CASE 37-YEAR-OLD FEMALE WITH XLH STUDY* No known abnormalities XLH confirmed by CRYSVITA therapy reported genetic testing initiated BIRTH 2 YEARS 13 YEARS 35 YEARS 36 YEARS 37 YEARS XLH Joint stiffness Symptoms diagnosis in hips, knees, improved and ankles MEDICAL HISTORY X-RAY 1: FEET During childhood • Age 2: diagnosed with X-linked hypophosphatemia L L (XLH) as a toddler – Initiated oral phosphate and calcitriol and was compliant XLH diagnosis was confirmed by • Age 13: Enthesophyte genetic testing R Family history • Mother and maternal grandmother had XLH XLH symptoms and associated complications in adulthood • Chiari malformation requiring two corrective surgeries Enthesophyte • Chronic ankle pain and swelling in joints At 35 years old: prominent bilateral calcaneal enthesophytes; • Gait abnormalities severe bilateral tibiotalar osteoarthritis; slight bilateral bowing in • Sustained pelvic fracture during childbirth tibias and fibulas. • Age 33: discontinued oral phosphate and calcitriol Evaluation prior to CRYSVITA • Age 35: presented to adult endocrinology with – Hypertrophic bone formation occurring at the bowing of upper and lower extremities and joint hip articulation and trochanters; sclerosis at stiffness in hips, knees, and ankles the sacroiliac joints; slight bilateral bowing of • Physical exam femurs (X-ray 2, page 2) – Height, 5'2" – Bowing deformity at each femur and – Required the use of assistive walking device degenerative changes of the knees including (cane) for long distances and handicap tags bilateral articular surface irregularities of the due to mobility challenges femoral condyles (X-ray 3, page 2) – Tinnitus in right ear – Bilateral bowing of femurs, tibias, and fibulas; • Calcifications noted on prior renal ultrasound bones diffusely demineralized and bilateral • Laboratory findings (Table, page 2) narrowing of joint space compartment also • Physical therapy evaluation noted (X-ray 4, page 2) – Required assistance to rise from seated to standing position DIAGNOSIS AND INITIAL TREATMENT – Tight hip flexors; limited range of motion in hips • XLH diagnosis reconfirmed • X-rays • Treatment: CRYSVITA – Prominent enthesophytes associated with the calcaneus bilaterally as well as ankle and midfoot arthritis; slight bowing seen bilaterally in lower legs (X-ray 1) INDICATION CRYSVITA® (burosumab-twza) is a fibroblast growth factor 23 (FGF23) blocking antibody indicated for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients 6 months of age and older. Please see Important Safety Information on pages 3 and 4 and accompanying full Prescribing Information. *The information for this case study was provided courtesy of Dr. Kathryn McCrystal Dahir, Professor of Medicine, Department of Endocrinology, Vanderbilt University Medical Center, Nashville. This case study represents a real patient and is intended to be illustrative, not a recommendation for treatment or management. Not all patients respond the same to CRYSVITA treatment. Results may vary. This case study does not claim to represent typical results. X-RAY 2: HIPS AND FEMURS X-RAY 3: KNEES R L R L At 35 years old: hypertrophic bone formation at hip articulation and trochanters At 35 years old: degenerative changes of the knees including bilateral articular (brackets); sclerosis at the sacroiliac joints; slight bilateral bowing of femurs. surface irregularities of the femoral condyles (arrows); diffusely demineralized bones with medial compartment joint space narrowing (arrow heads). DISEASE PROGRESSION CRYSVITA treatment, 35 weeks X-RAY 4: KNEES • Age 36: initiated CRYSVITA and over time reported progressive improvement in joint stiffness • After 10 weeks: CRYSVITA dose reduced after a 30-pound intentional weight loss due to diet and increased physical activity • Reported adverse events – Myalgias and fatigue, left knee swelling and pain during the first 3 months – Adverse events managed with over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid pain medication; resolved with subsequent CRYSVITA injections – No restless leg symptoms or injection site R L reactions were reported At 35 years old: bilateral bowing of femurs, tibias, and fibulas; diffused • Laboratory findings: biochemical improvements demineralization of bones; bilateral narrowing of joint space compartment. after 35 weeks (Table, below) LABORATORY TEST RESULTS Result (age) a Test (reference range unit) Early evaluation CRYSVITA 35 weeks (35 years) (37 years) Serum phosphorus (2.3-4.7 mg/dL) 1.6 2.6 1,25 (OH)2 (20-80 ng/mL) 40.3 - 25(OH)D (25-80 ng/mL) 35 60.6 BSAP (4.5-16.9 mcg/L) 25 19.1 PTH (16-88 pg/mL) 55 52 Creatinine (0.57-1.11 mg/dL) 0.74 0.70 1,25 (OH)2, 1,25 dihydroxy vitamin D; 25(OH)D, 25-hydroxy vitamin D (calcifediol); BSAP, bone-specific alkaline phosphatase, also known as BAP; PTH, parathyroid hormone. aIndicates normal range, age, and gender matched. Note that normal range values may vary depending on reference dataset. The range in this table was provided by the treating physician. SUMMARY • Patient was diagnosed with XLH as a toddler and suffered from XLH-associated symptoms throughout adulthood, including fractures, joint stiffness, pain, and diminished physical function • At age 36, CRYSVITA was initiated and after nearly a year, patient demonstrated improvements in serum phosphorus levels and joint stiffness • Adverse reactions reported during treatment included myalgia, fatigue, and left knee pain and swelling, which resolved within 3 months of treatment Please see Important Safety Information on pages 3 and 4 and accompanying full Prescribing Information. CRYSVITA CLINICAL TRIALS RESULTS CRYSVITA WAS EVALUATED IN TWO PHASE 3 CLINICAL STUDIES OF 148 ADULTS WITH XLH • Phase 3 study (Study 4): 24 weeks, randomized, – Baseline: 52% of patients had active fractures or double-blind, placebo-controlled, followed by pseudofractures; all had skeletal pain associated 24 weeks, open-label, during which all patients with XLH/osteomalacia received CRYSVITA, N=134, 19 to 66 years old • Phase 3 study (Study 5): 48 weeks, open-label, – One patient in the CRYSVITA group discontinued single-arm, N=14, 25 to 52 years old treatment during the 24-week placebo- – No patients discontinued controlled treatment period, and 7 patients discontinued CRYSVITA during the open-label • In both studies, oral phosphate and active vitamin D treatment period analogs were discontinued prior to enrollment CRYSVITA LED TO INCREASED AND SUSTAINED SERUM PHOSPHORUS LEVELS WITHIN THE NORMAL RANGE MEAN SERUM PHOSPHORUS LEVELS IN ADULTS RECEIVING Phase 3 (Study 4) CRYSVITA EVERY 4 WEEKS OR RECEIVING PLACEBO* (N=134, ages 19 to 66 years) Double-blind Treatment Period Open-label Treatment Period A significantly higher 4.5 proportion of patients, Normal range 94% (64/68), achieved 4.0 normalized serum 3.5 phosphorus with 3.0 CRYSVITA, compared with 8% (5/66) with placebo 2.5 LLN (95% CI: placebo [3.3 to 2.0 16.5]; CRYSVITA [85.8 to 97.7], P<0.0001). Serum Serum Phosphorus (mg/dL) (SD) 1.5 phosphorus was CRYSVITA to CRYSVITA (n=68) 68 61 64 66 63 65 67 65 64 66 62 66 Placebo to CRYSVITA (n=66) 66 60 64 65 64 66 62 61 65 66 62 65 66 maintained with continued CRYSVITA treatment 0 1 2 6 10 14 18 21 22 24 26 34 46 through Week 48. Time (Week) CRYSVITA (n=68) Placebo (n=66) Placebo to CRYSVITA (n=66) SD, standard deviation. *Serum phosphorus level (mg/dL) (mean ± the SD). The dotted line represents lower limit of normal (LLN, 2.5 mg/dL). Normal levels range from 2.5 to 4.5 mg/dL. Note that the normal levels vary by age and gender, and ranges may vary by testing laboratory. At baseline mean (SD) serum phosphorus levels were 2.0 (0.30) and 1.9 (0.32) mg/dL for the CRYSVITA and placebo groups, respectively. Mean serum phosphorus levels across midpoints of dose intervals (2 weeks post-dose) were 3.2 (0.53) and 2.1 (0.30) mg/dL for the CRYSVITA and placebo groups, respectively. CRYSVITA EVERY 4 WEEKS DEMONSTRATED HEALING OF OSTEOMALACIA Healing of osteomalacia was observed with CRYSVITA (Study 5, N=14) after 48 weeks of treatment: • Osteoid volume/bone volume decreased in 10 patients from a mean score of 26% at baseline to 11%, a change of -57% • Osteoid thickness declined in 11 patients from a mean of 17 µm to 12 µm, a change of -33% • Mineralization lag time declined in 6 patients from a mean of 594 days to 156 days, a mean change of -74% IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS • With oral phosphate and/or active vitamin D analogs (e.g., calcitriol, paricalcitol, doxercalciferol, calcifediol). • When serum phosphorus is within or above the normal range for age. • In patients with severe renal impairment or end stage renal disease. WARNINGS AND PRECAUTIONS Hypersensitivity • Discontinue CRYSVITA if serious hypersensitivity reactions occur and initiate appropriate medical treatment. Hyperphosphatemia and Risk of Nephrocalcinosis • For patients already taking CRYSVITA, dose interruption and/or dose reduction may be required based on a patient’s serum phosphorus levels. Injection Site Reactions • Discontinue CRYSVITA if severe injection site reactions occur and administer appropriate medical treatment. Please see Important Safety Information on pages 3 and 4 and accompanying full Prescribing Information. CRYSVITA CLINICAL TRIALS RESULTS (continued) CRYSVITA EVERY 4 WEEKS HEALED FRACTURES, INCLUDING IN PATIENTS WHO SWITCHED FROM PLACEBO CRYSVITA demonstrated a higher rate of complete fracture healing compared with placebo: 43% (28/65) vs 8% (7/91) total fracture healing