spine or any hip that
preclude scanning at these sites

2. severe degenerative changes or fracture deformity in the measurement area

3. other radiological investigations using contrast media or radionuclides within 7
days of Screening Visit 2

4. weight that precludes scanning at these sites

33. Subjects who have had a single or bilateral hip replacement

34. Subjects who have a current or pending disability claim, workers' compensation, or
litigation(s) that may compromise response to treatment

35. Subjects who are immediate family members (spouse, parent, child, or sibling;
biological or legally adopted) of personnel directly affiliated with the study at any
investigative site, or are directly affiliated with the study at any investigative
site

36. Subjects employed by Samumed, LLC, or any of its affiliates or development partners
(that is, an employee, temporary contract worker, or designee) responsible for the
conduct of the study, or who are immediate family members (spouse, parent, child, or
sibling; biological or legally adopted) of said employees responsible for the conduct
of the study