Burosumab Shows Sustained Efficacy in Rare Inherited Rickets

Nancy A. Melville

October 02, 2019

ORLANDO, Florida — Burosumab (Crysvita, Ultragenyx), an anti-FGF23 monoclonal antibody, shows long-term safety and efficacy out to almost 2 years in the treatment of X-linked hypophosphatemia (XLH), a rare, inherited form of rickets, according to the latest findings from a phase 3 clinical trial.

"The primary significance of these findings is that the drug continues to show efficacy, both in terms of biochemical improvement and symptomatic benefit in adults with X-linked hypophosphatemia," first author Karl L. Insogna, MD, Yale School of Medicine, New Haven, Connecticut, told Medscape Medical News.

"In particular, there was evidence for sustained improvement in physical function and stiffness," he said of the study, which he presented here at the American Society for Bone and Mineral Research (ASBMR) 2019 Annual Meeting.

Pain was a tougher symptom to tackle, Insogna said, but some patients do appear to get gradual relief with this agent.

Life-Long Therapy Needed

Asked to comment, Bente Langdahl, MD, PhD, Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark, told Medscape Medical News that as XLH involves life-long renal wasting and persistent impairments in bone growth and mineralization, a key consideration with burosumab is the still unknown effect of potentially life-long therapy.

"Although this is the longest study to date in adults, it is still short term [in terms of life-long therapy], and the most important caveat in this type of study is the question [of whether] a similar result could have been achieved if the standard treatment [phosphate, vitamin D supplements, and pain medication] had been further optimized," Langdahl said.

Insogna agreed: "The major caveat about this treatment is that there has never been a monoclonal antibody used to treat a disease that begins in infancy and continues through adulthood."

"It remains to be determined whether it is safe to give a monoclonal antibody every month for the majority of a patient's life," he added.

Notwithstanding these comments, the physicians said that burosumab does appear to be much less burdensome to use and monitor than standard therapy, but cost remains a major barrier to use.

Ultragenyx has reported the price will be approximately $160,000 per patient per year for children and $200,000 per patient per year for adults, depending on body weight.

"It needs to be acknowledged that this is not an inexpensive therapy, and so that, too, needs to be factored into a decision about treatment," Insogna noted.

Pain a Tougher Symptom to Tackle

Pediatric patients with XLH commonly have bent or bowed legs, bone pain, and dental pain, and adults can likewise have persistent pain, impaired mobility, and hearing loss.

Insogna acknowledged that the improvements in pain were not as dramatic as those seen with stiffness or physical function in the 96 weeks of the trial.

"This likely reflects the multifaceted origins of pain in this disease, including fixed skeletal defects from previous orthopedic surgery, osteoarthritis that involves both the weight-bearing bones of the lower extremities and the spine, and the peculiar complication of enthesopathy in this disease, which is the calcification of ligaments and tendons that restricts joint motion and causes chronic pain," he explained.

"Available evidence suggests that burosumab will not reverse any of these fixed deficits; however, I have been struck by the gradual, but progressive, improvement in pain in some patients treated with this medication long term," Insogna commented.

Study Details Out to 96 Weeks

Insogna reported on the final results at 96 weeks from the phase 3, double-blind CL303 trial, which was among the studies that supported the approval of burosumab in 2018 by the US Food and Drug Administration as the first treatment for patients age 1 year and older with XLH.

The drug was granted orphan drug status.

For the multicenter trial, 134 adults with XLH and serum phosphorus < 2.5 mg/dL were randomized to subcutaneous burosumab 1 mg/kg (n = 68) or placebo (n = 66) every 4 weeks until week 24.

Patients, who were blinded to prior treatment, were then entered into an open-label phase of either continued burosumab (n = 67) or crossed-over from placebo to the same dose of 1 mg/kg burosumab every 4 weeks until week 48 (n = 66).

In the final open-label extension, all patients (63 in each group) continued on the same dose of burosumab through week 96.

Patients had similar baseline characteristics. Participants were a mean age of 40 years, 65% were women, 81% were white, and mean serum phosphorus levels were 2.0 mg/dL.

Most patients (119, 89%) completed the 96 weeks of treatment, and 12 patients received 14 dose reductions.

As early as week 24, all of the participants receiving burosumab achieved the primary endpoint of having serum phosphorus levels above the lower limit of normal (above 2.5 mg/dL), and all remained above the lower limit throughout the remainder of the study.

Participants in the placebo group meanwhile showed no significant changes in their phosphorus levels until cross-over at week 24, when levels rose to those attained in the treatment group.

Patients also achieved increases in serum vitamin D that, after an initial spike, were maintained at normal levels.

For the key secondary endpoints of stiffness and physical function, each assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and for pain, measured using the Brief Pain Inventory score, reductions in scores, indicating improvements, were also seen at 96 weeks.

Importantly, at week 24, 43% of fractures identified at baseline had healed with burosumab, whereas only 8% had healed in the placebo group. And at the end of 48 weeks, the last timepoint for that data, 35% of fractures in the placebo cross-over group and 63% in the treatment group had healed.

The frequency, severity, and types of adverse events were consistent with previous data on burosumab, with no new safety concerns reported.

Most participants (132/134, 99%) experienced an adverse event, with the most common including injection-site reactions, nasopharyngitis, and pain. Serious adverse events were reported in 22 participants, with all cases resolved or resolving.

Meanwhile, there were no meaningful shifts in nephrocalcinosis scores and no positive tests for neutralizing antibodies.

Benefits Over Conventional Therapy

Langdahl said standard treatment for XLH involves a significantly more burdensome therapy: a combination of phosphate and active vitamin D. Phosphate needs to be taken several times a day and causes gastrointestinal discomfort, which can decrease adherence and compliance with treatment.

"[Treatment] is challenging, because the treatments available are not targeting the actual cause of the disease, high FGF23," she told Medscape Medical News.

Burosumab offers numerous benefits over current treatment, starting with a better safety profile, Insogna further explained.

"Conventional therapy requires very careful, frequent monitoring of both blood and urine for changes in parathyroid function and calcium metabolism to avoid hypercalcemia and hypercalciuria, and secondary and even tertiary hyperparathyroidism," he said.

"Further, patients on conventional therapy often have processive nephrocalcinosis. The risk for any of these complications with burosumab is much lower."

Patients taking burosumab do need monitoring, but not nearly as intense, and once a stable dose has been achieved, it does not require repeated, frequent dose adjustments, Insogna noted.

The study received funding from Ultragenyx. Insogna has reported receiving research support from Ultragenyx. Langdahl had reported no relevant financial relationships.

ASBMR 2019 Annual Meeting. Presented September 21, 2019. Abstract 1077.

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