Open Label Study of KRN23 on Osteomalacia in Adults With X-linked Hypophosphatemia (XLH)

• burosumab (Biological), also known as KRN23, UX023, Crysvita: solution for subcutaneous injection

Primary outcomes

• Percent Change From Baseline in OV/BV at Week 48 [Baseline, 48 weeks]: OV/BV: percent of a given volume of bone tissue that consists of unmineralized bone (osteoid).

Secondary outcomes

• Percentage of Participants Achieving Mean Serum Phosphorus Levels Above the Lower Limit of Normal (LLN) at the Mid-Point of the Dose Interval, as Averaged Across Dose Cycles Between Baseline and Week 24 [Baseline, up to 24 weeks]: The LLN was defined as 2.5 mg/dL (0.81 mmol/L). The 95% confidence interval (CI) was calculated using Wilson score method.
• Percent Change From Baseline in O.Th at Week 48 [Baseline, 48 weeks]: O.Th: mean thickness, given in micrometers, for osteoid seams.
• Percent Change From Baseline in OS/BS at Week 48 [Baseline, 48 weeks]: OS/Bs: percent of bone surface covered in osteoid.
• Percent Change From Baseline in MLt at Week 48 [Baseline, 48 weeks]: MLt: average time interval between osteoid formation and its subsequent mineralization; calculated by dividing the osteoid thickness by the adjusted apposition rate (O.Th/Aj.AR). Aj.AR; amount of new bone created (bone formation rate over the entire osteoid surface). Based on imputed MLt values.
• Change From Baseline in MAR at Week 48 [Baseline, 48 weeks]: MAR: linear rate of new bone deposition; mean distance between the double labels, divided by the time interval between them.
• Change From Baseline in MS/BS at Week 48 [Baseline, 48 weeks]: MS/BS: percent of bone surface that displays a tetracycline label reflecting active mineralization; calculated as the double-labeled surface plus one half of the single-labeled surface and is expressed as a function of total bone surface (\[dLS + sLS/2\]/BS). It is a measure of the proportion of bone surface upon which new mineralized bone was being deposited during the period of tetracycline labeling.
• Change From Baseline in BFR/BS at Week 48 [Baseline, 48 weeks]: BFR/BS: amount of new bone formed in unit time per unit of bone surface; calculated by multiplying MS/BS by the MAR. MS/BS: percent of bone surface that displays a tetracycline label reflecting active mineralization; calculated as the double-labeled surface plus one half of the single-labeled surface and is expressed as a function of total bone surface (\[dLS + sLS/2\]/BS). It is a measure of the proportion of bone surface upon which new mineralized bone was being deposited during the period of tetracycline labeling. MAR: linear rate of new bone deposition; mean distance between the double labels, divided by the time interval between them.
• Change From Baseline in BFR/OS at Week 48 [Baseline, 48 weeks]: BFR/OS: bone formation rate to osteoid surface ratio, related to the Aj.AR (amount of new bone created \[bone formation rate over the entire osteoid surface\]).
• Change From Baseline in BFR/BV at Week 48 [Baseline, 48 weeks]: BFR/BV: equivalent to bone turnover rate.
• Percentage of Participants Achieving Mean Serum Phosphorus Levels Above the LLN at the End of the Dosing Cycle Between Baseline and Week 24 [Baseline, up to 24 weeks]: The LLN was defined as 2.5 mg/dL (0.81 mmol/L). The 95% CI was calculated using Wilson score method.
• Mean Change of Serum Phosphorus Levels at the Mid-Point of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24 [Baseline, up to 24 weeks]
• Percent Change of Serum Phosphorus Levels at the Mid-Point of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24 [Baseline, up to 24 weeks]
• Mean Change of Serum Phosphorus Levels at the End of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24 [Baseline, up to 24 weeks]
• Percentage Change of Serum Phosphorus Levels at the End of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24 [Baseline, up to 24 weeks]
• Time-Adjusted Area Under the Curve (AUC) of Serum Phosphorus Between Baseline and Week 24 [Baseline, up to 24 weeks]
• Change From Baseline Over Time in Serum 1,25(OH)2D [Baseline, Week 1, Week 2, Week 4, Week 20, Week 21, Week 22, Week 24, Week 48, Week 60, Week 70, Week 72, Week 84, Week 94, Week 96, Week 108, Week 120, Week 132]
• Change From Baseline Over Time in 24-Hour Urinary Phosphorus [Baseline, Week 12, Week 24, Week 36, Week 48, Week 72, Week 96, End of Study II (EOSII) (up to Week 141)]
• Change From Baseline Over Time in TmP/GFR [Baseline, Week 2, Week 4, Week 12, Week 22, Week 24, Week 48, Week 60, Week 72, Week 84, Week 96, EOSII (up to Week 141)]: TmP/GFR: ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate.
• Change From Baseline Over Time in TRP [Baseline, Week 2, Week 4, Week 12, Week 22, Week 24, Week 48, Week 60, Week 72, Week 84, Week 96, EOSII (up to Week 141)]: TRP: tubular reabsorption of phosphate.
• Change From Baseline Over Time in P1NP [Baseline, Week 12, Week 24, Week 48, Week 72, Week 96, EOSII (up to Week 141)]: P1NP: procollagen type 1 N-propeptide.
• Percent Change From Baseline Over Time in P1NP [Baseline, Week 12, Week 24, Week 48, Week 72, Week 96, EOSII (up to Week 141)]
• Change From Baseline Over Time in CTx [Baseline, Week 12, Week 24, Week 48, Week 72, Week 96, EOSII (up to Week 141)]: CTx: carboxy-terminal cross-linked telopeptide of type I collagen.
• Percent Change From Baseline Over Time in CTx [Baseline, Week 12, Week 24, Week 48, Week 72, Week 96, EOSII (up to Week 141)]: CTx: carboxy-terminal cross-linked telopeptide of type I collagen.
• Change From Baseline Over Time in BALP [Baseline, Week 12, Week 24, Week 48, Week 72, Week 96, EOSII (up to Week 141)]: BALP: bone-specific alkaline phosphatase.
• Percent Change From Baseline Over Time in BALP [Baseline, Week 12, Week 24, Week 48, Week 72, Week 96, EOSII (up to Week 141)]: BALP: bone-specific alkaline phosphatase.

Sex: All, ages: 18 Years to 65 Years

Inclusion Criteria:

1. Male or female, aged 18 - 65 years, inclusive
2. Diagnosis of XLH supported by classic clinical features of adult XLH (such as short stature or bowed legs), and at least one of the following at Screening:

   * Documented phosphate regulating gene with homology to endopeptidases located on the X chromosome (PHEX) PHEX mutation in either the patient or in a directly related family member with appropriate X-linked inheritance
   * Serum intact FGF23 (iFGF23) level > 30 pg/mL by Kainos assay
3. Biochemical findings consistent with XLH based on overnight fasting (min. 8 hours):

   * Serum phosphorus < 2.5 mg/dL at Screening
   * Ratio of renal tubular maximum phosphate reabsorption rate to glomerular filtration rate (TmP/GFR) < 2.5 mg/dL at Screening
4. Presence of skeletal pain attributed to XLH/osteomalacia, as defined by a score of ≥ 4 on the Brief Pain Inventory question 3 (BPI-Q3, Worst Pain) at Screening. (Skeletal pain that, in the opinion of the investigator, is attributed solely to causes other than XLH/osteomalacia-for example, back pain or joint pain in the presence of severe osteoarthritis by radiograph in that anatomical location-in the absence of any skeletal pain likely attributed to XLH/osteomalacia should not be considered for eligibility)
5. Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min (using the Chronic Kidney Disease Epidemiology Collaboration \[CKD-EPI\] equation) or estimated glomerular filtration rate (eGFR) eGFR of 45 to <60 mL/min at Screening with confirmation that the renal insufficiency is not due to nephrocalcinosis
6. Provide written informed consent after the nature of the study has been explained, and prior to any research-related procedures. If the subject in a minor, provide written assent and have a legally authorized representative willing and able to provide written informed consent, after the nature of the study has been explained, and prior to any research-related procedures
7. Willing to provide access to prior medical records for the collection of biochemical and radiographic data and disease history
8. Females of child-bearing potential must have a negative urine pregnancy test at Screening and be willing to have additional pregnancy tests during the study. Females considered not to be of childbearing potential include those who have been in menopause for at least two years prior to Screening, or have had tubal ligation at least one year prior to Screening, or have had a total hysterectomy or bilateral salpingo-oophorectomy.
9. Participants of child-bearing potential or with partners of child-bearing potential who have not undergone a total hysterectomy or a bilateral salpingo-oophorectomy and are sexually active must consent to use two effective methods of contraception as determined by the site investigator (i.e. oral hormonal contraceptives, patch hormonal contraceptives, vaginal ring, intrauterine device, physical double-barrier methods, surgical hysterectomy, vasectomy, tubal ligation, or true abstinence) from the period following the signing of the informed consent through 12 weeks after last dose of study drug
10. Must, in the opinion of the investigator, be willing and able to complete all aspects of the study, adhere to the study visit schedule and comply with the assessments

Exclusion Criteria:

1. Use of any pharmacologic vitamin D metabolite or analog (e.g. calcitriol, doxercalciferol, and paricalcitol) within the 2 years before Screening
2. Use of oral phosphate within 2 years before Screening
3. Use of aluminum hydroxide antacids, acetazolamides, and thiazides within 7 days prior to Screening
4. Use of bisphosphonates in the 2 years prior to Screening
5. Use of denosumab in the 6 months prior to Screening
6. Use of teriparatide in the 2 months prior to Screening
7. Chronic use of systemic corticosteroids defined as more than 10 days in the 2 months prior to Screening
8. Corrected serum calcium level ≥ 10.8 mg/dL (2.7 mmol/L) at Screening
9. Serum intact parathyroid hormone (iPTH) ≥ 2.5 times the upper limit of normal (ULN) at Screening
10. Use of medication to suppress parathyroid hormone (PTH) (cinacalcet for example) within 60 days prior to Screening
11. Prothrombin time/Partial thromboplastin time (PT/PTT) outside the normal range at Screening
12. Evidence of any disease or use of anticoagulant medication (such as warfarin, heparin, direct thrombin inhibitors, or Xa inhibitors (xabans) that, in the opinion of the investigator, cannot be discontinued) that may increase the risk of bleeding during the biopsy procedure
13. Pregnant or breastfeeding at Screening or planning to become pregnant (self or partner) at any time during the study
14. Unable or unwilling to withhold prohibited medications throughout the study
15. Documented dependence on narcotics
16. Use of KRN23, or any other therapeutic monoclonal antibody within 90 days prior to Screening
17. Use of investigational product or investigational medical device within 30 days prior to Screening, or requirement for any investigational agent prior to completion of all scheduled study assessments.

    OR, in Japan, use of any investigational product or investigational medical device within 4 months prior to Screening, or requirement for any investigational agent prior to completion of all scheduled study assessments.
18. Presence or history of any hypersensitivity, allergic or anaphylactic reactions to any monoclonal antibody or KRN23 excipients that, in the judgment of the investigator, places the subject at increased risk for adverse effects
19. History of allergic reaction or adverse reactions to tetracycline or demeclocycline
20. Prior history of positive test for human immunodeficiency virus antibody, hepatitis B surface antigen, and/or hepatitis C antibody
21. History of recurrent infection (other than dental abscesses, which are known to be associated with XLH) or predisposition to infection, or of known immunodeficiency
22. Presence of malignant neoplasm (except basal cell carcinoma)
23. Presence of a concurrent disease or condition that would interfere with study participation or affect safety
24. Presence or history of any condition that, in the view of the investigator, places the subject at high risk of poor treatment compliance or of not completing the study

Participant flow

Outcome results

• Percent Change From Baseline in OV/BV at Week 48 (Primary), Mean, percentage change of unmineralized bone: Open-Label Burosumab Q4W -54.18 +/- 20.211 (p < 0.0001)
• Percentage of Participants Achieving Mean Serum Phosphorus Levels Above the Lower Limit of Normal (LLN) at the Mid-Point of the Dose Interval, as Averaged Across Dose Cycles Between Baseline and Week 24 (Secondary), Number, percentage of participants: Open-Label Burosumab Q4W 92.9 (68.5 to 98.7) (p <0.0001)
• Percent Change From Baseline in O.Th at Week 48 (Secondary), Mean, percentage change in thickness: Open-Label Burosumab Q4W -32.21 +/- 11.966 (p <0.0001)
• Percent Change From Baseline in OS/BS at Week 48 (Secondary), Mean, percent change of bone surface covered: Open-Label Burosumab Q4W -26.00 +/- 15.012 (p 0.0002)
• Percent Change From Baseline in MLt at Week 48 (Secondary), Mean, percent change in average time interval: Open-Label Burosumab Q4W -52.24 +/- 58.487 (p 0.0199)
• Change From Baseline in MAR at Week 48 (Secondary), Mean, µm/day: Open-Label Burosumab Q4W 0.04 +/- 0.506
• Change From Baseline in MS/BS at Week 48 (Secondary), Mean, percent of mineralizing surface: Open-Label Burosumab Q4W 1.32 +/- 4.365
• Change From Baseline in BFR/BS at Week 48 (Secondary), Mean, µm^3/µm^2/year: Open-Label Burosumab Q4W -4.90 +/- 27.356
• Change From Baseline in BFR/OS at Week 48 (Secondary), Mean, µm^3/µm^2/year: Open-Label Burosumab Q4W -1557.25 +/- 3139.075
• Change From Baseline in BFR/BV at Week 48 (Secondary), Mean, percentage of bone turnover/year: Open-Label Burosumab Q4W -13.50 +/- 32.904
• Percentage of Participants Achieving Mean Serum Phosphorus Levels Above the LLN at the End of the Dosing Cycle Between Baseline and Week 24 (Secondary), Number, percentage of participants: Open-Label Burosumab Q4W 78.6 (52.4 to 92.4)
• Mean Change of Serum Phosphorus Levels at the Mid-Point of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24 (Secondary), Mean, mg/dL: Open-Label Burosumab Q4W 1.07 +/- 0.300
• Percent Change of Serum Phosphorus Levels at the Mid-Point of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24 (Secondary), Mean, percent change of serum phosphorus level: Open-Label Burosumab Q4W 50.39 +/- 19.942
• Mean Change of Serum Phosphorus Levels at the End of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24 (Secondary), Mean, mg/dL: Open-Label Burosumab Q4W 0.46 +/- 0.303
• Percentage Change of Serum Phosphorus Levels at the End of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24 (Secondary), Mean, percent change of serum phosphorus level: Open-Label Burosumab Q4W 23.32 +/- 19.836
• Time-Adjusted Area Under the Curve (AUC) of Serum Phosphorus Between Baseline and Week 24 (Secondary), Mean, mg/dL: Open-Label Burosumab Q4W 3.023 +/- 0.2716
• Change From Baseline Over Time in Serum 1,25(OH)2D (Secondary), Least squares mean, pg/mL: Open-Label Burosumab Q4W 107.75 +/- 15.964
• Change From Baseline Over Time in 24-Hour Urinary Phosphorus (Secondary), Least squares mean, g/24 hours: Open-Label Burosumab Q4W 0.10 +/- 0.128
• Change From Baseline Over Time in TmP/GFR (Secondary), Least squares mean, mg/dL: Open-Label Burosumab Q4W 1.76 +/- 0.136
• Change From Baseline Over Time in TRP (Secondary), Least squares mean, fraction of phosphorus reabsorbed: Open-Label Burosumab Q4W 0.07 +/- 0.005
• 6 more outcome measures not shown.

Adverse events

Time frame: Week 0 to EOSII (up to Week 141). Mean (SE) duration of exposure to study drug was 716 (35.1) days

Serious adverse events by term

Other adverse events by term

96 more terms not shown.

• Results publication: Portale AA, Ward L, Dahir K, Florenzano P, Ing SW, Jan de Beur SM, Martin RM, Meza-Martinez AI, Paloian N, Ashraf A, Dixon BP, Khan A, Langman C, Chen A, Wang C, Roberts MS, Tandon PK, Bedrosian C, Imel EA. Nephrocalcinosis and kidney function in children and adults with X-linked hypophosphatemia: baseline results from a large longitudinal study. J Bone Miner Res. 2024 Sep 26;39(10):1493-1502. doi: 10.1093/jbmr/zjae127. PMID 39151033
• Results publication: Fratzl-Zelman N, Hartmann MA, Gamsjaeger S, Rokidi S, Paschalis EP, Blouin S, Zwerina J. Bone Matrix Mineralization and Response to Burosumab in Adult Patients With X-Linked Hypophosphatemia: Results From the Phase 3, Single-Arm International Trial. J Bone Miner Res. 2022 Sep;37(9):1665-1678. doi: 10.1002/jbmr.4641. Epub 2022 Aug 10. PMID 35775373

• Study Protocol (PDF, 2017-08-29)
• Statistical Analysis Plan (PDF, 2016-12-15)