The CRF Pathway Interrupted: Potential to Transform CAH Care

If an ideal treatment for 21-hydroxylase (21OH) deficiency congenital adrenal hyperplasia (CAH) could be developed, how would it work? “Well, the ideal treatment would be to replace the enzyme [21OH] deficiency and therefore obviate the need for glucocorticoids at all,” Richard Auchus, MD, PhD, professor of pharmacology and internal medicine, division of metabolism, endocrine, and diabetes at the University of Michigan replied during an interview with Patient Care.® “The normal negative feedback loop would be restored” and there would be “no need to compensate for the adrenal failure to produce cortisol.”

Auchus refers to restoring the negative hypothalamic pituitary adrenal (HPA) feedback loop, which, he explained, would restore to physiologic levels hypothalamic production of corticotropin-releasing factor (CRF), also called corticotropin-releasing hormone (CRH) and pituitary production of adrenocorticotrophic hormone (ACTH), the latter eliminating the overproduction of adrenal androgens.

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However, “We’re a long way off from that,” he added, referring to physiologic GC replacement and the body’s shift back to its normal circadian hormonal rhythms. But “absent that, what we’d like is to have a treatment that could directly lower ACTH and the adrenal androgen production. Then we wouldn’t have to use such high doses of GCs to suppress the androgens because another medication would do it.”

CAH Snapshot

The clinical goal for CAH therapy is to adequately replace cortisol to levels that check overproduction of hypothalamic CRF and the aberrant enzymatic-hormonal cascade that follows.¹ The longstanding treatment challenge, however, is that although physiologic doses of GCs are often sufficient to manage the inherent cortisol deficiency, current formulations are not able to replicate the physiologic circadian rhythm of endogenous cortisol.¹ To compensate for periods of low production, time that leaves individuals with CAH exposed to elevated androgens, supraphysiologic GC doses are typically required.^1-4 When effective, the high doses do reduce androgen levels and their clinical impact on the body but long-term exposure to elevated GC doses results in a myriad of well-recognized adverse effects of its own, including obesity and other cardiometabolic dysfunction, hypertension, osteoporosis, fertility challenges, and poor mental health.^1-4

Little has changed in the approach to CAH management in the past 60 years, a fact that prompted the original question to steroid biologist Auchus about the nature of an ideal treatment. And there is an active research agenda for an improved approach that more closely approximates the natural diurnal flux in cortisol. Potential strategies to mimic physiologic replacement include modified-release GC formulations as well as continuous GC replacement via implantable pump.^3,4,6,7

Auchus described a very different approach, that is, non-GC strategies that directly address pituitary ACTH-driven androgen excess, effectively separating control of that process from GC treatment of cortisol deficiency.^3,4,6,7 The GC-independent mechanism, which blocks release of hypothalamic CRF, has been shown to significantly reduce the amount of GC required in both children⁹ and adults,¹⁰ in many of them down to physiologic levels. There are currently 2 small CRF antagonists in early- to mid-stage development^4,7,8 one of which has recently been evaluated in phase 3 clinical trials and has the potential for FDA approval by the end of 2024 (crinecerfont; Neurocrine Biosciences).¹⁰ Data from the phase 3 CAHtalyst Adult trial, for which Auchus was primary investigator, highlight the promise of the mechanism of action.

CAHtalyst Adult

In this trial that enrolled 122 adults with poorly controlled 21OH-deficiency CAH, the primary endpoint was the percent change from baseline to week 24 in daily GC dose while maintaining androstenedione control. After initiating oral twice daily crinecerfont (100 mg), taken with the morning and evening meals, participants’ GC dose was kept stable for an initial 4-week period to allow assessment of androstenedione levels.¹⁰

Over the following 20 weeks, Auchus and colleagues reduced and optimized GC dose to reach the lowest dose that would maintain androstenedione control, ie, 120% of baseline value or within the normal reference range. After 24 weeks of treatment, GC dose among study-drug treated participants was reduced by 27.3%, with androstenedione control maintained. Among placebo-treated participants, dose reductions reached just 10.3%, for a statistically significant difference (P <.001).¹⁰ Nearly two-thirds (62.7%) of the participants who received crinecerfont achieved physiologic GC doses with steady androstenedione levels compared with 18% of those in the placebo group, also a statistically significant difference (P <.001).¹⁰ Auchus emphasized the magnitude of this reduction, pointing out that GC doses at the study’s outset on average were approximately 3 times the “normal physiologic dose.”

Richard J Auchus, MD, PhD

Crinecerfont also markedly lowered levels of androstenedione by 299 ng/dL while levels increased by 45.5 mg/dL among those treated with placebo (P <.001). Levels of 17-hydroxyprogesterone, a second biomarker used to assess CAH control, were also reduced.¹⁰

This reduction was particularly apparent during the early-morning hours when the normal rise in ACTH is exaggerated and leads to markedly increased production of androgen precursors. The reduced levels of the hormones at this strategic time of day when the potential for excess androgen exposure is highest, was potent evidence that crinecerfont is working to suppress ACTH, Auchus said.

The CAHtalyst Pediatric trial⁹ was of similar design, including a 4-week lead in period at stable GC doses. After week 28, mean GC dose had been reduced by 18% (with androstenedione control maintained) in children treated with crinecerfont but had increased by 5.6% among those treated with placebo (P <.001).⁹ For both adult and pediatric study participants, the most commonly reported adverse events were fatigue and headache.^9,10

The second investigational CRF1 antagonist, tildacerfont, has had less success in clinical trials, with no reduction observed in androstenedione levels from baseline at week 12 in a phase 2 study.¹¹ In a separate ongoing phase 2 trial, tildacerfont is being assessed for reduction of GC use in adults with CAH who have close to normal levels of androstenedione.¹¹

Rethinking CAH

Auchus said it is important to understand that “cortisol replacement therapy will always be required in patients with classic CAH,” unless the feasibility of gene therapy or adrenal transplantation is realized. Care is frustrating for patients and for their physicians, he said, with physicians often toggling between “Should I let the androgens go up so I can lower the glucocorticoids, or should I suppress the androgens, but then I'm going to give too much glucocorticoids; they gain weight; they don’t like that; they stop taking the medication.”

But with crinecerfont and medications like it that act on different parts of the steroidogenic pathway in the pipeline “we need to rethink this disease,” Auchus emphasized. “Outcomes are better than they were 30 years ago, even with conventional treatments, and they should be even better in the near future. We don’t have to say to patients any longer, ‘this is the best we can do.’”

Auchus believes that with treatment that reduces reliance on GC replacement, individuals will feel better, remain more invested in their treatment and their health. “I hope that these drugs will allow us to reduce the disease burden on the families and their children with this condition, and on adults living with CAH. With fewer doses of medications, less testing, better control, less angst…they [can] get on with their life and focus on whatever their goals are.”

References

1. Auer MK, Nordenström A, Lajic S, Reisch N. Congenital adrenal hyperplasia. Lancet. 2022;401(10374): 1-18. doi:10.1016/S0140-6736(22)01330-7

2. Speiser PW, Arlt W, Auchus RJ, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(11):4043-4088. doi:10.1210/jc.2018-01865

3. Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, et al. Congenital adrenal hyperplasia—current insights in pathophysiology, diagnostics, and management. Endocr Rev. 2022;43(1):91-159. doi:10.1210/endrev/bnab016

4. Mallappa A, Merke DP. Management challenges and therapeutic advances in congenital adrenal hyperplasia. Nat Rev Endocrinol. 2022;18(6):337-352. doi: 10.1038/s41574-022-00655-w

5. Merke DP, Auchus RJ. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N Engl J Med. 2020;383(13):1248-1261. doi:10.1056/NEJMra1909786

6. Prete A, Auchus RJ, ross RJ. Clinical advances in the pharmacotherapy of congenital adrenal hyperplasia. Eur J Endocrinol. 2022;186(1):R1-R14. doi: 10.1530/EJE-21-0794

7. Turcu AF, Auchus RJ. Novel treatment strategies in congenital adrenal hyperplasia. Curr Opin Endocrinol Diabetes Obes. 2016;23(3):225–232. doi:10.1097/MED

8. Schröder MAM, Claahsen ‑ van der Grinten HL. Novel treatments for congenital adrenal hyperplasia. Rev Endocr Metab Disor. 2022; 23:631–645. doi:10.1007/s11154-022-09717-w

9. Sarafoglou K, Kim MS, Lodish M; CAHtalyst Pediatric Trial Investigators. Phase 3 trial of crinecerfont in pediatric congenital adrenal hyperplasia. N Engl J Med. 2024;391(6):493-503. doi:10.1056/NEJMoa2404655

10. Auchus RJ, Hamidi O, Pivonello R, et al for the CAHtalyst Adult Trial Phase 3 trial of crinecerfont in adult congenital hyperplasia. N Engl J Med. Published online June 1, 2024. doi: 10.1056/NEJMoa2404656

11. Spruce Biosciences reports full year 2023 financial results and provides corporate updates. News release. Spruce Biosciences. March 13, 2024. Accessed June 24, 2024. https://investors.sprucebio.com/news-releases/news-release-details/spruce-biosciences-reports-full-year-2023-financial-results-and