A Safety, Tolerability, Pharmacokinetics (PK) and Target Engagement (TE) Study of GSK3858279 in Healthy Participants and Evaluation of the Efficacy of Repeat Doses in Participants With Osteoarthritis (OA)

Inclusion criteria

For Part A:

• Participants between 18 and 65 years of age inclusive, at the time of signing the informed consent.
• Volunteers who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring.
• Body weight within the range 50 to 100 kilogram (kg) and body mass index (BMI) within the range 18 to 32 kilogram per meter square (kg/m^2) (inclusive).
• Male participants are eligible to participate if they agree to the following for at least 28 weeks after the dose of study intervention: Refrain from donating sperm PLUS either be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR must agree to use contraception/barrier as detailed below: agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse with a woman of childbearing potential who is not currently pregnant.
• A female participant is eligible to participate if she is of non-reproductive potential.
• Capable of giving signed informed consent.

For Part B:

• Age between 40 and 75 years of age inclusive, at the time of signing the informed consent.
• OA of the index knee as defined by symptomatic for >=6 months with a clinical diagnosis of OA as per American College of Rheumatology (ACR) clinical diagnosis criteria.
• Average of daily pain score >=4 and <=9 by 11 point NRS (0 to 10) in index knee over 7 days prior to dosing (Day-7 to Day-1). Data should be recorded on at least 5 of 7 occasions by the participant to obtain a valid Baseline value.
• Kellgren and Lawrence (KL) score >=2 on X-ray obtained during screening. In addition, for participants with bilateral Knee OA, the index knee is determined at Baseline as the participant reported most painful knee over the 4 weeks prior to Baseline.
• A history of insufficient pain relief from, or inability to tolerate, or contraindication to, oral Non-steroidal anti-inflammatory drugs (NSAIDs).
• A participant must be willing and able to understand and participate in all scheduled evaluations and to complete all required tests and procedures including the use of patient diaries. This will be judged by the Investigator during the screening period.
• BMI within the range 19-34.9 kg/m^2 (inclusive)
• Male participants are eligible to participate if they agree to the following for at least 28 weeks after the dose of study intervention: refrain from donating sperm PLUS either: Be abstinent from heterosexual or homosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent or must agree to use contraception/barrier as detailed: Agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse with a woman of childbearing potential who is not currently pregnant.
• A female participant is eligible to participate if she is of non-reproductive potential.
• Capable of giving signed informed consent.

Exclusion criteria

For Part A:

• History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention; or interfering with the interpretation of data.
• Personal or family history of cardiomyopathy.
• Abnormal blood pressure at screening as determined by the investigator.
• History of symptomatic herpes zoster.
• Evidence of active or latent tuberculosis (TB) as documented by medical history, examination, and TB testing with a positive (not indeterminate) QuantiFERON test.
• Significant allergies to humanized monoclonal antibodies as per principal investigator's and GlaxoSmithKline (GSK) medical monitor's judgments.
• History or evidence of clinically significant multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear immunoglobulin A (IgA) dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis).
• Lymphoma, leukemia, or any malignancy except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years.
• Alanine transaminase (ALT) >1.5 times upper limit of normal (ULN).
• Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent.
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
• Corrected QT (QTc) >450 milliseconds (msec).
• History of Stevens Johnson Syndrome.
• Known immunodeficiency.
• Participants with a chronic infection (example given [e.g.], osteomyelitis), who have been receiving treatment within three months prior to dosing or individuals with an active infection.
• Previous or current history of bleeding diathesis.
• Previous history of hypertrophic or keloid scarring.
• Intended use of over-the-counter or prescription medication including herbal medications within 7 days prior to dosing until final follow-up visit.
• Live vaccine(s), or plans to receive such vaccines within 1 month of screening until final follow-up visit.
• Treatment with biologic agents (such as monoclonal antibodies including marketed drugs) within 3 months or 5 half-lives (whichever is longer) prior to dosing.
• Treatment with antiplatelet or anticoagulant agents within 7 days of dosing.
• Major surgery (as per investigator's judgment) within 3 months prior to dosing.
• Participation in the study would result in loss of blood or blood products in excess of 500 milliliter (mL) within 3 months.
• Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
• Current enrolment or past participation in any other clinical study involving an investigational study intervention or any other type of medical research within the last 30 days, 5 half-lives or twice the duration of the biological product before dosing day in the current study.
• Presence of Hepatitis B surface antigen (HBsAg) at screening.
• Presence of the Hepatitis B core antibody (HBcAb) at screening.
• Positive Hepatitis C antibody test result at screening.
• Positive Hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study intervention.
• Abnormal clinically significant echocardiogram at screening, as assessed by the investigator.
• Cardiac troponin levels out of normal range at screening.
• Positive pre-study drug/alcohol screen.
• Positive human immunodeficiency virus (HIV) antibody test.
• Regular alcohol consumption within 6 months prior to the study defined as: an average weekly intake of >21 units for males and >14 units for females. One unit is equivalent to 8 gram (g) of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
• Smokelyser levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
• Regular use of known drugs of abuse.
• Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.

For Part B:

• Diagnosis of one or more of the following, as per medical records: Significant pain in any joint other than the index knee or any referred pain that would impact ability to assess pain in the index knee as per investigator's judgement (Pain in other locations should be less than pain in target knee).
• Current inflammatory arthritis such as rheumatoid arthritis, autoimmune disorder affecting joints, seronegative spondyloarthritis, gout or pseudogout in any joint (defined as acute episodic attacks of swollen, painful joint in a participant with X-Ray chondrocalcinosis or calcium pyrophosphate dehydrate [CPPD] crystals).
• History of gout or pseudogout in any large joint.
• History or evidence of infectious arthritis, Paget's disease, ochronosis, Wilson's disease, primary osteochondromatosis, osteonecrosis and other causes of significant joint disease osteoarthritis as determined by the investigator.
• History of fibromyalgia.
• Current immunodeficiency diseases.
• Current osteoporosis with symptomatic vertebral or hip fractures.
• Current regional pain syndromes caused by lumbar or cervical compressions with radiculopathy.
• History of significant medical illness in the opinion of the investigator would interfere with the study procedures and / or assessments.
• Symptomatic herpes zoster within 3 months prior to screening.
• Evidence of active or latent TB as documented by medical history, examination and TB testing: either a positive tuberculin skin test (TST; defined as a skin induration >5 millimeter (mm) at 48 to 72 hours, regardless of Bacillus Calmette-Guerin (BCG) or other vaccination history) or a positive (not indeterminate) QuantiFERON test.
• History of significant allergies to humanized monoclonal antibodies.
• History or evidence of clinically significant multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linearIgA dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis.
• History of malignancy within the last 5 years, except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years.
• Breast cancer within the past 10 years.
• ALT >1.5 times the ULN.
• Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent)
• Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• QTc >450 msec or QTc >480 msec in participants with bundle branch block.
• History of primary cardiomyopathy and any major cardiac or vascular event within the last 6 months, including and not limited to myocardial infarction, unstable angina, cerebrovascular event, peripheral arterial or venous thrombosis.
• Current or history of renal disease, or estimated creatinine clearance <60 mL/minute/1.73/ m^2 or serum creatinine >1.5 times the ULN or urine albumin:creatine ratio of >300mg/g at screening.
• Planned surgical procedure over the duration of the study.
• Previous or current history of bleeding diathesis, excessive bleeding or coagulation disorders.
• History of Stevens Johnson Syndrome.
• Participants with active, recurrent or chronic infection (e.g., osteomyelitis), who have been receiving treatment within three months prior to dosing or individuals with an active infection.
• History of significant trauma or surgery to a knee, hip or shoulder within the last 6 months.
• Radiographic evidence of sub-chondral fractures or radiographic abnormalities not consistent with osteoarthritis of the index knee at screening.
• Live vaccine(s) within 1 month prior to screening, or plans to receive such vaccines during the study.
• Treatment with biologic agents (such as monoclonal antibodies including marketed drugs) within 3 months or 5 half-lives (whichever is longer) prior to dosing.
• Intra-articular therapy within 3 months prior to signing the informed consent.
• Immunosuppressant's, including corticosteroids (parenteral within 3 months of screening; oral within 1 month of screening).
• Unable or unwilling to discontinue all pain medication including topical analgesic or adjunctive treatment.
• Major surgery (as per investigator's judgement) within 3 months prior to dosing.
• Participation in the study would result in loss of blood or blood products in excess of 500 mL within 56 days.
• Exposure to more than 4 new chemical entities within 12 months prior to the dosing day.
• Current enrolment or past participation in a clinical study of an investigational drug intervention within the last 3 months or 5 half-lives (whichever is longer) of signing consent.
• Positive HIV antibody test.
• Presence of HBsAg at screening.
• Positive Hepatitis C antibody test result.
• Positive Hepatitis C RNA test result at screening or within 3 months prior to first dose of study intervention.
• Positive coronavirus (Coronavirus Disease strain 19 [COVID-19]: Severe acute respiratory syndrome- Coronavirus-strain 2 [SARS-CoV-2] polymerase chain reaction [PCR] test of a combined throat and nasopharyngeal swab).
• Clinically significant abnormal ECG at screening, as assessed by the investigator.
• Cardiac troponin or N-terminal pro B-type natriuretic peptide (NT-proBNP) levels out of normal range at screening.
• A positive pre-study drug/alcohol screen at screening.
• Regular alcohol consumption within 6 months prior to signing the informed consent defined as: an average weekly intake of >14 units for males and >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
• Regular use of known drugs of abuse
• Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.