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Ultragenyx and Kyowa Kirin Announce Topline Phase 3 Study Results Demonstrating Superiority of Crysvita® (burosumab) Treatment to Oral Phosphate and Active Vitamin D in Children with X-Linked Hypophosphatemia (XLH)

Substantial Healing of Rickets Observed in 72% of Patients Treated with Crysvita Compared to 6% of Patients Receiving Conventional Therapy at 40 Weeks
Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE), a biopharmaceutical company focused on the development of novel products for rare and ultra-rare diseases, Kyowa Hakko Kirin Co. Ltd (Kyowa Hakko Kirin), and Kyowa Kirin International PLC (Kyowa Kirin International) today announced that the Phase 3 study of Crysvita® (burosumab) met its primary endpoint demonstrating that Crysvita was superior to oral phosphate and active vitamin D (conventional therapy) in improving rickets in children with X-linked hypophosphatemia (XLH) after 40 weeks of treatment (LS Mean treatment difference  of +1.14, p<0.0001). The study also showed improvement in important metabolic and functional measures with Crysvita treatment, and a safety profile similar to that observed in other Crysvita pediatric XLH studies. Crysvita is an antibody that blocks fibroblast growth factor 23 (FGF23), a hormone that causes phosphate urinary excretion and suppresses active vitamin D production by the kidney.
“This is the first study that directly compares Crysvita to conventional therapy for XLH, and we have now clearly demonstrated that Crysvita has a rapid and profound effect on the underlying disease, an outcome that was not achieved with conventional therapy,” said Camille L. Bedrosian, M.D. Chief Medical Officer of Ultragenyx. “These data reinforce the results seen in our earlier Phase 2 studies, and we believe that Crysvita will transform the treatment of XLH in children.”
“The results of this important controlled study demonstrate the value of directing therapy at the mechanism of renal phosphate wasting in XLH,” said the lead study investigator, Erik Imel, M.D., Associate Professor of Medicine and Pediatrics at Indiana University School of Medicine. “While prior conventional therapy fails to improve renal phosphate wasting, Crysvita works to improve serum phosphorus by correcting the renal phosphate wasting. The differences in mechanism are clearly important to outcomes as demonstrated in this study. By comparing XLH patients treated with Crysvita to patients treated with conventional therapy, we are finally able to demonstrate the magnitude of benefit on parameters of serum phosphorus, bone metabolism, and improvements in the skeleton.”
“I am pleased that the study provides valuable data for pediatric patients with XLH,” said Mitsuo Satoh, Executive Officer, Vice President Head of Research and Development Division of Kyowa Hakko Kirin. “I believe Crysvita has the potential to be an effective treatment option for patients with XLH.”
Phase 3 Pediatric XLH Study
The randomized, open-label Phase 3 clinical study enrolled 61 patients ages one through 12 in the US, Europe, Canada, Australia, Japan, and Korea, and compared the efficacy and safety of Crysvita (n=29) to conventional therapy (n=32). The study’s primary endpoint was the change in rickets at 40 weeks, assessed by three independent blinded pediatric radiologists using the radiographic global impression of change (RGI-C) scale. Secondary endpoints included additional rickets assessments using the RGI-C scale and the Thacher Rickets Severity Scoring (RSS) system, pharmacodynamic assessments, changes in growth velocity and height, walking ability, patient-reported outcomes assessing pain, fatigue and physical function, and safety. Prior to study enrollment, all patients received conventional therapy for an average of approximately four years. Patients in the Crysvita treatment group received a starting dose of 0.8 mg/kg administered subcutaneously every two weeks, with dose increases up to 1.2 mg/kg implemented in five patients. Patients in the conventional therapy arm received the local standard regimen based on expert guidelines with ongoing optimization by each patient’s physician.
Bone Disease Results
The study met its primary endpoint demonstrating that Crysvita significantly improved rickets compared to conventional therapy, as assessed by three independent blinded pediatric radiologists using the RGI-C scale. In addition, substantial healing (RGI-C ≥ +2.0) was observed in 72% of patients receiving Crysvita compared to 6% of patients receiving conventional therapy.
Rickets severity was also assessed using the RSS scoring system, which showed that patients treated with Crysvita showed a 2.8-fold improvement in rickets compared to patients receiving conventional therapy.

Endpoint Treatment Effect Treatment difference
(95% CI)
Conventional therapy
Crysvita vs. conventional therapy
RGI-C Score (Primary Endpoint)
LS Mean* +1.92 +0.77 1.14
(0.83, 1.45)
Substantial healing, % patients
(RGI-C≥ +2.0)
72% 6% Odds ratio: 39.139
(7.238, 211.656)
RSS Total Score
LS Mean Change from Baseline -2.04 -0.71 -1.34 (-1.74, -0.94)
*LS Mean: Least Squares Mean      

Metabolic Measures and Other Secondary Endpoints
At baseline, patients in both the Crysvita and conventional therapy arms had mean serum phosphorus levels and mean renal phosphate reabsorption levels below the lower limits of normal.  In the Crysvita arm, mean serum phosphorus and renal phosphate reabsorption levels post-baseline through Week 40 were in the normal range. In the conventional therapy arm, mean serum phosphorus and renal phosphate reabsorption levels remained below the lower limits of normal over the 40-week period.

Endpoint Treatment Effect Treatment difference
Conventional therapy
Crysvita vs. conventional therapy
Serum Phosphorus (mg/dL)*
Mean baseline 2.42 2.30
Mean post-baseline 3.38 2.55
LS Mean Change from Baseline 1.00 0.23 0.77
*Serum phosphorus lower limit of normal: 3.2mg/dL

Patients in both the Crysvita and conventional therapy arms demonstrated increases in serum 1,25-dihidroxy vitamin D, and maintained levels within the normal range through 40 weeks.
Treatment with Crysvita showed a significant improvement in mean alkaline phosphatase levels into the normal range after 40 weeks of treatment, compared to conventional therapy. Patients treated with Crysvita also demonstrated a greater numeric but not statistically significant improvement in growth (height z-score and growth velocity) and in the six-minute walk test, compared to conventional therapy.
Safety and Tolerability
The Crysvita safety profile observed in this study was generally consistent with that seen in other Crysvita pediatric XLH studies. There were no treatment discontinuations and no deaths reported in the study. There were three serious adverse events in the Crysvita arm and one serious adverse event in the conventional therapy arm, none of which were considered treatment-related. In the Crysvita arm, 45% of patients had injection site reactions, all but one were mild and none were considered serious.  No clinically meaningful changes were observed in mean serum calcium and serum intact parathyroid hormone in either treatment arm. No clinically significant changes were observed in renal ultrasounds pre-and post-treatment in either treatment arm.
Full results will be presented at an upcoming medical meeting.
About X-linked hypophosphatemia (XLH)
XLH is a rare, hereditary, progressive and lifelong skeletal disorder characterized by renal phosphate wasting caused by excess FGF23 production. It affects both children and adults. In children, XLH causes rickets that leads to lower-extremity deformity, delayed growth and decreased height. Adults with XLH have an increased risk of fractures.