новости эндокринологогии-2

[Melnichenko]

Autoimmune polyendocrine syndrome type 1 (APS-1) responded to ruxolitinib (Jakafi) in a small study, researchers said, offering hope that one drug can relieve most of the symptoms of this rare but devastating disorder.

Five patients with APS-1 went into remission after starting the Janus kinase (JAK) inhibitor, with tests affirming that the treatment normalized interferon-γ, a defining biomarker in the condition, reported Michail Lionakis, MD, ScD, of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, and colleagues in the New England Journal of Medicineopens in a new tab or window.

Ruxolitinib was chosen somewhat arbitrarily for this pioneering study, as any of the eight approved JAK inhibitors would be expected to dampen interferon-γ, and other classes of immunomodulatory drugs may have similar effects. Consequently, Lionakis and colleagues didn't push ruxolitinib specifically as a promising APS-1 treatment. Rather, they concluded that the new study merely "provides the foundation for therapies that affect interferon-γ-mediated disease."

In an accompanying "Science Behind the Study" commentary, a researcher from the University of California Los Angeles agreed. "These results support the testing of JAK inhibitors as potential first-line immunotherapies for APS-1 in clinical trials," wrote Maureen Su, MD.

Indeed, the researchers' main goal was to elucidate more fully the pathophysiology of APS-1, a genetic disease in which, as the researchers explained, "self-reactive T cells escape to the periphery, infiltrate organs, and drive autoimmune damage." Almost any organ system may be affected: in the five patients treated in this study, symptoms included alopecia, thrush, malformed nails, gastrointestinal issues and nutrient malabsorption, arthritis, thyroiditis, urticaria, and anemia, and the specific constellation differed from one patient to another.

Previous studiesopens in a new tab or window have showed mortality rates in APS-1 of up to 30%, and treatment heretofore has focused on the specific symptoms. As Su explained in her commentary, "the [current] goals of medical management center on regular screening for the development of new clinical manifestations, hormone replacement for endocrine disease, and immunotherapies targeted at specific non-endocrine autoimmune conditions (i.e., hepatitis, pneumonitis, and pancreatitis). However, an immunotherapeutic approach is not yet available that broadly treats the many disease manifestations associated with [APS-1]."

Although the specific genetic defect underlying the disorder was known -- expressed as deficiency in an immunoregulatory protein called AIREopens in a new tab or window -- the exact steps by which it produces autoimmune pathology and organ involvement were not. Lionakis and colleagues first performed studies in AIRE-knockout mice, from which the group determined that excessive interferon-γ release was a critical driver. Knowing that interferon-γ expression is mediated by JAK activity, the researchers turned to ruxolitinib, a JAK inhibitor available from the NIH Clinical Center's pharmacy, to test first in their mouse model and then in patients.

The five patients included two middle-age U.S. adults (one man, one woman) and three adolescents from Europe (a boy and two girls). All suffered from bowel dysfunction, although in two patients it manifested as severe constipation while others had diarrhea. Beyond that, as noted earlier, their symptom sets differed considerably. But they all showed high levels of interferon-γ.

Ruxolitinib was started at 5 mg twice daily in four of the patients; for reasons not explained in the published paper, the fifth (the American man) received a starting dose of 5 mg three times weekly. Patients were followed for 8 to 12 months while on the drug. Notably, these doses were far less than allowed under the drug's FDA-approved label, which carries a maximum of 25 mg twice daily.

In all cases, their symptoms resolved, though not always right away, and some patients needed higher doses to reach full remission. The American man, for example, eventually took the drug at 15 mg three times weekly, and a 12-year-old boy had his dose raised to 10 mg twice daily before his diarrhea finally normalized. Interferon-γ was normalized in all patients.

APS-1 had left the adolescents undersized. A 12-year-old boy and a 15-year-old girl each weighed less than 30 kg when starting treatment, while an 11-year-old girl weighed about 36 kg. Once on the drug, all three showed marked gains, reaching nearly 60 kg in the boy's case.

Future research should examine other JAK inhibitors such as tofacitinib (Xeljanz), Lionakis and colleagues wrote, as well as the biologic drug emapalumab (Gamifant)opens in a new tab or window that neutralizes interferon-γ directly. The investigators also noted that dosing might be further optimized.

[Melnichenko]

n December, the U.S. Food and Drug Administration (FDA) approved crinecerfont capsules and oral solution adjunctive treatment to glucocorticoid replacement to control androgens in adult and pediatric patients four years of age and older with classic congenital adrenal hyperplasia (CAH).

Crinecerfont is a selective oral corticotropin-releasing factor type 1 receptor (CRF1) antagonist that directly reduces excess adrenocorticotropic hormone (ACTH) and downstream adrenal androgen production, allowing for glucocorticoid dose reduction. Neurocrine Biosciences is marketing the drug as CRENESSITY.

The FDA approval is supported by the largest-ever clinical trial program of classic CAH, the CAHtalyst Pediatric and Adult Phase 3 global registrational studies. CAHtalyst Phase 3 data results in pediatric and adult patients with classic CAH were published in The New England Journal of Medicine.

In both CAHtalyst studies, CRENESSITY enabled lower steroid doses and decreased androgen levels.

Phase 3 CAHtalyst Pediatric Study:

The CAHtalyst Pediatric study met its primary endpoint, with CRENESSITY significantly decreasing androstenedione levels from baseline to Week 4 versus patients taking placebo who experienced a substantial increase in androstenedione levels.
Children taking CRENESSITY were also able to significantly reduce their GC doses at Week 28 while maintaining or improving androgen levels, a key secondary endpoint.
Children taking CRENESSITY saw approximately four times greater reduction in androstenedione compared with those taking placebo.
Approximately four times greater steroid dose reduction in children taking CRENESSITY was seen compared with those taking placebo.
Children taking CRENESSITY saw approximately 12 times greater reduction in 17-hydroxyprogesterone (17-OHP) compared with those taking placebo.
Headache, abdominal pain, fatigue, nasal congestion and nosebleed were the most common adverse drug reactions (ADRs) among the pediatric population treated with CRENESSITY. Most side effects were temporary and mild to moderate in severity.
“In this phase 3 trial,” the authors write in their conclusion, “crinecerfont was superior to placebo in reducing elevated androstenedione levels in pediatric participants with CAH and was also associated with a decrease in the glucocorticoid dose from supraphysiologic to physiologic levels while androstenedione control was maintained.

“Chronic treatment with supraphysiologic glucocorticoids can cause a number of short- and long-term health consequences, such as obesity, hypertension, and osteoporosis, so the ability for patients with CAH to lower their glucocorticoid dose to a more physiologic level can have profound benefits.” – Richard Auchus, MD, PhD, professor, University of Michigan Health

Phase 3 CAHtalyst Adult Study:

The CAHtalyst Adult study met its primary endpoint with CRENESSITY enabling significant GC dose reductions at Week 24 (while maintaining or improving baseline androstenedione levels) and key secondary endpoint of decreasing androstenedione levels at Week 4.
A significantly higher number of patients taking CRENESSITY (63%) achieved a GC dose in the physiologic range while androstenedione was maintained or improved compared with patients taking placebo (18%).
Approximately two times greater steroid dose reduction was seen in people taking CRENESSITY compared with those taking placebo.
People taking CRENESSITY saw an eight times greater reduction in androstenedione compared with those taking placebo.
People taking CRENESSITY saw a 37 times greater reduction in 17-OHP compared with those taking placebo.
Fatigue, headache, dizziness, joint pain, back pain, decreased appetite and muscle pain were the most common ADRs in the CRENESSITY treatment group. Most side effects were temporary and mild to moderate in severity.
The authors conclude: “Among patients with CAH, the use of crinecerfont resulted in a greater decrease from baseline in the mean daily glucocorticoid dose, including a reduction to the physiologic range, than placebo following evaluation of adrenal androgen levels.”

“The clinical results across both CAHtalyst studies support the efficacy and safety profile of CRENESSITY and its ability to reduce the overproduction of adrenal androgens, allowing for a meaningful reduction in glucocorticoid dosage, while maintaining or enhancing control of these androgens,” says Richard Auchus, MD, PhD, a professor at the University of Michigan Health, and principal investigator. “Chronic treatment with supraphysiologic glucocorticoids can cause a number of short- and long-term health consequences, such as obesity, hypertension, and osteoporosis, so the ability for patients with CAH to lower their glucocorticoid dose to a more physiologic level can have profound benefits.”

[FilippovaYulia]

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