Treating Rare Endocrine Disorders with Therapeutic Peptides

December 16, 2022

Hypoparathyroidism is a rare condition that is caused by the lack of functional parathyroid glands. The condition can lead to a long list of complications including muscle pain, brain fog, and damage to the kidneys. Amolyt Pharma is developing a therapeutic peptide to treat hypoparathyroidism. We spoke to Mark Sumeray, chief medical officer of Amolyt, about what its like for people living with the condition, why it is difficult to manage with current medical approaches, and why therapeutic peptides offer a compelling approach for hypothyroidism and other endocrine disorders.


Daniel Levine: Mark, thanks for joining us.

Mark Sumeray: It’s a pleasure. Thanks for having me.

Daniel Levine: We’re going to talk about hypoparathyroidism, Amolyt, and its efforts to develop a therapeutic peptide to treat people with the condition. Let’s start with hypoparathyroidism. For people not familiar with the condition, what is it?

Mark Sumeray: Well, most people will never have heard of hypoparathyroidism. It’s a rare disease that it probably affects around 80,000 people in total in the United States, and it’s caused by a damage to or removal of the parathyroid glands, which are very, very tiny glands that produce a hormone called parathyroid hormone. These glands actually sit behind the thyroid gland in the neck and usually patients with this condition have had surgery, sometimes radiotherapy to the thyroid gland. And in the process, their parathyroid glands have been injured or inadvertently removed by the surgeon. Very rarely, patients have this condition because they have a genetic disease, which obviously they’ve been born with, where they don’t develop normal parathyroid glands, or occasionally an autoimmune condition where the body’s own immune system attacks the tissues of the parathyroid glands itself. But the most common situation, as I mentioned, is surgery to the thyroid gland.

Daniel Levine: This is a condition that can have broad effects on tissue and organ systems throughout the body. How does it manifest itself and progress?

Mark Sumeray: Well, the main problem that you get when your parathyroid glands don’t work well is difficulty maintaining normal levels of calcium and phosphorus in the blood. In particular, the symptoms of the condition are related to low levels of calcium, which occur once the glands stop working properly. And this can result in neurological symptoms such as tingling, pins and needles, numbness, muscle symptoms like muscle pain and muscle cramps, even muscle spasms, which can be very painful. And also, a more insidious condition, which patients describe as brain fog, which is really best explained as difficulty concentrating, performing normal everyday task, remembering routine things. It can be very debilitating for patients. Those are the main symptoms and sometimes they can occur very dramatically, often after a surgical procedure like the one I mentioned, the removal of the thyroid. But sometimes they can come on more slowly and when that happens, it can take quite some time for the condition to be diagnosed properly.

Daniel Levine: I suspect when it’s a result of a surgical procedure, whether it’s intentional or accidental, people are quite aware of what’s happened. But how difficult is this to diagnose in cases where people have it due to other causes?

Mark Sumeray: Well, it can be quite difficult because like many rare diseases, it’s not front of mind. In particular, when patients develop these kinds of symptoms slowly, they start off relatively mild but they become more troublesome over time. Usually, the first physician that a patient will go to may be a general internist or general medicine or general practitioner who may not be a specialist, an endocrinologist or a specialist that deals with hormones like this. So, sometimes the diagnosis can be delayed for months, even possibly longer years, until the patient eventually reaches a knowledgeable specialist who thinks about the diagnosis. And then the diagnosis is made very quickly with a simple blood test. Looking at the levels of parathyroid hormone in the blood and the level of calcium.

Daniel Levine: What’s generally the greatest risk someone with the condition faces?

Mark Sumeray: Well, I guess I’d split it into two. The first would be the very acute severe presentation when perhaps for reasons that nowadays I think probably are quite rare: it hasn’t been realized or considered or thought of as a complication after thyroid surgery. And that can be quite a dramatic presentation, even life threatening, and can require the patient to be in hospital and treated with intravenous medication, including calcium. The other more likely scenario is that it occurs more gradually. And then once the diagnosis has been made, the patient will normally be treated by giving them calcium tablets, supplementing their diet with calcium, as well as an active form of vitamin D which is necessary to help absorb calcium from the diet.

Daniel Levine: This is a condition that affects far more women than men. Is it particularly difficult to diagnose men with the condition?

Mark Sumeray: No. Perhaps because it occurs more often in women, it may not be quite so readily considered as a diagnosis. But actually, the reason that it occurs more frequently in women than men is because women of a certain age, usually peri- or post-menopausal women are more commonly in a situation where they need to have their thyroid gland removed, usually for thyroid cancer, because thyroid cancer occurs more commonly in middle aged or elderly women than it does in men. So, that’s the reason. But the condition can occur in men; it’s just a bit less common.

Daniel Levine: And it’s one of these diseases where people can suffer symptoms long before they’re actually diagnosed. What’s the impact of this condition on the quality of life for patients?

Mark Sumeray: It has a substantial impact, actually. And I divide that into two reasons. The first is that even on standard treatment, which as I mentioned is calcium tablets, often large doses of calcium tablets and the active form of vitamin D, it can be difficult to control the blood calcium levels as well as you would be able to if you had normal functioning parathyroid glands. So the treatment that doctors use to manage patients is simply not that good. And as a result of the poor control of calcium levels in the blood, the patients suffer from the symptoms I mentioned before, and particularly debilitating is this brain fog problem that they have. But the other part of this is the longer term complications of the disease because with the difficulty that results from not having parathyroid hormone in the body, it results in excessive amounts of calcium being lost in the urine and this is damaging to the kidneys because it increases the risk of kidney stones and also a disease called nephrocalcinosis, which is really a deposition of calcium salts in the tissue of the kidney itself. And that’s damaging to the kidney. Over time, patients develop progressively deteriorating kidney function. So, that’s a serious issue and doctors try to minimize the amount of calcium that leaks into the urine, but they’re not always that successful in doing it. And the other part of this is that calcium, as well as phosphate, which I mentioned right at the beginning, can conform deposits in other organs, particularly in the brain, and that can cause much longer term complications as well. So, it’s quite a serious debilitating disease, partly because of the symptoms I mentioned, but also because of the long term complications.

Daniel Levine: You joined the company after six years as chief medical officer of Amryt Pharma, a commercial stage rare disease company. What attracted you to take a job at a development stage company?

Mark Sumeray: Well, I certainly enjoy the challenge of developing new drugs to treat rare diseases. And I would say that the attractive part of working at Amolyt is the opportunity to work with a very innovative novel peptide which is the drug, the molecule that we had in development, which has the potential to really make a substantial difference to patients who are suffering from this condition. The chance to be involved with the molecule early on and to help shepherd it through the various stages in clinical development, and then ultimately through, hopefully, the approval process with the FDA and other health authorities around the world is very rewarding. So, I get a lot of personal satisfaction out of being involved in that process from early on all the way through. And of course, there’s more of the focus in that area at Amolyt rather than Amryt, which was a little bit more later stage commercial company, as you said.

Daniel Levine: Amolyt is focused on peptide therapeutics. What makes these compelling therapies for endocrine disorders like hypothyroidism?

Mark Sumeray: Well, the nice thing about working with endocrine disorders is that usually the mechanism of the disease is quite well understood. So, we can think of lots of examples of other diseases, which unfortunately have been very difficult and very challenging for the pharmaceutical industry to develop new drug treatments for, because we don’t really understand what’s the pathology and what’s gone wrong. And so, we don’t understand what to target. In the case of endocrine diseases, it is usually more straightforward because we understand in general how various hormones work to maintain control or balance of different factors in the blood and around the body, which are important to keep constant. We understand how those hormones act, where they act and which receptors, for example, and which tissues. So, in that situation, it provides an opportunity to either treat the endocrine or the hormonal problem with the missing hormone itself. And there’s plenty of examples of that and probably insulin for diabetes is the one that people would be most familiar with, or to come up with a copy or something, which is very similar to the natural hormone, like a peptide therapeutic drug such as the one that Amolyt is developing, which mimics the activity of the natural hormone. So, it’s a nice area to work in because you have probably a better chance of success because of all of this knowledge and being able to predict how these therapeutic drugs will work.

Daniel Levine: Let’s talk about your lead therapeutic candidate AZP 3601, which is being developed as a treatment for a hypoparathyroidism. What is it and how does it work?

Mark Sumeray: Well, it’s a peptide, which is basically a short protein made up of individual building blocks that are called amino acids. And it’s actually been created, if you like, by medicinal chemists and scientists who worked at the Mass General Hospital in Boston who have an expert knowledge of how the parathyroid hormone receptor works and how to design a peptide molecule that will interact with that receptor in exactly the right way to create the effects that’s missing when parathyroid hormone isn’t being produced by the parathyroid glands. So, these scientists started with a sequence of amino acids, which come from the natural hormone, parathyroid hormone, and also a related hormone called parathyroid hormone related peptide. And they joined these two molecules together and then they started to play around with them by changing some of the amino acids. As they did that they were able to come up with a particular sequence, a unique peptide, which had exactly the right properties in terms of being able to interact with the receptor for the hormone in the right way and produce a very long effect so that when you give this drug by injection, it gives you a very sustained impact on calcium levels so that you can control calcium over a long period of time, even though the drug is just a single injection once a day and it has a short half-life, so it doesn’t circulate in the bloodstream very long. So these are all basically ways that the scientists manipulated the basic sequence of the peptide to come up with exactly the properties that they were looking for.

Daniel Levine: The company announced positive results from a phase 2a study. What’s known about the safety and efficacy of AZP-3601 to date?

Mark Sumeray: Well, it hasn’t been in a very large number of patients yet, but as you say, the phase 2a data we announced recently are very promising. So, what we did was we took 26 patients with hyperparathyroidism and they were entered into the study and treated with the new drug, AZP-3601, and we were able to demonstrate that we could control the level of calcium in their blood over a three month period by adjusting the dose of the drug and at the same time withdrawing the supplements that they were taking, the oral calcium supplements and the active form of vitamin D. So they ended up on the drug alone without the need to be taking these large doses of calcium and vitamin D, which is exactly what we wanted to try to achieve. At the same time, we also saw a very nice promising effect on calcium in the urine, I mentioned this earlier. You don’t want to have high amounts of calcium in the urine. The kidney should be able to reabsorb calcium and stop it from leaking into the urine. And with this drug, this ability of the kidneys to reabsorb calcium is restored. So, normalizing the amount of calcium in the urine. And the other observation that we made, which is very important, is that we saw the bone metabolism started up again. So, one of the things I didn’t mention earlier is that in this disease, because parathyroid hormone is missing, you don’t have the normal turnover of bone. It’s something that people often don’t realize. All the time your bone is being broken down and being formed so that you break down old bone and produce new bone. In this condition of hyperparathyroidism, that doesn’t happen. And so, these patients accumulate old bone, which is not normal in terms of its structure, and it’s not normal in terms of its ability to resist stress. So, it’s at increased risk of fracturing. With the drug, we saw a resumption of normal turnover, a balanced increase in both bone formation and bone resorption. So, that’s all very important. And in addition, perhaps most importantly, we saw that the drug was well tolerated, so we didn’t see any side effects that we were concerned about. There were no issues in keeping the patients on the drug. They weren’t dropping off the drug because they couldn’t tolerate it for any reason. So we were very encouraged overall by the safety profile as well as the efficacy that we saw in this relatively small short study.

Daniel Levine: And what’s the development path forward?

Mark Sumeray: So now we need to enlarge the pool of patients that we’re going to study from the 26 patient study that I mentioned to one that would probably have, let’s say, approximately 160 patients. And that’s what we call a phase 3 study or a pivotal study. And we’re going to randomize patients either to placebo treatment plus their usual care, which is calcium tablets and vitamin D, or the drug. And if they get randomized to the drug, then they will probably be able to come off those supplements. And we’re going to compare how those two groups of patients do during a six month treatment period. At the end of the six months, we’re going to look at how well controlled is the blood level of calcium and how successful were we in withdrawing the supplements, as well as looking at some of the other factors that we’ve already mentioned, like the amount of calcium in the urine, and also the impact on patients’ quality of life. So, we’re going to collect information using special questionnaires that patients will fill in and that information will tell us how they’re feeling and how they’re functioning. And those two things are incredibly important to patients, of course, and very valuable information, not just for health authorities like the FDA, but also for healthcare systems and physicians that are considering whether or not to use the product and whether or not to pay for it ultimately if it gets approved.

Daniel Levine: Is this something the company expects to commercialize on its own or is it going to seek a partner to do that?

Mark Sumeray: Well, it’s a good question. I would say at this point we haven’t made any firm decisions. I think it’s likely that the company would commercialize the product on its own in the United States, and in other countries around the world, I think that’s an open question. So, we may choose to do it in Europe. Some countries in Europe, we may choose to partner with another company that has the resources to be able to market and distribute the product in places around the world where it probably is more sensible for them to do it than for a small company like Amolyt to do it. So, we’ll see as we get closer to the time

Daniel Levine: Mark Sumeray, chief medical officer of Amolyt Pharma. Mark, thanks so much for your time today.

Mark Sumeray: It’s a pleasure. Thanks for having me.


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