Experimental Therapy for Rare Endocrine Disorder Offers Hope of Improved Care
July 2, 2021
Classic congenital adrenal hyperplasia, or CAH, is a potentially life-threatening rare genetic disorder characterized by an inability to produce the stress hormone cortisol while causing excess production of androgens, or male sex hormones. The condition has long-been treated with steroids, but about 70 percent of patients with the condition have poorly controlled disease. The problem is that it is difficult to give someone with CAH enough steroids to control the androgens without causing problems such as weight gain, increased blood sugar, and high cholesterol. As a result, doctors often underdose patients. Spruce Biosciences is developing an experimental therapy called tildacerfont, a non-steroidal therapy that binds to a receptor on the pituitary glands to limit the production of adrenal androgens and address that aspect of the disease. We spoke to Richard King, CEO of Spruce Biosciences, about CAH, how tildacerfont works, and what the company is doing to build a pipeline of other rare endocrine therapies behind it.
Daniel Levine: Richard. Thanks for joining us.
Richard King: Danny. Great to be here. Thanks for having me.
Daniel Levine: We’re going to talk about Spruce Biosciences, a rare life-threatening endocrine condition known as congenital adrenal hyperplasia, or CAH, and Spruce’s efforts to develop the first novel therapy for the condition in nearly 50 years. Let’s start with CAH, for listeners not familiar with the condition, what is it and how does it manifest itself and progress?
Richard King: Great question. First and foremost, it is a rare condition and it affects about 30,000 people in the United States and about 50,000 in Europe. It is a relatively large population for a rare disease. The underlying issue for patients with congenital adrenal hyperplasia is that they cannot make cortisol, which is a key stress hormone required for life. They also have an excess production of male sex hormones, or androgens, and most of them also cannot make another key steroid called aldosterone. How does it manifest itself? Well, this is one of those diseases that’s diagnosed at birth. It’s genetic, as you mentioned. Newborns in every state in the country, and most countries around the world, have a standard test, which is a foot-prick test, for newborn babies. One of the evaluations they undertake is for this condition of congenital adrenal hyperplasia. If it’s found, these patients are immediately started on a glucocorticoid steroid therapy and they’ll be on that therapy for life. That’s the only treatment option that they have at the moment.
Daniel Levine: What are the steroids actually doing to someone with the condition?
Richard King: First and foremost, what they’re doing is replacing the missing cortisol, which is the underlying core condition. Interestingly, steroids have been around for about 50 years, and before steroids were available these poor patients would be born, they wouldn’t know they had congenital adrenal hyperplasia, and at some stage in their first couple of years of life they would face an infection or some other stressor on the body. One of the first agents to react to that stress situation is cortisol. So, they would try to react and find that they couldn’t react and they would go into what is called an adrenal crisis and that can oftentimes lead to death. The advent of glucocorticoids basically allowed physicians to give patients medication that would replace this missing agent, cortisol. Hydrocortisone, which is one of the glucocorticoids, is effectively a synthetic form of cortisol. So, that’s great and it really does keep these folks alive. The challenge is the secondary feature set, which is the overproduction of androgens or male sex hormones that causes a variety of issues for these patients. The glucocorticoid not only can replace the missing cortisol, but if you increase the dose higher, you can also suppress the overproduction of these androgens. The challenge there is that you’ve cured one problem, which is androgen excess, but you’ve given the patient a second issue, glucocorticoid steroid excess, and that has its own challenges and problems.
Daniel Levine: Let’s take each of those. What are the problems of using high dose steroids over a prolonged period of time?
Richard King: Let me describe to you first the androgen problem. This is the underlying condition and if we don’t control androgens, patients have these issues. If you’re a child born with congenital adrenal hyperplasia and you have all these excess androgens swirling around your body, the first thing that will tend to happen is you’ll be driven into puberty very early. Often as early as 5, 6, 7 years of age. Because you enter puberty early, your bones will fuse earlier than they should and you’ll end up potentially being quite short as an adult. As you continue to grow, androgens cause a variety of issues for you, they make you hairier, you have excess body hair growth, they may give you classic male pattern baldness, and acne and a variety of other kinds of dermatological conditions. Then, as you reach adulthood each of the two sexes, male and female, has different fertility issues. In the case of males, this angiogenic cascade can cause what are called testicular adrenal rest tumors, or tarts. These are benign tumors, but they grow in the testes and cause pain and also impair sperm production, hence, render the male infertile. In the case of women, these high androgens caused disruption of their menstrual cycle. They’ll get a complete absence of their menstrual cycle to render the females infertile as well. That’s why many physicians will use high doses of these glucocorticoids to try and suppress the androgens. Then, what you end up with is classic steroid related issues, such as obesity, which is one of the first things that’s noticeable and that obesity can turn into insulin resistance and other metabolic diseases; also cardiovascular diseases like elevated blood pressure, and then osteoporosis is a common challenge associated with these high doses of steroids. These are the two challenges and the two choices these patients face, and what we’re trying to engineer a solution to.
Daniel Levine: What’s it like to live with this condition and what’s the prognosis for someone who has it?
Richard King: Since the advent of glucocorticoids, these patients are living into later life. If you’re taking a lot of glucocorticoids to suppress the androgens, then you worry about those longer-term consequences of metabolic effects, cardiovascular disease, and osteoporosis. In the short run, you’ve got these issues, such as fertility to try to address. As a young kid, you’ve got this worry about reaching full adult height and at the same time trying to avoid the issue of adrenal crisis. There’s a number of events that occur throughout the course of life, which are challenging and which require thoughtful approaches to disease management at each stage of life.
Daniel Levine: Well, can you expand on that? What do you mean?
Richard King: When you are a child, the way in which physicians manage this disease today is to try and use a lot of glucocorticoids to suppress the androgens that are present. But those glucocorticoids aren’t causing obesity and other challenges during the course of childhood. As you get to teen years and into the early twenties, you’re not so worried about fertility at that stage, but you are worried about complexion and excess hair growth and so on. Again, you worry about excess androgens and so steroids are a part of the picture of that stage. Again, as you go into your fertile years you’ve got these other challenges that you face. All the time you’re adding these steroids to try and control those different stages, you’re also storing up for a lot of later life problems in terms of obesity and these other diseases. What we’re trying to do here is offer a different way, a non-steroidal way, to control those androgens. You get the androgens under control with a nonsteroidal therapy, and that should allow a continual low level of the steroid, which you need to prevent adrenal crisis, but you don’t need to control all the androgen issues because those are being controlled by our drug, tildacerfont.
Daniel Levine: Let’s talk about your experimental nonsteroidal therapy tildacerfont. What is tildacerfont and how does it work?
Richard King: Tildacerfont is what’s called a CRF1 receptor blocker. CRF stands for corticotropin-releasing factor. This is a substance which is produced in the middle of the brain in the hypothalamus, and ultimately starts the cascade of events that leads to either production of cortisol in healthy people, or the production of androgens in these patients with congenital adrenal hyperplasia. We’re trying to block the actions of that initial hormone on the pituitary gland, which is where you get conversion from CRF into a different hormone called adrenocorticotropic hormone, which starts this whole cascade leading to these two events. By controlling it there and not using the steroid to control it, we think that we can provide an alternative, and hopefully a better, therapy than pure steroids for these patients.
Daniel Levine: This was part of a portfolio of drugs that Spruce licensed from Lilly. What was it originally being developed for and how did Spruce come to see its potential as a therapy for CAH?
Richard King: Great question. If you go back to the early 2000s, these CRF1 receptor antagonists were being developed by lots of different pharmaceutical companies as potential treatments for anxiety and depression. They didn’t pan out there ultimately. Our founder, who was doing her Ph.D. thesis on these agents, did think that congenital adrenal hyperplasia could be a very good target disease for these drugs. Lilly’s compound, which we now call tildacerfont, is a second-generation compound, and the first ones were very lipophilic and were challenging to use, but the second generation had solved that to a large extent. So, our founder thought that Lilly’s compound was very attractive and thus began a discussion with Lilly that ultimately resulted in Spruce capturing the asset in 2016.
Daniel Levine: Is there a relationship with Lilly going forward?
Richard King: Only in the sense of owing them a small royalty and a couple of milestones, but other than that we have full control over the development of tildacerfont.
Daniel Levine: You recently published phase 2 data results from tildacerfont. What’s known about its safety and efficacy at this time?
Richard King: What we showed in our phase 2 studies was a number of things. First, over a period of 12 weeks of continual exposure to tildacerfont, these patients were able to reduce their very high levels of androgens down, from 5 to 10 times the upper limit of normal into the normal range or close to the normal range in some patients. That was particularly exciting. It was the first time that a nonsteroidal therapy has been able to show the ability to control these androgens without using a glucocorticoid. The second thing we showed from a safety standpoint was this drug was very well tolerated. Very good tolerability over the course of 12 weeks, and no serious adverse events. Only your fairly typical events of some headache and so on that you see in the majority of clinical studies. We’re very pleased with the tolerability profile for the product.
Daniel Levine: What’s the regulatory path forward?
Richard King: We’re currently in the process of doing, what are technically, phase 2b studies, and these are late stage studies, but they correspond to the FDA’s phase 2b stage. There are two of them ongoing. The first study is looking at the ability to control androgens, these elevated male sex hormones, in patients who have what we call poor disease control. That’s an inability to control androgens on their own. The second study is looking at patients who have what we call, good disease control, where patients have control of androgens, but they’re using a huge amount of the steroid to be able to get that control. We’re looking at the ability to retain control of androgens while we reduce the steroid. If those two turnout as we hope, then we would hope to be able to take the data from these two studies to the regulators, both in Europe and the U.S. and to find a pathway forward that will allow these two studies to be registrational for this program.
Daniel Levine: What’s the commercial strategy and at what point do you start building a commercial organization?
Richard King: We’ve already begun to a certain extent because we’re evaluating the marketplace as we go. We do see, from a commercial standpoint, the ability to build a commercial organization, both in the U.S. and in Europe. We also will look for partners outside of those geographies, in Asia, Africa, Australia, et cetera, but building that capability ourselves. We have a view to hopefully seeing these products to market sometime around 2024 – 2025.
Daniel Levine: You’re looking at potential indications beyond CAH. What else are you looking at?
Richard King: Firstly, later this year, we are starting a program in children with CAH. Our initial study program that I described to you is in adults with CAH, but we are also starting a study in children with CAH. We want to be able to give children, down to the age of two, alternatives to the glucocorticoids that they use today, just the same as we want to give to adults with disease. That’s first on the list. Secondly, we’re also interested in treating other diseases where there is an implication for either adrenal androgens, androgens which come from the adrenal glands, or sensitivity to adrenocorticotropic hormone, which is one of those key cascading hormones that I’ve talked to you about. One of the diseases that we’re focused on in that regard is polycystic ovary syndrome. There’s a subset of women with polycystic ovary syndrome whose source of elevated androgen, which is the underlying condition for these women, is from the adrenal glands. It’s due to a hyper sensitivity to this ACTH hormone. So, we are starting a proof of concept study in these women later this year and hope to bring some therapeutic alternatives to women with POS.
Daniel Levine: How about the plan for building a pipeline beyond tildacerfont? Do you expect to continue to focus on endocrine disorders, or are you going to look at other rare diseases?
Richard King: We think that there’s a lot of rare endocrine diseases that would benefit from additional therapeutic options to the existing therapies that are available. Our focus is very much on these endocrine rare disorders. We would, over the course of time, like to leverage the organizational capability that we built in developing these agents, understanding endocrine disorders, and bringing forward drugs that we think will be useful for patients with these conditions. We fully expect to add to the portfolio over time and to build a company which is focused on both developing and commercializing for patients with rare endocrine disease.
Daniel Levine: In that context, would you expect to do that through other licensing deals?
Richard King: I think that’s the most likely scenario for us at the moment. We don’t have an internal research capability, but we do have internal development capabilities. We’d like to leverage that piece and bring in assets which are newly discovered or programs that hold promise for patients with rare diseases.
Daniel Levine: You completed an IPO in late 2020, how far will that funding take you?
Richard King: A good way actually. The funding takes us through the all the programs that I described to you. So, the adult CAH program, the two adult studies which are ongoing and in the clinic right now, the pediatric study, which is currently on the starting blocks and going later this year, and also the polycystic ovary syndrome program. All three of these programs that will be initiated in 21 will be fully funded by available funds. Then, we would look to additional funds to commercialize tildacerfont for adult CAH and finish the development of tildacerfont for these other indications.
Daniel Levine: Richard King, CEO of Spruce Biosciences. Richard, thanks so much for your time today.
Richard King: Thank you, Danny. Appreciate it. Good to talk.
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