All right. Good evening, everybody. Welcome to Boston and welcome to tonight's program. I wanted to welcome all of you and also welcome the virtual attendees as this is being live broadcast as a webinar. So as a matter of introduction, my name is Anand Vaidya. I'm here in Boston, so welcome to our home. And I'm joined by two esteemed faculty, Dr. Phyllis Spicer, who is emeritus professor of pediatrics at the Zucker School of Medicine, Hofstra Northwell in New York, and also Dr. Richard Aukus, who is a professor of translational medicine in the division of endocrinology at the University of Michigan, two superstars in the field, and we have a great program for you today. So here's the agenda. I'll start us off with some introductions, and then I'll hand it over to Dr. Spicer, who will go through a pediatric case of CAH to discuss some therapeutic dilemmas. I'll take over from there and share with you some adult CAH cases and dilemmas, and then we'll turn it over to Dr. Aukus, who will go through several of the treatment potentials, novel treatments that are being developed and on the horizon, and then we'll debrief together going back through the cases that we had discussed and think about how they might be handled in the future. Okay. So let's get started. So we're going to start with a couple of polling questions just to see who you all are and what you know and what you feel about CAH. How many patients with CAH do you care for? Okay. So the answers are in, and it looks like the vast majority of you, almost 80%, said less than five. Okay. That's great. And then there's a smattering of you who have five to ten, a few super experts who have 20 to 30 or more than 30. But it looks like for the vast majority of patients, people in this room, you're seeing very few patients, and so maybe this next question is equally pertinent. How comfortable do you feel with the management of CAH? So very few of you feel very comfortable, and then about a third each of somewhat comfortable, uncomfortable, and very uncomfortable. And I think I take care of a lot of patients with CAH, and I'm not completely comfortable either, so that's good. You shouldn't be that comfortable because it's somewhat uncomfortable at times. Hopefully at the end of this session, you'll be more comfortable. So let's go a little bit more granular. What aspect of CAH management do you feel most uncomfortable with? And you're going to have to pick one, so pick the one that you're most uncomfortable with. Pretty even series of responses. About 25% adrenal insufficiency, hyperandrogenism, infertility or pregnancy. Less so for nocturnal glucocorticoid dosing, and most of you feel pretty comfortable with monitoring of breast tumors. So kind of a fair distribution of discomfort, and hopefully we'll solve that tonight, at least some of it. Okay, so since 77% of you said that you only take care of five or fewer congenital adrenal hyperplasia patients, let me just walk you through what might be a basic diagram, but so that we're all on the same page. This is the adrenal cortex and stereogenesis. What we're dealing with today is 21-hydroxylase deficiency. So you can either have an insufficiency or a deficiency of this enzyme, and the lack of enzymatic activity here is going to impair the production of steroids distal to this enzyme, namely cortisol and aldosterone. The deficiency or insufficiency of cortisol is going to result in a decreased negative feedback to the hypothalamus and pituitary, which will respond by revving up the system. So as ACTH rises and stimulates the adrenal cortex to increase stereogenesis, you hit this block, and the precursors are shunted towards the androgen pathway. Okay, so in this way, CH is a unique disorder because it's a disorder of a simultaneous deficiency and an excess. And this can result in a buildup of these proximal metabolites, including 17-hydroxyprogesterone, which, as you know, is used in the diagnosis, and then this can also be shunted to other alternative androgens that can play a role in the androgenization clinically. So CH is a heterogeneous syndrome. You can call it a disease, but I think the word syndrome better encapsulates the fact that it has a heterogeneous set of phenotypes. It's a syndrome of endocrine hormone insufficiency and excess. The clinical phenotypes are highly variable, dictated in part by the severity of the enzymatic insufficiency, but then a whole host of factors that are superimposed on top of that throughout life. The treatment of CH requires an understanding, therefore, of the pathophysiology, which I very briefly went over, but also the balance and tradeoffs between the risks and benefits of the treatments you prescribe. So the main treatment we're going to discuss today in part, or at least at the beginning, is glucocorticoid therapy. And as you all know, there's a double-edged sword here. On one hand, glucocorticoids are needed for the treatment of adrenal insufficiency to lower ACTH and hence lower androgens to improve fertility and reduce the likelihood of developing rest tumors, but they simultaneously can increase the risk of developing features of the Cushing syndrome and increasing cardiometabolic risk. And so how to balance these benefits and risks is part of the discomfort that many of you highlighted in treating CH, and these tradeoffs change between pediatrics, newborns, children, adolescents, adults, and different stages of adulthood. So I'm going to turn it over to my colleague, Dr. Spicer, who's going to start off with the pediatric cases for you. All right. Thank you, Dr. Baja, for that excellent introduction. So as a pediatric endocrinologist, we have special concerns that don't exist in the adult population, and the main one is growth. So I'm going to present a case of a three-year-old boy who was adopted and had a six-month history of penile enlargement, pubic hair, underarm odor, and the pediatrician sends him to you, and you observe a height that's above the chart, greater than 98th percentile, a weight that's at the 95th percentile, normal blood pressure, some facial acne, and stage 2 pubic hair and 10 or stage 1 testes, in other words, normal prepubertal-sized testes, and a stretch penile length that's kind of generous at 8 centimeters. So this is the growth chart as of his initial examination, and you can see the height above the normal pediatric growth curve on the top and the weight all near the top of the weight chart. And the bone age is advanced. It's five to six years of age. And below you see on the left side the lab values, including a 17-OHP that's markedly elevated in the morning at 8 a.m. before his medications were given, 5,200 nanograms per deciliter, androstenedione also way above, even for a pubertal child, at 250 nanograms per deciliter, and testosterone of 30. Again, in most labs for children, the testosterone ought to be below 10 nanograms per deciliter, and DHEA sulfate is pretty much unremarkable. The gonadotropins are rather suppressed, LH unmeasurable, FSH 0.2 milli-international units per liter, and the bone age is two standard deviations above his chronologic age, as we mentioned. So the differential diagnosis of CAH in a case like this would be ordinary premature adrenarche, not associated with an enzyme deficiency in the steroidogenic pathway. However, in this case, it was pointed out that the serum 17 hydroxyprogesterone was uniquely and selectively elevated in addition to the androstenedione. And if you think about central precocious puberty as a cause, this isn't a likely possibility because the FSH and LH are suppressed. There is a condition that we used to call testotoxicosis, now referred to as familial male limited precocious puberty, and that's unlikely because there's only a mildly elevated testosterone, and this boy has small testes. So that tends to point to a defect in the adrenal steroidogenic pathway, selectively elevating the 17 hydroxyprogesterone, and that would lead you to think about classic 21-hydroxylase deficiency, CAH, which is the most common type of virilizing CAH and is prevalent in the population at a rate of about 1 in 14,000 live births. So this business of chronic growth acceleration associated with an advanced bone age, small testes but rather generous looking penile length, body hair, premature puberty, and these elevated adrenal cortical steroids all support that diagnosis. So the child is monitored regularly, and five years later at age eight, his bone age has advanced even more, and it's now 13 years, whereas his growth rate has slowed down, and you can see that in the growth chart on the right. His hydrocortisone is being given as prescribed, so non-adherence is really not in consideration here. He's already up to a dose of 17 milligrams per meter square per day, and our guidelines put this at about the very top of the recommended dose level, whereas physiologic would be something at around 10 milligrams per meter square per day or less. And his predicted adult height is really not good compared to his mid-parental target height, so he's going to end up being short, and that's what those horizontal lines are showing you on the growth curve on the right. So with a bone age that's five years advanced compared to his chronologic age, and previously it was about two to three years advanced, this is not a good height prognosis. And as I said, that's one of our main considerations as pediatricians, as pediatric endocrinologists, that we try to maximize the growth potential for these individuals. So at this point in time, at age eight with a bone age of 13, he has 10 or two testicular volumes, so that would indicate at three to four ml in a testicular volume that he is entering central precocious puberty, and you see the LH rising, and here it is definitely measurable in the pubertal range with a testosterone that's higher than it was in the past, and some of that may be coming from the testes themselves in addition to the adrenal cortex. Now, the early morning serum 17-hydroxyprogesterone and androstenedione are both about 10 percent the upper limit of normal for his chronologic age, and this despite the child's being on a fairly generous dose of hydrocortisone in terms of his body's surface area. So at this juncture, what are your options? So many of you favored the use of a GnRH analog, and in this situation you could use that treatment as an ancillary drug because, as we've pointed out, this child is entering central precocious puberty. Another substantial proportion of the audience said, let's put in some nighttime prednisolone because the hydrocortisone doesn't seem to be really fully effective. Other choices were an aromatase inhibitor to reduce the amount of further bone maturation, and then sort of an equal number of you said either growth hormone or to continue just with the hydrocortisone three times daily as above. So obviously this is not the end of the story, so let's continue to discuss this. And in another few years, the child is now 14, and he's 167 centimeters tall, about one standard deviation below the mid- parental height, and in the CAH literature, in a meta-analysis, systematic review and meta-analysis of the case reports and systematic reviews of CAH populations in large centers, this is about as tall as you generally expect CAH patients in the past to attain a height, and they're going to be generally a little bit below their mid-parental height, but still within the short normal range. Now the child's pubertal status is 10 or stage 4, so nearly fully mature from a pubertal perspective. His bone age is 15, meaning he has only a small amount of statural growth remaining, and his testicular ultrasound is beginning to show small bilateral tarts. So depending on which series you look at, and there are some data that are coming out in the New England Journal, you'll see that a substantial proportion, even of children at this age, will begin to show testicular adrenal rest tumors, which is not a good sign, and that means that intermittently, at least, this child has not been in good hormonal control. So in the meantime, the clinician taking care of this child decided to just continue with standard of care, that is three times a day hydrocortisone, and not to rock the boat with any ancillary medications to enhance growth or delay puberty. So now the question is, with what we know at age 14, how would you manage this child differently? And so most of you said switch to prednisolone twice daily. Some people said, almost an equal number said give dexamethasone once daily. Some said hydrocortisone three times daily, and some said stop the glucocorticoid treatment. Well, clearly we don't want to stop glucocorticoid treatment. Any patient with classic 21-hydroxylase deficiency, CAH, needs to continue on glucocorticoid treatment lifelong. You could continue hydrocortisone as the primary glucocorticoid, but as we pointed out, his levels are not reaching what we would consider adequate hormonal control, and so some clinicians might introduce prednisolone. Now, dexamethasone is problematic in a child, even if it's somebody who is nearing the end of his growth. The more potent and long-acting synthetic glucocorticoids tend to have many more adverse side effects, including the cardiometabolic syndrome, extra elevations in blood pressure, all of those cushingoid features that we tend to associate with chronic excessive glucocorticoid use. So in the guidelines that were published from the Endocrine Society, we kind of discourage the use of dexamethasone and emphasize if you need to go away from hydrocortisone treatment to think about a less long-acting and less potent prednisolone. So the pitfalls of glucocorticoid treatment in childhood include the precipitation of central precocious puberty, as we saw in this case, and that happens often when the glucocorticoid treatment is begun at an already advanced or advancing bone age, and you'll see actual pubertal progression. Excessive glucocorticoid treatment also, as was pointed out in the introduction, leads to iatrogenic Cushing syndrome, and in our pediatric population, growth suppression is a prominent part of that, with excess weight gain and a cardiometabolic syndrome that may be apparent even in adolescence. And as far as inadequate glucocorticoid treatment, there's overstimulation of the hypothalamic pituitary axis, excess adrenal sex steroid production with ongoing virilization, and the development, even at a young age, of adrenal rest tumors, which may be difficult to suppress or control. And then adrenal insufficiency comes along with stress if the patient is either not taking his medicine or not being treated adequately during those episodes of an extreme dangerous febrile illness, extensive vomiting, going off to surgery without adequate preparation. So the take-home lessons for those of you who take care of pediatric patients is that CAH screening among newborns is not standard in all countries. So remember, this boy was three years old at presentation and had not been diagnosed in the newborn period, presented late, already with signs of virilization, bone age advancement, so you are already behind the eight ball when you see them at a late age. And before the introduction of newborn screening in this country and in many Western countries, that was the way we began to see these patients. And those patients who were salt wasters didn't even survive to that age because they succumbed to their adrenal crises. So the diagnosis of 21-hydroxylase deficiency can be overlooked. Even in the best of newborn screening programs, there are some who slip through the cracks. And in the United States, some people have home deliveries or somehow bypass the system and aren't tested in the newborn period. If you suspect the diagnosis, you must test for it. The bone age-based height predictions sometimes are inaccurate in CAH. Remember that the grulic and pile-based height predictions are really standardized for typically growing children and not for children with advanced or delayed puberty. The guidelines that have been mentioned from the Endocrine Society and cited in the references, they do not recommend growth-enhancing drugs for most children with CAH, nor do they recommend the very highly potent synthetic glucocorticoids for routine use. And randomized controlled trials with new therapeutic options do show promise, and Dr. Aukus is going to discuss some of those. And early diagnosis and mitigation of glucocorticoid overdosing can potentially avoid these perturbations in growth and puberty. So that's something we'll look forward to hearing from Dr. Aukus about in the next few minutes. Thank you. All right. Thank you, Dr. Spicer. Okay, so now we'll move to the adult realm. I have two cases. The first one is an adult man. So this is a 35-year-old adult man. He had a salt-wasting crisis at birth. Actually, his older sister did as well. So the doctors and parents were on alert. He was diagnosed quickly and treated with glucocorticoids and mineralocorticoids. Thereafter, he reported normal growth, development, and puberty. And when I saw him at age 35, he was on hydrocortisone 20 milligrams in the morning, five milligrams in the early afternoon, and fludrocortisone 0.2 milligrams daily. He said he felt great. He had good energy and strength, normal libido. He was a very active guy doing a lot of outdoor work. He had really no complaints. The main issue was that he and his wife were trying to get pregnant. They had been trying for one year without success. She was 35 years old, which added to the anxiety, time sensitivity of the nature, and she had had a full infertility workup that did not reveal any maternal factors that could be corrected. So here are his morning labs. You can see his 17-hydroxyprogesterone is over 18,000 nanograms per deciliter. His androstenedione is nearly 14 nanograms per deciliter. His total testosterone is low at 180 nanograms per deciliter. So his A to T ratio is about 7.7. Free testo is also low. SHBG is 80. LH and FSH are both very low. His testicular ultrasound showed normal testicular size and volume without any rest tumors. His semen analysis showed only 14 or 15 million sperms, so that's low. The morphology was almost entirely abnormal, and there was 46% immodal sperm. Okay, so based on this, what would you recommend for him? Looks like the number one answer, 40% of you said nocturnal glucocorticoid therapy, followed by a referral to urology to do a testicular biopsy or aspiration for sperm retrieval, and a spattering of other responses. You could send him for sperm retrieval if you didn't think there was another reversible way to handle this, or maybe you could do it even without it, considering the alternative. Let's see what happens. So what's going on here? This patient has hypogonadotropic hypogonadism, resulting in low testosterone oligospermia, and the driving force here is the adrenal hyperandrogenism. So we discussed the risks and benefits of initiating glucocorticoid therapy, particularly at night, to try to turn the ACTH down, to reduce the adrenal hyperandrogenemia, and break this vicious cycle. We did talk about referring him to urology, but he preferred this medical approach, if possible. And so I started him initially at 2 milligrams of nocturnal methylprednisolone, and then slowly escalated to 3 milligrams. And five months later, you can see his 17-hydroxyprogesterone has come down from 18,000 to 3,100. His total testosterone has risen from 180 to 550, which is the mid-normal range. His androstenedione has come down from 1,400 to 160. The androstenedione to testosterone ratio is about 0.29. Both gonadotropins are now detectable. And I think most impressive is the semen analysis. His sperm count is now a robust 125 million, 95% modal, and they're moving forward. That's a good sign. So here's the downside. He's gained 20 pounds in five months. But the good news is, a month or two later, he and his wife reported having a spontaneous pregnancy, which went to term. They had a healthy baby girl, and they were so happy that they wanted to get pregnant again almost immediately thereafter. And I actually repeated this entire cycle of nocturnal glucocorticoids. There was a time sensitivity to helping them get pregnant. And so the downside of all of this is he gained 35 pounds in two years. And I didn't tell you this. I probably should have. He was already kind of borderline obese to begin with. So this is a serious thing to happen at 35 to 37 years in this man's life. But they were ecstatic that they were able to have two children. So this kind of highlights the pros and cons of glucocorticoid therapy. They're wonderful at treating adrenal insufficiency, at lowering ACTH, at normalizing androgens, and in this case, improving fertility. But they have real adverse effects. And even though he didn't have the full stigmata of the Cushing syndrome, he certainly gained weight, which is an adverse metabolic risk factor. And if we had continued this way, he would have developed more and more stigmata of glucocorticoid excess. This is an adult woman with hyperandrogenism. So this is a 29-year-old woman. She had a salt-wasting crisis at birth. She was diagnosed and treated with glucocorticoids and mineralocorticoids. She reported menarche at age 12 and thereafter always had irregular menses and was prescribed in her early teenage years an oral contraceptive pill. She's currently 30. She works full time. She's adherent to her medications. She has an administrative job. She's very good about medication compliance. Her main issues are facial hirsutism that's requiring frequent shaving and laser therapy. In some way, she's been dealing with this almost her entire adult life. But this is the one thing that bothers her, and she's wondering if there's anything we can do about it. So here are her morning labs. She's on hydrocortisone 15 in the morning, 10 in the early afternoon, and 5 in the early evening, flugicortisone 0.1 twice a day, and an oral contraceptive containing estrogen. Her 17-hydroxyprogesterone level in the morning ranges between 6,000 and 13,000 nanograms per deciliter, and her androstenedione fluctuates between 300 and 1,000 nanograms per deciliter. SHBG is nice and high on the OCP, and her total testosterone is high for the female range, 77 to 213. So what would you advise her to do for her unwanted facial hirsutism? So a fairly even split between antiandrogen therapy, so non-glucocorticoid, and nocturnal glucocorticoid therapy. Almost nobody wanted to increase daytime or recommend topical therapy. So all of these are reasonable options. I think the key thing is to discuss with her how pressing the issue is, and what she's willing to do to make it better. Because you can actually make the hyperandrogenism better by giving her nocturnal steroids. There's a downside to that. And she's a very sophisticated, well-educated person. We had these discussions, and she actually wanted to avoid glucocorticoids if possible. So I actually started her on a relatively wimpy dose of spironolactone. And the main reason is she's taking a mineralocorticoid, fludrocortisone. She was taking 0.1 twice a day. And now I'm initiating a mineralocorticoid receptor antagonist, but for the purpose of the antiandrogen effect. So we escalated to 50 milligrams. I would say the benefit was minimal several months later. We could have kept escalating it to a full dose. That might have helped. But after 10 months, we had a conversation. And she said she was willing to try nocturnal glucocorticoids. What we did was we shifted our strategy to what I consider another wimpy dose of nocturnal steroids. I just didn't want her to gain weight for a cosmetic issue if we could avoid it. So I said nocturnal hydrocortisone, 20 milligrams at night rather than a long-acting glucocorticoid. So in the middle column here on the left shows us where we started. And what I did on the right is changed her hydrocortisone, the nocturnal dose, from 5 to 20. So it's an extra 15 milligrams total for the day. But it's all coming at night. Everything else stayed the same. And actually, her morning 17-OHP was down to 271 nanograms per deciliter. Anderstein died on 30 nanograms per deciliter. And SHBG is still elevated. The hirsutism over the next several months improved. It didn't completely get better. But she was happy with it. What she wasn't happy about was the fact that she gained 5 pounds. She was relatively petite, so 5 pounds was a lot for her. So again, there's a balance between improving one thing and causing another problem. And your patient really needs to be involved in this decision making, so not an easy position to be in. We're going to circle back to all three of these cases. But I'm going to hand it over to Dr. Aukes now, who's going to walk us through all the potential therapies that we have and that we may have in the future so that we can come back to these clinical cases and discuss various options. Dr. Aukes. Thank you. So I think you can tell from the discussions that Dr. Spicer and Dr. Vaidya gave you that our current regimens don't work all that great and that there are a lot of problems with trying to get people in control and without the cushion going side effects. So I'm going to tell you about what we've been doing in the field to try to get a better approach going for this disease. Deborah Merck and I reviewed this topic recently. And if you think about it, as an endocrinologist, which we all are, is that there are actually a number of potential points of intervention in this disease. Because we know that the adrenal androgens are driven by the hypothalamic pituitary adrenal axis. So the hypothalamus releases CRH or CRF. And then that stimulates the pituitary to make corticotropin, ACTH, which then binds to its receptor on the adrenal gland. And then through a cascade of enzymes, missing 21-hydroxylase shunts the steroids to androgens. So we can block the production or the receptor for CRF. We can either neutralize or block the receptor for corticotropin. We can inhibit the enzymes that make androgens. We can try to reintroduce the enzyme with gene therapy. We can remove or try to destroy pharmacologically the adrenal glands. Or we can block the androgens, as Dr. Baija did in the last case. So let's see what's been done so far. Before we do that, I want to ask you how familiar are you with the merging treatments for CAH? OK, so half of you are not familiar. A quarter of you are slightly familiar. And the rest know something about this. OK, I guess that's why you're here tonight. So we'll go through this now. I'm going to talk about there are a couple others that have been tried, either not successfully or too early to say. But I'm going to talk about modified release hydrocortisone, DNL-0200, gene therapy, BBP-631, the P450-17A1 inhibitor, abiraterone acetate, and then the CRF receptor antagonist, NBI-77860, which is no longer in development, tildesafon, and crinesafon. And then I'll touch upon a few that are getting out of the gate now as well. So this is the modified release hydrocortisone, DNL-0200. This is currently approved by the European Medicines Agencies. And it's being developed in the United States. The phase three trial results, which were done largely in Europe but also at NIH under Dr. Merck, they did 24-hour sampling and compared patients taking either this modified release hydrocortisone or standard glucocorticoid therapy. And so what you can see is where this drug really excels is where the modified release formulation, it's enteric-coated. So the hydrocortisone isn't absorbed immediately. It has to get into the small intestine where these granules that are in a capsule then are able to dissolve under basic pH and then are absorbed in a more gradual way than the sharp peak that we get with the current oral hydrocortisone. And then a plateau of the peak, and then it comes down slowly afterwards. And so where this drug excels is in the early morning hours. So the bedtime dose actually gives you your morning replacement. So unlike the way we treat a patient with Addison's disease, where we give the biggest dose in the morning and a smaller dose in the afternoon, you actually give the biggest dose in the evening at bedtime to cover the morning rise of glucocorticoids and then a smaller dose in the morning to go through the afternoon. And so the 24-hour profiles of both 17-hydroxyprogesterone and androstenedione show almost no rise in the patients taking the modified release hydrocortisone, whereas that bedtime dose or late day dose of hydrocortisone, unless you give a large dose like Dr. Vaidya did in his last patient, don't really make it until morning. And so this modified release preparation was able to blunt that morning rise of the 17-hydroxyprogesterone and androstenedione. Now, you'll notice in the bottom where I've talked about the doses, the patients came in on about 25 milligrams a day, very similar to his patients. But by 24 weeks, they actually went up. They went up to 30 milligrams a day of either the immediate release or the modified release hydrocortisone in order to achieve this level of control. So that doesn't sound so good. But actually, over time, one point I want to make throughout all these new therapies is that once you get people in good control, it's easier to maintain them in control. Because remember, the disease is congenital adrenal hyperplasia. ACTH is not only tropic, but is also trophic to the adrenal cortex. And so there is growth of the adrenals that occurs under chronic ACTH stimulation. Once people are controlled well, there is atrophy of the gland. And you have less tissue to suppress. So over time, the investigators then were able to do whatever they wanted. And they relaxed the control. They let the 17-OHP go up a little bit. And they were actually able to come down over 1.5 to 2 years down to about 20 milligrams a day, which is not bad. Maybe still a little bit higher than physiologic, but pretty good. And they were able to actually still maintain the 17-hydroxyprogesterone control and androsine diione control reasonably well. OK, now the BBP631 is an adenovirus 5 system which delivers the human CYP21A2 or 21-hydroxylase gene through an adenovirus-mediated system. So what I'm showing you is data from mouse experiments where the viral particles were delivered systemically. You might think you might have to stick a catheter up into the adrenal arteries and squirt it in right there. But just giving it systemically, the virus was able to actually infect the adrenal and then drive the production of the human 21-hydroxylase gene in these mice. So this study is ongoing now. It's a phase one trial. There was a press release the other day that they're seeing some 21-hydroxylated steroids being produced in these patients. So there is some progress being made on gene delivery. And the unique aspect of this therapy would be that if people could have replacement therapy for the gene, that they would then not need glucocorticoid therapy at all if their cortisol production was truly normal. I think we're a little ways off from that, but there is progress being made. All right, so those are two possibilities. So if you then compare the axis and you think about suppressing, so the hypothalamic pituitary adrenal axis is trying to make cortisol. The enzyme block shifts the precursors to androgens. We've been using glucocorticoids to suppress the hypothalamic pituitary axis. Why not just block androgen production instead? And so we did that, actually. We added abiraterone acetate. So this is a drug that's used to treat prostate cancer because the enzyme P45017A1 that you can see on the left of the pathway going downward is the only enzyme that we have that can convert pregnenolone and progesterone onto androgens. And so the concept was in CAH, the block lowers androstenedione and cortisol production. The shunt with the curved arrow is over to androgens. If we add abiraterone to block that overflow, we can then remove the pathway and lower testosterone. So we did this study in six adult women with classic CAH who were taking a birth control pill. We used an escalating dose starting at 100 milligrams a day. In prostate cancer, 1,000 milligrams a day is used. And then we stopped the study at the second dose level because on day seven, everybody had a normal androstenedione below the dotted line on these curves. And you can see the percent reductions as well. You'll also notice that the last dose was given on day six. And after that last dose, the androstenedione levels came down very low, well into the normal range, in some cases undetectable. And it took in two days, the androstenedione still didn't even rise back to baseline because the drug is an irreversible inhibitor of the enzyme, meaning that it's conceivable that this drug doesn't need to be taken every day, as long as people were taking some glucocorticoid. And I'm not going to show you today, but there's parallel reduction seen in testosterone and urine androgens in this study, which we published about 10 years ago. Now it's hard to believe it was 10 years ago. And if you remember from Dr. Vaidya's slide, the adrenal in the CH patient is also making these 11 oxygenated androgens, in particular, 11-hydroxyandrostenedione, which is metabolized to 11-ketotestosterone. And if any of you were marine biology majors as an undergraduate, you would know that the bony fishes, the teleost fish, make actually 11-ketotestosterone, not testosterone, as their main androgen. And it is as effective at the androgen receptor, maybe 20% less than testosterone is. So we also looked at these 11 oxygenated androgens. And indeed, they decline as well, 11-ketotestosterone getting into the normal range in all patients at 250 milligrams a day. I just want to point out, you may have been wondering about the male patient that Dr. Vaidya presented, who had suppressed gonadotropins with a testosterone of 180. You might be asking, how can that be? That's because his 11-ketotestosterone is probably 10 times higher. And that's what's suppressing his gonadal axis. So don't be fooled when you're assessing men with CAH by measuring just the testosterone and being confused about why their gonadotropins might be suppressed with a lower normal testosterone level. All right, so then with this as a sort of proof of concept that we could use an alternative strategy, a non-glucocorticoid strategy to lower androgen production in this disease, we next study whether, instead of glucocorticoids, we could use something else to suppress ACTH production. And ACTH is driven by CRF from the hypothalamus, which binds to the type 1 receptor on the corticotropes. And that drives ACTH production, which in turn drives androgen production. And so many years ago, 20, 30 years ago, people started to develop antagonists of this receptor, which were originally developed to treat depression based on the phenotype of the knockout mouse. So what we did was repurpose these drugs that were already tried in phase 1 trials, and in some cases, even in phase 3 trials, to use in this disease. So I'm going to show you two drugs, Tildacifon and Cranesifon. So Tildacifon was studied in 14-day trial in adults at different dose levels. So across the top, you have different dose levels. And you see what happens to ACTH, 17-OHP, and androstenedione. And you see that the majority of the patients have quite a good lowering of these three biomarkers of the disease. And then that drug was then taken forward into a three-month study. And in people with poor disease control, the ACTH came down rapidly and stayed down. The 17-OHP bounced around a little bit, but by three months was down substantially. And the androstenedione gradually and somewhat linearly came down to the top of the normal range by three months of therapy, which again emphasizes the point I made before. Once you get people in good control, it's easier to keep them in good control. And then when the drug was stopped, the biomarkers came back up. So crinosophon was studied in phase two 14-day studies in adults and children. I'm going to walk you through the adult phase two crinosophon study next. So people, this was actually a pretty intense study because we had to take people, we brought them into the clinical research unit overnight and did 24-hour sampling for their baseline steroid production. And then they came in again on the first night they took a drug. And then finally, a third overnight sampling on the last day that they took the drug. We had four different cohorts, 50 milligrams once a day at bedtime, 100 milligrams at bedtime, or 100 milligrams with the evening meal, and then finally, 100 milligrams twice a day with the morning and evening meal. So the entry criteria was they had to have an elevated 17-hydroxyprogesterone greater than 1,000 nanograms per deciliter, a stable glucocorticoid dose. Dexamethasone use was excluded in this study because we wanted to really be able to see the decline in the biomarkers. And so the primary endpoints were 17-hydroxyprogesterone and ACTH, but we also measured androstenedione, testosterone, and a variety of other things. And so we had these four cohorts going into this study. So what did we find? Well, we found that at every dose level, there was 50% to 70% reductions in ACTH in 17-hydroxyprogesterone. And then with androstenedione, there was a dose-dependent reduction to about 64% of baseline with the highest dose of crinacerfone. What this means numerically is that ACTH went from several hundreds to generally 100 or less 17-hydroxyprogesterone from tens of thousands to a few thousand. And androstenedione, where the upper limit of normal is about 200 or so in most assays into the normal range in most of the participants. There was a smaller study done in children. And in children, you see again that morning rise. And I will point out that the morning dose of glucocorticoids in these overnight studies was held until after, in this case, until 10 o'clock in the morning. So we could really see what the drug was doing in the absence of glucocorticoid. Could the CRF antagonist still hold down the ACTH despite the absence of that morning cortisol dose? And indeed, the ACTH, 17-hydroxyprogesterone, and particularly the androstenedione were greatly flattened after 14 days of treatment in the pediatric cohort. Now, you might also be asking me, why am I not talking about testosterone? Well, testosterone is complicated because in the women, it makes sense. It's easy to interpret. But in the men, you want their testes to be able to make testosterone. So Dr. Vaidya's patient, when we intensified treatment, his testosterone went up because it was now being produced by his testes. So what we looked at is, as he alluded to earlier, the androstenedione-to-testosterone ratio. When that ratio is elevated, the testosterone is coming from the adrenals. When it's low, the testosterone is coming from the testes, which don't normally make androstenedione. So in the females in this study, the testosterone came down up to 75% in the female cohort. In the males, it actually didn't change. But the androstenedione-to-testosterone ratio went down as much as the testosterone went down in the females. And the only way that I can explain this is that these adolescents were starting to make testosterone from their testes, but I don't have direct evidence to that effect. So that led to the CATALYST studies, which I presented the results of the 3003 adult study yesterday. And Dr. Sarafoglu had a poster today on the results of the pediatric study, the 2006 study. The 3003 study was a phase three, randomized, double-blind, placebo-controlled trial, two-to-one chronesophon versus placebo for 24 weeks, followed by a crossover, which we did not present yet. The primary endpoint was met in this study. The primary endpoint was the percent glucocorticoid reduction at 24 weeks while androstenedione was maintained. The difference was 17% between the chronesophon and placebo groups. A secondary endpoint, a key secondary endpoint, was the androstenedione reduction at week four before we started to reduce the glucocorticoid dose. And that difference was 299 nanograms per deciliter, about a 50% reduction in the chronesophon group versus a rise in the placebo group. So the difference between the two groups was about 345 nanograms per deciliter. Baseline androstenediones were over 600 nanograms per deciliter, so over 50% difference in the two groups. And I already mentioned the difference in glucocorticoid reduction. The number of people who reached what we consider a physiologic dose of less than 11 milligrams per meter squared per day of hydrocortisone equivalent was 63% in the chronesophon group versus only 18% in the placebo group. Now, very similar design for the 2006 pediatric study for 24 weeks. Again, the glucocorticoid was kept constant for the first four weeks, and in this case, the primary endpoint was the reduction in androstenedione at week four. And that difference was 268 nanograms per deciliter. These children were in slightly better control than in the adult study, but again, about a 50% reduction in androstenedione by addition of chronesophon after four weeks. And then the glucocorticoid dose was reduced, secondary endpoint being glucocorticoid dose reduction, 18% reduction versus an actual rise in hydrocortisone dosing in the placebo arm. 30% reached a physiologic dose in the chronesophon group. Nobody in the placebo group was able to get down to physiologic. This drug was well-tolerated. Over 95% of participants finished the pediatric trial. Over 97% in the adult study finished the trial. So these people were really looking for something better than what they're being treated with now. So these papers are both now online in the New England Journal of Medicine. I encourage you to look at those now as they're publicly available. So we did do the abiraterone study. There is a trial that Perrin White and several of our colleagues started in children, which has been suspended because of issues with drug availability that's funded by the NIH. But that study did dose a few children. It was designed to be used in prepubertal children only. And then, as I mentioned, the diurnal studies have been completed in both the United States and in Europe. We're waiting for the data from the U.S. trial. Nevanamide, I didn't talk about. That study was completed, but the drug was not continued forward. Cronacephant and tildacephant, the studies are still ongoing, and some of the data have been released from those trials. BBP631 is still ongoing. And then the latest two studies, CRN04894 atumelanate has been started and is recruiting. And this LUAG13909, an anti-ACTH antibody, that study has been started and is recruiting now as well. All right, so that's where we are now, and I'll turn it back to Dr. Vijay to orchestrate the rest of the discussion. Thanks. All right. Great, so thanks, Rich, Dr. Ruckus. So I think what we'll do now is, Dr. Ruckus went through a whole series of potential therapies, and we'll just go through these cases that we went through. Not all of the therapies you mentioned are available or approved, but like us, I'm sure many members of the audience are excited at the potential of having access to these therapies in the near future and how that might change the way we approach our patients. So Dr. Spicer presented this case, and either of you can comment. This is an eight-year-old with precocious puberty, and you took us through his entire life through adolescence and the challenges he encountered. Given all the potential therapies that are coming down the pipeline, how would he be managed differently if you had access to some of these medications? Right, we've all had a lot of experience with hydrocortisone. That's still the gold standard, and I just want to emphasize that none of the adjunctive therapies that were spoken about just now have the potential to completely replace glucocorticoids, save for perhaps gene therapy, although so far, as I understand it, that may be a temporary fix, too, and it may have to be re-administered from time to time, and those gene therapy trials in the past have always been a little bit complicated and fraught with other side effects. So I think if we talk about ancillary medical treatments to reduce glucocorticoid dosing, I think the one that's in the lead so far and has been fast-tracked by FDA, although not yet approved so we can't prescribe, is Nesrfant, which, you know, in my experience as a participant in this trial, a couple of my patients did very well, and I should say that even though they may not have been as poorly controlled as some of the adult cases, they were in poor control, and one of my subjects had actually been lost to follow-up for a time, and so we all know that those types of patients are very, very difficult to get back under control. Once you get them in control, that's great, and I think overall, the pediatric participants in this trial had a very favorable response that you can be seen in the New England Journal preprints, and I think that that may be the way to go. That's not to say that we couldn't use a modified-release glucocorticoid to also even out their response to therapy with a glucocorticoid, maybe in a lower dose that had been used in the past. As far as I understand, the doses weren't particularly geared to children, so that will have to be worked out for the future, but I don't think that these are necessarily all either-or treatments. I think that we'll figure out over time how to use these in tandem or in combination to work things out and provide a better quality of life for all our patients. Okay. Phyllis, I was gonna ask you, in this, this child, unfortunately, wasn't picked up by newborn screening, so by the time he saw you, he was way behind the curve with an advanced bone age, so then at that point, you try to cool the things off, and you know that bone age is a lagging indicator, so how long would you wait until you decided that the conventional therapy wasn't working? Yeah, good question, and hard to know. You know, I think the lower age limit for the Cranester Pediatric Trial was two. I don't know how many kids went down to that lower age limit. From my perspective, you probably shouldn't wait until you get behind the eight ball. Once you realize that you're having difficulty achieving adrenal cortical control and your steroids are ranging high, consistently visit over visit, it's probably time to try something else, so whether that would be a modified release glucocorticoid in the future, whether it would be a CRH receptor antagonist, or either of those or both of those, that is going to show up in, I think, further studies, phase four studies, et cetera, but I think this is all very promising, and I just want to emphasize to the audience that this is the first time in 70 years that we've had any potential new drugs for the treatment of classic congenital adrenal hyperplasia, and these are randomized controlled trials, whereas some of the other things that have been tried ad hoc were never adequately tested in prospective randomized controlled trials, so this is very encouraging development. There was a question from the audience for you, Dr. Spicer, did you by any chance know what his newborn screen results were? Oh, so the child was apparently born outside the country and adopted, so we didn't get newborn screening, and that's one caveat, that not everybody gets newborn screening, especially if they're born in a lesser resourced country, or if for some reason they just sort of slip through the screen, and there are incidents of false negative results. So the second case we had discussed was a 35-year-old man who functionally felt well. His adrenal insufficiency was treated, but he had a very high 17-OHP, his androstenedione was high, his sperm count was very low, his total testosterone was low, gonadotropins were low, and we managed to fix all of this with nocturnal glucocorticoids and then induced a lot of weight gain. Given the options, Rich, do you have thoughts on what you think in an ideal world or an ideal future he might benefit from? Yeah, I think you would probably do exactly what you did initially, but then I wouldn't take him off the methylprednisolone without adding something else, because a lot of these new drugs, we don't have safety data for pregnancy, so it would just be the same if I was trying to get a woman pregnant, I would treat her with glucocorticoids, I would get her pregnant and through the pregnancy, and then rather than letting her go back into her prior poor control, I would try to add something to keep her in better control so the next time it wouldn't be so difficult. Yeah, yeah, the gene therapy is very exciting, I really want to see that there was sufficient cortisol production before even thinking about coming off glucocorticoids, but I take care of many patients with primary adrenal insufficiency without CAH, and though it has its caveats, in general, the management for most patients can result in a very good quality of life, so the possibility of reducing the supraphysiologic glucocorticoid dosing and replacing that control with something like a CRF inhibitor is very exciting, and we could have this guy live a very high quality of life with treatment of his adrenal insufficiency with another agent like a CRF inhibitor taking care of the risk for hyperandrogenemia and hypogonadism. From the natural history studies that have been done at the NIH and the CHASE study from the UK, these people have a lot of problems with osteoporosis and the metabolic syndrome and other things, and somewhat disproportionate to what you would expect to the total dose of glucocorticoid that they're getting, and I think that's a lot because of the non-physiologic way that we administer glucocorticoids to these patients, like three milligrams of methylprednisolone at bedtime. You would never give an Addison's disease patient three milligrams of methylprednisolone. You would never give them dexamethasone except for emergencies, so I think we're underestimating the problems with these late-night doses, and so I think other things like sleep quality and so on, we haven't even measured those yet, so I think people will tell you that they feel okay, they sleep okay, but then you say, how many cups of coffee do you take to get you up in the morning? So some people then, when you are able to eliminate these doses, people don't realize how badly they were doing beforehand. Okay, and then the third case we had talked about was a 29 or 30-year-old woman who's actually well-controlled clinically except for facial hirsutism. Her numbers weren't perfectly in range, but her main complaint was facial hirsutism, and in the end, tried a little bit of spironolactone, didn't go too high, but then ramped up a little bit of nocturnal hydrocortisone and got things, the numbers at least, into better control. How would you consider her management, either of you? Yeah, so I just wanna point out, when you look at her doses, her levels when she came in, from studies that Idina Turku's done, the 11-kilo testosterone in women is about three, four times higher than their testosterone. So this woman has a male level of androgens at that, and that's why she's having hirsutism. Now, fortunately, because she's on a birth control pill, her SHBG is nice and high, so that's buffering some of those androgens. But so she's, you know, it's not a surprise to me that she's having unwanted androgen excess signs. Now, I think you can do this in the short term, but this is not gonna be a good thing for her 30 years from now. So having evidence that what's actually, I mean, even that she's on, what, 30 milligrams a day, so she's on quite a lot. She said she was a small person. Yeah, that's a lot of glucocorticoids, so I would not want to leave her on that for the long run, especially if it causes unwanted androgen excess. If she's not trying to get pregnant, I would leave her on the birth control pill, because that's a freebie. You know, unless she has a contraindication, you just get that SHBG up nice and high, but this is not gonna be good for her in the long run. And if she does want to become pregnant, then, you know, as Rich said, you'd have to take her off the birth control pill. That's a no-brainer. But also, you'd probably want to be measuring her progesterone levels, because her endogenous progesterone, coming often from the adrenal cortex in the CAH patient female, would be acting as a mini pill, actually, and not doing good things for her potential fertility, too. And out of curiosity, when you do use spironolactone, what types of doses do you use on patients who are already on flutricortisone? I don't use spironolactone. I use bicalutamide, actually, if I'm gonna use an anti... I use spironolactone in non-classic patients who don't want to take glucocorticoids, and who are not mineralocorticoid deficient. But you can, and I have had some people come to me who are already taking it, and I usually just have to... I put them on whatever dose of spironolactone I think they need, and then I have to raise their flutricortisone dose. And in some cases, you can manage that. In other cases, you can't. But I generally try to avoid that problem. And many of the newer OCPs also have an antiandrogenic receptor effect. So you have that built in, in a way. I don't think small doses of spironolactone would add very much. Yeah, the drosperinone doses, though, are relatively on the smaller side. They are in the combination pills, unless they're using the drosperinone monotherapy. And do you ever have, when you use androgen receptor antagonists, issues with approval, payment? No, not with bicalutamide, because it's actually pretty cheap now. I don't use flutamide, because it has a lot of GI toxicities but bicalutamide is generic now. If they have to pay for it out of pocket, it's not that bad. So with that, I want to thank our faculty speakers, Dr. Aukes and Dr. Spicer. I hope you had a great evening and learned a lot, because we did, too. Thank you so much.

congenital adrenal hyperplasia

CAH treatment advancements

modified release hydrocortisone

gene therapy for CAH

CRF antagonists for CAH

anti-adrenal androgens therapy

CRF inhibitors for CAH

glucocorticoid therapy challenges

pediatric CAH cases

adult CAH cases