In an interview with PharmaShots, Thierry Abribat, Founder and Chief Executive Officer at Amolyt Pharma shares his views on the data from the P-I trial of AZP-3601 for the treatment of Hypoparathyroidism

Shots:

• The P-I trial evaluates the safety, tolerability, PK, PD, and preliminary efficacy of AZP-3601 in 102 healthy volunteers including 52 in the SAD and 50 in the MAD cohorts in patients with Hypoparathyroidism. The results are expected in mid-2022
• The results showed that a rapid, dose-dependent increase in serum calcium, decrease in endogenous PTH, no increase in urinary calcium, no change in bone biomarkers were observed at any dose tested, was generally well tolerated & no safety concerns were observed
• AZP-3601 is a therapeutic peptide analog of PTH designed to target a specific configuration of the PTHR. The therapy has a short half-life and produces a long PK effect

Tuba: Discuss the symptoms, causes, diagnosis, and pathophysiology of hypoparathyroidism

Thierry Abribat: Hypoparathyroidism is a rare endocrine disease that is characterized by a deficiency of parathyroid hormone (PTH). PTH is produced by four small parathyroid glands that are located on the thyroid. A deficiency or absence of PTH results in decreased calcium and elevated phosphorus levels in the blood and affects the overall calcium metabolism, particularly at the kidney and bone levels. Loss of PTH most commonly occurs due to damage or removal of the parathyroid glands during thyroid or neck surgery.

There is a high burden of illness driven primarily by cognitive and neuromuscular symptoms, including brain fog or inability to focus, muscle pain, cramping, fatigue, tingling of the hands or feet, and hair loss. Hypoparathyroidism is usually diagnosed through a blood test.

There are approximately 80,000 and 110,000 people with hypoparathyroidism in the U.S. and E.U., respectively. It is estimated that about 25% of people with hypoparathyroidism have chronic kidney disease or kidney failure. Additionally, more than 50% of people with hypoparathyroidism are peri- and post-menopaused women who are at an increased risk of developing osteoporosis. Close to 20% have concurrent osteopenia or osteoporosis. 

Tuba: Tell us more about AZP-3601. Discuss its MoA, RoA, formulation, and its potential to treat hypoparathyroidism.

Thierry Abribat: AZP-3601 is a therapeutic peptide analog of PTH designed to target a specific configuration of the PTH receptor (PTHR), to have a short half-life, and to produce a long pharmacodynamic effect. This particular profile is intended to produce sustained normal levels of calcium in the blood and thereby lessen the symptoms of hypoparathyroidism.

AZP-3601 may also decrease high levels of urinary calcium, which may help prevent long-term chronic kidney disease, a long-term side effect commonly seen with calcium and vitamin D supplementation. In addition, AZP-3601 is expected to have a neutral effect on the bone, which might be a key advantage, since a high percentage of women with hypoparathyroidism are at risk of developing osteoporosis.

Tuba: Discuss the clinical design of the P-I clinical trial in detail

Thierry Abribat: The Phase 1 clinical trial of AZP-3601 is designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy following single and multiple ascending doses (MAD) in healthy subjects and patients with hypoparathyroidism. We have completed both the single and multiple ascending dose parts of the trial in healthy volunteers. The patient part of the Phase 1 trial is ongoing, and we expect to communicate top-line results in mid-2022. 

Tuba: What are the key takeaways from the data presented at ASBMR 2021?

Thierry Abribat: We presented positive data from the single ascending dose (SAD) and MAD portions of our Phase 1 trial evaluating AZP-3601 in healthy volunteers. Key takeaways included:

• A rapid, dose-dependent increase in serum calcium over the entire treatment period. No increase in urinary calcium, indicative of increased kidney calcium reabsorption. 
• No change in bone biomarkers, reflecting a neutral effect on bone turnover.
• No safety concerns or severe or adverse events were observed.

Tuba: How is this therapy unique from the competitor therapies available in the market?

Thierry Abribat: Conventional therapies for patients with hypoparathyroidism include calcium supplements and activated vitamin D. These therapies do not adequately control symptoms, and long-term treatment with these therapies may result in dangerously elevated levels of calcium in the urine that can cause kidney stones, chronic kidney disease, and impaired kidney function.

Recombinant human PTH (1-84) is a once-daily injection approved for adult patients with hypoparathyroidism who do not respond to conventional therapies. Because of its short half-life, it does not adequately regulate levels of calcium in the body for a full 24 hours, resulting in poor symptom control, and continued long-term risk to the kidneys. This product was withdrawn from the market in the U.S. in September 2019 because of manufacturing issues and is currently not available.

AZP-3601 is designed to have a short half-life and be selectively active through a distinct conformation of the PTH receptor to increase its pharmacodynamic effect. This unique design may result in 24-hour symptom control, decreased urine calcium excretion to prevent chronic kidney disease, and bone integrity preservation.

Tuba: What is the importance of reduction in urinary calcium in hypoparathyroidism patients and unchanged bone biomarkers?

Thierry Abribat: Reduction of urinary calcium may help alleviate chronic kidney disease or kidney failure. This is a key treatment goal because 26% of people with chronic hypoparathyroidism are diagnosed with chronic kidney disease and many more are at risk of developing this disease. 

Bone biomarkers measure the balance between bone loss and bone formation. Preserving bone integrity is critical because 17% of people with chronic hypoparathyroidism have osteopenia or osteoporosis and 53% are peri- and post-menopause women who are at risk of developing these conditions.

Tuba: What other indications is Amolyt assessing for AZP-3601?

Thierry Abribat: Since AZP-3601 is specifically designed for the treatment of hypoparathyroidism, we are currently focused on its development for this indication, a rare endocrine disease with a high unmet need. 

Tuba: What are the different programs targeting different diseases in your portfolio?

Thierry Abribat: We are committed to building an expansive pipeline of therapeutic peptides for the treatment of rare endocrine and related diseases. Our product candidate for the potential treatment of acromegaly, AZP-3813, is currently undergoing Investigational New Drug enabling studies. Our portfolio also includes AZP-3404, which is at the research stage.

Tuba: What next steps should we expect from Amolyt in terms of clinical programs, collaborations, and other aspects?

Thierry Abribat: We recently completed an $80M Series B equity financing round with the support of a strong international syndicate of investors. The proceeds will support our ongoing clinical development and we look forward to sharing the first clinical data for AZP-3601 in patients with hypoparathyroidism in 2022. Other near-term objectives include advancing AZP-3813 into the clinic to evaluate its safety and efficacy in healthy volunteers and patients with acromegaly. We also actively exploring additional pipeline expansion opportunities.

Source: Verywell Health

About Author: Thierry Abribat is the Founder and Chief Executive Officer at Amolyt Pharma. He holds a Doctorate of Veterinary Medicine and a Ph.D. from the National Polytechnic Institute of Toulouse

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