Ultragenyx To Proceed with Phase 2 Study for Inherited Form of Rickets (X-linked hypophosphatemia)

James Radke

Ultragenyx Pharmaceutical announced positive results from a long-term Phase 1/2 extension study of the investigational fully human anti-FGF23 monoclonal antibody KRN23 (UX023) in adult patients with X-linked hypophosphatemia which is an inherited form of rickets.  The cumulative 16-month data (4 month study plus 12 month extension) was presented at the American Society of Bone and Mineral Research (ASBMR) Annual Meeting in Houston, TX.  The data was presented by Kyowa Hakko Kirin Pharma, Inc. the Japanese based company who partnered with Ultragenyx to develop and market KRN23.

The Phase 1/2 extension study was designed to evaluate long-term safety and efficacy in 22 adult patients with X-linked hypophosphatemia following an initial four-month dose escalation study. Patients received monthly subcutaneous injections of KRN23 administered at a dose range of 0.1 to 1.0 mg/kg.

Details of the study are limited but in a press release, it was announced that the increases in “serum phosphorus levels, urinary phosphorus reabsorption, and 1,25 dihydroxy vitamin D levels observed in the initial 4 month study were generally sustained during the 12-month extension. All patients continued to demonstrate increases in serum phosphorus levels. Approximately 52.6%-85.7% of subjects in the extension study had serum phosphorus levels that reached the normal range (2.5 to 4.5 mg/dL) at peak time on Day 7 or Day 14 after each dose over this 12-month period.”

The most common treatment-related adverse events were injection site reaction, arthralgia, diarrhea, restless legs syndrome, injection site erythema, injection site pain, upper abdominal pain, headache, and decreased neutrophil count (the neutrophil changes were not associated with any significant infections).

Based on the data, the companies plan to continue the clinical development of KRN23 in adults with X-linked hypophosphatemia.  Sunil Agarwal, M.D., Chief Medical Officer of Ultragenyx said, "Based on these encouraging results, we plan to continue development in adult X-linked hypophosphatemia patients and are enrolling pediatric X-linked hypophosphatemia patients in our ongoing Phase 2 study."

The companies have already begun a Phase 2 study of KRN23 in pediatric patients.

About X-Linked Hypophosphatemia

X-linked hypophosphatemia is an inherited disorder due to a mutation in phosphate-regulating gene homologous to endopeptidases on the X chromosome (PHEX) which controls fibroblast growth factor 23 (FGF23) – a phospaturic hormone. Patients with X-linked hypophosphatemia have severe hypophosphatemia which can lead to a plethora of problems including rickets, progressive bowing of the leg, osteomalacia, bone pain, waddling gait, short stature, gross motor impairment, muscle weakness, osteopenia, frequent/poorly healing microfractures, spinal stenosis, enthesopathy, and osteoarthritis.

Most patients are managed using oral phosphate replacement and vitamin D (calcitriol) therapy, with limited success.

The investigative drug KRN23 is a  monoclonal IgG1 antibody against FGF23 which is high in X-linked hypophosphatemia. By blocking excess FGF23 in patients with the X-linked hypophosphatemia, the drug KRN23 is “intended to restore normal phosphate reabsorption from the kidney and increase the production of vitamin D, which enhances intestinal absorption of phosphate and calcium.”

X-ray image of child with rickets courtesy wikipedia commons.
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