Novel drug may provide symptom control in hypoparathyroidism
Chronic hypoparathyroidism can be a debilitating disease for those living with the condition, with patients reporting daily symptoms such as physical fatigue, muscle cramps, and limb heaviness and tingling.
As Healio previously reported, adults with inadequately controlled hypoparathyroidism have reported that health-related quality of life can be compared with other severe, chronic diseases. Researchers have noted substantial knowledge gaps regarding the overall burden of illness associated with chronic hypoparathyroidism, including symptom severity, impact on activities of daily living, and caregiver burden, particularly when the disease is not adequately controlled with conventional therapy.
Healio spoke with John P. Bilezikian, MD, PhD (hon), the Silverberg Professor of Medicine and vice chair for international research and education at Columbia University Vagelos College of Physicians and Surgeons, about the symptoms of hypoparathyroidism, the need for new treatments, and therapies currently in the pipeline.
How prevalent is hypoparathyroidism, and what are some of the effects of living with this condition?
Bilezikian: Hypoparathyroidism is an orphan disease, as defined by the FDA, affecting fewer than 200,000 people in the United States. Current estimates place the prevalence at about 66,000 to 110,000 in the U.S. About 80% are women, mostly middle-age.
The disease is characterized by a deficiency in parathyroid hormone (PTH), a critical hormone that maintains calcium and phosphorus homeostasis. The loss of PTH most commonly occurs due to damage to or removal of the parathyroid glands during thyroid surgery.
These patients are at risk for short-term and long-term complications. The tendency to develop hypocalcemia can lead to symptoms involving the neuromuscular system, such as muscle cramps, spasms and, when severe, even spasms of the throat and seizures, and the cognitive system, such as “brain fog,” lethargy, inability to function. As a result, quality of life is affected as some patients experience symptoms regularly. Long-term complications include kidney stones, reduced renal function, calcifications in other organs and poor bone quality.
What are the current treatment options for hypoparathyroidism?
Bilezikian: Conventional therapy consists of calcium and the active form of vitamin D, known as calcitriol. Some patients require large amounts of both calcium and active vitamin D. This conventional therapy can control the biochemical abnormalities and keep some patients from becoming symptomatic. However, some patients require very high amounts of calcium and active vitamin D. This approach does not deal specifically with what is missing in this disease, namely parathyroid hormone. In 2015, the FDA approved the first parathyroid hormone replacement therapy. Hypoparathyroidism became the last classical endocrine deficiency disease for which the missing hormone became available.
What is currently in the pipeline or in early-stage research?
Bilezikian: While the native parathyroid hormone has been shown to be efficacious, the single once-daily regimen does not provide control, in many individuals, throughout a 24-hour period. This is because the half-life of parathyroid hormone is too short to provide round-the-clock protection in many patients. Several analogues of parathyroid hormone in different formulations are being developed to provide more long-lasting effects of the molecule. AZP-3601 (Amolyt Pharma) is one of several approaches to provide a parathyroid hormone-like molecule that provides effects that are more lasting.
Hypoparathyroidism is diagnosed more frequently in women, so osteoporosis risk is also high. How does AZP-3601 work and potentially address that risk?
Bilezikian: While it is true that hypoparathyroidism and osteoporosis are found more commonly in women, it is for different reasons. In fact, hypoparathyroidism is not a risk factor for osteoporosis. Patients with hypoparathyroidism have bone density values that are typically above average. However, the age range of highest incidence of hypoparathyroidism coincides with the time period when postmenopausal women without hypoparathyroidism are at highest risk for osteoporosis.
AZP-3601 has been specifically designed for the treatment of hypoparathyroidism and targets a specific conformation of the PTH receptor. Through this mode of action, AZP-3601 is expected to adequately control blood calcium levels, decrease urinary calcium excretion and improve quality of life. Additionally, AZP-3601 is expected to preserve bone integrity.
What are the next stages of research?
Bilezikian: Current studies are designed to provide evidence that longer-lived PTH or PTH-like molecules can provide safe and longer-lasting effects in controlling serum calcium and other electrolytes in hypoparathyroidism. Amolyt Pharma, the biotech company that is developing AZP-3601, recently announced that they enrolled the first participant in a phase 1 clinical trial, designed to demonstrate proof-of-concept for AZP-3601 as a treatment for hypoparathyroidism and to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy following single and multiple ascending doses in healthy participants as well as adults with hypoparathyroidism. The healthy participants will be treated at a single clinical phase 1 unit, whereas individuals with hypoparathyroidism will be treated at several European sites that specialize in the disease. Approximately 130 healthy volunteers and patients are expected to be enrolled in these early studies.