Finding Relief in Osteoarthritis

F

Learning Objectives • Review the pathophysiology of OA-related chronic pain, including potential therapeutic targets • Evaluate patients with OA for persistent pain, functional status, and potential risks related to treatment options • Discuss the challenges associated with current analgesic modalities for chronic pain in patients with OA • Compare the clinical profiles of current and emerging treatment options for OA-related chronic pain

OA, osteoarthritis.

OSTEOARTHRITIS PATHOPHYSIOLOGY AND NOVEL TREATMENT TARGETS

Pain in OA • Multidimensional burdens of OA undertreatment: biopsychosocial consequences • The role of the orthopedic surgeon in OA chronic pain management • Evaluating persistent pain in patients with OA • Burdens and risks of commonly prescribed analgesics • Efficacy and safety of anti-NGF antibodies • Additional emerging strategies for OA chronic pain

NGF, nerve growth factor.

MULTIDIMENSIONAL BURDENS OF OSTEOARTHRITIS UNDERTREATMENT

Osteoarthritis • Affects 17 million Americans1 – Nearly 1 in 3 people older than age 652 • Increasing risk factors of OA2 – Aging – Obesity – Physical inactivity – Joint injuries • 59% - 87% of patients with OA have ≥1 chronic, comorbid condition2 – Obesity, metabolic syndrome • Undertreatment leads to avoidance of physical activity2

Hip Knee

1. Min J, et al. Drug Saf. 2018;41(3):313-320; 2. Hawker GA. Clin Exp Rheumatol. 2019;37 suppl 120(5):3-6.

Rising Disability and Mortality With OA Increasing Disability With OA – 63% increase in YLD since 19901 – 31% increase in YLD since 20071 • Comparable increases in both hip and knee OA

– OA is the 12th leading cause of YLD2

OA Increases Risk of Mortality and CVD – OA is associated with increased all-cause mortality (SMR 1.55)3 • CVD in OA SMR = 1.71

– Walking disability independently predicted both all-cause mortality and composite CVD outcome4 – WOMAC function score independently predicted all-cause mortality4

CVD, cardiovascular disease; SMR, standardized mortality ratio; YLD, years lived with disability; WOMAC, Western Ontario and McMaster Universities Arthritis Index.

1. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Lancet. 2018;392(10159):1789-1858; 2. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators.

Lancet. 2017;390(10100):1211-1259; 3. Palazzo C, et al. Ann Phys Rehabil Med. 2016;59(3):134-138; 4. Hawker GA, et al. PLoS One. 2014;9(3):e91286.

THE ROLE OF THE ORTHOPEDIC SURGEON IN OA PAIN MANAGEMENT

Nonpharmacologic and Pharmacologic Treatment Options for OA Nonpharmacologic • Low-impact aerobic and strengthening exercise1 • Weight loss1 • Self-management program1 • Physical therapy3

a

Pharmacologic • NSAIDs (oral or topical)1 • Tramadol1 • Opioids1,2,a • IA corticosteroids1,2,b • IA hyaluronic acid1,2,c

Conditionally recommended against by ACR, inconclusive recommendation by AAOS; bInconclusive recommendation by AAOS for knee OA but strong recommendation for hip OA, strong recommendation by ACR for both; cThough an available option, it is not recommended by ACR or AAOS guidelines.

AAOS, American Academy of Orthopaedic Surgeons; ACR, American College of Rheumatology; IA, intra-articular; NSAID, nonsteroidal anti-inflammatory drug.

1. Jevsevar DS. J Am Acad Orthop Surg. 2013;21(9):571-576; 2. Kolasinski SL, et al. Arthritis Rheumatol. 2020;72(2):220-233; 3. AAOS. https://www.aaos.org/globalassets/quality-andpractice-resources/osteoarthritis-of-the-hip/oa-hip-cpg_6-11-19.pdf. Accessed July 20, 2020 .

Surgical Management of OA Knee OA1 • Arthroscopy • Repair of focal chondral lesion • Realignment osteotomy – Proximal tibial osteotomy – Distal femoral osteotomy

• Unicompartmental knee arthroplasty • Patellofemoral arthroplasty • TKA

Hip OA2 • Pelvic osteotomy – Insufficient acetabular coverage of the femur – Early OA

• Hip arthroscopy – Femoroacetabular impingement – Early OA

• Joint resurfacing – May be more ideal in younger patients

• THA

THA, total hip arthroplasty; TKA, total knee arthroplasty.

1. Hussain SM, et al. Scott Med J. 2016;61(1):7-16; 2. Gandhi R, et al. CMAJ. 2014;186(5):347-355.

Multimodal Pain Management Pharmacologic and nonpharmacologic multimodal therapies1 Preoperative

Intraoperative

Postoperative

Celecoxib, gabapentin, or pregabalin

Local anesthetic infiltration

Acetaminophen, NSAIDs, gabapentin, or pregabalin

Spinal or epidural anesthetic IA local anesthetic

Patient-controlled analgesia Peripheral nerve block

Multimodal pain regimens result in significantly reduced postoperative pain, increased walking distance, shortened hospital stays, and decreased opioid use.2 1. Chou R, et al. J Pain. 2016;17(2):131-157; 2. Peters CL, et al. J Arthroplasty. 2006;21(6 suppl 2):132-138.

Enhanced Recovery Protocols Preoperative

Peri- and Intraoperative

• Patient education

• Surgery admission

• Outpatient consultation

• Follow multimodal pain management approach

• Expectation discussion • Discharge planning – social support, occupational or physical therapist • Preassessment outpatient clinic – anesthesia, comorbidities

Adapted from Galbraith AS, et al. Ir J Med Sci. 2018;187(1):97-109.

• Pre-op physical therapy • Regional injections

Postoperative • Follow multimodal pain management approach • Day of surgery mobilization • Venous thromboembolic prophylaxis • Rehabilitation program • Early discharge

Revision Surgery • Less improvement following revision surgery than primary TJA1 • Some patients report dissatisfaction following revision surgery1 – Primary reasons are persistent pain and functional impairment

• Important to set realistic expectations with patients1 • Patients report increased pain intensity at rest, while walking, and average pain during the last 24 hours following revision surgery vs primary TJA2 – 47% of patients undergoing TKA revision surgery reported severe pain following revision surgery

• Increased risk of revision surgery in patients taking opioids 91-180 days post TJA3 TJA, total joint arthroplasty.

1. Postler AE, et al. Hip Int. 2017;27(2):180-186; 2. Petersen KK, et al. Clin J Pain. 2015;31(1):1-6; 3. Inacio MC, et al. BMC Musculoskelet Disord. 2016;17:122.

Opioids in Postsurgical Pain • A study found 7% of patients persistently used opioids in the year following TJA • Risk factors for persistent opioid use following TJA – TKA vs THA – Longer hospital stay – Discharge to rehabilitation facility – Preoperative opioid use – Comorbidities such as back pain or fibromyalgia – Benzodiazepine use

Kim SC, et al. Osteoarthritis Cartilage. 2017;25(9):1399-1406.

EVALUATING PERSISTENT PAIN IN OA

Differential Diagnosis of OA Joint Pain • Red flags for further investigation – Age1 – Morning stiffness >30 minutes1 – Sudden onset of significant new joint pain2 – Progressive, well-localized pain that does not vary1 – Pain not relieved by rest1

• Possible other diagnoses1 – Inflammatory arthritis – Bursitis (trochanteric, anserine) – Subchondral insufficiency fracture – Referred pain (radicular pain) – Osteonecrosis

1. National Clinical Guideline Centre (UK). Osteoarthritis: Care and Management in Adults. London: National Institute for Health and Care Excellence (UK); 2014 Feb. (NICE Clinical Guidelines, No. 177.) 5. Osteoarthritis: Care and Management in Adults. Diagnosis. Available from: https://www.ncbi.nlm.nih.gov/books/NBK333067/; 2. Hsu H, Siwiec RM. Knee Osteoarthritis. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2020.

Imaging in OA for Confirming Diagnosis • Plain radiographs: hallmarks of OA are osteophytes and joint space narrowing • Structural damage does not necessarily correlate with pain level in OA • May distinguish OA from other conditions in patients with knee pain

MRI, magnetic resonance imaging.

Wang X, et al. Rheumatology (Oxford). 2018;57(suppl_4):iv51-iv60.

• MRI can answer specific questions when radiographs are not diagnostic – Meniscal or labral tear – Osteonecrosis – Insufficiency fracture

• Ultrasound can examine only tissues superficial to bone – May be helpful to eliminate inflammatory arthritis in differential diagnosis

The Role of Patient Self-Report in OA Pain • Pain interview1 – Structured/unstructured • Type of sensation • Severity, frequency, and location • Precipitating factors • Impact on QoL and independence

• HOOS and KOOS scales ask about symptoms, pain, stiffness, function, and quality of life2 – Short forms available

• PROMIS: patient-reported outcomes3 – Assess physical, mental, and social health in general population or patients with chronic conditions

HOOS, Hip disability and Osteoarthritis Outcome Score; KOOS, Knee Injury and Osteoarthritis Outcome Score; PROMIS, Patient-reported Outcomes Measurement Information System; QoL, quality of life.

1. Goodin BR, et al. In: Cordts GA, Christo PJ, eds. Effective Treatments for Pain in the Older Patients. New York, NY: Springer; 2019:131-152; 2. Gandek B, et al. Osteoarthritis Cartilage.

2019;27(5):746-753; 3. Brodke DJ, et al. J Am Acad Orthop Surg. 2016;24(11):744-749.

Establishing Functional Goals • Self-efficacy and self-management programs aid in goal setting1 – Goals can include reducing pain, improving range of motion, and increased ability to perform daily activities2

• Graded relationship between increased physical activity and improved physical function in OA3 • Patient-clinician communication is important when establishing functional goals and managing pain4

My Functional Goals ! Reduce morning stiffness ! Go up and down stairs a few times per day ! Walk on a flat surface with only mild pain ! Swim 50 meters ! Stand for 1 hour to cook dinner

1. Kolasinski SL, et al. Arthritis Rheumatol. 2020;72(2):220-233; 2. Ganji R, et al. Open Access Maced J Med Sci. 2018;6(6):1062-1066; 3. Dunlop DD, et al. Arthritis Rheum. 2011;63(1):127-136; 4. Marconcin P, et al. Clin Rehabil. 2018;32(2):223-232.

BURDENS AND RISKS OF AVAILABLE ANALGESICS

Medical Management of OA • Nonpharmacologic interventions – Physical therapy/exercise – Weight control

• Pharmacologic Management – Acetaminophen – NSAIDs – Opioids – Other centrally acting drugs: duloxetine, TCAs, etc.

TCA, tricyclic antidepressant.

Jevsevar DS. J Am Acad Orthop Surg. 2013;21(9):571-576;

Simple Analgesics • Acetaminophen is generally safe but less effective than NSAIDs1 – Patient preference for oral NSAID vs acetaminophen

• NSAIDs work – provide pain relief and improve function – Oral NSAIDs recommended by both US and international guidelines for patients with symptomatic OA1-3 – Topical NSAIDs can be effective with fewer adverse events4 – Lowest possible dose for shortest possible time2 – Similar efficacy among COX-2 selective, partially selective, and nonselective NSAIDs5 COX-2, cyclooxygenase-2.

1. Pelletier JP, et al. Semin Arthritis Rheum. 2016;45(suppl 4):S22-S27; 2. Kolasinski SL, et al. Arthritis Rheumatol. 2020;72(2):220-233; 3. Jordan KM, et al. Ann Rheum Dis. 2003;62(12):11451155; 4. Taylor N. Clin Geriatr Med. 2017;33(1):41-51; 5. Chou R, et al. Analgesics for Osteoarthritis. An Update of the 2006 Comparative Effectiveness Review. Rockville, MD: Agency for Healthcare Research and Quality; 2011.

Safety and Toxicity of NSAIDs • Boxed warnings in label for all NSAIDs – Increased risk of serious CV thrombotic events1 • Contraindicated in CABG surgery • May occur early in use and increase with duration of use

– Increased risk of serious GI

AEs1

• Greater risk in elderly and those with history of peptic ulcer disease or GI bleeding

• Renal effects – Increased risk of acute kidney injury1 • Higher in first 30 days after NSAID initiation

– Exacerbates renal insufficiency

• Anticoagulants – Because of inhibition of platelet activity, NSAIDs should be avoided in patients taking anticoagulants3

• Increased mortality rate from GI bleeding2 AE, adverse event; CABG, coronary artery bypass grafting; GI, gastrointestinal.

1. Cooper C, et al. Drugs Aging. 2019;36(suppl 1):15-24; 2. Straube S, et al. BMC Gastroenterol. 2009;9:41; 3. Risser A, et al. Am Fam Physician. 2009;80(12):1371-1378.

Role of Opioids in OA Pain Efficacy, Safety, and Tolerability

• Opioids effective for short-term acute pain relief1 • Efficacy for long-term (>3 months) opioid use is lacking1 – No evaluation of opioid use ≥1 year – Prescribing for acute pain can lead to long-term use

• Consider alternative options because of safety and tolerability – Associated with increased risk of constipation, dizziness, drowsiness, fatigue, nausea, pruritus, and vomiting2 – Long-term use often leads to misuse, abuse, and addiction1

1. Dowell D, et al. JAMA. 2016;315(15):1624-1645; 2. Els C, et al. Cochrane Database Syst Rev. 2017;10(10):CD012509.

Role of Opioids in OA Pain Considerations for TJA

Pre- and postoperative1-3 • Limit to short-term use for pain • Use short-acting opioids; ER/LA opioids are to be avoided • Evaluate for tolerance prior to prescribing • Consider multimodal pain management to limit opioid use

Perioperative1,2 • Short-term opioid use may be appropriate for immediate postsurgical pain – Taper opioids relatively quickly – ER/LA opioids are not appropriate

• Evaluate for tolerance prior to prescribing • Obtain history of opioid use prior to surgery

ER, extended-release; LA, long-acting.

1. US Food and Drug Administration (FDA). https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020553s059lbl.pdf. Accessed July 20, 2020; 2. Lespasio MJ, et al. Perm J. 2019;23:18-169; 3. Halawi MJ, Leiberman JR. J Arthroplasty. 2018;33(8):2341-2343.

2016 CDC Chronic Opioid Dosing Guidelines Clinicians should use caution when prescribing opioids at any dosage and clinicians should prescribe the lowest effective dosage when opioids are started.

Clinicians should carefully reassess evidence of individual benefits and risks when increasing dosage to ≥50 mg morphine equivalents/day.

Clinicians should avoid increasing dosage to ≥90 mg morphine equivalents/day or carefully justify a decision to titrate dosage to ≥90 mg morphine equivalents/day.

For patients already on ≥90 mg morphine equivalents/day, clinicians should reevaluate continued high-dose opioid therapy and offer to work with patients to taper opioids based on the association between opioid dosage and overdose risk.

Dowell D, et al. MMWR Recomm Rep. 2016;65(1):1-49.

Opioid Analgesic REMS • Patient assessment: patient history, screening tools to evaluate risk for chronic pain and risk for opioid use disorder, informed consent – Pain and functional assessment

• Pain treatment plan: goals, patient and clinician responsibilities, pharmacologic and nonpharmacologic approaches, patient provider agreements, patient education on opioid use – General precautions with opioids, indications, contraindications, drug-drug interactions, adverse events, administration, patient risk for SUD, and dosing

• Continued review of pain and functional goals, adverse events, prescription refills, aberrant behavior – – – –

PDMP Urine drug testing Identify signs and symptoms of misuse, abuse, and SUD Refer to addiction specialist if patient develops SUD

PDMP, prescription drug monitoring programs; REMS, Risk Evaluation and Mitigation Strategy; SUD, substance use disorder.

FDA. https://www.accessdata.fda.gov/drugsatfda_docs/rems/Opioid_Analgesic_2019_11_14_FDA_Blueprint.pdf. Accessed July 16, 2020.

Considerations for Special Populations Older Patients

• Increased risk of drug-drug interactions in older patients1 – Polypharmacy and comorbidities are more likely to occur

• NSAIDs poorly tolerated and need to be used with care1 – History of CVD and longer NSAID use increases risk of NSAID-related CV events2 – Increased risk for renal toxicity with NSAIDs2 • Age-related reduced renal function • Exacerbate congestive heart failure; patients also taking diuretics or ACE inhibitors

• Reduce opioid dose in older patients and titrate slowly1,3,4 – CNS symptoms may be more pronounced and limiting, eg, dizziness – Potential for increased risk of falls and fractures in older patients taking opioids

ACE, angiotensin-converting enzyme inhibitors; CNS, central nervous system.

1. Cooper C, et al. Drugs Aging. 2019;36(suppl 1):15-24; 2. McCarberg BH. Pain Med. 2013;14 (suppl 1):S43-S44; 3. Argoff CE, et al. In: Cordts GA, Christo PJ, eds. Effective Treatments for Pain in the Older Patients. New York, NY: Springer; 2019:71-108; 4. Dowell D, et al. JAMA. 2016;315(15):1624-1645.

Additional Pharmacologic Treatment Options for OA Pain • IA therapy – Corticosteroid injections1 • Good safety profile • Short-term efficacy

– IA hyaluronic acid injection2 • Data supporting efficacy is weak • Recommended against in 2019 ACR guidelines and AAOS guidelines

• Topical capsaicin1 – Efficacy data limited – Requires frequent application – No systemic toxicity, but often associated with local skin irritation

• Nonopioid centrally acting agents2 – Duloxetine is conditionally recommended in 2019 ACR guidelines – TCA or anticonvulsants • Use caution with TCAs in older patients3

1. Taylor N. Clin Geriatr Med. 2017;33(1):41-51; 2. Kolasinski SL, et al. Arthritis Rheumatol. 2020;72(2):220-233; 3. van Laar M, et al. Open Rheumatol J. 2012;6:320-330.

EFFICACY AND SAFETY OF ANTI-NGF MONOCLONAL ANTIBODIES

A History of Anti-NGF Monoclonal Antibody Clinical Trials • Clinical trials began in 2006 – Phase 2 data demonstrated efficacy with no serious safety concerns

• FDA halted all clinical trials in 20101,2 – Concerns raised about joint safety

• Plan to mitigate risks devised in 20122 • Trials resumed in 20151 • Biologics License Application for tanezumab 2.5 mg accepted by the FDA in 20203

1. Miller RE, et al. Clin Exp Rheumatol. 2017;35 suppl 107(5):85-87; 2. Mullard A. Nat Rev Drug Discov. 2015;14(5):297-298; 3. https://www.nasdaq.com/articles/pfizer-eli-lilly%3A-fda-to-review-bla-for-tanezumab-quick-facts-2020-03-02. Accessed July 16, 2020.

Tanezumab Efficacy in OA Onset of Benefit

0

Placebo Tanezumab 2.5 mg Tanezumab 2.5/5 mg

-1 a,b

-2

a,b

a

a,b

a,b

-3

-4 0

2

4

6

8

Weeks aP≤0.05

WOMAC Physical Function

10

12

14

16

LS Mean (SE) Change From Baseline

LS Mean (SE) Change From Baseline

WOMAC Pain

0

Placebo Tanezumab 2.5 mg Tanezumab 2.5/5 mg

-1 a,b

-2

a,b

a,b

a,b

a,b

-3

-4 0

2

4

6

8

10

12

14

16

Weeks

tanezumab 2.5 mg vs placebo; bP ≤0.05 tanezumab 2.5/5 mg vs placebo.

LS, least squares; SE, standard error; SQ, subcutaneous.

N=696 adults diagnosed with hip or knee OA according to ACR criteria who had documented insufficient pain relief from acetaminophen or insufficient pain relief from, intolerance to, or contraindication to NSAIDs, tramadol, or opioids (or unwillingness to use opioids) were randomized to placebo, tanezumab 2.5 mg SQ at baseline and week 8, or tanezumab 2.5 mg SQ at baseline and 5 mg SQ at week 8. WOMAC scores range from 0 (no pain/difficulty) to 10 (extreme pain/difficulty).

Schnitzer TJ, et al. Semin Arthritis Rheum. 2020;50(3):387-393.

Tanezumab Efficacy in OA

Responder Threshold Rates vs Placebo Tanezumab Increases Response Rate in WOMAC Pain at 16 Weeks

Response Rate, %

80 70

a

60

Placebo Tanezumab 2.5 mg Tanezumab 2.5/5 mg

b

b

b

50 40

c

a

30 20 10 0 ≥30% Reduction

aP≤0.01

≥50% Reduction

≥70% Reduction

≥90% Reduction

vs placebo; bP≤0.001 vs placebo; cP<0.05.

N=696 adults diagnosed with hip or knee OA according to ACR criteria who had documented insufficient pain relief from acetaminophen or insufficient pain relief from, intolerance to, or contraindication to NSAIDs, tramadol, or opioids (or unwillingness to use opioids) were randomized to placebo, tanezumab 2.5 mg SQ at baseline and week 8, or tanezumab 2.5 mg SQ at baseline and 5 mg SQ at week 8.

Schnitzer TJ, et al. JAMA. 2019;322(1):37-48.

General Safety of Tanezumab in OA Week 40

Adverse Event

Placebo, %

Tanezumab 2.5 mg, %

Tanezumab 2.5/5 mg, %

Treatment-related AE

13.4

17.3

14.2

Serious AE

3.9

3.0

4.7

Arthralgia

17.2

14.7

14.6

Joint swelling

2.2

3.9

2.6

Musculoskeletal pain

4.7

7.4

3.4

N=696 adults diagnosed with hip or knee OA according to ACR criteria who had documented insufficient pain relief from acetaminophen or insufficient pain relief from, intolerance to, or contraindication to NSAIDs, tramadol, or opioids (or unwillingness to use opioids) were randomized to placebo, tanezumab 2.5 mg SQ at baseline and week 8, or tanezumab 2.5 mg SQ at baseline and 5 mg SQ at week 8.

Schnitzer TJ, et al. JAMA. 2019;322(1):37-48.

Joint Safety of Tanezumab in OA Week 40

Joint Safety Outcomes

Placebo, %

Tanezumab 2.5 mg, %

Tanezumab 2.5/5 mg, %

2.2

3.5

7.3

RPOA type 1 (adjudicated)

0

1.3

0.4

RPOA type 2 (adjudicated)

0

0.9

0

Other (eg, preexisting SIF; adjudicated)a

0

0.4

0

1.7

3.5

6.9b

Normal OA progression (adjudicated)

≥1 joint replacement

SIF, subchondral insufficiency fracture. a A condition was adjudicated as “preexisting” if it was not identified by the central reader at screening, but the adjudication committee determined it to be preexisting after reviewing all available postbaseline clinical and imaging information for the joint safety event in question; bOne patient had 2 joints replaced.

N=696 adults diagnosed with hip or knee OA according to ACR criteria who had documented insufficient pain relief from acetaminophen or insufficient pain relief from, intolerance to, or contraindication to NSAIDs, tramadol, or opioids (or unwillingness to use opioids) were randomized to placebo, tanezumab 2.5 mg SQ at baseline and week 8, or tanezumab 2.5 mg SQ at baseline and 5 mg SQ at week 8.

Schnitzer TJ, et al. JAMA. 2019;322(1):37-48.

Fasinumab Efficacy in OA

WOMAC Pain and Physical Function Fasinumab Reduces WOMAC Pain Score

0

Placebo Fasinumab 1 mg Fasinumab 3 mg Fasinumab 6 mg Fasinumab 9 mg

-0.5 -1.0 -1.5

Mean (SE) Change From Baseline

Mean (SE) Change From Baseline

0

Fasinumab Improves WOMAC Physical Function Score

-2.0 -2.5 -3.0 -3.5 -4.0 -4.5

Placebo Fasinumab 1 mg Fasinumab 3 mg Fasinumab 6 mg Fasinumab 9 mg

-0.5 -1.0 -1.5 -2.0 -2.5 -3.0 -3.5 -4.0 -4.5

0 2 4

8

12

16

20

Weeks

36

0 2 4

8

12

16

20

Weeks

P<0.05 at week 16 for all doses vs placebo for both pain and physical function scores.

N=421 patients aged 40-80 years diagnosed with hip or knee OA according to ACR criteria who had insufficient pain relief with or intolerance to acetaminophen, â&#x2030;Ľ1 oral NSAID, or â&#x2030;Ľ1 opioid (including unwillingness to use opioids) were randomized to placebo or fasinumab 1 mg SQ, 3 mg SQ, 6 mg SQ, or 9 mg SQ every 4 weeks. WOMAC scores range from 0 (no pain/difficulty) to 10 (extreme pain/difficulty).

Dakin P, et al. Arthritis Rheumatol. 2019;71(11):1824-1834.

36

General Safety of Fasinumab in OA Weeks 0 – 16 Treatment Period Placebo, %

Fasinumab 1 mg, %

Fasinumab 3 mg, %

Fasinumab 6 mg, %

Fasinumab 9 mg, %

TEAE

54.9

63.5

61.9

64.7

57.8

Musculoskeletal

17.1

18.8

17.9

21.2

16.9

Arthralgia

2.4

10.6

6

9.4

6

0

1.2

7.1

3.5

0

8.5

17.6

16.7

17.6

15.7

Adverse Event

Joint swelling Nervous system disorders

TEAE, treatment-emergent adverse event.

N=421 patients aged 40-80 years diagnosed with hip or knee OA according to ACR criteria who had insufficient pain relief with or intolerance to acetaminophen, ≥1 oral NSAID, or ≥1 opioid (including unwillingness to use opioids) were randomized to placebo or fasinumab 1 mg SQ, 3 mg SQ, 6 mg SQ, or 9 mg SQ every 4 weeks. WOMAC scores range from 0 (no pain/difficulty) to 10 (extreme pain/difficulty).

Dakin P, et al. Arthritis Rheumatol. 2019;71(11):1824-1834.

Safety of Fasinumab in OA Joint Safety Outcomes

Placebo, %

Fasinumab 1 mg, %

Fasinumab 3 mg, %

Fasinumab 6 mg, %

Fasinumab 9 mg, %

1.2

2.4

4.8

7.1

12

0

2.4

2.4

5.9

8.4

• Subchondral insufficiency fracture

1.2

0

2.4

1.2

3.6

≥1 joint replacement

3.7

3.5

3.6

4.7

3.6

Joint Safety Outcomes ≥1 arthropathy • RPOA

RPOA, rapid progression of OA. N=421 patients aged 40-80 years diagnosed with hip or knee OA according to American College of Rheumatology criteria who had insufficient pain relief with or intolerance to acetaminophen, ≥1 oral NSAID, or ≥1 opioid (including unwillingness to use opioids) were randomized to placebo or fasinumab 1 mg SQ, 3 mg SQ, 6 mg SQ, or 9 mg SQ every 4 weeks.

WOMAC scores range from 0 (no pain/difficulty) to 10 (extreme pain/difficulty).

Dakin P, et al. Arthritis Rheumatol. 2019;71(11):1824-1834.

Selected Ongoing Clinical Trials • Signs and symptoms of OA – Fasinumab vs placebo and NSAID in knee or hip OA1 – Fasinumab vs placebo and naproxen in knee or hip OA2 – CNTX-4975-05 (trans-capsaicin) in knee OA3,4

• Structure modifications in OA – IA injection of lorecivivint (Wnt inhibitor) vs placebo in knee OA5 – GLPG1972/S201086 (oral ADAMTS-5 inhibitor) vs placebo in knee OA6

ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs.

1. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03304379. Accessed July 16, 2020 2. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03161093. Accessed July 16, 2020; 3. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03660943. Accessed July 16, 2020; 4. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03661996. Accessed July 16, 2020; 5. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03727022. Accessed July 6, 2020; 6. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03595618. Accessed July 6, 2020.

Conclusions • OA is the leading cause of joint replacement surgery • Orthopedic surgeon plays an important role in management of OA pain • Significant risks and burdens associated with currently available analgesics • NGF plays a role in both peripheral and central sensitization • Anti-NGF monoclonal antibodies are in clinical trials for both hip and knee OA