Crinecerfont Sustains Glucocorticoid Reduction, Improves Cardiometabolic Outcomes in Classic CAH

2-year data from the phase 3 CAHtalyst Adult Study suggest treatment with crinecerfont (Crenessity) enables durable reductions in glucocorticoid (GC) dosing while supporting improvements in weight, body composition, and insulin resistance among adults with classic congenital adrenal hyperplasia (CAH).¹

Endocrine Society (ENDO) Annual Meeting 2026

, the findings extend evidence supporting the December 2024 FDA approval of crinecerfont as an adjunct to GC replacement therapy for patients aged ≥4 years with classic CAH.¹

"We were able to take these supraphysiologic doses and maintain patients on physiologic replacement as early as 24 weeks, and that improvement was maintained even up to 24 months," said study presenter and investigator Oksana Hamidi, DO, associate professor in the division of endocrinology and metabolism at UT Southwestern Medical Center, in an interview with 

. "It's not just a fluke. We saw a persistent, sustained, substantial reduction in glucocorticoid dose, and there was not a significant escape from that."

Durable Glucocorticoid Reduction Maintained Through 24 Months

The analysis included 182 adults with classic CAH enrolled in the CAHtalyst Adult Study (NCT04490915), a phase 3 randomized, double-blind, placebo-controlled trial with an ongoing open-label extension. Investigators evaluated changes in GC dose, body weight, body composition assessed by dual-energy X-ray absorptiometry, and insulin resistance through 24 months of treatment. At baseline, participants had a mean daily GC dose of 17.6 mg/m²/day hydrocortisone equivalents (HCe), corresponding to 32.3 mg/day.¹

Mean GC dose decreased by 37% from baseline to 10.9 mg/m²/day (19.9 mg/day) HCe at month 12 and remained reduced by 38% at month 24, reaching 10.6 mg/m²/day (19.4 mg/day) HCe. According to investigators, these reductions moved participants from clearly supraphysiologic GC exposure toward physiologic replacement levels.¹

Cardiometabolic Improvements Accompany GC Dose Reduction

At baseline, 71% of participants were overweight or obese, defined as a body mass index (BMI) ≥25 kg/m², and 42% had insulin resistance, defined as a homeostatic model assessment of insulin resistance (HOMA-IR) score >2.5. Mean reductions in body weight (-1.8 kg) and BMI (-0.7 kg/m²) observed at month 12 were maintained through month 24.¹

Among participants who were overweight or obese at baseline, 31% achieved >5% body weight reduction at month 12, increasing to 38% at month 24. Body composition analyses showed reductions in fat mass exceeded reductions in lean mass at both time points. By month 24, mean fat mass declined by 1.6 kg compared with a 0.8-kg reduction in lean mass.¹

Investigators also observed sustained improvements in insulin resistance. Mean HOMA-IR reductions from baseline were -0.6 at both months 12 and 24 across the overall study population. Among participants with insulin resistance at baseline, mean HOMA-IR reductions were -1.5 at month 12 and -1.7 at month 24.¹

Adults with classic CAH experience elevated rates of obesity, hypertension, dyslipidemia, and insulin resistance, although the relative contribution of chronic supraphysiologic GC exposure versus androgen excess remains an ongoing clinical question.

Hamidi noted many cardiometabolic complications observed in CAH, including increased fat mass, hypertension, osteoporosis, and insulin resistance, are commonly associated with excessive GC exposure, whereas accelerated bone growth and early puberty are more characteristic of uncontrolled androgen excess.

The findings suggest reductions in GC exposure can be achieved without sacrificing androgen control. As GC doses declined during treatment with crinecerfont, investigators observed concurrent improvements in weight, body composition, and insulin resistance.¹

"As we were able to lower glucocorticoids, while also maintaining control of androgens, we saw improvements in weight, improvements in BMI, favorable improvements in body composition with reduction in fat mass, improvement in lean mass, and improvements in insulin resistance," Hamidi said.

Crinecerfont was generally well tolerated through 24 months, with investigators reporting no new safety signals during long-term treatment.¹

Investigators noted the study was not powered to detect differences between salt-wasting and simple virilizing forms of classic CAH. Hamidi also highlighted the importance of monitoring mineralocorticoid replacement in patients with salt-wasting disease, as reductions in hydrocortisone dosing may increase the need for fludrocortisone supplementation over time.

The open-label extension lacked a placebo comparator, limiting conclusions regarding the direct contribution of GC dose reduction to observed cardiometabolic improvements. However, the findings suggest long-term treatment with crinecerfont may enable sustained reductions in glucocorticoid exposure while supporting favorable cardiometabolic outcomes in adults with classic CAH.¹

Crinecerfont is a first-in-class oral corticotropin-releasing factor type 1 (CRF1) receptor antagonist that reduces adrenocorticotropic hormone-driven adrenal androgen production in classic CAH. The agent received FDA approval in December 2024 for patients aged ≥4 years based on results from the phase 3 CAHtalyst clinical program.³˒⁴

Editor’s Note: Hamidi reports relevant disclosures wi

Neurocrine Biosciences, Xeris Pharma, Camurus, Crinetics Pharmaceuticals, and Recordati Rare Diseases.

Hamidi O, Chalmers LJ, Falhammar H, et al. Crinecerfont improves weight-related outcomes and insulin resistance in adults with classic congenital adrenal hyperplasia: 2-year results from the CAHtalyst Adult Study. Presented at: Endocrine Society Annual Meeting; June 14, 2026; Chicago, IL. Abstract ORF32-07.

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

Neurocrine Biosciences. Neurocrine Biosciences announces FDA approval of CRENESSITY (crinecerfont), a first-in-class treatment for children and adults with classic congenital adrenal hyperplasia. Press release. December 13, 2024. 

https://neurocrine.gcs-web.com/news-releases/news-release-details/neurocrine-biosciences-announces-fda-approval-crenessitytm

Auchus RJ, Hamidi O, Pivonello R, et al. Crinecerfont in classic congenital adrenal hyperplasia in adults. N Engl J Med. 2024;390(20):1865-1876. doi:10.1056/NEJMoa2313917

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Two-year CAHtalyst data show crinecerfont sustained glucocorticoid reduction and improved metabolic outcomes in classic CAH.


HPA-Axis Assessment Allows for Improved Corticosteroid Response Analysis

According to recent research, dual-dose cosyntropin testing effectively provides a practical framework for hypothalamic-pituitary-adrenal (HPA) axis safety assessment in a non-endocrine corticosteroid trial.

 in Chicago, Illinois, by Elena Christofides, MD, the chief executive officer of Endocrinology Associates, scientific and medical advisor for Sparrow Pharmaceuticals, and a clinical associate professor at the Ohio University Heritage College of Osteopathic Medicine, effectively provide clinicians with a way of monitoring HPA-axis safety and differentiating treatment-emergent suppression from adrenal dysfunction.

“The difficulty in this trial, like in any steroid trial in any non-endocrine condition, is the risk of adrenal suppression,” Christofides told 

 in an exclusive interview. “My job as the safety endocrinologist was to design a protocol to assess safety and avoid adrenal suppression during the course of the trial.”

The HPA axis is intrinsically associated with the body’s physical reaction to stress. Following a moment of severe stress, the axis – which includes the hypothalamus, pituitary gland, and adrenal glands – is activated to return the body to homeostasis. It releases a series of corticotropic hormones, leading to the synthesis and secretion of glucocorticoids, mineralocorticoids, and adrenal androgens.

However, in trials involving corticosteroids outside of an endocrine specialty, baseline HPA-axis status is rarely considered relevant. This limits clinicians’ ability to determine the full effects of corticosteroids on the patients, as adrenal dysfunction and standard, treatment-emergent suppression may present similarly. To this end, Christofides and colleagues undertook the present study, titled CESSA.

CESSA was a randomized, double-blind, placebo-controlled study in adults with ulcerative colitis of the rectum. A total of 200 patients were randomly assigned to either next-generation hydrocortisone acetate (ngHCA) 90 mg once daily or twice daily, or to placebo. Patients were not permitted to use alternative corticosteroids.

The team initially used standard-dose 250 µg cosyntropin to filter out primary adrenal insufficiency. Follow-up safety visits utilized 1 µg cosyntropin at days 29, 39, and, if indicated, 53. Additionally, investigators conducted pharmacokinetic sampling for plasma corticosteroid levels on days 1, 15, and 28.

Of the 200 participants initially included and randomized, 25 were referred for targeted safety follow-up. Overall, 104 patients showed alterations to the HPA axis during the study; of these, 3 placebo recipients had persistent secondary adrenal suppression requiring endocrinology referral, which showed non-study corticosteroid exposure. All patients who were administered active study drug recovered HPA-axis function by the end of the safety period at day 53.

While the trial’s results ultimately included potential confounding for both safety and efficacy assessments, Christofides and colleagues determined that this study provided an effective framework to help address a significantly overlooked risk in patients assigned to receive corticosteroid treatment.

“We’re in need of more precise drug therapy metrics so that we can track that during a PK study,” Christofides said. “My preference would be if we could have some sort of continuous metabolic monitor where we’re measuring cortisol constantly, and we know what the patient’s endogenous cortisol rhythm is going into a trial – it would not be hard to then extrapolate whether their cortisol rhythm is expected based on the drug pharmacokinetics or not.”

Editors’ Note: Christofides reports disclosures with Ascendis, Eli Lilly, Novo Nordisk, Recordati, Corcept, Crinetics, and others.

Christofides E, Ensign M. Dual-dose Cosyntropin Stimulation Testing to Assess HPA-axis Safety and Identify Non-Study Corticosteroid Exposure in a Phase 3 Ulcerative Colitis Trial. Abstract presented at the Endocrine Society (ENDO) Annual Meeting 2026, Chicago, IL. June 13-15, 2026.

Joseph DN, Whirledge S. Stress and the HPA Axis: Balancing Homeostasis and Fertility. Int J Mol Sci. 2017;18(10):2224. Published 2017 Oct 24. 

Elena Christofides, MD, discusses her recent analysis of patients with ulcerative colitis receiving corticosteroids.

Abdominal Pain and Bloating: When to Consider HAE, MCAS, and EGIDs

Abdominal pain and bloating rank among the most common complaints in clinical medicine and the hardest to pin down.

and immunologists, the challenge is knowing when to step in and what to look for when traditional GI workups come back unremarkable. Conditions including hereditary angioedema (HAE), mast cell activation syndrome (MCAS), and eosinophilic GI disorders can all present with episodic abdominal symptoms, yet they remain low on the radar of most primary care providers and even gastroenterologists seeing these patients first.

The topic was among those addressed at the 

 spoke with presenter Brian E. Lacy, PhD, MD, a board-certified gastroenterologist at the Mayo Clinic in Jacksonville, about how he approaches this differential from the gastroenterology side and where collaboration with allergy and immunology becomes essential.

When a patient presents with intermittent bloating and no clear etiology, Lacy organizes the differential around 5 major causes: dietary indiscretion such as lactose or fructose excess, constipation, intestinal methanogen overgrowth or SIBO, visceral hypersensitivity as seen in IBS and functional dyspepsia, and abdominophrenic dyssynergia, a motility disorder in which patients become severely bloated after eating and often describe looking pregnant.

He noted that abdominal pain requires a separate framework. He said that he breaks it down into new-onset versus chronic abdominal pain to help clinicians narrow down the impacted pathway.

HAE is typically the last condition a clinician thinks to check for. Because the condition affects roughly 1 in 50,000 people, it sits well below more common diagnoses on most clinicians' working lists. Rather, clinicians will often look for more prevalent conditions, such as an ulcer, a hernia, or new-onset inflammatory bowel disease.

After standard workup fails to produce a diagnosis, Lacy said that a clinician should start thinking about allergic etiologies. Clinically, HAE abdominal attacks tend to present as discrete episodes separated by symptom-free intervals, with significant bloating and distension and, crucially, dilated intestinal loops on imaging.

"Usually, the diagnostic test, some imaging study, sets a light bulb off in a lot of clinicians' heads that something else is going on,” he said.

MCAS presents a related but distinct diagnostic challenge. Lacy cautioned that despite growing patient awareness of the condition, true MCAS is uncommon. He uses episodic symptom patterns and multi-organ involvement as the primary clinical filters.

"When somebody reports daily abdominal pain or daily bloating, that is not likely to be MCAS," he said. "They should have episodes separated in time by where they don’t have symptoms, [and] they should have at least two different organ systems involved.”

He noted that skin and GI tract symptoms are a classic pairing. If a patient has these episodes, Lacy recommends checking the serum tryptase to ensure it is above baseline.

For eosinophilic GI disorders, the diagnostic gap lies largely in procedural practice. Because the mucosa can appear grossly normal on endoscopy, the condition is frequently dismissed after a "normal" scope. Lacy stressed that gastroenterologists need to take multiple biopsies across GI segments and alert the pathologist in advance to stain specifically for eosinophils—and for mast cells when MCAS is also on the table.

"There has to be a heightened sense of awareness and…good communication with the person doing the procedure [and] the pathologist,” he said.

Editor’s note: Relevant disclosures for Lacy include Ardelyx, Salix Pharmaceuticals, and IRONWOOD PHARMACEUTICALS.

Upper Abdominal Pain. Cleveland Clinic. Accessed June 15, 2026. 

https://my.clevelandclinic.org/health/symptoms/24736-upper-abdominal-pain

Lacy B. Evaluation and Management of Intermittent Abdominal Pain and Bloating. Poster presented at the Eastern Allergy Conference (EAC) in Palm Beach, Florida, on May 29. 

Gastroenterologist Brian Lacy, MD, PhD, discusses how to differentiate HAE, MCAS, and eosinophilic GI disorders in patients with unexplained abdominal pain and bloating.

In a real-world study of 36,647 adults receiving injectable semaglutide (Wegovy), investigators identified baseline factors associated with weight loss trajectories, including sex, cardiometabolic comorbidities, and prior challenges with weight consistency.

Endocrine Society (ENDO) 2026 Annual Meeting

 in Chicago, Illinois, by senior author Hans Johnson, MBChB, MRes, MSc, of the University of Bristol, and co-authors from Voy and Boston Children’s Hospital. The study aimed to characterize real-world patterns of weight loss ancand identify factors that may inform individualized prediction tools.

“Whilst weight loss outcomes with injectable semaglutide are well characterised in randomised trials, emergent evidence suggests that the magnitude of weight loss with GLP-1 receptor agonists may be associated with baseline comorbidities,” wrote Johnson and colleagues. “Understanding factors associated with weight loss outcome variation could inform the development of individualised prediction tools.”

Investigators conducted a retrospective open cohort analysis of adults initiating injectable semaglutide through a UK-based digital weight loss service. Cox proportional hazards models and mixed-effects models were used to evaluate factors associated with weight loss outcomes. Data extraction occurred in November 2025.

The final analysis cohort included 36,647 adults with a mean age of 45.76 years. Of these, 7,077 (19.31%) had 6-month follow-up data and 2,329 (6.36%) had 12-month follow-up data available.

Women were more likely than men to achieve ≥20% total body weight loss at 12 months (Hazard Ratio [HR], 1.93; 

Several baseline comorbidities were associated with a lower likelihood of achieving ≥20% total body weight loss at 12 months, including diabetes (HR, 0.71; 

 <.001), hypertension (HR, 0.76; P <.001), and sleep apnea (HR, 0.62;

 <.001). No significant associations were observed for metabolic dysfunction-associated fatty liver disease or asthma.

In multivariate mixed-effects models evaluating 12-month weight loss trajectories, prior challenges with weight consistency, erectile dysfunction, polycystic ovary syndrome, and sleep apnea were significantly associated with lower percentage weight loss during semaglutide treatment.

Investigators noted that baseline clinical and behavioral factors may help “pattern” weight loss responses in real-world semaglutide use. They added that factors influencing treatment persistence may also contribute to observed variability in outcomes, representing a potential source of bias. Future research should consider integrating these variables into clinical prediction tools to support counseling, goal setting, and treatment decision-making.

“Future research should consider integrating these factors into clinical prediction tools to provide individualised estimates of the benefits of semaglutide. These could be beneficial for counselling, expectation/goal setting and treatment decisions,” investigators concluded.

Johnson H, Clift AK, Reisel D, Huang D, Reis B. Baseline predictors of real-world weight loss outcomes with injectable semaglutide: cohort analysis of over 36,000 individuals. Poster presented at: ENDO 2026 Annual Meeting; June 14, 2026; Chicago, IL.

Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. 

 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183

Articles

A retrospective open-cohort analysis of 36,647 adults initiating injectable semaglutide via a UK digital weight-loss service evaluated baseline predictors of real-world weight-loss trajectories. Follow-up was limited (19.3% at 6 months; 6.4% at 12 months). Female sex was associated with higher likelihood of achieving ≥20% total body weight loss at 12 months, whereas diabetes, hypercholesterolemia, hypertension, and sleep apnea were associated with reduced likelihood. Mixed-effects modeling also linked prior weight-consistency challenges and select comorbidities to attenuated 12-month percentage weight loss.

Baseline characteristics, including sex and comorbidities, were associated with semaglutide weight loss outcomes in >36,000 adults.


Sex, Comorbidities Linked to Semaglutide Weight Loss Trajectories

A pooled analysis of the phase 3 SKYLIGHT 1, 2, and 4 trials found low rates of central nervous system (CNS) adverse events with fezolinetant (Veozah), a selective neurokinin 3 (NK3) receptor antagonist approved for moderate to severe menopausal vasomotor symptoms (VMS).

Presented at the Endocrine Society (ENDO) Annual Meeting 2026 by Marla Shapiro, C.M., CCFP, MHSc, FRCPC, FCFP, MSCP, Professor in the Department of Family and Community Medicine at the University of Toronto, the analysis included > 3100 women followed for up to 52 weeks.

Rates of CNS adverse events were low and generally similar between fezolinetant and placebo, with no signal for depression, memory impairment, somnolence, abuse liability, or suicidal ideation or behavior. The findings help address questions about CNS safety that have accompanied fezolinetant since its introduction as the first non-hormonal, non-gabapentinoid treatment for VMS, given its central action within the hypothalamus.

The HCPLive content team spoke with Shapiro about the findings, their clinical relevance, and what they mean for women who cannot or choose not to use menopausal hormone therapy.

: Can you provide a brief overview of your study and its findings?

Shapiro: What this looked at was the central nervous system safety effect of this NK3 antagonist, fezolinetant. Looking at all the data that we have out there, we looked at several things in terms of treatment-emergent adverse events, which were things like headache, dizziness, fatigue, and somnolence. I'm often asked about things like brain fog, which is a very popular term, but not a term that we actually can tease out — that may come in under things like effect on memory, which is another CNS safety adverse event that we looked at.

When we looked at these treatment-emergent adverse events, be they headache, dizziness, fatigue, or somnolence, what we found was that compared to our placebo group, or our 45 mg treatment — that's our on-label dose, which came to North America and everywhere all over the world — there was really no significant differences in the drug-related treatment-emergent adverse events in each of those categories. For example, if you look at things like headache in our placebo group, of about the 7.5 to 8% that we saw, about less than 3% were thought to be related to the drug as adjudicated by our adjudicators. If you look at fezolinetant, you see the exact same thing — the same treatment-emergent adverse events of headaches were about 8.2%, but only 2.3% were thought to be related to the drug. The same is true for dizziness, fatigue, and somnolence.

One thing that's really important is that the incidence of these effects — whether they're fatigue or dizziness or headache or somnolence or mood changes — they really did not lead to treatment withdrawal. We also did the Columbia Suicide Severity Rating Scale, and there was really no treatment effect of fezolinetant on suicidal ideation or behavior. So really, when we look at the safety-reported events in any of the treatment arms, including the 30 mg that didn't come to market, what we saw was a remarkable similarity between all of them. There really was nothing that we saw in any of the exposure-adjusted incidence rates in these particular areas that were identified as so-called central nervous system safety concerns.

: Fezolinetant represents a different therapeutic approach for vasomotor symptoms, targeting neurokinin 3 receptors rather than estrogen pathways. What motivated the need to specifically examine central nervous system safety, and what were the key concerns clinicians had when this mechanism was introduced?

Shapiro: Whenever this is our first on-label, non-hormonal option, understanding what hot flashes and vasomotor symptoms are — we now understand the relationship between stimulation and antagonism of both estrogen and neurokinin B at the level of the KNDy neuron. We now understand that when estrogen is withdrawn in menopause, you get overstimulation of the KNDy neuron because of the neurokinin impact in terms of the receptor. So the notion of developing a drug with a targeted mechanism of action is very exciting for women who cannot, will not, or do not want to use menopausal hormone therapy, which typically has been used as the on-label gold standard.

This represents novel science and on-label new therapeutics. And I think that when a new therapeutic comes, everybody wants to know the same thing: does it work? Is it safe? Does it work? Yes — we saw marked reductions as early as one week in both the frequency of hot flashes and, of the residual hot flashes, the severity. So now you want to know, what about safety? And people say, well, this is a brain mechanism, this is working in the brain. So are there CNS safety signals we should be aware of, because we're talking about the hypothalamus and the medial preoptic nucleus, which is where these receptors are. So it was important to be able to do the data work to look at the typical CNS safety signals that one would expect — things like fatigue, dizziness, headache, and somnolence. We wanted to make sure there was no signaling or alarm telling us that there are CNS events here that are impacting these women, particularly when it comes to, for example, next-day somnolence, or next-day fatigue, or dizziness, or headache. And it's very reassuring that, particularly in the placebo and the fezolinetant 45 mg, which is the dose that came to market, we really do not see any treatment-emergent adverse events related to the medication versus placebo.

: This pooled analysis of SKYLIGHT 1, 2, and 4 included more than 3,000 women and found similar rates of CNS adverse events across groups. Which findings do you consider most clinically meaningful?

Shapiro: I think what's clinically meaningful is all of it. If we look at things like effect on memory — women often talk about brain fog, and that's one of the things they worry about. You want to make sure that the medication you're using is not exacerbating what one typically associates with menopause, and even late perimenopause. The fact that there was no change in depression, no change in dizziness or headache, or next-day fatigue or somnolence — these are critical for us to be able to say to women that the things you're concerned about, in terms of quality of life, are not going to be exacerbated by the medication you're using.

We know this medication will separate out very quickly in terms of responders. As early as week one, we saw a 61% reduction in the frequency of hot flashes, and then of the residual hot flashes that remain, we saw marked decreases in severity. So being able to answer the questions about safety is very important for women. They want to know: does it work? Is it safe? Those are the two big questions that everybody has.

: How do these safety findings affect your approach when considering fezolinetant for women who cannot or prefer not to use menopausal hormone therapy?

Shapiro: The elegant science behind the NK3 antagonist is just so exciting, because it allows us to understand the mechanism of action of what a hot flash and a night sweat actually is. We never knew that before. By having this very elegant science — recognizing that when estrogen is removed, the agonist activity on the KNDy neurons means that having antagonists at the NK3 receptors blocks this overstimulation, and therefore makes a difference in hot flashes and night sweats — is just so exciting.

For many women who are either a hormone caution or a hormone contraindication, but also women who see themselves as not wanting menopausal hormones as their therapeutic option, this opens the doorway to an effective medication. And having safety data allows us to say safe and effective — which is the goal of any new therapeutic.

: Are there particular patient populations — such as women with a history of mood disorders, sleep disturbances, or sensitivity to CNS-active medications — where these data are especially relevant?

Shapiro: One would imagine that when you identify that population, you want to make sure you're not going to give them a medication that's going to exacerbate something that may be pre-existing. These are not contraindications to using the medication, and the fact that these were not exclusion criteria for women who entered into the study is meaningful. Given the large number of women in the study and the randomization, you often have women with these concerns already represented. It's very difficult to tease them out because they're non-entrance criteria.

So one would imagine that if we do not see a difference in any of these red-flag events in either the placebo group or the pooled analysis of SKYLIGHT 1, 2, and 4 — which is a very large, representative sample of women in that age group — I think that we can be very reassured.

In clinical practice, many menopausal symptoms overlap with mood changes, sleep disruption, and cognitive concerns. How should clinicians distinguish underlying menopausal symptoms from potential treatment-related effects when evaluating these patients?

Shapiro: The first question before that question is, how do we evaluate women to know whether something is related to a menopause symptom or is it comorbid and pre-existing — and often that's very difficult to do. For many women who come in with multiple symptoms, many of which may or may not be exacerbated by menopause, what we talk about is: what is our goal of treatment? Our goal of treatment is usually, in women who are having 30, 40, 50 hot flashes, to reduce the frequency and the severity so that they can be in the workplace, not be disrupted in their activities of daily living.

So I think that's what we focus on, and to be able to say to them that we don't have any evidence that this medication will exacerbate any of these underlying symptoms. We'll have to see — as your hot flashes and night sweats get better, does your mood get better? We know from the PROMISE data that there is improvement in sleep. Does the improvement in sleep improve some of these other symptoms, or are they really comorbid conditions that merit treatment in and of themselves, separate from their hot flashes and sweats?


Editor’s Note: Shapiro reports relevant disclosures with Astellas Pharmaceuticals and others. 

Shapiro M. Central Nervous System Safety of Fezolinetant From Pooled Analysis of 52-Week, Phase 3 Studies (SKYLIGHT 1, 2, and 4). Presented at: ENDO 2026; June, 2026; Chicago, IL.

Safety of Fezolinetant for Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause: Pooled Analysis of Three Randomized Phase 3 Studies.

 Adv Ther. 2025;42:1147-1164. doi:10.1007/s12325-024-03073-8.

Pooled phase 3 data from SKYLIGHT 1, 2, and 4 (>3100 women; up to 52 weeks) showed low, placebo-like rates of CNS adverse events with fezolinetant 45 mg. Headache, dizziness, fatigue, and somnolence were uncommon and rarely adjudicated as drug-related, with minimal impact on discontinuation. No signals emerged for depression, memory impairment/“brain fog,” abuse liability, or suicidal ideation/behavior on C-SSRS. These findings mitigate concerns related to hypothalamic NK3 antagonism while supporting a rapid-onset, nonhormonal option for vasomotor symptoms.

Fezolinetant's CNS safety Profile Reassures Across More Than 3,000 Women in Pooled Phase 3 Analysis at ENDO 2026

Fezolinetant Shows No CNS Safety Signal in Pooled Analysis of 3100 Women, With Marla Shapiro, CM

CAPTAIN-T2D: Interim Results Display High Cortisol Prevalence in Difficult-to-Control T2D

Interim data from the phase 2 CAPTAIN-T2D trial have indicated a substantial unmet need among patients with difficult-to-control 

, specifically in elevated post-dexamethasone suppression test (DST) cortisol.

 in Chicago, Illinois, by Elena Christofides, MD, the chief executive officer of Endocrinology Associates, scientific and medical advisor for Sparrow Pharmaceuticals, and a clinical associate professor at the Ohio University Heritage College of Osteopathic Medicine, this trial ultimately aims to evaluate clofutriben for the reduction of intracellular cortisol in several major tissues among these patients.

, Christofides discussed the rationale for the trial’s structure, highlighting the unmet need faced by many patients with subtle cortisol increases. As most clinicians are trained to view hypercortisolism primarily – and sometimes exclusively – as an indication of classic Cushing’s syndrome, patients with less pronounced elevations are often missed or undertreated.

“We need to reframe the conversation around what the consequences are of elevated cortisol, and when we should intervene,” Christofides told 

. “That’s the real struggle – we have been very dismissive as a general rule around the comorbidities associated with elevated cortisol, because it’s all too easy to blame societal changes, environmental changes, or personal changes, and so we end up gaslighting the patients about the disease process.”

Clofutriben is a selective inhibitor of human 11b-hydroxysteroid dehydrogenase type 1 (HSD-1), currently in development by Sparrow Pharmaceuticals to reduce intracellular cortisol in liver, adipose, muscle, and pancreas tissues, among others. Previous animal studies have indicated the drug’s efficacy in preventing corticosterone toxicities.

The CAPTAIN-T2D trial aims to assess the prevalence of elevated cortisol in patients with difficult-to-control T2D, as well as attempting to establish clofutriben’s dose-response relationship for HbA1c reduction in these patients. Christofides and colleagues plan to investigate roughly 1500 patients – of these, 332 have been screened via DST to date.

Difficult-to-control T2D was defined as HbA1c ≥7.5% despite ≥2 antidiabetic medications (ADMs), as well as the use of either ≥3 ADMs or ≥2 

, or the presence of a diabetes complication, osteoporosis, or prior Cushing syndrome diagnosis. Following screening, investigators expect to enter roughly 210 patients with post-DST cortisol >1.8 µg/dL into 24 weeks of randomized, placebo-controlled treatment to identify the appropriate dose for HbA1c reduction in a future phase 3 trial.

Of the 332 patients currently screened, 27.7% displayed post-DST cortisol levels >1.8 µg/dL. Analysis of demographic and clinical characteristics, including medications, T2D duration, and complications, as well as comorbidities and laboratory measures across post-DST cortisol categories is currently ongoing, according to Christofides and colleagues. In the meantime, the team has determined that, following their tracking of elevated post-DST cortisol in patients with difficult-to-control T2D, they have uncovered a significant unmet need in cardiometabolic disease. The full results of the study, including the response of HbA1c, body habitus, lipids, blood pressure, and other cardiometabolic risk factors to clofutriben, are expected to publish in Q4 2027.

“The data is clear historically that patients who still have persistent hypercortisolism and disrupted rhythm, even if their comorbidities are managed, their mortality is increased,” Christofides said. “So, yes, look for a solution that may be surgical for that patient, because that’s obviously going to be curative for that person, but in the meantime, do not ignore the fact that they’re metabolically compromised and marching towards a premature death, while you ignore that metabolic abnormality looking for a surgical solution.”

Christofides E, Buse J, Fonseca V, et al. Prevalence of Elevated Cortisol in Difficult-to-Control Type 2 Diabetes: Interim Results for CAPTAIN-T2D, a Phase 2 Trial of Clofutriben. Abstract presented at the Endocrine Society (ENDO) Annual Meeting 2026, Chicago, IL. June 13-15, 2026.

Buttgereit F, Everding A, Andreica I, et al. Effects of clofutriben, a selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, on the efficacy and toxicity of prednisolone in patients with polymyalgia rheumatica: a single-blind controlled trial with sequential cohorts. Ann Rheum Dis. 2026;85(5):921-931. 

Elena Christofides, MD, discusses the interim results of CAPTAIN-T2D, a trial that plans to evaluate clofutriben’s efficacy in these patients.

VIASKIN Peanut Patch Efficacy Holds in Kids With Atopic Comorbidities

New data from the Phase 3 VITESSE trial of the VIASKIN Peanut Patch (DBV Technologies) presented at the European Academy of Allergy and Clinical Immunology (EAACI) Congress 2026 in Istanbul, Turkey, show that the epicutaneous immunotherapy device produced statistically significant efficacy versus placebo in children aged 4 to 7 years with 

and ≥ 1 additional atopic condition. Response rates at 12 months ranged from 46.8% to 48.3% across subgroups defined by concomitant asthma, additional food allergies, or atopic dermatitis, all closely tracking the overall responder rate of 46.6% in the patch arm compared with 14.9% for placebo.

The findings are particularly meaningful given how well the enrolled population mirrors patients seen in real-world allergy practice. In VITESSE, atopic comorbidities were highly prevalent: 61.8% of the 654 randomized participants had atopic dermatitis, 56.6% had ≥ 1 additional food allergy, and 35.8% had asthma. For David Fleischer, MD, director of allergy and immunology at Children's Hospital Colorado, the composition of the trial population was not surprising.

"Most of our patients with food allergy often have atopic dermatitis. Many of them have other food allergies… [or] asthma,” Fleischer said in an interview with 

“It’s very reassuring to show that the typical patient we're going to see in our clinic was seen in this trial and that patients with these atopic conditions did well.”

The risk difference between the patch and placebo arms was largest in the atopic dermatitis subgroup, at 34.0 percentage points (95% confidence interval [CI], 25.09 to 42.94; response rates: 47.2 vs 13.2%), compared with 33.2 points in the food allergy subgroup (95% CI, 23.50 to 42.83; response rates: 46.8% vs 13.6%) and 28.8 points in the asthma subgroup (95% CI, 15.79 to 41.76; response rates: 48.3% vs 19.6%). Fleischer said the signal in the atopic dermatitis group, while notable, was consistent with the broader understanding of skin-mediated immunologic responses.

“While we think that atopic dermatitis sets patients up for developing food allergy because they can become sensitized to the skin, the skin can actually desensitize patients, meaning [it] actually [does] what it's supposed to do here by increasing the threshold of the amount that patients can tolerate,” Fleischer said. He added that the data confirm the patch is safe to use in this population and that the localized skin reactions associated with its use are typically self-resolving or manageable with topical steroids.

A recurring theme in Fleischer's assessment was the practical advantages of epicutaneous delivery in a patient population that is already complex to manage. Unlike oral immunotherapy, the VIASKIN Peanut Patch does not require dose holds during illness or exercise restrictions, which Fleischer described as meaningful for families juggling concurrent atopic conditions.

"Throwing a peanut patch, a cutaneous immunotherapy, into your treatment regimen, along with treating your eczema… [or] asthma, is not going to add a significant burden onto what you're already managing," Fleischer said. “It's really an easy product that’s practical and easy to use."

He also acknowledged that patients need to be prepared for a longer timeline to response and that patients need to be patient with the product. Fleischer said that expectation-setting with families is part of appropriate counseling.

Looking ahead, Fleischer said the next steps include publication of the data and submission of a US Food & Drug Administration (FDA) application. DBV Technologies announced in late February that the company plans to submit a biologics license application (BLA) to the FDA this year.

 A separate safety study in children aged 1 to 3 years, requested by the FDA, is also underway. Fleischer said that data, once available, will support an application to extend the indication to that age group.

“Hopefully by next year, 1–7-year-olds will have the opportunity to be treated with a very safe, effective treatment that's very practical for families,” he said.

Editor’s note: Relevant disclosures for Fleischer include DBV Technologies, ARS Pharmaceuticals; UpToDate, Bryn Pharma, Aquestive Therapeutics, Nasus, and Genentech, and Grow Happy.

Jonathan. DBV Technologies to Present New Positive Data from VITESSE Study and Preview Recently Initiated THRIVE Study at the EAACI Congress 2026 | DBV Technologies. Dbv-technologies.com. Published June 8, 2026. Accessed June 15, 2026. 

https://dbv-technologies.com/press_releases/dbv-technologies-to-present-new-positive-data-from-vitesse-study-and-preview-recently-initiated-thrive-study-at-the-eaaci-congress-2026/

Fleischer D. VIASKIN Peanut Patch Shows Strong Phase 3 VITESSE Results, With David Fleischer, MD. HCPLive. March 23, 2026. Accessed June 15, 2026. 

https://www.hcplive.com/view/viaskin-peanut-patch-shows-strong-phase-3-vitesse-results-david-fleischer-md

Phase 3 VITESSE subgroup data show response rates of 46% to 48% in children with peanut allergy and concomitant asthma, atopic dermatitis, or food allergies, says David Fleischer, MD.

2026 Society of Dermatology Physician Assistants (SDPA)

 editorial team spoke with Michelle Min, MD, MSCi, about the growing need for cross-specialty collaboration between dermatology and rheumatology clinicians during her session, “The Rheum-Derm Connection: Diagnostic and Therapeutic Pearls.”

Emerging therapies and ongoing phase 3 trials may significantly expand treatment options for patients with dermatomyositis, cutaneous lupus, and other rheumatologic skin diseases.

Dermatologists play a critical role in diagnosing autoimmune and connective tissue diseases, with clinical examination often providing insights beyond laboratory testing and biopsies.

Even when rheumatologists manage systemic disease, dermatologists can offer unique skin-directed treatments such as botulinum toxin for Raynaud phenomenon and hyaluronidase for scleroderma-associated microstomia.

Early recognition of rheum-derm conditions can be life-changing, as patients may initially present to dermatology with symptoms that mimic common disorders such as eczema or routine hair loss.

In this interview, Min highlighted the growing momentum in rheum-dermatology, pointing to emerging therapies for conditions such as dermatomyositis and cutaneous lupus. She noted that patients with skin manifestations of rheumatologic diseases historically have had limited 

-approved treatment options, but ongoing research and late-stage clinical development could significantly expand the treatment armamentarium.

Min also emphasized that dermatologists play a critical role in diagnosing autoimmune and connective tissue diseases, often identifying characteristic clinical findings before laboratory testing or biopsies provide definitive answers. The following Q&A interview highlights her responses to inquiries by 

 regarding the takeaways from this session at SDPA:

Are there any systemic agents you feel are important to highlight and that you hope clinicians are aware of, either recent or upcoming approvals?

Yeah, that's a great question. It's a really exciting time for room derm right now, because there are a lot of new treatments that are in phase 3. There's 1 that's even likely to get approved by the FDA this August for dermatomyositis. It's a TKY2, JAK1 inhibitor, brepocitinib. It'll probably be available on the market the first week of September, so we have a lot of exciting advancements coming for a long time. When it came to skin manifestations of rheumatologic diseases, we actually had nothing FDA-approved. So technically, we've had a hydroxychloroquine anti-malarial for systemic lupus. It's not actually, if you look at the package insert, approved for skin lupus, of course.

We do use it, and then IVIG got approved in 2021 for dermatomyositis, but before that we had nothing approved for dermatomyositis. So it's exciting because there's a lot of research, and I think this is changing. Another great example is we have anifrolumab that was also approved in the last few years for systemic lupus, but not cutaneous lupus. There are there's an ongoing phase 3 clinical trial right now specifically looking at cutaneous lupus, and I'm very hopeful that we'll get an FDA indication.

It's already a drug that we're using off-label to help our patients with skin lupus. We know there are many, many patients where the skin lupus is actually the only manifestation of their lupus, or they might have systemic lupus, but the systemic lupus is actually doing all right; it's the skin lupus that's not doing well. Again, as derms, as we have more medications available for us to prescribe. I think we need to be able to take back some of these patients, because no one's going to care about skin disease more than the patient, of course.

Were there any other notable clinical pearls that you wanted to highlight from your session at the SDPA meeting?

I really want to emphasize that the physical exam is so critical. Yes, biopsies can be helpful, additional lab tests can be helpful, but your clinical suspicion for a lot of these diseases trumps everything, and even for systemic diseases, again, derms can offer very unique treatments. A treatment that we'll talk about is botulinum toxin for Raynaud's phenomenon for severe systemic sclerosis patients. That's something that a rheumatologist is not going to be comfortable managing. Even as a [dermatology clinician], if you don't want to be the primary person managing systemic sclerosis, and that's understandable.

There are still treatments that you can offer as a dermatologist that a rheumatologist is not going to be able to. Another treatment that we'll be talking about is hyaluronidase injections around the mouth for scleroderma patients with oral microstomia. That's difficulty opening the mouth because the skin is so tight. Again, as derms, even if you're not the primary one prescribing a systemic medication that's outside of your comfort zone, being able to understand what we can offer that's unique from the rheumatologist is something that we're going to emphasize as well.

For any dermatologists, PAs, or NPs who are attending, would you point to a key takeaway you would like attendees to walk away from your talk with?

The one that I mentioned, that their physical exam is powerful. I think a lot of [dermatology clinicians] feel like a rheumatologist will be able to better differentiate some of these autoimmune diseases, because autoimmune diseases are primarily what they do. But you'd be surprised. And it shouldn't be the case. No one should understand skin diseases better than dermatologists. I also want to emphasize that rheumatologists are concerned about the patient as a whole.

I mean, we all are concerned about patients as a whole, but they're looking at lab values, how the heart and lungs are doing. Obviously, those are very important things, but there have been instances where a rheumatologist has reassured a patient with a rheumatoid condition, saying, ‘Hey, your labs look great. Yes, your skin disease, it's on your face, it's disfiguring, it's scarring, but you're not going to die.’ The patient obviously is very bothered by a disfiguring skin disease, and so again, as derms, skin is our baby; that's the organ that we're the most worried about. I think it's a mistake for us as dermatologists just to assume the rheumatologists are going to care about the skin disease or be as aggressive about skin disease as much as dermatologists would.

Were there any other notable elements of your session that you hope clinicians walk away with?

The other thing I want to emphasize is in dermatology, if a patient doesn't know their diagnosis, they may come to dermatology before they see rheumatology or primary care. If the primary problem is the skin, and a lot of times people come in thinking they have eczema but it's actually dermatomyositis, or they think that they have routine hair loss, but it's actually discoid lupus on the scalp.

You know, you never know what's going to land in your office, and I think it's really important for us to be equipped to be able to experience and be able to help make these diagnoses. [It’s also important] to make some of these rheum and derm diagnoses correctly early on. It can really be life-changing. We have a lot of power here to help patients, and we should remember that and utilize it.

Disclosures: Min had no relevant disclosures of note.

Min M. The Rheum-Derm Connection: Diagnostic and Therapeutic Pearls. Presented at SDPA Summer 2026. Jun 10-14, 2026.

Min M. Key Diagnostic and Therapeutic Pearls for Connective Tissue Disease, With Michelle Min, MD. HCPLive. June 14, 2026. 

https://www.hcplive.com/view/key-diagnostic-therapeutic-pearls-connective-tissue-disease-michelle-min-md

Cross-specialty collaboration between dermatology and rheumatology is increasingly essential as late-stage programs expand therapeutic options for dermatomyositis and cutaneous lupus, long areas with limited labeled treatments. Near-term regulatory activity includes a likely FDA approval of brepocitinib (TYK2/JAK1 inhibitor) for dermatomyositis, building on IVIG’s 2021 approval and broader lupus advances such as anifrolumab. Dermatologists’ pattern recognition and physical examination often drive earlier diagnosis than labs or biopsy, and dermatology-specific procedural interventions can materially improve morbidity in systemic sclerosis.

In her SDPA interview, Min discusses dermatology and rheumatology collaboration, exploring treatment options for connective tissue disease.

Diagnostic Pearls and New Therapies in Connective Tissue Disease, With Michelle Min, MD

Implications of the Phase 4 Trial of Metreleptin in Patients With General Lipodystrophy

The recently completed phase 4 analysis of the impact of drug-neutralizing antibodies created during metreleptin treatment on patient outcomes has provided a window into the efficacy of metreleptin and its clinical implications for 

 in Chicago, Illinois, by Elif Oral, MD, a professor in the Division of Metabolism, Endocrinology, and Diabetes at the University of Michigan, after the conclusion of the aforementioned phase 4 study, which was mandated by the 

 following metreleptin’s approval in 2014.1

“I think our new assay that was developed appears to be super sensitive and maybe detecting a signal that may not be clinically significant,” Oral told 

 in an exclusive interview. “Where do you draw the line of clinical significance? It’s only through studies like these, which are done longitudinally and followed over long periods of time, that we could potentially come up with the cutoff for clinical significance.”

Metreleptin is a recombinant analog of human leptin, differing from naturally produced leptin by an additional methionine. Administered by either a once or twice daily subcutaneous injection, metreleptin received approval for general lipodystrophy as an adjunct to diet in 2014 after demonstrating improvements to insulin resistance, diabetes, and hypertriglyceridemia.2

The current study implemented 2 separate assays to analyze anti-drug-antibody-positive patients. The first, an in vitro cell-based assay, was an established system measuring cell proliferation after exposure to metreleptin. The second, a more sensitive electro-chemiluminescent leptin receptor blocking (RB) assay, was largely developed for the purpose of the study, and ultimately provided what the team determined to be more accurate and informative data.1

The trial screened 11 patients, of whom 6 had congenital GL and 5 had acquired GL, and enrolled and assessed 10. Median duration of metreleptin exposure was 35.1 months (range, 4 days to 37.5 months; minimum-maximum dose, 1.25-7.5 mg/day). These patients were monitored for ≤36 months – Oral and colleagues took and tested serum samples for antibodies to both metreleptin and natural leptin via an immunoassay, conducted at months 1, 2, 4, 6, 9, 12, 18, 24, 30, and 36.1

Median time to peak titer for anti-drug antibodies was 4.2 months, compared to 6.6 months for RB neutralizing activity. Oral and colleagues saw a decline in anti-drug antibody response after peak titer in over half of patients, resolving in 1 patient. RB neutralizing activity also decreased after peak titer in ≥70% of antibody-positive patients, resolving in 5. The CB assay only detected neutralizing activity in 1 patient, who later tested negative at month 30.1

Ultimately, the team concluded that testing based on neutralizing antibody activity had confirmed that the RB assay was significantly more sensitive. Additionally, they failed to find a correlation between the neutralizing activity of these antibodies and treatment outcomes, indicating no need for further safety signals outside of what is currently known.1

Oral also addressed the lack of a consistent association between the neutralizing antibodies and loss of metabolic response. She noted that, while the current trial was unable to fully answer whether this lack of association will become a clinical issue, further research over longer periods of time will likely be capable of providing further information.

“Some of these answers, I think, will emerge over a longer period of time, and with the collation of more data now that this new assay is developed,” Oral said. “We’re actually compiling data that stands over a course of a decade and a half of patient trajectories, so I’m hoping that we’ll be able to give better answers to these questions soon.”

Editors’ Note: Oral reports disclosures with Ionis, Akcea, Regeneron, Third Rock Ventures, Amryt Pharmaceuticals, Novo Nordisk, and others.

Oral E, Christofides E, Wyne K, et al. A 36-Month, Multicenter, Open Label Phase 4 Study to Evaluate the immunogenicity of Daily Metreleptin Treatment in Patients with Generalized Lipodystrophy. Abstract presented at the Endocrine Society (ENDO) Annual Meeting 2026, Chicago, IL. June 13-15, 2026.

Chan JL, Koda J, Heilig JS, et al. Immunogenicity associated with metreleptin treatment in patients with obesity or lipodystrophy. Clin Endocrinol (Oxf). 2016;85(1):137-149. 

Elif Oral, MD, discusses the clinical implications of the recent data emphasizing metreleptin’s anti-drug antibodies and their llack of impact on efficacy.

New data suggest that tirzepatide (Zepbound) improves glycemic control and reduces body mass index (BMI) in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) with severe obesity, thereby improving renal transplant eligibility.

The poster was presented at the Endocrine Society (ENDO) Annual Meeting 2026 by Angel Mary Joseph, MBBS, MD, MRCP, Specialist Trainee Registrar at Leeds Teaching Hospitals NHS Trust. The findings underscore the potential to enhance quality of life and survival, as well as drive the development of new care pathways for this patient population.

Tirzepatide use in patients with T2DM, advanced CKD (dialysis or eGFR <18 mL/min/1.73 m²), and severe obesity was associated with clinically meaningful reductions in weight, BMI, and HbA1c over a mean 10-month follow-up. Mean weight fell from 112.7 to 102.6 kg, BMI from 41.2 to 37.5 kg/m², and HbA1c from 61.9 to 52 mmol/mol. Eight patients achieved BMI <35 kg/m², enabling renal transplant assessment eligibility, without severe hypoglycemia.

ENDO 2026 data suggest tirzepatide may improve renal transplant eligibility in patients with T2D, CKD, and severe obesity. 

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