Pam Harrison

September 22, 2016

ATLANTA — Dramatic strides are being made in the treatment of several rare bone diseases, X-linked hypophosphatemia (XLH) rickets and hypophosphatasia (HPP) among them, new research indicates.

The studies were all presented here at the American Society of Bone and Mineral Research 2016 Annual Meeting..

"In children with XLH treated with KRN 23 [Ultragenyx Pharmaceutical] for up to 64 weeks, rickets improved significantly despite previous conventional treatment for nearly 7 years, and improvement in rickets scores was greater in children with more severe baseline rickets," Thomas Carpenter, MD, professor of pediatrics (endocrinology), orthopedics, and rehabilitation, Yale University, New Haven, Connecticut, told attendees.

KRN 23 is a fully humanized monoclonal antibody that binds and inhibits the action of fibroblast growth factor (FGF) 23 and is in phase 3 studies for adult XLH and phase 2 trials for the same indication in children.

"So we believe than inhibition of FGF 23 is a useful strategy to improve clinical outcomes in this disease, as approximately 90% of patients at week 40 and at week 64 had substantial healing of rickets," Dr Carpenter said.

Asked by Medscape Medical News to comment on the findings, session cochair Jonathan Adachi, MD, professor of medicine, McMaster University, Hamilton, Ontario, called the work done by Dr Carpenter et al and colleagues "really exciting."

"They looked at FGF 23 for patients with X-linked hypophosphatemic rickets, and preliminary data show that treatment with KRN 23 helps children in terms of growth and it helps correct osteomalacia, so this treatment will improve outcomes compared with standard treatment to date with phosphate and calcitriol, which has not been the best treatment for this disease," Dr Adachi said.

"KRN 23 also has less toxicity than standard treatment, and it offers a more physiological approach for correcting the underlying problem," he added.

X-Linked Hypophosphatemia

The study reported by Dr Carpenter involved 52 children between the ages of 5 and 12 years of age with X-linked hypophosphatemia, with a mean rickets severity score of 1.4 despite prior long-standing treatment with oral phosphate and active vitamin D.

The primary analysis was done at 40 weeks, but a limited number of patients made it out to 64 weeks, allowing for an extended analysis.

Two scoring systems were used to assess improvement in rickets, the first being the rickets severity score (RSS), in which the higher the score, the worse the rickets, Dr Carpenter noted.

Investigators also compared baseline films with follow-up films from each individual to assess rachitic change from baseline to week 40 and week 64 for the extended analysis. Comparisons were made using the radiographic global impression of change (RGI-C), where a +2 indicates substantial healing and a +3 indicates complete healing.

Half of participants received KRN 23 at a dose of 1.0 mg/kg every 2 weeks and the other half got the same dose every 4 weeks. The dose of the drug could be titrated up to a maximum of 2 mg/kg per dose administered.

As Dr Carpenter explained, excess FGF 23 drives the pathophysiology of X-linked rickets, which leads to diminished levels of active vitamin D and reduced phosphate absorption at the level of the intestine, along with increased urinary phosphate excretion.

This in turns leads to mineralization defects, bone deformity, and widespread impairment in linear growth.

As an antibody that binds and inhibits the action of FGF 23, KRN 23 allows for restoration of normal vitamin D metabolism, increased phosphate absorption, and reduced urinary phosphate excretion, restoring serum phosphate over time.

"In the entire group, there was about a 50% reduction in the rickets severity score at 40 weeks, but within this group, the every-2-week-dosing group tended to have a greater drop in the rickets severity score than the every-4-week group," Dr Carpenter reported.

At 40 weeks, the mean change on the RGI-C scale was +1.6 in the every-2-week group and +1.2 in the every-4-week group, with a mean of +1.4 across both groups (P = .0001 for all groups).

When investigators limited the analysis to patients who had a baseline severity score ≥1.5, there was a more exaggerated drop in rickets severity scores across the board, but there was still a preference for the every-2-week dosing group, Dr Carpenter observed. In this group, the mean change in the RGI-C score was +2 in the every-2-week group and +1.7 in the every 4-week-group for a mean of +1.9 across both groups (P = .001 for all groups).

In the extended analysis out to 64 weeks, a very similar pattern emerged, with a greater reduction in the rickets severity score in patients with more severe rickets at baseline, and the changes in both dosing groups were very similar to those found on the 40-week analysis.

Growth was also substantially greater compared with baseline as reflected by substantially higher Z scores at the 40-week assessment point. For those in the every-2-week group, there was about an inch/year-greater growth velocity compared with baseline. For more severe patients, growth was closer to 1.25 inches/year in the every-2-week group.

Investigators also documented a "substantial improvement" in the functional 6-minute-walk test among patients who had impaired walking ability at baseline, again more so in the every-2-week group.

"Most treatment-related adverse events were mild," Dr Carpenter reported, transient injection-site reactions being the most common.

Substantial Healing With Asfotase Alfa in Severe Hypophosphatasia

In a separate phase 2 study involving infants and young children with life-threatening hypophosphatasia, Jill Simmons, MD, associate professor of pediatric endocrinology, Vanderbilt University School of Medicine, Nashville, Tennessee, reported on their experience treating 9 such patients with asfotase alfa for 5 years.

Another very rare bone disease, hypophosphatasia is characterized by low levels of serum alkaline phosphatase.

Asfotase alfa (Strensiq, Alexion Pharmaceuticals) is a bone-targeted form of the enzyme and replaces the missing alkaline phosphatase in the skeleton.

At baseline the median age of the group was 13.6 months.

"RGI-C scores documented significant skeletal improvement by 6 months that was sustained through 5 years," Dr Simmons reported. For example, by year 5, the mean RGI-C score had improved by +2, a signal of substantial healing.

Weight Z scores also improved from a mean of -3.8 at baseline to a mean of -1.2 at year 5.

"We've been equally excited about the improvement in functional status of these children," Dr Simmons told Medscape Medical News.

Their motor skills are approaching normal for their age, and what is "really important is how their parents talk about how their children are doing," she observed.

Not only were these children not really destined to live very long, "but many of them were on feeding tubes and ventilators before treatment, and now they are walking and going to school and holding a pencil and writing, so that's really quite a substantial improvement," she said.

Again, the most common adverse events with asfotase alfa were injection-site reactions. Otherwise, treatment was well-tolerated.

Prior to the approval of asfotase alfa late last year, the majority of infants and children born with the more severe forms of hypophosphatasia died.

There has been controversy over the cost of this medication, however, with the UK drugs watchdog saying the $500,000 price tag for each patients is too expensive.

KRN 23 in Osteomalacia

In another small dose-finding study, also presented by Dr Carpenter, the effects of KRN 23 were assessed in patients with either tumor-induced osteomalacia (TIO) or epidermal nevus syndrome (ENS).

Again, the rationale to use KRN 23 is similar to that of X-linked hypophosphatemic rickets, namely both TIO and ENS result in reduced renal phosphate reabsorption and impaired active vitamin D synthesis.

The study involved 16 patients in total and data are available on eight subjects who've made it out to 24 weeks out of a 48-week protocol. Mean age of patients on enrollment was 52 years, and time since diagnosis ranged from 1 to 37 years.

"These were severe patients who could not be treated by conventional means, either because the tumor was in an inoperable location or they were sufficiently small that they couldn't be identified," Dr Carpenter explained.

Baseline serum phosphate levels ranged from 1.0 to 3.0 mg/dL, where normal levels range from 2.5 to 4.0 mg/dL, and serum FGF 23 levels were all well above normal.

KRN 23 was administered subcutaneously, starting at a low dose of 0.3 mg/kg every 4 weeks. As Dr Carpenter observed, this was the first time that KRN 23 had been used outside the setting of X-linked hypophosphatemia, and they needed to proceed with caution.

Within 1 week of treatment, mean serum phosphate levels increased from 1.7 mg/dL to 2.9 mg/dL, and these increases were accompanied by increases in serum 1,25(OH)2D values in all but one patient.

"We had [dual-energy X-ray absorptiometry] DEXA scans for each subject at the lumbar spine, and at 24 weeks, there was a mild increase in bone-mineral density [BMD] in most patients," he reported. Markers of bone turnover also improved at week 24.

One patient who completed the full 48-week protocol also had evidence of "dramatic increases" in osteoid parameters at study end point.

"This patient is no longer in a wheelchair, and he is able to stand and sit much more easily, so he achieved what we think is a dramatic response to just a few injections of KRN 23," Dr Carpenter enthused.

"And the increases in BMD and bone-turnover markers we observed at 24 weeks in other patients provide further clinical evidence that treatment with KRN 23 improves skeletal health."

Commenting on the study, Michael Collins, MD, chief, skeletal disorders and mineral homeostasis section, National Institutes of Health, Bethesda, Maryland, told attendees that it should be emphasized that cure is still the goal in TIO.

"The terms 'can't be identified' and 'unresectable' are relative terms in that one should still continue to try to find these tumors even when patients are on therapy," Dr Collins noted.

"And we need to keep in mind, too, that some tumors that are not resectable in one place are resectable in another, and that one of the paths of the natural history of this disease is metastatic, untreatable, and lethal, so that has to be kept in mind as well."

Dr Carpenter received funding from Ultragenyx. Dr Simmons receives funding from Alexion Pharmaceuticals. Dr Collins had no relevant financial relationships.

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American Society of Bone and Mineral Research 2016 Annual Meeting; September 19, 2016, Abstract 1165; September 16, 2016, Abstract FR0327; September 18, 2016, Abstract 1198; Atlanta, Georgia.

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