SBIR-STTR Award

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 metabolic issues including hypocalcemia, which can be life-threatening. Current management of the disease for the majority of patients consists of supplemental doses of calcium and active vitamin D to manage hypocalcemia. While this approach is intended to maintain serum calcium, it does not correct the underlying PTH deficiency. Therefore, the physiological aspects of hypoparathyroidism, including lack of endogenous 1,25-dihydroxyvitamin D production, hypercalciuria, hyperphosphatemia, and metabolic bone abnormalities can still occur. Moreover, supplementation is associated with several challenges, namely, long-term complications from the use of these vitamins in the absence of endogenous PTH hormone, which contributes to renal function deterioration, kidney stones, and soft tissue calcifications. Clinical trials have demonstrated that PTH(1-34) must be dosed continuously via a pump in humans in order to 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 is proposing to develop a long-acting version of PTH(1-34) that could be dosed far less frequently and still achieve a prolonged pharmacokinetic profile that approximates endogenous levels. Our proprietary carrier molecule lengthens circulating half-life and improves subcutaneous bioavailability, but is small enough so as not to interfere with the activity of a peptide to which it is conjugated. Preliminary results show that carrier- conjugated PTH has the same EC50 for receptor activation as unconjugated PTH. Additionally, when the carrier is conjugated to PTH, it significantly extends the half-life in rodents. The studies proposed in this Phase I application will analyze the pharmacological properties of the long-acting PTH(1-34) and investigate efficacy in an animal model of hypoparathyrodism by looking at the ability of the long-acting PTH to reverse several markers of disease. This will show the feasibility and in vivo functionality of long-acting PTH(1-34). SBIR Phase II funding will focus on IND-enabling studies including GLP production, dose range finding and toxicology/immunogenicity studies. Once fully developed, this long-acting PTH(1-34) derivative would provide a patient-friendly therapy for hypoparathyroidism that will significantly improve the prognosis and quality of life in patients with this disease.

Public Health Relevance Statement:


Public Health Relevance:
Untreated or inadequately treated hypoparathyroidism leads to severe calcium deficiency, which is life- threatening. Extend Biosciences is proposing to develop a long-acting hormone replacement therapy that the patient can self-administer at home.

NIH Spending Category:
Kidney Disease; Rare Diseases

Project Terms:
1,25 (OH) vitamin D; ADME Study; Affect; Animal Model; base; Binding (Molecular Function); Biodistribution; Biological Assay; Biological Availability; Blood; bone; bone cell; Bone remodeling; bone turnover; calcification; Calcium; Cells; Chronic Disease; Clinical Trials; clinically significant; commercialization; Conjugated Carrier; Continuous Infusion; conventional therapy; Data; Deterioration; Disease; Disease Management; Disease Marker; Dose; Drug Kinetics; Enzyme-Linked Immunosorbent Assay; Excretory function; Feces; Feeling; Funding; Grant; Half-Life; heart rhythm; Home environment; hormone deficiency; Hormone replacement therapy; Hormone use; Hormones; Hour; Human; hypercalciuria; Hypocalcemia result; Hypoparathyroidism; immunogenicity; improved; In Vitro; in vivo; in vivo Model; Infusion procedures; Injection of therapeutic agent; insight; Kidney Calculi; Kidney Failure; Label; Laboratories; Left; Life; Mediating; Metabolic; Methods; Minerals; Monitor; Muscle Cramp; Needles; Nephrocalcinosis; Oral; Organ; Osteoclasts; outcome forecast; Parathyroid gland; parathyroid hormone (1-34); Parathyroid Hormone Receptor; Paresthesia; Patients; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phosphorus; Physiological; Plasma; Play; Production; Property; public health relevance; Pump; Quality of life; Radioactive; Radioactivity; Radiolabeled; radiotracer; Rare Diseases; Rattus; receptor; Receptor Activation; receptor internalization; Receptor Signaling; Renal function; Replacement Therapy; Research Contracts; Rivers; Rodent; Role; Route; Seizures; Self-Administered; Serum; Serum Calcium Level; Signal Transduction; Small Business Innovation Research Grant; soft tissue; subcutaneous; Subcutaneous Injections; Supplementation; System; Technology; Tissues; Toxic effect; Toxicology; Urine; Vitamin D; Vitamin D Analog; Vitamins; whole body imaging; Work

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), recently approved by the FDA for a subset of hypoparathyroidism patients, only partially alleviates the need for vitamin supplementation due to its short half- life, and some patients still must take >10 pills/day. 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) (EXT601) that could be dosed once a day and achieve a prolonged pharmacokinetic profile that approximates endogenous PTH levels. Our proprietary carrier molecule lengthens circulating half-life and improves subcutaneous bioavailability, but is small enough so as not to interfere with the activity of a peptide to which it is conjugated. SBIR Phase I results show that EXT601 has the same EC50 for receptor activation as unconjugated PTH, and a mean retention time of 10 hrs. In healthy rats, a single dose of EXT601 increases and maintains calcium levels at physiological levels for more than 24 hrs. In a rat model of hypoparathyroidism, EXT601 dosed once daily was able to maintain calcium levels, reduce phosphate levels and return markers of bone turnover to wild-type levels over the seven day study. Thus, we have identified a true PTH replacement therapy and potential breakthrough drug to treat hypoparathyroidism. The studies proposed in this Phase II application will focus on a longer term animal model and dose range finding study, as well as IND-enabling studies including toxicology/immunogenicity studies. This long-acting PTH(1-34) derivative 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 night, thereby significantly improving quality of life for patients.

Public Health Relevance Statement:
PROJECT NARRATIVE Hypoparathyroidism is a classic hormone deficiency disorder that does not have a true replacement therapy. Untreated or inadequately treated hypoparathyroidism leads to severe calcium deficiency, which is life- threatening. Extend Biosciences is developing a long-acting hormone replacement therapy that the patient can self-administer at home.

Project Terms:
Alpha Cell; Animal Model; Arrhythmia; Back; base; Biological Assay; Biological Availability; Biological Markers; Biological Sciences; bone; Bone remodeling; bone turnover; calcification; Calcified; Calcium; calcium phosphate; calcium supplementation; Chronic Disease; Clinical; clinical candidate; Clinical Trials; clinically significant; Continuous Infusion; conventional therapy; cost; Cyclic GMP; Data; design; Deterioration; Development; Diagnostic; Disease; Disease Management; Dose; Drug Kinetics; Ensure; Enzyme-Linked Immunosorbent Assay; FDA approved; Feeling; Formulation; Forteo; Grant; Half-Life; heart rhythm; Home environment; hormone deficiency; Hormone replacement therapy; Hormones; Human; hypercalciuria; Hypocalcemia result; Hypoparathyroidism; immunogenicity; improved; Infusion procedures; inorganic phosphate; Isotonic Exercise; Kidney Calculi; Kidney Failure; Left; Life; Manufacturer Name; manufacturing process; Maximum Tolerated Dose; Mediating; Metabolic; Minerals; Modeling; Monitor; Muscle Cramp; Needles; Nephrocalcinosis; nonhuman primate; oral supplementation; Osteoporosis; parathyroid hormone (1-34); Paresthesia; patient subsets; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Phase; Phosphorus; Physiological; pill; Plasma; Play; Process; PTH gene; Pump; Quality of life; Rare Diseases; Rattus; Receptor Activation; Renal function; Replacement Therapy; Role; Safety; Sampling; scale up; Seizures; Self-Administered; Serum; Serum Calcium Level; Small Business Innovation Research Grant; soft tissue; Spasm; subcutaneous; Subcutaneous Injections; Supplementation; System; Time; Toxic effect; Toxicology; Urine; Vitamin D; Vitamin D Analog; Vitamins; vocal cord; Work