Before you read on, make sure to check out Part 1 of our interview. In Part 1, we discussed Dr. Sumeray’s background, what hypoparathyroidism is, and its symptoms and treatments. Today, we’re discussing AZP-3601, Phase 2a study findings, and the challenges and rewards of drug development.

What is AZP-3601?

The Amolyt website describes AZP-3601 as:

a parathyroid hormone receptor 1 (PTHR1) agonist with a novel mechanism of action rationally designed to meet the therapeutic goals of hypoparathyroidism.

Dr. Sumeray dives into a bit more detail, explaining:

“AZP-3601 identifies a unique feature of the PTH1 receptor, which allows the receptor to be activated very briefly with a drug that has a short half-life, or residence time, in the blood. A signal is created when the drug binds to the receptor in a special conformation. The impact on urine calcium reabsorption in the kidney lasts over twenty-four hours after a single dose, while also restoring bone turnover.”

Prior to this Phase 2a study, Amolyt evaluated AZP-3601 in a Phase 1 clinical trial with healthy volunteers. The therapy was found to be safe and well-tolerated. It also induced rapid, dose-dependent increases in serum calcium levels that remained stable during the treatment period. Urinary calcium excretion did not increase.

The Phase 2a Study Findings on AZP-3601 for Hypoparathyroidism

For the Phase 2a trial, patients were divided into two patient cohorts. In the first portion of the trial, patients received a fixed starting dose of 20µg daily. After two weeks, the dose could be increased to 40µg. This was maintained in the first portion of the treatment period, or the main treatment period. As Dr. Sumeray explains:

“The idea is to get patients off of their supplements and onto AZP-3601. Once patients began at 20µg, we started withdrawing vitamin D and oral calcium supplements.”

Data from the second cohort was announced in mid-October 2022. Within the second cohort, patients started at a lower dose of 10 µg and could receive up to 80 µg daily within the trial’s extension phase.

Findings from Cohort 2 include that after three months, 93% of patients were able to discontinue active vitamin D and oral calcium supplementation. Dr. Sumeray shares that only one patient in each cohort had to stay on supplements. He says:

“This isn’t a single-dose drug. You adjust the dose based on the patients’ individualized requirements. So different patients will need different doses and varying levels of supplementation, though our goal is to reduce or eliminate the need for that supplementation.”

In a large majority of patients, urinary calcium excretion normalized. Only one patient did not see this effect. Dr. Sumeray shares:

“24-hour urinary excretion of calcium was rapidly normalized in all but one patient. There was still slightly elevated urinary calcium in this patient, but AZP-3601 had a very quick and dramatic effect for the other patients within the study and restored the kidneys’ ability to normalize calcium.”

AZP-3601 was safe and well-tolerated. While some mild and moderate adverse reactions occurred, such as injection site reactions, there were no serious adverse events.

Bone mineral density remained stable, including in patients who were osteopenic. Additionally, biomarkers showed that there was a balanced increase in bone turnover. Says Dr. Sumeray:

“Many patients with hypoparathyroidism have an increased risk of bone fracture. When we looked at the blood of patients in our two cohorts, we measured chemicals in the blood that reflect bone turnover. The levels we observed suggest that bone breakdown and bone creation were balanced. In our imaging on bone mineral density, we saw that there was little change. That’s reassuring to some extent. It’s still not long enough to assess the impact of AZP-3601 on bone density, but it is encouraging.”

Amolyt and Future Research

So what kind of research and development is Amolyt looking to do in the future? First, the company is planning to hold a Phase 3 trial on AZP-3601 using 20µg as the recommended starting dose. In terms of AZP-3601, Dr. Sumeray says:

“We’re also working on an oral version, which is very exciting. Peptides are difficult to form in an oral way as they’re vulnerable to enzymes and conditions in the gut. Nevertheless, we know that technology exists that could help us to do this.”

Currently, there is no product identified for the oral formulation; Amolyt is still in early developmental stages there.

Another therapy in the pipeline that Dr. Sumeray is looking forward to developing further is a peptide hormone for the treatment of acromegaly. He explains that around 50-60% of individuals with acromegaly are cured through surgical tumor removal. However, the remaining patients need to control the activity and reduce the production of growth hormone (GH) in the body. While acromegaly has a long treatment history, Dr. Sumeray believes that there are substantial needs for therapeutic improvement. He states:

“This is a very interesting opportunity from a scientific and medical point of view. Using a combination of our drug, with existing drugs, would address the needs of patients who do not respond well to monotherapy.”

This peptide is currently in preclinical development, though Dr. Sumeray hopes to see it in the clinic at some point in 2023.

The Challenges and Rewards of Rare Disease Drug Development

The process of drug development within rare diseases can be complicated. One of the challenges, he notes, is that:

“You have such smaller sample sizes of patients, so it can be difficult to enroll large numbers of patients into a clinical study. So, we have to do our best with what we have and design the study in a way that encourages patients to want to participate. The importance of gathering information about the natural history of the disease is additionally critical in rare diseases as it’s an opportunity to gather information on patients over a long period of time. There’s a challenge in translating the information generated in the conduct of these studies into useful, meaningful information that will influence decision-making both by physicians but also by agencies that determine whether publicly funded healthcare systems are willing to pay for an innovative new treatment.”

Despite the challenges within this field, Dr. Sumeray also believes that this is an incredibly rewarding area in which to work, especially as many rare diseases have, historically, not gotten much attention in respect to drug development in pharma and biotech. As Dr. Sumeray explains:

“There are so many rare diseases that have been overlooked, so the nice thing about working with a small company in the rare disease sphere is having the opportunity to be closer to patients and patient associations and the chance to build those 1-on-1 relationships. Patients have valid and necessary input into the way clinical studies are designed. Working with patients also helps to collect data not only on imaging and blood tests, but also on the impact of their disease on daily function and feeling. These aspects need to be included in studies as they are valid reflections of the real-life impact on the patient. It’s important that patients are able to access information on what’s going on. Education about the condition is also something that Amolyt can do to support patients. I love working with patients and my team and feel that’s a really important relationship that needs to be nurtured.”