Project Grant R01FD007824

A PHASE 2 STUDY INVESTIGATING THE SAFETY, TOLERABILITY AND EFFICACY OF EXT608 IN ADULTS WITH HYPOPARATHYROIDISM (IND146180; OCTOBER 14, 2022) - PROJECT SUMMARY HYPOPARATHYROIDISM IS A RARE DISEASE THAT RESULTS FROM A DEFICIENCY OR INABILITY TO MAKE SUFFICIENT AMOUNTS OF PARATHYROID HORMONE (PTH). UNTREATED OR INADEQUATELY TREATED HYPOPARATHYROIDISM LEADS TO CLINICALLY SIGNIFICANT MINERAL-RELATED METABOLIC ISSUES INCLUDING HYPOCALCEMIA, WHICH LEADS TO HEART ARRHYTHMIAS, SPASMS OF THE VOCAL CORDS, AND SEIZURES. CURRENT MANAGEMENT OF THE DISEASE FOR THE MAJORITY OF PATIENTS CONSISTS OF SUPPLEMENTAL DOSES OF CALCIUM AND ACTIVE VITAMIN D TO MANAGE THE HYPOCALCEMIA. WHILE THIS APPROACH IS INTENDED TO MAINTAIN SERUM CALCIUM, IT DOES NOT CORRECT THE UNDERLYING PTH DEFICIENCY AND THE PHYSIOLOGICAL ASPECTS OF HYPOPARATHYROIDISM CAN STILL OCCUR. MOREOVER, SUPPLEMENTATION IS ASSOCIATED WITH LONG-TERM COMPLICATIONS FROM THE USE OF SUPRAPHYSIOLOGICAL DOSES OF CALCIUM IN THE ABSENCE OF ENDOGENOUS PTH HORMONE, WHICH CONTRIBUTE TO RENAL FUNCTION DETERIORATION, KIDNEY STONES, SOFT TISSUE CALCIFICATIONS AND ABNORMALITIES IN BONE REMODELING. NATPARA (PTH 1-84), WAS APPROVED BY THE FDA FOR A SUBSET OF HYPOPARATHYROIDISM PATIENTS, BUT ONLY PARTIALLY ALLEVIATES THE NEED FOR VITAMIN SUPPLEMENTATION DUE TO ITS SHORT HALF-LIFE, AND IT WAS RECENTLY ANNOUNCED THAT MANUFACTURING WILL CEASE IN 2024. CLINICAL TRIALS HAVE DEMONSTRATED THAT IF PTH(1-34) IS DOSED CONTINUOUSLY VIA A PUMP IN HUMANS, IT CAN MIMIC PHYSIOLOGICAL LEVELS OF PTH TO RESTORE NORMAL LEVELS OF CALCIUM, PHOSPHORUS AND MARKERS OF BONE TURNOVER. HOWEVER, A PUMP-MEDIATED, CONTINUOUS INFUSION OF PTH WOULD BE COSTLY AND INCONVENIENT FOR PATIENTS. EXTEND BIOSCIENCES HAS DEVELOPED A LONG-ACTING VERSION OF PTH(1-34) (EXT608) THAT ACHIEVES A PROLONGED PHARMACOKINETIC PROFILE THAT APPROXIMATES ENDOGENOUS PTH LEVELS. BASED ON AN INTERIM DATA ANALYSIS OF PHASE 1 RESULTS PRIOR TO DATABASE LOCK, EXT608 WAS SAFE AND WELL-TOLERATED AND IS PROJECTED TO BE DOSED ONCE-WEEKLY IN HUMANS. THE STUDIES PROPOSED IN THIS GRANT APPLICATION WILL FOCUS ON A PHASE 2 DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL IN PATIENTS. THIS TRIAL WILL HELP DEMONSTRATE THAT THIS LONG-ACTING PTH(1-34) DERIVATIVE IS PROVIDES A SUPERIOR PTH BASED THERAPY TO TREAT HYPOPARATHYROIDISM THAT RETURNS SERUM AND URINARY CALCIUM AND PHOSPHATE TO PHYSIOLOGICAL LEVELS AND MAINTAINS IT OVER THE COURSE OF WEEK, THEREBY SIGNIFICANTLY IMPROVING COMPLIANCE AND QUALITY OF LIFE FOR PATIENTS.