ENDO2020 New Frontiers: Bone and Mineral Metabolism

Four takeaways from the clinical pipeline for osteomalacia and osteoporosis

With Farzana Perwad MD, Thomas O. Carpenter MD, and Robert G. Feldman MD

Researchers presented the newest research on preventing bone loss.

The New Frontiers in Bone and Mineral Metabolism presentations at ENDO2020, the virtual conference of The Endocrine Society, focused on expanding clinical understanding of antibody therapies for the treatment of osteomalacia and osteoporosis.

The purposes of the therapeutic monoclonal antibodies covered by the four researchers were to either facilitate bone formation (burosamab) or prevent the breakdown of bone tissue (romosozumab and densomab followed by zoledronic acid).

Burosamab clinical trials in both XLH and TIO

Burosamab is a fully human monoclonal antibody which binds and disables FGF23, a bone-derived hormone that suppresses renal phosphate reabsorption and vitamin D metabolism. An over production of FGF-23, either through mutations in the phex gene leading to X-linked Hypophosphatemia (XLH) or through tumor overproduction, are two disorders in which burosamab is being studied therapeutically.

Patients with unregulated FGF23 activity suffer from osteomalacia (bone softening), muscle weakness, fatigue, severe bone pain with reduced mobility, fractures and pseudofractures. Current treatments focus on increasing serum phosphate levels through oral phosphate and active vitamin D supplements. Burosamab is a treatment focused on reducing the activity of FGF23, which should elevate serum phosphorus levels and mitigate symptoms.

X-linked hypophosphatemia

Farzana Perwad, MD, an Associate Professor in Pediatrics at University of California San Francisco, presented the final 96 week safety and efficacy data from their FDA Phase III clinical trial of burosamab in the treatment of XLH. Originally, this was a double-blind multicenter study in where XLH patients were randomized to either the burosamab (1mg/kg, subcutaneous every 4 weeks) or placebo groups for 24 weeks. An open-label period ran from 24 to 48 weeks, followed by an extension period up to 96 weeks during which all patients were given burosamab.

For those patients reaching 96 weeks (n= 63 original burosamab, 63 placebo cross-over), burosamab increased serum phosphorus levels above the lower limit of normal for the duration of the study. Scores on the Brief Pain Inventory (BPI) and WOMAC subscales for stiffness and physical function were also significantly improved by week 48 and sustained through week 96.

No adverse event (AE) lead to a discontinuation of treatment, and most were mild to moderate in severity. AEs typical of subcutaneous protein therapeutics were the most common, followed by nasopharyngitis (common cold). Most patients tested negative for antidrug antibodies (ADA) and of those with a positive test, the neutral antibodies were not burosamab specific.

Tumor-induced osteomalacia

Thomas O. Carpenter, MD, Professor of Pediatrics, and Orthopaedics and Rehabilitation at the Yale School of Medicine, presented data from a small but long-running open-label single arm safety and efficacy study using burosamab in patients with tumor-induced osteomalacia (TIO).

Unique to this FDA Phase II studywas that burosamab dose was titrated up to maintain normal serum phosphorus levels (2.5-4.0 mg/dL). All TIO patients started with a 0.3 mg/kg subcutaneous dose, then every 4 weeks over the course of 16 weeks, burosamab was adjusted upwards to achieve normal serum levels. Fourteen patients started treatment, 13 patients reached 48 weeks, and ten have completed 144 weeks. Baseline serum phosphorus levels were 1.68 ± 0.47 mg/dL (mean ± SD) and median serum FGF23 was 416 pg/mL (min-max 94-2569).

At 48 weeks, patient serum phosphorus levels increased to the lower limit of normal (n= 13) and was conserved in the patients (n=10) reaching 144 weeks. Indicators of osteomalacia were quite variable at 48 weeks but tended to favor improvement over time. The ratio of osteoid to bone volume was shifted towards increased bone volume. Osteoid thickness was significantly reduced and mineralization lag time was typically shorter.

Bone scans revealed more fully healed and partially healed fractures after treatment starting at 48 weeks. By 144 weeks, 35.3% of fractures were fully healed compared to only 1.2% at week 24. Fewer new fractures were also reported over time.

Safety profile in the TIO patient group were reflective of the underlying disease processes (.ie. tumor progression). AEs observed in TIO patients were similar to those in XLH patients treated with burosamab.

Osteoporosis treatments attack the problem from different angles

The persistence of romosozumab

Robert G. Feldman MD, Medical Director of Senior Clinical Trials Inc. in Laguna Hills, California, presented long-term treatment persistence data from two completed FDA trials of romosozumab in post-menopausal women, the FRAME study and the ARCH study. Romosozumab is a humanized monoclonal antibody against sclerostin, an antagonist of bone morphogenetic proteins (BMP) activity.

Both studies had a double-blind phase (0-12 months) followed by an open-label standard treatment phase, (12-24) months. During the double blind phase, patients were treated with monthly subcutaneous injections of romosozumab (210 mg), placebo (FRAME study) or weekly oral dosed of alendronate (70mg oral; ARCH study). During the open-label phase, 12-24 month period, patients were removed from romosozumab and treated with either denosumab (60 mg, subcutaneous every 6 months; FRAME study) or alendronate (ARCH study). Daily calcium and vitamin D supplements were used throughout both arms of the study.

The persistence of romosozumab effects was determined during the 12-24 month period. Lateral radiographics were used to identify vertebral spine factures (VFx), and graded for severity with the same scale used at baseline and 12 months:

          0- None (<20% loss in vertical height)

          1- Mild (20-25% loss in vertical height)

          2-Moderate (25-40% loss in vertical height)

          3-Severe (>40% loss in vertical height)

At 24 months, the significant reduction in new moderate and severe VFx grades observed at 12 months persisted in both the FRAME and ARCH studies. Furthermore, the effects of romosozumab were seen across the entire treatment group, regardless of baseline severity when patients entered the study.

Dr. Feldman concluded by saying, “We hope these data will be useful in treating women with postmenopausal osteoporosis with existing vertebral fractures.”  

Blocking osteoclast function in osteoporosis

Anne Sophie Sølling, an MD and PhD student at Aarhus University Hospital, Denmark, gave the final presentation of data from an ongoing FDA clinical trial evaluating the use of zoledronic acid after stopping denosumab treatment in osteoporosis patients.

Zoledronic acid blocks the activity osteoclasts, a type of cell which breaks down bone tissues. Denosumab is a human monoclonal antibody against RANK, a ligand in the tumor necrosis factor family of receptors. Blocking RANK activity reduces the maturation of osteoclasts. In theory, the two drugs should complement the actions of each other.

Three groups were studied, a 6 month start group, 9 month start group, and an observational group. The 6 month group was give i.v. 5mg zoledronic acid 6 months after the last denosumab treatment, the time point that if denosumab treatment continued would have been the next scheduled dose, baseline for this extension of the study. The 9-month group was treated 9 months after the last denosumab injection, thus having a 3-month washout period prior to starting zoledronic acid. Twelve months of zoledronic acid data was presented.

During this time, lumbar spine and total hip bone mineral density (BMD) declined across all groups, with an overall loss of 4.6% and 3.2% respectively. There were no clinically meaningful differences between the groups regardless of treatment.

Changes in the bone turnover marker, CTX, in the 6-month group revealed that zoledronic acid was not able to keep CTX within the premenopausal range (~0.0-0.6 ug/L) after the discontinuation of denosumab. It did limit the rise such that levels hovered just above the premenopausal limit  In the 9-month group, CTX levels rose above reference levels during the 3 month washout period. Once zoledronic acid was initiated, CTX levels fell and were preserved within the premenopausal levels.

The zoledronic acid study will be ongoing for another 12 months.

Dr. Bjugstad and Ms. Sølling report no conflicts with regard to discussing these studies. Drs. Perwad and Carpenter reports financial interests with Ultragenyx Pharmaceuticals Inc. Dr. Feldman reports financial interests with Amgen.

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