Date: 2018-05-18
Type of information: Results
phase: 3
Announcement: results
Company: Ultragenyx Pharmaceutical (USA - CA) Kyowa Hakko Kirin (Japan)
Product: burosumab - KRN23
Action
mechanism:
Disease: X-Linked hypophosphatemia
Therapeutic area: Rare diseases - Genetic diseases - Metabolic diseases
Country: Australia, Canada, Denmark, Germany, Ireland, Italy, Japan, Republic of Korea, Spain, Sweden, UK, USA
Trial
details:
Latest
news: 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. 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. • On October 26, 2016, Ultragenyx Pharmaceutical announced the initiation of the Phase 3 study of KRN23 for the treatment of pediatric patients with X-linked hypophosphatemia (XLH). Kyowa Hakko Kirin and Ultragenyx entered into a collaboration and license agreement in August 2013 to develop and commercialize KRN23.
• On May 17, 2018, Ultragenyx Pharmaceutical, Kyowa Hakko Kirin and Kyowa Kirin International 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.
The randomized, open-label Phase 3 clinical study enrolled 61 patients ages one through 12 in the U.S., 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.
The Phase 3 study is a randomized, open-label clinical study comparing the efficacy and safety of KRN23 to oral phosphate and active vitamin D therapy. The study will enroll approximately 60 patients ages one through 12 in the US, EU, Canada, Japan, and Korea. The primary endpoint is the change in rickets at 40 weeks, assessed by the radiographic global impression of change (RGI-C) scale. Secondary endpoints include additional rickets assessments using the RGI-C scale and the Thacher Rickets Severity Scoring (RSS) system, changes in growth velocity and height, pharmacodynamic assessments, walking ability, patient reported outcomes assessing pain, fatigue and physical function, and safety. All patients were previously treated with oral phosphate and active vitamin D therapy, and go through a 7-day washout period prior to randomization. Patients in the KRN23 treatment group receive a starting dose of 0.8 mg/kg administered biweekly, and the dose may be increased up to 1.2 mg/kg.
Endpoint
Treatment Effect
Treatment difference
(95% CI)
Crysvita
n=29
Conventional
therapy
n=32
Crysvita vs. conventional therapy
RGI-C Score (Primary Endpoint)
LS Mean*
+1.92
+0.77
1.14
(0.83, 1.45)
P<0.0001
Substantial healing, % patients
(RGI-C? +2.0)
72%
6%
Odds ratio: 39.139
(7.238, 211.656)
P<0.0001
RSS Total Score
LS Mean Change from Baseline
-2.04
-0.71
-1.34 (-1.74, -0.94)
P<0.0001
*LS Mean: Least Squares Mean
Endpoint
Treatment Effect
Treatment
difference
Crysvita
n=29
Conventional
therapy
n=32
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
p<0.0001
*Serum phosphorus lower limit of normal: 3.2mg/dL
