Long-acting PTH for hypoparathyroidism

Project Summary Hypoparathyroidism is a rare disease that results from a deficiency or inability to make sufficient amounts of parathyroid hormonePTHUntreated or inadequately treated hypoparathyroidism leads to clinically significant mineral related metabolic issues including hypocalcemiawhich leads to heart arrhythmiasspasms of the vocal cordsand seizuresCurrent management of the disease for the majority of patients consists of supplemental doses of calcium and active vitamin D to manage the hypocalcemiaWhile this approach is intended to maintain serum calciumit does not correct the underlying PTH deficiency and the physiological aspects of hypoparathyroidism can still occurMoreoversupplementation is associated with long term complications from the use of supraphysiological doses of calcium in the absence of endogenous PTH hormonewhich contribute to renal function deteriorationkidney stonessoft tissue calcifications and abnormalities in bone remodelingNatparaPTHrecently approved by the FDA for a subset of hypoparathyroidism patientsonly partially alleviates the need for vitamin supplementation due to its short halflifeand some patients still must take rtpills dayClinical trials have demonstrated that if PTHis dosed continuously via a pump in humansit can mimic physiological levels of PTH to restore normal levels of calciumphosphorus and markers of bone turnoverHowevera pump mediatedcontinuous infusion of PTH would be costly and inconvenient for patientsExtend Biosciences has developed a long acting version of PTHEXTthat could be dosed once a day and achieve a prolonged pharmacokinetic profile that approximates endogenous PTH levelsOur proprietary carrier molecule lengthens circulating half life and improves subcutaneous bioavailabilitybut is small enough so as not to interfere with the activity of a peptide to which it is conjugatedSBIR Phase I results show that EXThas the same ECfor receptor activation as unconjugated PTHand a mean retention time ofhrsIn healthy ratsa single dose of EXTincreases and maintains calcium levels at physiological levels for more thanhrsIn a rat model of hypoparathyroidismEXTdosed once daily was able to maintain calcium levelsreduce phosphate levels and return markers of bone turnover to wild type levels over the seven day studyThuswe have identified a true PTH replacement therapy and potential breakthrough drug to treat hypoparathyroidismThe studies proposed in this Phase II application will focus on a longer term animal model and dose range finding studyas well as IND enabling studies including toxicology immunogenicity studiesThis long acting PTHderivative will provide a true replacement therapy to treat hypoparathyroidism that returns calcium and phosphate to physiological levels and maintains it over the course of a day and nightthereby significantly improving quality of life for patients