Effect Of BGJ398 On Insulin Sensitivity In A Patient With Tumor-induced Osteomalacia

Presentation Number: SAT-150
Date of Presentation: March 17, 2018, 2018

Sri Harsha Tella, MD1, Florenzano Valdes Pablo, MD1, Caroline Sedmak, BS2, Lori C. Guthrie, RN-C, BSN1, Millwood Michelle, BSN1, Issacs Randi, MD3, Carole Miller, MD4, Rachel Ilana Gafni, MD5, RANGANATH MUNIYAPPA, MD PhD6, Michael T. Collins, MD7.
1National Institutes of Health, Bethesda, MD, USA, 2NIH NIDDK, Rockville, MD, USA, 3Novartis, NJ, NJ, USA, 4St. Agnes Hospital, Baltimore, MD, USA, 5NIH, Bethesda, MD, USA, 6National Institutes of Health Clinical Center Endocrine Fellowship Program, Bethesda, MD, USA, 7National Institute of Health, Bethesda, MD, USA.

Abstract

Background: In several animal studies, Fibroblast Growth Factor 23 (FGF23) has been shown to alter insulin sensitivity. In humans, however, studies have shown inconclusive and conflicting results. Clinical case: A 35-year old woman with a history of type 2 diabetes mellitus developed osteomalacia at the age of 20 years. Initial evaluation was consistent with tumor-induced osteomalacia (TIO): Phosphorous 0.9 (2.5-4.5 mg/dl), tubular maximum reabsorption of phosphate to GFR ratio (TMP/GFR): 0.82 (2.97-4.45), 1, 25 (OH)2 vitamin D: 19 (18-78 pg/ml), alkaline phosphatase 160 (37-116 U/L), PTH: 69.3 (15-65 pg/ml) and elevated FGF23. Functional (Octreotide, FDG-PET, and DOTATATE scans) and anatomical imaging failed to localize the lesion, and the patient was placed on medical management with calcitriol and phosphorous supplements. She was not able to tolerate the regimen and was later switched to BGJ398. BGJ398 is an investigational, orally bioavailable, selective pan-FGFR tyrosine kinase inhibitor currently being evaluated for the management of inoperable TIO due to the established role FN1/FGFR1 translocations as molecular drivers in TIO. FGFR blockade by BGJ398 decreases FGF23 levels. It is administered in cycles; 3 weeks on-drug and one week off. Prior to starting BGJ398, the patient’s diabetes (A1C:7.4) was managed with a stable regimen of oral metformin 1000 mg twice daily and glipizide 10 mg twice daily with no hypoglycemic episodes. BGJ398 treatment normalized serum phosphorous and 1, 25 (OH)2 vitamin D levels and reduced plasma FGF23 levels. However, during the 3rd week of each drug cycle, the patient developed hypoglycemic episodes that were unexpected. Suspecting a possible but unknown drug interaction between BGJ398 and glipizide, glipizide was discontinued. However, she continued to have hypoglycemic events. Maturity-onset diabetes of young (MODY) was excluded by genetic testing. Oral glucose tolerance testing (75 g-OGTT) she was performed on-drug (last day of the 3rd week) and off-drug (last day of the 4th week). Metformin and Glipizide were discontinued at least 5 days prior to the test. During OGTT, fasting blood glucose values on and off the drug were 147 mg/dl and 182 mg/dl, respectively; and 2-hour glucose levels were 276 mg/dl and 363 mg/dl, respectively. Hepatic insulin resistance index (HIRI), muscle insulin sensitivity index (MISI), homeostatic model to assess insulin resistance (HOMA-IR) and disposition index were derived from the OGTT. She had high MISI (48.58 vs 6.54) with no appreciable difference in HOMA-IR or HIRI when she was on BGJ398, indicating that she had higher insulin sensitivity at the muscle. Conclusion: This is the first case demonstration altered insulin sensitivity in TIO patients. Further study is needed to determine the effect(s) of rapidly changing FGF23 levels and/or FGFR blockade on glucose homeostasis and insulin sensitivity.

Disclosures

 S. Tella: None. F. Pablo: None. C. Sedmak: None. L.C. Guthrie: None. M. Michelle: None. I. Randi: Employee; Self; Novartis Pharmaceuticals. C. Miller: None. R.I. Gafni: None. R. Muniyappa: None. M.T. Collins: None.