Benefit of burosumab in adults with X-linked hypophosphataemia (XLH) is maintained with long-term treatment

Abstract

Objectives: To report the impact of continued burosumab treatment on clinical laboratory tests of efficacy, patient-reported outcomes (PROs) and ambulatory function in adults with X-linked hypophosphataemia who continued from a 96-week phase 3 study into a 48-week open-label extension.

Methods: Eligible participants from the phase 3 study continued on the burosumab regimen received at the end of the phase 3 study for a further 48 weeks (n=31). Some (not all) received compassionate burosumab treatment between the two studies (a period of 6-18 months). The primary efficacy outcome was fasting serum phosphate concentration; secondary outcomes were serum 1,25 dihydroxyvitamin D concentration, renal phosphate reabsorption, PROs and ambulatory function.

Results: Improvements in fasting serum phosphate, serum 1,25 dihydroxyvitamin D and renal phosphate reabsorption at 96 weeks were maintained through the 48-week extension. Improvements were also maintained in stiffness and physical function measured using the Western Ontario and McMaster Universities Osteoarthritis Index, pain and fatigue endpoints measuring using the Brief Pain Inventory short-form and Brief Pain Inventory, respectively, and in ambulatory function (6-Minute Walk Test).A post-hoc exploratory analysis exploring outcomes in participants who discontinued burosumab treatment between the studies (n=7) and those who received at least one dose (n=23) indicated that the benefits of burosumab on clinical laboratory tests of efficacy, PROs and ambulatory function may be lost when treatment is interrupted but recover over time when treatment is reinstated.

Conclusion: Continued treatment with burosumab appears necessary for sustained clinical benefit.

Trial registration numbers: Phase 3: NCT02526160; open-label extension: NCT03920072.

Keywords: Outcome Assessment, Health Care; Patient Reported Outcome Measures; Therapeutics.

Figure 1

Administration of burosumab during the interval between the end of the phase 3 study and the start of the open-label extension study. n=30; one participant who did not complete the phase 3 study through to week 96a was excluded from this exploratory analysis.

Figure 2

Effect of burosumab maintenance on clinical laboratory tests of efficacy. Data available for 31 participants at BL, 24 at week 48b for fasting serum phosphate and serum 1,25 dihydroxyvitamin D and 23 at week 48b for phosphate reabsorption (TmP/GFR). Analysis weeks in the phase 3 study and open-label extension are indicated by ‘a’ and ‘b’ suffixes, respectively. Samples from the two studies were measured at different central laboratories, with different LLN values for trough fasting serum phosphate (0.81 mmol/L in the phase 3 study (LLN¹) and 0.74 mmol/L in the open-label extension (LLN²)); 1,25 dihydroxyvitamin D (43 and 48 pmol/L) and phosphate reabsorption (Tmp/GFR; 0.81 and 0.80–1.00 mmol/L). Serum 1,25 dihydroxyvitamin D and TmP/GFR were not measured at all analysis visits. BL, baseline; LLN, lower limit of normal range; TmP/GFR, ratio of tubular maximum reabsorption rate to glomerular filtration rate.

Figure 3

Effect of burosumab maintenance on PROs and 6MWT. Data available for 31 participants at BL, 28 at week 48b for WOMAC, 27 at week 48b for BPI-SF and BFI and 16 at week 48b for 6MWT. Analysis weeks in the phase 3 study and open-label extension are indicated by ‘a’ and ‘b’ suffixes, respectively. A decrease in score indicates improvement on the WOMAC, BPI-SF and BFI. An increase in distance indicates improvement on the 6MWT. BPI-SF and BFI data were captured at a single site visit and were not completed as part of a patient diary at weeks 72a and 96a. *p<0.05 for LSM change from BL (generalised estimating equation repeated-measures analysis). Six participants (19%) used an assistive device during the 6MWT at the phase 3 baseline, decreasing to three (10%) at phase 3 week 72a, and one from week 12b. BFI, Brief Fatigue Inventory; BL, baseline; BPI-SF, Brief Pain Inventory short-form; LSM, least squares mean; MCID, minimum clinically important difference; 6MWT, 6-Minute Walk Test; PRO, patient-reported outcome; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

Figure 4

Effect of burosumab treatment interruption on serum phosphate, PROs and 6MWT. Interim burosumab, n=23; no interim burosumab, n=7. Analysis weeks in the phase 3 study and open-label extension are indicated by ‘a’ and ‘b’ suffixes, respectively. A decrease in scores indicates improvement on the WOMAC, BPI-SF and BFI. An increase in distance on the 6MWT indicates improvement. BPI-SF and BFI data were captured at a single site visit and were not completed as part of a patient diary at weeks 72a and 96a. Fasting serum phosphate p values are for the difference between the groups (end of dosing cycle) at week 0b (tested using Fisher’s exact test); 52% of the interim burosumab group but none of no interim burosumab group had values ≥LLN at the start of the open-label extension period (p=0.01; Fisher’s exact test). PROs and 6MWT (tested using the Mann-Whitney U test) p<0.05 was considered significant. There was no significant difference between the groups at study baseline. Serum phosphate samples from the two studies were measured at different central laboratories, with different LLN values: 0.81 mmol/L in the phase 3 study (LLN¹) and and 0.74 mmol/L in the open-label extension (LLN²). BFI, Brief Fatigue Inventory; BL, baseline; BPI-SF, Brief Pain Inventory short-form; LLN, lower limit of normal range; 6MWT, 6-Minute Walk Test; PRO, patient-reported outcome; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.