HCP Education Portal

Patricia Stark: [00:00:17] Well. Good evening. I’m Patricia Stark, the host for tonight’s broadcast. I’d like to welcome you to the live presentation of Advancing Care in Classic Congenital Adrenal Hyperplasia (CAH): Study Insights from Catalyst Adult. This evening’s broadcast is sponsored by Neurocrine Biosciences and presented by Dr. Richard Joseph Auchus, professor of pharmacology and internal medicine at the University of Michigan Medical School. So let’s get started. Here’s Dr. Auchus.

Richard Joseph Auchus, M.D., Ph.D.: [00:00:47] Well, thank you Patricia. Good evening, everyone, and thanks for joining. Congenital adrenal hyperplasia, or CAH, is a rare autosomal recessive disorder. Worldwide, the incidence of classic CAH is about 1 in 14 to 18,000 live births. Most commonly, the disease is due to a deficiency of the enzyme 21 hydroxylase, about 95 percent of cases. This is an enzyme that’s required for the biosynthesis of both cortisol and aldosterone. Now, the loss of, or attenuated cortisol mediated negative feedback that the body normally has allows for excessive CRF drive from the hypothalamus corticotropin-releasing factor, and that drives excessive ACTH secretion from the pituitary. And this ACTH leads to the enlargement of the adrenal and to excessive production of cortisol precursors, which are metabolized onto the only pathway left, which is to androgens. So it is congenital. It’s a genetic defect. It involves the adrenal specifically in the cortisol pathway. And there is hyperplasia as a result of the lack of cortisol and the elevated ACTH.

[00:02:03] Now in 21 hydroxylase specifically, the defect in that enzyme then causes an increase in the steroids in orange, primarily 17 hydroxy progesterone or 17-OHP, which is then converted to androstenedione and further down to testosterone inactive androgen. In addition, upstream of 17-OHP, progesterone accumulates and this also causes reproductive problems, particularly in the adult females with 21 hydroxylase deficiency. And of course, downstream of the block in blue, there is deficient cortisol production, and when the block is complete or nearly complete, deficient aldosterone production.

[00:02:46] Now patients with CAH and their families face multiple challenges and comorbidities throughout their lifetime. Because of the cortisol deficiency, there is a risk of adrenal crisis with intercurrent illness throughout lifetime, particularly in infancy. In fact, babies can have salt wasting adrenal crisis even when they’re not sick because of the severe deficiency in cortisol and aldosterone. They also experience poor feeding, poor weight gain, and the girls have atypical genitalia at birth because of the androgen excess in fetal life.

[00:03:22] Throughout childhood, the adrenal androgens can drive accelerated growth and advancement of the Bone Age, which leads to early fusion of the growth plates and short stature in adulthood. They can also have poor growth because of the exposure to the typical doses of glucocorticoids required to control the androgen excess, and they can also have problems with puberty, either early puberty or delayed puberty as a result of the dysregulation of the adrenal hormones and the cortisol treatment that they receive.

[00:03:56] Now in adulthood, the problems with the pubertal axis continue, and fertility impairment is common in both men and women with classical CAH. They also have a high prevalence of mood disorders, possibly from the chronic treatment with high doses of glucocorticoids, and those glucocorticoids can also cause osteopenia and osteoporosis. We already talked about the reduced adult stature and increased cardiovascular risk. The second most common cause of death in patients with CAH is cardiovascular disease behind adrenal crises. The women suffer from hirsutism, acne, irregular menses, and polycystic ovaries, all related to the androgen and progesterone excess, and the males also have fertility problems, both from suppression of the gonadal axis but also from the development of testicular adrenal rest tumors in their testes.

[00:04:56] So 60, 70 years ago, Lawson Wilkins decided that he could treat congenital adrenal hyperplasia with glucocorticoids. But there’s two purposes of this cortisol treatment. So one is to replace the cortisol deficiency. And the daily cortisol production rate is about 7mg/m² per day. And a dose of about that much is required to replace that deficiency. But you also use the glucocorticoids to suppress the ACTH and the adrenal androgen production, and this requires significantly more glucocorticoids. I think the way that I think about this is that the normal cortisol production is micrograms per deciliter, whereas androgens are ng/dl. So you really have to suppress the adrenal steroid production substantially to get the androgens down to what’s normal, particularly in children’s where they make very little androgens, or none. So, so then it becomes a difficult balancing act, particularly throughout childhood of titrating the glucocorticoid dose. Too little glucocorticoid and the androgens rise and advance the bone age. Too much glucocorticoid and the child doesn’t grow well, even though the androgens are controlled. So this is challenging.

[00:06:20] Now in addition, mineralocorticoid replacement therapy is required, and we use fludrocortisone acetate to replace the aldosterone deficiency in the majority of patients with classic CAH. But it is a difficult balancing act, and you can think of patients being in four quadrants. And we want to have patients in the one quadrant where their androgens are at goal with a physiologic dose of glucocorticoids. Now unfortunately this is the minority of patients. There’s only a handful of people that I know of that can have androgens at goal with a physiologic dose of glucocorticoids.

[00:06:55] You can also imagine two other groups. Either the androgens are at goal, but it requires supraphysiologic glucocorticoids to suppress those androgens. Or the androgens are not at goal, but they’re on a lower dose of glucocorticoids that can be considered physiologic. And finally, unfortunately, there are a lot of people who have the worst of all situations, which are the androgens not being at goal and the glucocorticoid dose is still supraphysiologic. So despite that super physiologic dose, we can’t get their disease under control.

[00:06:25] And furthermore, patients can oscillate between these various states throughout their life. And so what this illustrates is the failure of traditional glucocorticoid-only therapy to consistently manage patients, both to prevent the long-term complications of glucocorticoid therapy and to keep their androgens under control for their long-term health outcomes.

[00:07:50] Now, I and my colleagues have been working for some time now to come up with other treatments that are not glucocorticoids to control this disease. And so one strategy is using crinecerfont, which is a potent and selective antagonist of the corticotropin-releasing factor type one receptor or the CRF1 receptor, which is the receptor that’s expressed on the cells in the anterior pituitary gland that make ACTH. So in the normal state, what’s shown here on, on the left is the hypothalamus produces a normal amount of CRF, which binds to its receptors on the anterior pituitary gland and produces a normal amount of ACTH, which leads to a small amount of systemic androgens coming from the adrenal gland. In the CAH patient with the loss of negative feedback, then there is excessive drive, the hypothalamus makes more CRF. That drives the pituitary to make more ACTH, and then there’s an excess of adrenal androgens produced.

[00:08:59] Now crinecerfont binds to that CRF1 receptor in a noncompetitive manner with CRF and it prevents the action of CRF on that receptor. And that reduces the amount of ACTH that’s produced from the same amount of CRF, and therefore reduces the amount of androgens that the adrenal makes. So we hypothesize that reduced androgen production through CRF antagonism might enable glucocorticoid dose reduction to more physiologic levels while maintaining control of the disease.

[00:09:37] Now based on the work I’m going to show you, Crenessity or crinecerfont, was approved by the FDA, and it is indicated as an adjunctive treatment to glucocorticoid replacement to control androgens in adults and pediatric patients four years of age and older with classic congenital adrenal hyperplasia. The contraindication is that Crenessity is contraindicated in patients with hypersensitivity to crinecerfont, or to any of the excipients in Crenessity. So now I’m going to show you the data that led to this approval of Crenessity.

[00:10:17] So the adult study was called the CAHtalyst Adult Study. Not surprisingly, the pediatric study was the CAHtalyst Pediatric study, and it involved a protocolized glucocorticoid dose reduction. So this was a complicated study that involved 24 weeks with a randomized, double-blind, placebo-controlled, multicenter, phase three trial. We started with patients who were taking a glucocorticoid dose that was high. It was at least 13mg/m² per day, which is above the normal cortisol production rate plus two standard deviations. And their androstenedione levels had to be not suppressed. So this is depicted by the red and the yellow balloons, respectively.

[00:11:02] Now what we first did, they came into the study on a variety of, of glucocorticoid regimens, some hydrocortisone, some prednisone. And we left that glucocorticoid dose constant for four weeks and added either Crenessity or placebo to the patients. And we saw what that did to the androstenedione, which was our primary biomarker to demonstrate reduction of adrenal androgens by Crenessity. So that was done for four weeks. And that was a key secondary endpoint, the reduction in androstenedione in the crinecerfont group compared to placebo. We also looked at 17 hydroxy progesterone change from baseline at four weeks. But again this was where the glucocorticoid dose was kept whatever they came into the trial on.

[00:11:55] Then we dropped the glucocorticoid dose. So that’s the red balloon going down. And we allowed the androstenedione to come up, but we tried to keep it below or at baseline compared to day one. So we would let the androstenedione drift back up but that was at the expense of reducing the glucocorticoid dose. So the primary endpoint for this study was the glucocorticoid dose reduction, the change from baseline at week 24 as long- provided that the androstenedione was kept at or below baseline. There was a key secondary endpoint, which was the percent of patients who reached the physiologic range of glucocorticoid dosing, which was defined as 11mg/m² per day, which is the median plus two standard deviations of cortisol production in normal individuals.

[00:12:48] Okay. So three phases to this trial. So hypothesis one was that crinecerfont addition will reduce androstenedione. And hypothesis two is that that reduction will allow for reduction in glucocorticoid dose. And that glucocorticoid dose reduction was done over a very short time, over eight weeks. So every two weeks, people could have a reduction in their in their glucocorticoid dose from whatever they came in the trial on with the goal of getting it down to 8 to 10mg/m² per day. So a very steep reduction in four steps or less.

[00:13:28] And then in the following 12 weeks, before the primary endpoint time at week 24, if the androstenedione was higher than baseline, we could raise the glucocorticoid dose to optimize glucocorticoid therapy. And the prediction would be that the crinecerfont group would keep the glucocorticoid dose down, but the placebo group would have to go up. After that, the placebo arm was crossed over to receive Crenessity, and after a year, there was an open-label extension phase where patients could continue. So at the bottom, I’m showing you, hypothetically, what we expect to see that the androstenedione levels during the first four weeks when the glucocorticoid dose was kept constant would drop in the crinecerfont group, but not the placebo group. And then we would reduce the glucocorticoids on a schedule in both groups and the androstenedione would come up somewhat. And then we would adjust that dose over the following 12 weeks to keep the androstenedione below baseline and see how low the glucocorticoids got.

[00:14:35] Okay. So 182 adult participants were enrolled in this study. The key inclusion criteria were a confirmed diagnosis of classic 21 hydroxylase deficiency, the supraphysiologic glucocorticoid dose of greater than 13mg/m² of hydrocortisone dose equivalent, with conversion factors for people taking prednisone, prednisolone, and dexamethasone. They had to be on that regimen for a stable one-month period of time. The key exclusion criteria were some other condition other than CAH that required long-term glucocorticoid treatments such as psoriasis, known or suspected diagnosis of some other form of classic CAH, and evidence of substantial glucocorticoid overtreatment, meaning that their androstenedione was below the normal range, below the lower limit of the normal range on screening.

[00:15:33] So the two groups that received Crenessity or placebo were well matched, 222 received Crenessity, 60 received placebo. About half of them were women. Their average age was about 30. They were overweight, with an average body mass of 80kg. Their average glucocorticoid daily dose was 17 to 18mg/m² per day, which equals about 32 mg total per day. So it’s about twice physiologic. About 60 percent were receiving hydrocortisone alone. Another 30 percent were receiving other glucocorticoids with or without hydrocortisone, and 10 to 15 percent were receiving dexamethasone with or without another drug. Now, in this laboratory, the mean androstenedione, the upper limit of normal, was about 200 ng/dl. And the study participants were about 600 ng/dl. So about three times the upper limit of normal. And the 17 hydroxyprogesterone was 9 to 10,000. So these people are in that fourth quadrant, largely. These are people who are in poor control despite a high dose of glucocorticoids.

[00:16:44] Alright, furthermore, about two-thirds of the men had testicular adrenal rest tumors. About half or more of the women had menstrual irregularities. There was a high percentage of women that had hirsutism and acne. There was a high percentage of people who had anxiety and depression and other mood disorders and complications that we think of in older people; osteopenia, hypertension, hyperlipidemia, osteoporosis, were significantly prevalent in this group at an average age of 30 years old, so not doing very well.

[00:17:17] So let me review the efficacy in the CAHtalyst Adult Study with this protocolized glucocorticoid dose reduction. So again, hypothesis one that was tested in the first four weeks while we held the glucocorticoid dose constant, was that in a placebo-controlled setting, we could show that Crenessity reduced the adrenal androgens better than placebo. Now, I will say that there is a warning that a hypersensitivity reaction, including throat tightness, angioedema a generalized rash, occurred in a subject after three days treatment with Crenessity. So therefore, if a clinically significant hypersensitivity reaction occurs, you should initiate appropriate therapy and discontinue Crenessity.

[00:18:05] Alright, so in the first four weeks we saw a- basically a 300 ng/dl, or a 50 percent reduction in androstenedione in the Crenessity group. No change or a slight rise in androstenedione in the placebo arm. And that equated to a least squared mean difference at week four of -345 ng/dl in the Crenessity arm versus placebo, which was highly statistically significant. In parallel, we saw a reduction of 17 hydroxyprogesterone of about 6000 ng/dl, minimal change in placebo. So the least squared mean difference was almost 6000 ng/dl, also significant.

[00:18:53] Okay. So now we’ve done hypothesis one. So hypothesis two was to show that we could reduce the glucocorticoid dose and keep that androstenedione from rising back to above baseline. So from week 4 to week 12 every two weeks, we made a dose reduction to a target of 8 to 10mg/m² per day, and then went back up as necessary in the following 12 weeks to the endpoint, the primary endpoint at week 24, which was the reduction in glucocorticoid dosing. So the study goal was to hit at least 11mg/m² per day or less, while maintaining that androstenedione at baseline or better in those with that glucocorticoid reduction of four steps and that maintenance- that optimization phase to week 24.

[00:19:48] Now, importantly, what I want to emphasize is that we tried to decrease the most nonphysiologic dose and type of glucocorticoid first. So for example, if someone was taking dexamethasone, which is very nonphysiologic, we would try to switch them to prednisone or hydrocortisone. If they were taking a bedtime dose of prednisolone with hydrocortisone during the day, the first thing we would do is try to stop the bedtime prednisolone. Those are the doses that are best for controlling the androgens, but they are the most toxic and the least physiologic. So we actually use the strategy that would work against our achieving the primary endpoint and to see what we could accomplish with crinecerfont.

[00:20:35] Now as we did this study, it’s important to recognize that the risk of acute adrenal insufficiency or adrenal crisis with inadequate concomitant glucocorticoid therapy persists. So acute adrenal insufficiency or adrenal crisis, which is potentially life threatening, can occur in patients with underlying adrenal insufficiency who are taking inadequate daily glucocorticoid doses, especially in situations associated with increased cortisol need, such as acute intermittent illness, serious trauma, or surgical procedures. Continue glucocorticoids upon initiation of and during treatment with Crenessity. Do not reduce the glucocorticoid dose below the dose required for cortisol replacement. Patients should continue to use stress dose glucocorticoids in case of increased cortisol need. So in the trial we never dropped the dose to less than physiologic. And we always kept people informed of what their stress dosing regimen was, which did change during the trial as we reduced the glucocorticoid dose for day-to-day treatment.

[00:21:45] Okay, now we were supposed to keep the androstenedione at or below baseline by week 24. And we succeeded in doing this in the Crenessity group. But the placebo group actually rose another 388 ng/dl. Now, the participants in this trial were trying to get their glucocorticoid dose reduced. The investigators were hoping to reduce the glucocorticoid, so there was some reluctance in going back up on the glucocorticoid dose in the placebo group. And that’s something to bear in mind. Now, there was a statistical penalty applied to this. But, but I want you to bear this in mind when we go through the primary endpoint.

[00:22:30] So despite what I just showed you, the reduction in glucocorticoid dose was greater with crinecerfont than with placebo. A 28.1 percent reduction with Crenessity, which is about a nine milligram per day hydrocortisone dose reduction versus 11.6 percent with placebo. And you can see that the nadir was at week 12 in placebo and it drifted back up, whereas the dose was kept down from weeks 12 to week 24 with Crenessity. So the least squared mean dose reduction of glucocorticoids of the Crenessity group versus placebo was 17 percent, and that was the highly statistically significant and the primary endpoint was met.

[00:23:19] So the percentage of patients that achieve that less than 11mg/m² per day in the crinecerfont group was 63 percent. You can see that it was quite stable from week 12 to week 24, and it peaked at week 12 in the placebo group and gradually drifted back down. And it was only 18 percent at the end of the study. This was also statistically significant.

[00:23:43] So we demonstrated efficacy across two distinct and critical aspects of CAH management. First was the androgen reduction that Crenessity significantly reduced androstenedione at week four and concurrently reduced 17 hydroxyprogesterone while holding the glucocorticoid dose stable. And then after that, we reduced the glucocorticoid dose Crenessity significantly, allowed reduction of glucocorticoid daily dosing at week 24, while maintaining or improving androstenedione relative to the baseline. 63 percent of participants on Crenessity were able to achieve a physiologic glucocorticoid dose by week 12, versus 18 percent on placebo.

[00:24:25] I want to go through the safety data now, and the most important thing to know about safety is that in adult patients, the most common adverse reactions that occurred in at least 4 percent for Crenessity and greater than placebo are fatigue, headache, dizziness, arthralgias, back pain, decreased appetite, and myalgias.

[0024:47] About 80 percent of the participants in both arms experienced any treatment emergent adverse event. There were four serious adverse events in the Crenessity group, none in the placebo, and none of those serious adverse events were judged being related to the study drug. There were four adverse events that led to study drug discontinuation in the Crenessity group. Most of the adverse events were either mild or moderate and resolved spontaneously.

[00:25:20] This is comparing the adverse event profile in patients treated with Crenessity versus placebo. And as I mentioned before, fatigue, headache, dizziness, arthralgias, back pain, decreased appetite, and myalgias. Many of these are the same things that we see with the glucocorticoid withdrawal syndrome, and could be related to the glucocorticoid dose reduction in both the Crenessity and placebo groups. The, the- there were no safety concerns related to vital signs, clinical laboratory tests, electrocardiographic findings, or neuropsychiatric assessments with Crenessity in the phase three trial.

[00:26:00] I think this is one of the most telling statistics about the study. 96 percent of the adults participants completed the 24-week, double-blind, placebo-controlled period of the phase two trial with 117 of 122 whether they were on the drug or placebo. And I think that is a testament to how dedicated these patients were to getting a new drug approved, how desperate the community is for seeing better treatment, and how motivated the investigators are to getting a new treatment for this vexing disease. A total of 3 percent of Crenessity treated subjects and no placebo treated subjects discontinued because of adverse reactions which were restlessness, apathy, dyspepsia, nausea, and vomiting. 174 of the 182 adult participants continued on after a whole year into the open-label extension, and several of them are still in the open-label extension now. 1.6 percent of patients taking Crenessity experienced an adrenal crisis. No patients in the placebo arm experienced an adrenal crisis, however, 1.7 percent experienced adrenal insufficiency. So it’s important for you to talk with your patients about the importance of continuing glucocorticoid dosing while taking Crenessity and have a plan for glucocorticoid stress dosing and for rescue parenteral hydrocortisone injection.

[00:27:30] In pediatric patients, the most common adverse reactions are headache, abdominal pain, fatigue, nasal congestion, and epistaxis. You are encouraged to report negative side effects of all prescription drugs to the FDA. Visit MedWatch at FDA.gov/MedWatch, or call 1-800-FDA-1088.

[00:27:53] So, to summarize, Crenessity reduces androstenedione levels and enables a reduced glucocorticoid dose while maintaining or improving androstenedione levels in adult patients with CAH. As a novel mechanism of action by selectively blocking the function of CRF1, Crenessity directly reduces ACTH and the downstream production of adrenal androgens. Proven efficacy in this phase three trial, Crenessity enables significantly reduced glucocorticoid daily dose while maintaining or improving androstenedione levels in adult patients with CAH. Crenessity significantly reduced androstenedione at week four and concurrently reduced 17 hydroxyprogesterone, while glucocorticoid doses remain unchanged. And safety, the most common adverse reactions in adults are fatigue, headache, dizziness, arthralgias, back pain, decreased appetite, and myalgias.

[00:28:49] Dosing is pretty simple. The drug is taken twice, twice a day with a morning and evening meal. Crenessity must be taken with a meal. You shouldn’t take it with a cup of black coffee. So, morning and evening meal. It’s available as capsules or an oral solution for children. The capsules should be swallowed whole with liquid and not chewed. The oral solution should be taken with an oral syringe for precise dosing. Do not reduce the glucocorticoid dose below the dose required to replace the cortisol deficiency.

[00:29:23] Dosing considerations, the only one is that Crenessity is a CYP3A4 substrate, and so concomitant use with a strong or moderate CYP3A4 inducer will decrease Crenessity exposure, which may reduce its efficacy. So in patients who are taking a strong 3A4 inducer, something like phenytoin or rifampin, you should increase both the morning and evening dosages twofold. Whereas if they’re taking a moderate CYP3A4 inducer, you should only double the evening dose. And so the dose is in adults 18 and older and in children weighing greater than 121 pounds, 100 mg twice daily, for a total of 200 mg a day. For children weighing 44 to 121 pounds, the dose is 50 mg twice daily. And for children weighing 22 to 44 pounds, the dose is 25 mg twice daily. The Crenessity is available in both 50 and 100 mg capsules, and as an oral solution of 50 mg/mL. There is no dosage change with concomitant CYP3A4 substrates, only with CYP3A4 inducers.

Patricia Stark: [00:30:35] We hope that you thoroughly enjoyed this evening’s broadcast. On behalf of Neurocrine Biosciences, I’m Patricia Stark, and thanks so much again. Have a great night.

Patricia Stark: [00:00:22] Good afternoon. I’m Patricia Stark, the host for this afternoon’s broadcast. I’d like to welcome you to the live presentation of Advancing Care in Classic Congenital Adrenal Hyperplasia, CAH: Study Insights from CAHtalyst Pediatric: Androgen and GC Dose Reduction. This afternoon’s broadcast is sponsored by Neurocrine Biosciences and presented by Dr. Kiki Sarafoglou, Professor of Pediatric Endocrinology and Pediatric Genetics and Metabolism at the University of Minnesota. Let’s get started. Here’s Dr. Sarafoglou.

Kyriakie Sarafoglou, M.D.: [00:00:58] Thank you for the introduction, and thank you, everyone, for joining the Congenital Adrenal Hyperplasia webinar. CAH is a rare autosomal recessive disorder with a worldwide estimated incidence of 1 in 14 to 1 in 18,000 live births. Approximately 95 percent of classic CAH cases are due to a deficiency of the 21-hydroxylase enzyme, which is an adrenal-specific enzyme required for cortisol and androsterone synthesis. Normally, there is a negative feedback inhibition between cortisol and both hypothalamic corticotropin-releasing factor and pituitary hormone ACTH. In CAH, because of cortisol deficiency, there is attenuation of cortisol-mediated negative feedback, which allows for excessive CRF drive from the hypothalamus, leading to increased ACTH secretion. Now, increase ACTH stimulation results in enlargement of the adrenal glands and production of cortisol precursors, which are then metabolized to the only pathway left, which is the androgen pathway.

[00:02:16] Now, in 21-hydroxylases specifically, the defect in this enzyme causes an increase in the steroids, primarily 17-hydroxyprogesterone, which is then converted to androstenedione and further down to testosterone. In addition, upstream of 17-OHP, progesterone accumulates, which can cause reproductive problems, especially in adult females with 21-hydroxylase deficiency. Downstream of the block in blue, there is deficient cortisol production. When the block is complete or nearly complete, there is deficient androsterone production, too.

[00:03:06] Patients with CAH face multiple comorbidities because of the disease and its treatment throughout their lives. So, CAH patients are at risk of adrenal crisis across their lifespan, which can be triggered by physical stress due to illness, trauma, or surgery. Infants with CAH are at the highest risk of salt-wasting and adrenal crisis, as they are most susceptible to intercurrent illnesses. Other presenting symptoms during infancy could be poor feeding, poor weight gain, and poor growth, which can be sign of inadequate glucocorticoid therapy. Now, on the other hand, glucocorticoid excess can lead to growth failure, weight gain, and early adiposity rebound, which sets the ground for increased comorbidities during adulthood, such as obesity, metabolic syndrome, and cardiovascular disease.

[00:04:07] During childhood, androgen excess can result in growth acceleration, visualization of the external genitalia, early development of pubic hair, precocious puberty, and advanced bone maturation, which can eventually lead to early growth plate fusion and, ultimately, short adult stature. Now, in order to suppress androgen excess, high glucocorticoid doses are typically used, which can lead to growth failure, decreased puberty growth spurt, and ultimately, again, short adult stature.

[00:04:45] In adulthood, both androgen access or glucocorticoid access can lead to impaired hypothalamic-pituitary gonadal axis and secondary hypogonadism and fertility impairment in both men and women. Also, chronic elevation of ACTH due to poor disease control can lead to the development of TARTS, also known as testicular adrenal rest tumors, which can develop as early as early as seven years of age. TARTS can lead to both decreased spermatogenesis and decreased testicular testosterone production. Females can also have adrenalized tumors in their ovaries, but it’s difficult to visualize them with a pelvic ultrasound. Other symptoms seen in females with CAH are acne, irregular menses, polycystic ovaries, and infertility, which are all related to androgen and progesterone excess.

[00:05:45] Now, chronic glucocorticoid excess can relate to osteopenia and osteoporosis. And may play a role in the high prevalence of mood disorders frequently encountered. In addition, adult patients with CAH are at an increased risk for cardiovascular disease and metabolic syndrome. Cardiovascular disease is the second most common cause of death behind adrenal crisis.

[00:06:15] Over the last 70 years, glucocorticoids have been the only option to treat CAH. Now, what is important to keep in mind is that glucocorticoid therapy serves two important functions in the treatment of CAH. Its first function is to replace deficient cortisol, as cortisol plays an important role in glucose and blood pressure regulation, immune function, sleep, mood regulation. In unaffected individuals, endogenous cortisol production ranges between 5 and 11 milligrams per meter square per day, with a mean of 7 milligrams per meter square per day. Now, the wide range is due to many factors such as weight, age, sex, puberty status, and variability of cortisone pharmacokinetics and glucocorticoid receptor sensitivity among individuals, just to name a few.

[00:07:17] Now, glucocorticoid therapy’s second function is to reduce ACTH-driven excess adrenal androgen production. And the ongoing challenge in treating patients with CAH is balancing excess androgens against the impact of chronic high-dose glucocorticoid therapy.

[00:07:40] Now, in broad terms, patients with CAH can be categorized into four quadrants based on their glucocorticoid dosing and their adrenal androgen response to glucocorticoid therapy. One quadrant has patients whose androgen are at goal with physiologic glucocorticoid dosing, which unfortunately does not represent the majority of patients with CAH. Another quadrant. Patients whose androgen are at goal but they require supraphysiologic glucocorticoid doses to suppress their androgens. A third quadrant has patients with the worst of all situations where androgens are not at goal, while the glucocorticoid dosing is supraphysiologic. And the fourth quadrant has patients whose androgens are not at goal while on physiologic glucocorticoid dosing.

[00:08:40] Typically, patients do not remain in one quadrant but oscillate between the various quadrants throughout their life. What this illustrates is the current glucocorticoid therapy is suboptimal and underscores the need of better treatment options to keep androgens under control and prevent chronic over-exposure to glucocorticoids.

[00:09:07] A new treatment option that has recently become available is crinecerfront. A corticotropic-releasing factor-one antagonist. Normally, the hypothalamic-pituitary-adrenal axis drives teratogenesis through binding of the hypothalamic CRF1 to its type-one receptor on corticotropes in the anterior pituitary. This, in turn, stimulates ACTH release and, subsequently, adrenal androgen production. As I mentioned earlier, in CAH, because of cortisol deficiency, there is attenuation of cortisol-mediated negative feedback, which allows for excessive CRF drive and ACTH secretion. In turn, increased ACTH stimulation drives excessive adrenal androgen production.

[00:10:01] Crinecerfront binds to the CRF1 receptor and, in a non-competitive manner, prevents the CRF1 from binding to the CRF receptor on the pituitary, leading to reduction of pituitary ACTH secretion. Less ACTH means less stimulation of the adrenal glands and a subsequent decrease in downstream adrenal androgen production. A decrease in androgen secretion could allow for glucocorticoid dose reductions to more physiological levels and circadian dosing in patients with CAH while maintaining control of their disease. Normally, cortisol is secreted in a classic circadian pattern. Cortisol is at its lowest levels at midnight, then begins to rise and peak overnight in the early morning hours and gradually decrease throughout the day. Instead, the highest dose can be given in the morning when the kids are the most active, and the lowest hydrocortisone dose in the evening for better growth and sleep outcomes. High hydrocortisone doses in the evening can interfere with growth hormone secretion and impairs sleep by increasing the time that it takes the child to fall asleep.

[00:11:30] Based on the results of the clinical trial that I will present it to you shortly, Crenessity was approved by the FDA as a non-steroidal adjunct therapy to glucocorticoid replacement to control androgen in adults and pediatric patients four years of age and older with classic congenital adrenal hyperplasia. Crenessity is contraindicated in patients with hypersensitivity to crinecerfront or any excipients of Crenessity.

[00:12:05] Now, I’m going to discuss the data from the pediatric trial that led to the FDA approval of Crenessity. The CAHtalyst Pediatric Trial was conducted at 37 centers in the United States, Canada, and Europe. The objective of the CAHtalyst Pediatric Study was to evaluate the safety and efficacy of twice-a-day Crenessity. The study was designed as a Phase Three Multicenter Trial with a 28-week, randomized, double-blind, placebo-controlled treatment period.

[00:12:42] The baseline glucocorticoid and androstenedione levels of the participants are represented by the purple and yellow balloons. Participants were randomized to receive Crenessity or placebo and remain on the same glucocorticoid dose for four weeks. By keeping the participants on a stable glucocorticoid dose for four weeks, any reduction in androstenedione levels, which was the primary endpoint of the study, would be a direct result of the action of Crenessity. A key secondary endpoint, not shown here, was the change in serum 17-hydroxyprogesterone level from baseline to week four. All androstenedione and 17-hydroxyprogesterone measurements were performed prior to morning glucocorticoid dose.

[00:13:35] From week 4 to week 28, glucocorticoid doses were decreased stepwise to a target daily dose of less than 11 milligrams per meter square per day of hydrocortisone dose equivalents with the goal of achieving the lowest glucocorticoid dose by week 28 while maintaining androstenedione at levels similar to or better than baseline. The percent of glucocorticoid change from baseline to week 28 was a key secondary endpoint.

[00:14:10] On day one, patients were randomly assigned in a two-to-one ratio to receive Crenessity or placebo twice daily with morning and evening meals. The amount of the Crenessity dose was based on weight. Children weighing between 10 kilos to less than 20 kilos received 25 milligrams of Crenessity twice daily. Children weighing between 20 kilos to less than 55 kilos receive 50 milligrams twice daily. And children weighing equal or more than 55 kilos receive 100 milligrams twice a day.

[00:14:54] Hypothesis one was that during the 4-week stable glucocorticoid period, the addition of Crenessity would reduce androstenedione levels, but they would remain the same in the placebo group. Hypothesis two was that during the 24-week gradual glucocorticoid dose reduction period, the Crenessity group would be able to reduce glucocorticoid dosing at week 28 while androstenedione was maintained or improved relative to day one baseline. Whereas the placebo group would have no deduction in glucocorticoid dosing. In the pediatric clinical trial, because of the negative impact that rapid glucocorticoid dose reduction could have on growth and skeletal maturation in children, glucocorticoid dose reduction was gradually, adjusting every four weeks in one to four steps to a target dose of 8 to 10 milligrams per meter square per day in hydrocortisone equivalence, provided that androstenedione level was maintained or improve relative to day one baseline values. Blood samples were collected before the morning glucocorticoid dose at the end of every four weeks. Now, after the 24-week dose reduction period, the participants in the placebo crossover to receive Crenessity for a 24-week open-label treatment period.

[00:16:30] This was followed by open-label extension period. 100 pediatric participants completed the pediatric trial. The key inclusive criteria were a confirmed diagnosis of congenital adrenal hyperplasia in children age 2 to 17 years of age. All participants had to be on a total daily hydrocortisone or hydrocortisone equivalent greater than 12 milligrams per meter square per day for at least one month prior to screening. Androstenedione levels measured prior to the morning glucocorticoid dose had to be greater than the midpoint of the reference range based on sex and either- age for pre-puberty participants or for participants that were in puberty. 17-hydroxyprogesterone levels had to be above twice the upper limit of normal range.

[00:17:28] Key exclusion criteria were: known or suspected diagnosis of another form of classic CAH, any clinically significant medical condition or chronic disease that would interfere with the study endpoints, a history of bilateral adrenalectomy, hypopituitarism, or other conditions requiring chronic daily therapy with oral glucocorticoids.

[00:17:56] Demographics and baseline characteristics were generally similar between the Crenessity and placebo groups. Overall, about half the participants were female, and the mean age was 12 years. Of note, the youngest patient enrolled was four years old. More than 90 percent of all participants were on hydrocortisone, and the mean baseline glucocorticoid, daily dose, and hydrocortisone equivalents of both groups was supraphysiologic at 16.4 milligrams per meter square per day. Mean androstenedione and 17-hydroxyprogesterone concentrations were significantly elevated at baseline in both groups. This indicates that despite supraphysiologic glucocorticoid dosing, adrenal androgen control was poor. What this shows is that children in both the placebo and Crenessity groups were mostly in the third quadrant, where androgens are not at goal, and the glucocorticoid dosing is supraphysiologic.

[00:19:03] Notable medical conditions of interest of the participants upon entering to the study were that 55 percent- 58 percent of the kids who entered the study were either overweight or obese. At the scoring- that control of adrenal androgens is at the expense of high glucocorticoid exposure. In addition, high glucocorticoid exposure starting in infancy can lead to early adiposity rebound and makes children and young adults more susceptible to obesity. Also of note was that 6 percent of the male participants reporting testicular adrenal rest tumors upon entering the study. However, after baseline of the sonography, testicular adrenal rest tumors were found in 33 percent of the male patients. This tells us that testicular adrenal rest occur more frequently and at a young age, suggesting ACTH levels are chronically high in these patients between hydrocortisone doses and the early morning hours, even though they are on supraphysiologic dosing. And the chronic elevation of ACTH highlights the shortcomings of hydrocortisone therapy, the preferred glucocorticoid for treating children with CAH.

[00:20:34] Let us now discuss the efficacy data in the CAHtalyst Pediatric Study. As a reminder, hypothesis one was that the addition of Crenessity during the four-week stable glucocorticoid period would reduce androstenedione levels, whereas, in the placebo group, androstenedione levels would remain the same.

[00:20:58] At the end of the four-week glucocorticoid stable period, the Crenessity group had a substantial decrease in mean androstenedione of 405 to 208 nanograms per dL compared to the placebo group, which had an increase from 483 at baseline to 545 nanograms per dL at week 4. The study met its primary endpoint with a statistically significant least squares mean treatment difference of minus 267.8 nanograms per dL, which underscores the efficacy of Crenessity in reducing adrenal androgen.

[00:21:47] We saw a similar significant decrease in mean 17-hydroxyprogesterone levels at the end of week four in the Crenessity group, with levels going from 8,513 to 2,772 nanograms per dL compared with an increase in 17-hydroxyprogesterone levels in the placebo group. The study met a key secondary endpoint with a significantly squares mean treatment difference in 17-hydroxyprogesterone levels of minus 6,421 nanograms per dL between the Crenessity and placebo groups.

[00:22:30] Hypothesis two was to test that while gradually reducing the daily glucocorticoid dose over the 24-week period, children in the Crenessity group will maintain or improve androstenedione levels relative to baseline values. Whereas the placebo group would have no reduction in glucocorticoid dosing.

[00:22:55] The goal of the glucocorticoid dose reduction strategy in children was to reach a target dose of 8 to 10 milligrams per meter square per day of hydrocortisone equivalents at week 28, provided that androstenedione level was maintained or improved relative to the day one baseline values. Glucocorticoid dose reduction was done gradually, every four weeks, in up to four steps over the 24-week period, and was guided by the androstenedione level from the previous visit and the availability of glucocorticoid dose strengths needed for treatment. The target glucocorticoid dose reduction at each step was approximately 1 to 4 milligrams per meter square per day and followed the guideline of first reducing the most non-physiologic glucocorticoid time- type and timing.

[00:23:51] Since we are discussing glucocorticoid dose reduction, it’s important to recognize the risk of acute adrenal insufficiency or adrenal crisis with inadequate glucocorticoid therapy, especially in situations associating with increased cortisol need, such as acute intercurrent illnesses, serious trauma, or surgical procedures. Therefore, reduction of glucocorticoid dosing should be individualized with careful monitoring for persistent symptoms associating with cortisol deficiency, such as headache, fatigue, lack of concentration at school, and emotional ability. Glucocorticoid therapy should continue upon initiation and during treatment with Crenessity. Remember, Crenessity’s role is to reduce androgen levels between doses and in the early morning hours. But Crenessity does not have cortisol biologic functions on glucose, blood pressure regulation, and stress response. All children on Crenessity should have an emergency care plan reflecting the glucocorticoid dose changes on oral cortisol stress dosing guidelines.

[00:25:08] On week 28, after adjustments in glucocorticoid dose, the mean androstenedione in the Crenessity group, shown in purple, reduced from baseline by 89 nanograms per dL but rose in the placebo group by 111 nanograms per dL. Similarly, the mean 17-hydroxyprogesterone level in the Crenessity group reduced from baseline by 2,413 nanograms per dL. The placebo group also saw a reduction of 737 nanograms per dL.

[00:25:44] Overall, the daily glucocorticoid dose at the end of the 28-week study period reduced from 16.5 to 12.8 milligrams per meter square per day in the Crenessity group, a 17.5 percent decrease. While the mean glucocorticoid daily dose increased from 16.3 to 17 milligrams per meter square per day in the placebo group, a 6.1 percent increase. The least squares mean treatment difference of minus 23.5 percent between the Crenessity and placebo groups were statistically significant, which was a key secondary endpoint.

[00:26:30] Among Crenessity-treated pediatric participants, 30 percent achieved a physiologic glucocorticoid dose less than or equal to 11 milligrams per meter square per day in hydrocortisone equivalents at week 28 while maintaining or improving androstenedione levels from baseline. As compared with 0 percent glucocorticoid dose reduction in the placebo group. This is a clinically meaningful result, as it shows that Crenessity can help patients achieve a more physiologic glucocorticoid dosing while maintaining control of their adrenal androgens.

[00:27:00] To summarize this part of the results, Crenessity demonstrate efficacy across two critical aspects of CAH management. While keeping a stable glucocorticoid dose, Crenessity significantly reduced androstenedione and 17-hydroxyprogesterone levels at week 4. Crenessity significantly reduce glucocorticoid daily dose at week 28 while maintaining or improving androstenedione levels relative to day one baseline. 30 percent of participants treating with Crenessity were able to achieve a physiologic dose of glucocorticoids by week 28 versus 0 percent on placebo.

[00:27:47] And now, we move on to the safety data of the CAHtalyst Pediatric Study. The percentage of participants who had any treatment-emergent adverse events during the treatment period was similar in the two groups. 84 percent with Crenessity and 82 percent with placebo. Most treatment-emergent adverse events were mild to moderate in severity. Five participants experienced serious treatment-emergent adverse events, none of which were related to the trial regimen or led to discontinuation of the study drug. All participants recover or had resolution of symptoms. A total of 3 percent of Crenessity-treated subjects and no placebo-treated subjects discontinued treatment because of adverse reactions of abdominal pain, myalgia, or dizziness, which were considered unrelated to the study drug. No deaths occur during the trial period.

[00:28:58] This table compares the adverse reaction profile in patients treated with Crenessity versus placebo. Most adverse reactions were mild or moderate in intensity and spontaneously resolved. Headache, fatigue, and abdominal pain were the most frequent adverse events. These symptoms were more frequent in the Crenessity group and were most likely related to the glucocorticoid dose reduction. No safety concerns regarding Crenessity were reported with respect to vital signs, clinical laboratory tests, electrocardiographic findings, or neuropsychiatric assessments during the phase three pediatric trial.

[00:29:43] To summarize Crenessity safety and tolerability profile, the most common adverse reactions that occur in the Crenessity group and which were greater in the placebo group were headache, abdominal pain, fatigue, nasal congestion, and epistaxis. A total of 3 percent of Crenessity-treated subjects discontinued treatment because of adverse reaction of abdominal pain, myalgia, and dizziness. No adrenal crises were reported in pediatric patients being treated with Crenessity. 97 pediatric participants who completed the double-blind period continue on to the open-label period.

[00:30:27] Another important safety consideration to note was that a hypersensitivity reaction occur in a subject after three days of treatment with Crenessity, with symptoms of throat tightness, angioedema, and generalized rash. Therefore, if a clinically significant hypersensitivity reaction occurs, initiate appropriate therapy and discontinue Crenessity. Patients should be advised to seek immediate medical attention if they experience any signs or symptoms of hypersensitivity reactions, including rash, itching, swelling, or difficulty breathing.

[00:30:55] Again, in pediatric patients, the most common adverse reactions are headache, abdominal pain, fatigue, nasal congestion, and epistaxis. In adult patients, the most common adverse reactions are fatigue, headache, dizziness, arthralgia, back pain, decreased appetite, and myalgia. You’re encouraged to report negative side effects of prescription drugs to the FDA. Visit MedWatch at www.fdagov/MedWatch or call 1 800 FDA 1088. Please visit www.crenessity.com/hcp to view full Prescribing Information.

[00:31:36] To summarize. Crenessity reduces ACTH and the downstream production of adrenal androgens by selectively blocking the function of CRF1. Crenessity significantly reduce androgen and other precursor levels as measured by androstenedione and 17-hydroxyprogesterone at week 4 while glucocorticoid doses remain unchanged. Crenessity enabled reduction of the daily glucocorticoid dose while maintaining or improving androstenedione levels in pediatric patients with CAH. And finally, Crenessity demonstrate an excellent safety profile.

[00:32:23] Now, let’s move from the phase three pediatric trial to the dosing of Crenessity. Crenessity it is to be taken with a meal twice daily. And Crenessity is available as capsule and an oral solution for children. Capsules should be taken orally and swallow whole with liquid. An oral dosing syringe is required to measure and deliver the dose accurately when the liquid form of Crenessity is prescribed. Crenessity does not address the cortisol deficiency. Therefore, patients must continue taking glucocorticoids.

[00:33:03] Since Crenessity is a CYP3A4 substrate, concomitant use with a strong or moderate CYP3A4 inducer decreases Crenessity’s exposure, which can potentially reduce its efficacy. In patients that are taking a strong CYP3A4 inducer such as phenytoin or rifampin, both the morning and evening doses of Crenessity should be increased twofold. Now, if the patient is taking a moderate CYP3A4 inducer, only the evening Crenessity dose would be double. Specific dose regimens for adults 18 and older and children weighing equally to greater than 55 kilos, the recommended dose is 100 milligrams twice daily for a total of 200 milligrams per day. For children weighing 2 kilo- 20 kilos to less than 55 kilos, the dose is 50 milligrams twice daily for a total of 100 milligrams per day. And for children weighing 10 to less than 20 kilos, the dose is 25 milligrams twice daily for a total of 50 milligrams per day. Crenessity is available in 50 milligrams and 100 milligrams capsule as an oral solution of 50 mg/mL.

Patricia Stark: [00:34:20] Well, thank you very much, Doctor. And a warm thank you, really, to Dr. Sarafoglou. So much great information there. We do hope that you thoroughly enjoy this afternoon’s broadcast. On behalf of Neurocrine Biosciences, I’m Patricia Stark. Thank you so much for joining us.