A New Approach to Treating a Rare Endocrine Disorder

December 24, 2021

Most endocrinologists focus on the level of corticosteroids circulating in the bloodstream when treating conditions like the rare endocrine disorder Cushing syndrome. Sparrow Pharmaceuticals believes it is active intracellular steroids that are primarily responsible for causing toxicity in patients. It is developing therapies that target HSD-1, the key regulator of active intracellular steroids. We spoke to David Katz, founder and chief scientific officer of Sparrow Pharmaceuticals, about the company’s efforts to develop new approach to treating Cushing syndrome, how it works, and why this has the potential to address the unmet needs of patients with endogenous Cushing syndrome.



Daniel Levine: David, thanks for joining us.

David Katz: Thanks Danny. Glad to be here.

Daniel Levine: We’re going talk about Cushing’s disease, corticosteroid biology, and Sparrow’s efforts to develop a new therapy for the condition. For listeners not familiar with Cushing’s disease, what is it?

David Katz: Sparrow is actually developing drugs for three different conditions. One is Cushing’s syndrome of which Cushing’s disease comprises a substantial majority, probably about 70 or 80 percent. Cushing’s syndrome is a condition in which a patient has a tumor that either secretes a large excess of the hormone cortisol or through a series of molecular events causes them to secrete a large amount of cortisol, and cortisol is one of the body’s main stress hormones. At normal levels, it’s involved in the regulation of a whole lot of physiological processes. It can be things that are pretty much invisible to us, like our ability to metabolize sugars and fats, our blood pressure. It also in some ways regulates our mood, our cognition, our ability to sleep. Cortisol is one of the things that helps wake you up in the morning—it’s not just caffeine. It also, for example, helps keep your eyeball round because it helps regulate the pressure of the liquid in the eye so that you can see. But in excess, it can cause all of those things to go awry. So, you can wind up having excess blood sugar, which is diabetes, excess cholesterol and triglycerides, high blood pressure, deficits in cognition, mood swings, inability to sleep well, and, increased pressure in the eye, which is glaucoma, as well as, you know, other effects like it makes your bones brittle and it can make your muscles and skin atrophy. So, really pretty bad all around. Patients with Cushing syndrome often show many or all of those symptoms and the distinction between Cushing’s disease and Cushing syndrome is that Cushing’s disease is specifically a tumor on the pituitary, which is a gland that is just at the base of your brain, whereas Cushing’s syndrome more broadly includes not only pituitary tumors, but also tumors that are in other places in the body. The other two conditions that we study are actually much more common: autonomous cortisol secretion, which is also caused by a tumor that secretes excess cortisol. In this case, it’s on a gland that’s called the adrenal, which sits on top of your kidney. So adrenal, literally from Latin, is on top of the kidney that is the gland that normally secretes cortisol in our bodies, but when there’s a tumor sometimes it excretes too much. The cortisol excess in autonomous cortisol secretion is not as severe as in Cushing’s syndrome, but the morbidity, the spectrum of morbidity is pretty much the same. So, these are patients who have excess risk of death. They can present with diabetes, hypertension, dyslipidemia. They also have a very high proportion of what are called low impact fractures, for example, fractures of the vertebrae, and it’s estimated that as many as 50 to 80 percent of patients who have ACS will ultimately suffer a vertebral fracture. ACS is probably the most underrecognized condition in endocrinology. We don’t know for sure, but think that possibly as many 97 percent of patients who have ACS don’t know it, and there may be as many as 3 million of those in the U.S. The third condition or set of conditions for which we’re developing drugs is sometimes called exogenous Cushing’s and that’s a condition when people are given glucocorticoid medicines like prednisone. Those are medicines that actually mimic cortisol in the body, but they’re synthetic, and they are used chronically for the control of autoimmune disease, prevention of organ transplant rejection, and other conditions. And they carry as side effects, all of the same symptoms we just talked about of Cushing’s and ACS. In fact, the glucocorticoids or steroid medicines are responsible for over 10 percent of all reported drug side effects in the U.S. and also responsible for more than 10 percent of drug related hospitalizations in the U.S. So, there are about 2 million patients in the U.S. who rely on long term use of steroid medicines to control various medical conditions. So it’s really a lot bigger than just Cushing’s syndrome.

Daniel Levine: Let’s focus on Cushing’s syndrome for now. It strikes me that the manifestations of the condition can be somewhat general. How easy is it for a doctor to recognize a patient that actually has this and diagnose it correctly?

David Katz: It’s not, and in fact, many patients go for years without a correct diagnosis until it’s ultimately determined that they have Cushing’s syndrome and a lot of damage can be done to their bodies during that time. It’s a pretty hard diagnosis to make. It’s not very common and a lot of physicians will never see a case of Cushing’s syndrome so they’re not necessarily attuned to think of that as the first thing. There are some outward physical manifestations. Patients tend to have a characteristic pattern of obesity—a lot of central obesity and thin limbs. They often have something called moon face, which is just what it sounds like—that the person’s face looks like, those old cartoon moons, and also stria, which are basically stripes, reddish purple stripes commonly along the abdomen. So there are some physical signs that can make one think of Cushing’s, but also some of the initial damage may be diabetes and osteoporosis, those are sort of nonspecific things and a lot of people have them who don’t have Cushing’s.

Daniel Levine: Is there a predictable progression to the condition?

David Katz: Not really. I think patients present in many different ways before they’re diagnosed with Cushing’s, and sometimes even the Cushing’s is misdiagnosed. I, spoke to one patient who initially was thought to have a Cushing’s tumor on her adrenal, which was removed. Then it turned out that that was actually a secondary tumor to a tumor on her pituitary. So, basically she went through two sets of, um, long periods of not being appropriately diagnosed because they were thinking they really didn’t understand what was going on with her after the tumor had been removed, because removal of an adrenal tumor should be curative.

Daniel Levine: What’s it like to live with the condition?

David Katz: You’d really have to ask a patient that, but it just sounds like it can be quite unpleasant. There’s everything from not being able to think straight, having mood swings, being concerned about your appearance, and then having your physician telling you you’re diabetic, your bones are fragile. “I’m having trouble controlling your high blood pressure.” So, I would imagine that there’s going to be, for a lot of people, kind of constant worry about what’s going to happen next, does this ever end, when do I get off this roller coaster? Those are actually things the Cushing’s Syndrome Research Foundation has put out some work on, looking at what patients say, and those are all sorts of things that patients have said in their surveys.

Daniel Levine: How is the condition treated today and what’s the prognosis for someone with it?

David Katz: So the first line of treatment is surgery and that is curative in about half of people. But then the other half, either the tumor isn’t completely excised, or the tumor comes back, and so then they go on to, most commonly, medical therapies, sometimes radiation therapy is used as well. The medicines that are used, they’re basically three classes of medicines, and they have all been around, for the treatment of Cushing’s for at least 35, 40 years. There are somewhat better versions of each of those classes either now on the market or close to coming on the market, assuming they receive regulatory approval. But there really hasn’t been a fundamentally new approach to the disease for 35 to 40 years. And that’s what Sparrow potentially would bring to that particular group of patients.

Daniel Levine: What are the HSD-1 and HSD enzymes? What role do they play and the biology of corticosteroids?

David Katz: So, first of all, the test that I will give you at the end of this is HSD stands for 11β-hydroxysteroid dehydrogenase. And I’ll ask you to repeat that back to me at the end of the interview, if that’s okay. These are enzymes that control the levels of cortisol within your cell. Traditionally, cortisol is thought of as a hormone—that it is something that acts at a distance. So, in medical school, physicians learn cortisol is secreted from the adrenal, and then it goes throughout the body and it acts on various tissues. That is only part of the story and maybe not even be most of the story. So, there are some tissues in the body, such as the kidney in which cortisol is acutely toxic. Those tissues contain an enzyme that inactivates cortisol and that has a protective function. Our drug doesn’t touch that—that’s called HSD-2. HSD one, which is the target of our enzyme converts the inactive form back to the active form within cells, in tissues such as liver, fat, bone, brain, muscle, and skin where cortisol at normal levels has all those beneficial physiological functions that I talked about at the very beginning, and in excess they have those deleterious pathological functions. And it turns out that most of the regulation of cortisol that really matters is what happens through HSD-1 because it’s the cortisol that is formed and present within the cell that can access the receptors for cortisol, which are also inside the cell. And so, in a way we think of this as cortisol is what’s called an autocrine effector. That is, it has action, and in the same cell in which it’s made, as opposed to an endocrine effector, and that perhaps some physicians should be called autocrinologists rather than endocrinologists. There’s quite a lot of evidence for the supposition that the intracellular cortisol is what’s really important, and that there are some rare patients who have both Cushing’s syndrome and a natural deficit of HSD-1 and their Cushing’s syndrome was discovered entirely by accident because they were asymptomatic. With substantially reduced HSD-1 activity, they simply didn’t have any symptoms of the disease, but they had ragingly high levels of circulating cortisol, and their tumors were found by imaging and removed surgically. And then both of them were fine.

Daniel Levine: What is your lead experimental therapy SPI 62 and how does it work?

David Katz: It inhibits HSD-1, so it blocks the formation of a lot of intracellular cortisol and it’s net effect, is that when you give SPI 62, the amount of cortisol in the patient’s cells goes down, and we’ve actually demonstrated that directly in the liver. We’ve also demonstrated it indirectly in both brain and fat where we’ve measured enzyme activity, or enzyme binding, but actually haven’t measured the consequent decrement of cortisol levels, but we can infer it.

Daniel Levine: What advantages might this approach have over other treatments that exist today?

David Katz: Well, this gets into the realm of speculation, of course. One thing is when you have a disease like Cushing’s syndrome or ACS, or dealing with the side effects of steroids, that perhaps one approach doesn’t fit all. We already see this in Cushing’s syndrome that patients frequently cycle between medicines, in part because the medicines don’t retain efficacy, also in part, because all of the medicines that are available for patients with Cushing’s have some combination of being difficult to use or having substantial safety effects. We hope that we can provide not only efficacy that’s comparable to, or perhaps better than, what’s available on the market today, but do that with something that is better tolerated, easier to use, and perhaps more accessible to patients. So, one of the things that all of the current drugs for Cushing’s have as a liability is called adrenal insufficiency. That’s what happens when the drugs control cortisol too well and so then the patient has two little cortisol, which also is not very consistent with life, and particularly not with life after a shock to the system. President Kennedy had primary hypocortisolism, which is called Addison’s disease, and he was treated for that for much of his life. It’s hypothesized that he actually died so quickly after he was shot because his body couldn’t mount an adequate stress response, to handle the shock to his system. That’s a common issue for all current Cushing’s drugs. There’s no way that you can get rid of all the cortisol simply by inhibiting HSD-1. So, the other drugs, for example, inhibit the original synthesis of cortisol and it’s possible with those to get down pretty close to zero cortisol. Other drugs that are used for Cushing’s inhibit the ability of cortisol to interact with its main receptor and again possible to overdo it and completely prevent cortisol from having any action, even though it’s there. Ours—with HSD-1 inhibition—there’s always going to be a buffer of cortisol that remains. Obviously it has to be proved in clinical trials that ours will be a drug that doesn’t carry risk of adrenal insufficiency. That would mean not only better safety for patients, but also would mean a lot less of the intrusive monitoring that has to be done for the current therapies that are used in Cushing syndrome.

Daniel Levine: And what’s known of about the safety and efficacy of SPI 62 from studies that have been done to date?

David Katz: So, four clinical trials have been completed of SPI-62 in a total of 165 people. Most of those were healthy volunteers and elderly adults in general good health. Some of them were patients with type 2 diabetes. Generally, for this stage of development of a drug, it has been associated with relatively few adverse events and most of them have been mild in severity, the most common one being headache.

Daniel Levine: What’s the development path forward?

David Katz: Sparrow is currently initiating three phase 2 clinical trials, one in Cushing’s syndrome, one in autonomous cortisol secretion, and one in a disease called polymyalgia rheumatica, which is the most common autoimmune disease of the elderly, a disease for which the only approved treatment is steroid medicines and also the number one indication for long term use of the steroid medicines. In the first two [trials] we’re using SPI-62 by itself to reduce endogenous cortisol. In the last trial, we will dose SPI-62 together with a steroid where the idea is that it will block the side effects of the steroid, but not the efficacy—at least that’s the aspiration.

Daniel Levine: Sparrow completed a $50 million series A in May. How’s that money being used and how far will it take you?

David Katz: It’s paying mine and my colleagues’ salaries for one thing, and that’s nice. Mostly it’s being used for the clinical trials, as well as some associated activities like animal studies that are needed to support the trials, manufacturing. That gives us runway into, I think, 2024.

Daniel Levine: David Katz, founder, and chief scientific officer of Sparrow Pharmaceuticals. David, thanks so much for your time today.

David Katz: Thanks, Danny. Take care. Bye.

This transcript has been edited for clarity and readability.

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