H. Miles Prince, MD, MBBS, Professor at the University of Melbourne, Australia, and Director, Peter MacCallum Cancer Center, and Director of Molecular Oncology and Cancer Immunology, Epworth HealthCare describes the objectives and results of a new investigation which studied the previous results from the MAVORIC trial in patients with cutaneous T-cell lymphoma with those of patients in an Australian cancer registry.

The mogamulizumab versus vorinostat therapy in previously treated cutaneous T-cell lymphoma (MAVORIC) trial sought to compare the efficacy of the monoclonal antibody mogamulizumab against the standard of care (vorinostat) in patients with mycosis fungoides or Sézary syndrome, which together comprise cutaneous T-cell lymphoma (CTCL).

Patients were eligible if they had failed at least one previous systemic therapy. They were randomized to one of two treatment arms: mogamulizumab or vorinostat. Researchers found that the study was superior in terms of the main clinical endpoint of the study—progression-free survival (PFS) (7.7 mo vs. 3.1 mo; hazard ratio = 0.53; P less than .0001).

The study also included a crossover arm for patients who could not tolerate vorinostat or whose disease progressed. Total overall survival (OS) for the intent-to-treat population taking mogamulizumab was just less than 5 years, but the difference from the comparator group was not statistically significant, possibly due to the crossover arm, according to Dr. Prince. Yet, the regulatory authorities of several countries, including those in northern Europe and Australia, require OS as primary clinical endpoint when seeking market authorization.

To determine whether mogamulizumab exhibited a true OS benefit, his team of researchers evaluated an Australian cancer registry, seeking patients who took vorinostat and who fulfilled MAVORIC study inclusion criteria. Matched to those in the study arm of MAVORIC, they were able to confirm a distinct improvement in OS in those taking mogamulizumab.

The results of this research help fulfill the OS data requirements for regulatory approval of mogamulizumab, but it also raises questions as to whether it should be used first line, especially in patients with aggressive forms of CTCL. Furthermore, it might be interesting to consider mogamulizumab as a foundation for drug combinations in managing this difficult-to-treat cancer.

CHAPTERS
Introduction 00:00
Mogamulizumab Clinical Trial 00:35
Role in Relapsed/Refractory Mycosis Fungoides and Sézary Syndrome 3:24
Influencing Treatment Decisions and Research Efforts 4:53
Regulatory Impact 6:43

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Lena Specht, MD, DMSc, Professor of Clinical Oncology, and Chief Oncologist at Rigshopitalet, University of Copenhagen, Denmark, discusses her Danish study supporting the use of mogamulizumab in Danish patients with CTCL.

Mogamulizumab was approved in 2018 in Europe based on the results of the MAVORIC trial, which was a randomized study comparing progression-free survival outcomes against vorinostat, an FDA-approved treatment, in patients with CTCL.

Vorinostat was never approved in Europe, because it was associated with data issues and was not considered a valid study comparator. As a result, the Danish regulatory authorities approved mogamulizumab for use only after a trial of one prior line of systemic chemotherapy. In comparison, the US FDA approved mogamulizumab for use as first-line treatment of CTCL.

Dr. Specht’s group of researchers attempted to compare the randomized phase 3 trial comparing mogamulizumab and the Danish standard of care by utilizing the MAVORIC study data along with data from a real-world registry of Danish patients with CTCL from 1996 to 2024. They selected comparator patients from the registry according to MAVORIC inclusion criteria (including patients with either myocosis fungoides or Sézary syndrome who failed at least one line of systemic therapy). In addition, they evaluated data from the vorinostat arm in MAVORIC (i.e., those patients who did not switch over to mogamulizumab therapy).

The main outcome of interest was overall survival. They found overall survival to be longer (with a statistically significant difference) for those receiving mogamulizumab first line compared with the Danish patients with CTCL in the real-world registry. Although making treatment comparisons using nonrandomized patient data is problematic, Dr. Specht and her researchers were reassured that there was not any significant difference in the outcomes of those in the vorinostat treatment arm of MAVORIC and in the Danish registry population receiving standard of care.

Normally, Sézary syndrome is very difficult to treat, but mogamulizumab seems to work better in these patients than in those with mycosis fungoides, which is generally considered a less-aggressive cancer. According to Dr. Specht, this is a strong argument for first-line access to mogamulizumab in patients with Sézary syndrome.

CHAPTERS
Introduction 00:00
Mogamulizumab Clinical Trial 00:58
Key Findings in Overall Survival 3:15
Patient Subgroup Analysis 4:29
Key Takeaway 6:11

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Christiane Querfeld, MD, PhD, dermatologist and and Director, Multidisciplinary Cutaneous Lymphoma Program, Professor at the City of Hope National Medical Center and the Beckman Research Institute, discusses the results of a new drug trial that increased the dosing interval of mogamulizumab in patients with CTCL.

Currently, treatment with the oncolytic agent mogamulizumab-kpkc (Poteligeo) in patients with Sézary syndrome and mycosis fungoides, which is collectively called cutaneous T-cell lymphoma (CTCL), consists of weekly infusions during the first month of therapy, followed by double doses administered twice monthly. A new trial, called the MOGA-2 mg q4w study, sought to evaluate the effectiveness and safety of mogamulizumab given by weekly infusions for the first month, followed by once monthly injections of 2-mg doses, for each subsequent month.

Another aspect of the study is to gather data around the appearance of a rash that is associated with mogamulizumab use. This seems to be an indication of an “immune flare,” which varies in severity by patient but can be debilitated in those most affected. Dr. Querfeld pointed out that the rash is more common in patients who respond to mogamulizumab therapy than those with do not.

By reducing the number of infusions, this may improve patient’s quality of life and lessen the transportation burden on patients and their caregivers. The key, according to Dr. Querfeld, is using the data obtained from the study to determine if certain subgroups of patients respond favorably to this regimen. She hopes these cohorts may be identified by their gene signatures, or classifications of variants in multiple genes.

Currently, 65 gene mutations have been identified as drivers of CTCL. The trial found that patients who responded well to the modified mogamulizumab regimen had more mutations compared with nonresponders.

It is thus critical for any diagnosed patient to have their skin biopsied and evaluated on a molecular level, identifying gene mutations, and especially CCR4 status. It will allow patients earlier access to personalized, targeted medicine, and perhaps optimally effective treatment.

CHAPTERS
Introduction 00:00
MOGA-2MG-Q4W Clinical Trial 00:39
Determining Patients Most Likely to Benefit 6:31
The Future of Personalized Care 8:18
Key Takeaway for Physicians 9:28
Next Steps 10:52

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Oksana Hamidi, DO, Associate Professor at the University of Texas Southwestern Medical Center, discusses 2-year data on crinecerfont for the treatment of patients with congenital adrenal hyperplasia (CAH).

CAH refers to a group of genetic conditions that affect the adrenal gland production of hormones, particularly, the production of cortisol and androgen hormones. Persons with severe forms of the condition can be dramatically impacted. For example, females with a severe form of the condition may have ambiguous genitalia at birth and if not properly diagnosed, develop dehydration, poor feeding, diarrhea, vomiting and other health problems soon after. People with milder forms may not be diagnosed with the condition until adolescence or adulthood when they experience early signs of puberty or fertility problems. Excess androgens can also cause accelerated bone age maturation, leading to reduced adult height.

Crinecerfont Improves Weight-Related Outcomes and Insulin Resistance in Adults with Classic CAH: 2-Year Results from the CAHtalyst Adult Study

This study evaluated outcomes related to body weight and insulin resistance (IR) in CAHtalyst Adult (NCT04490915) participants who received up to 2 years of crinecerfont. Crinecerfont is a first-in-class corticotropin releasing factor type 1 receptor antagonist that is approved by the US Food and Drug Administration (FDA) as an adjunct to glucocorticoid replacement to control androgens in patients with classic CAH, including both salt-wasting and simple virilizing forms, thereby enabling glucocorticoid dose reduction.

A total of 182 randomized participants had a baseline mean daily glucocorticoid dose of 17.6 mg/m2/d hydrocortisone equivalents (HCe). At baseline, mean body weight was 79.3 kg, mean BMI was 29.8 kg/m2 and 71% were overweight or obese. Mean homeostatic model assessment of insulin resistance (HOMA-IR) was 3.2 and 42% had IR. Glucocorticoid dose decreased from baseline by a mean±SEM of -37±1% to 10.9±0.3 mg/m2/d HCe at month 12 and was maintained at month 24. In all participants, mean reductions from baseline in weight and BMI at month 12 were sustained at month 24.

Sustained reductions in BMI were also observed in participants who were overweight or obese at baseline, and 31% and 38% of this subgroup achieved greater than 5% reduction in weight at months 12 and 24, respectively. At both time points, these participants had mean decreases in fat mass exceeding that in lean mass, with reductions of -1.5±0.5 kg versus -0.8±0.2 kg, respectively, at month 12 and -1.6±0.7 kg versus -0.8±0.3 kg, respectively, at month 24. Mean reductions from baseline in HOMA-IR were sustained from month 12 and month 24 in all participants overall and in participants with IR at baseline.

Crinecerfont was well tolerated, and no new safety signals were observed during long-term treatment.

Adults with Classic CAH Taking Crinecerfont Demonstrated Sustained Decreases in Glucocorticoid Doses: 2-Year Results from the Cahtalyst Adult Study
This study evaluated changes in glucocorticoid doses in adults who received up to 2 years of crinecerfont in the phase 3 CAHtalyst Adult trial (NCT04490915).

Of a total of 182 enrolled participants, the mean total daily glucocorticoid dose at baseline was 17.6 mg/m2/d, and mean androstenedione after morning glucocorticoid dose was 349 ng/dL. The mean percent change from baseline in glucocorticoid dose while maintaining or improving androstenedione relative to baseline was -26% at month 12, -28% at month 18, and -25% at month 24.

Additionally, 45% of participants achieved a glucocorticoid dose of 11 mg/m2/d or less while maintaining or improving androstenedione at month 24. The observed mean percent decrease from baseline in glucocorticoid dose (without imputation based on androstenedione) was -38% at month 18 and -38% at month 24, with observed mean glucocorticoid doses of 10.6 mg/m2/d at month 18 and 10.6 mg/m2/d at month 24. In addition, 71% and 69% of participants achieved a glucocorticoid dose in the physiologic range at months 18 and 24, respectively, without imputation based on androstenedione. Even with these decreases in glucocorticoid dose, mean changes from baseline in androstenedione were -11.5 ng/dL at month 18 and 56.6 ng/dL at month 24.

Crinecerfont was overall well tolerated and no new safety signals were observed during long-term treatment.

To learn more about CAH and other rare endocrine disorders, visit https://checkrare.com/diseases/endocrine-disorders/

CHAPTERS
Introduction 00:00
Cardiometabolic Problems in CAH 00:13
Disease Severity and Treatment Effectiveness 1:05
2-Year Data on Crinecerfont 2:16
Next Steps 6:20

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Elif Oral, MD, Professor at the University of Michigan, discusses advances in lipodystrophy research presented at ENDO 2026.

Lipodystrophies are rare metabolic disorders characterized by the loss of adipose tissue. This leads to complications such as insulin resistance, diabetes mellitus, hypertriglyceridemia, and fatty liver. Lipodystrophies generally begin in childhood and have an underlying autoimmune component associated with its etiology. The disorder can be genetic or acquired. Symptoms that may indicate lipodystrophy include thin arms and legs, prominent muscular veins, cutaneous fat around the abdomen, and difficult to treat diabetes. Current management of patients includes cosmetic surgery, diet, and drug therapy for control of diabetes and dyslipidemia. Leptin replacement therapy is the only lipodystrophy-specific treatment.

New research presented at ENDO 2026 highlighted progress in the treatment, diagnosis, and clinical understanding of lipodystrophy, with studies examining long-term metreleptin therapy, ongoing clinical trials in partial lipodystrophy, disease characterization, and new approaches to earlier diagnosis.

Long-term findings from a 36-month phase 4 study evaluated the immunogenicity of metreleptin in patients with generalized lipodystrophy (GL). Although most participants developed anti-drug antibodies and transient neutralizing antibody activity, these responses generally declined over time and did not appear to have a lasting impact on treatment safety or metabolic efficacy. The findings provide additional reassurance regarding the long-term use of metreleptin despite the development of immune responses.

Researchers also presented baseline data from the METRE-PL phase 3 trial, the first randomized, placebo-controlled study evaluating metreleptin in familial partial lipodystrophy (FPLD). The enrolled population demonstrated a substantial metabolic disease burden, with nearly all patients having diabetes or hypertriglyceridemia and many experiencing complications such as pancreatitis and diabetic neuropathy. The ongoing trial will determine whether metreleptin can improve glycemic control and triglyceride levels in this underserved patient population.

Data from the LD-Lync natural history study revealed important differences between acquired and genetic forms of lipodystrophy. While patients with genetic lipodystrophy experienced higher rates of metabolic complications—including hypertriglyceridemia, fatty liver disease, and polycystic ovary syndrome—those with acquired lipodystrophy were more likely to have autoimmune disorders, inflammatory conditions, and cancer, often diagnosed at younger ages. These findings emphasize the need for subtype-specific management strategies, including greater attention to cancer surveillance and immune evaluation in acquired disease.

Finally, investigators from the RADIANT study reported a new clinical prediction model designed to identify lipodystrophy among patients with atypical diabetes using routinely collected clinical and laboratory data. The model demonstrated high specificity while maintaining good sensitivity after threshold adjustment, suggesting it could serve as an effective screening tool to help clinicians recognize patients who may benefit from specialized evaluation and genetic testing. Researchers noted that future refinements incorporating biomarkers and genomic data may further improve diagnostic accuracy.

Together, these studies presented at ENDO 2026 underscore continued progress in improving the diagnosis and management of lipodystrophy. From supporting the long-term safety profile of metreleptin to advancing clinical trials, refining disease characterization, and developing practical screening tools, the research reflects a growing effort to enable earlier diagnosis and more personalized care for patients with these rare disorders.

To learn more about lipodystrophy and other rare metabolic disorders, visit https://checkrare.com/diseases/metabolic-disorders/

CHAPTERS
Introduction 00:00
Lipodystrophy Treatment History 00:11
Lipodystrophy Overview 1:58
Research Presented at ENDO 2026 3:28
Recognizing Different Types of Lipodystrophy 9:23
Acknowledging Patients 12:26

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Evelien Gevers, PhD, MD, Consultant Pediatrician and Reader in Endocrinology and Diabetes at Barts Health NHS Trust, discusses effects of diazoxide choline extended release (DCCR) on hyperphagia in patients with Prader-Willi syndrome (PWS).

PWS is a rare genetic condition that affects many parts of the body but its most dominant symptom is overwhelming hyperphagia. Infants with PWS also have severe hypotonia, feeding difficulties, slow growth, short stature, hypogonadism, developmental delays, cognitive impairment, and distinctive behavioral characteristics such as temper tantrums, stubbornness, and obsessive-compulsive tendencies. PWS is caused by missing or non-working genes on chromosome 15.

An abstract presented at ENDO 2026 evaluated long-term reductions in hyperphagia with DCCR in patients with PWS. DCCR is a potent activator of the adenosine triphosphate (ATP)-sensitive potassium channel. It was approved in March 2025 by the US Food and Drug Administration (FDA) as a treatment for hyperphagia in patients 4 years of age and older with PWS.

Results for up to 3 years from participants who received DCCR compared to real-world natural history data from the PATH for PWS study (PATH) were included.

A total of 352 participants were evaluated. Baseline Hyperphagia Questionnaire for Clinical Trials (HQ-CT) total scores were 21.6 ± 6.7 and 18.2 ± 5.0 for DCCR and PATH groups. Significant reductions in hyperphagia occurred at all time points for DCCR compared to the PATH cohort. Change in HQ-CT from Baseline between DCCR and PATH was -6.2 at year 1, -6.5 at year 2, and -6.2 at year 3.

To learn more about PWS and other rare endocrine conditions, visit https://checkrare.com/diseases/endocrine-disorders/

CHAPTERS
Introduction 00:00
Prader-Willi Syndrome Overview 00:25
Early Signs and Symptoms 1:11
Diagnostic Challenges 1:54
Current Treatment 3:23
Diazoxide Choline Extended Release Clinical Trials 3:51
Measuring Hyperphagia 11:20
The Future of Prader-Willi Treatment 12:47

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Robert Rapaport, MD, Professor of Pediatric Endocrinology, and Director of the Comprehensive Growth Center at the Icahn School of Medicine, Mount Sinai Medical Center, New York City, discussed the differences between severe, primary IGF-1 deficiency and growth hormone (GH) deficiency in patients with short stature.

In young patients with short stature, GH deficiency is the most common cause. However, in a small subset of patients, the underlying problem is not GH deficiency but an abnormality in insulin-like growth factor-1 (IGF-1) levels. This peptide hormone was first discovered 50 years ago, and IGF-1 deficiency has been found to be caused by mutations in the GH receptor and defects in the IGF-1 gene. In patients with a specific subtype of severe, primary IGF-1 deficiency (SPIGF1D) called Laron syndrome, the specific cause is GH-receptor mutations.

Severe, primary IGF-1 deficiency is generally associated with the following patient characteristics: severe postnatal growth failure, short limb length, typical facial features (e.g., small forehead), and delays in sexual development and skeletal maturation. Crucially, affected children do not respond to a GH stimulation test.

Patients who have abnormally low GH levels can also be considered IGF-1 deficient. On the other hand, if the patient has normal GH levels, IGF-1 concentrations may still be abnormally low. According to Dr. Rapaport, patients with IGF-1 deficiency may be found to have abnormal IGF-1 levels across a spectrum from borderline low to extremely low, the latter of which represents the main feature of SPIGF1D (IGF-1 levels are 5–6 standard deviations below the mean for healthy individuals).

The only effective treatment for SPIGF1D is IGF-1 supplementation, with mecasermin, a human recombinant IGF-1 preparation. Although mecasermin is proven to increase patients’ growth velocity, patients taking the product are expected to attain “near normal” adult height only. It is given twice daily, and it does carry a risk of hypoglycemia, as IGF-1 lowers blood glucose levels. It is thus important that patients and their caregivers are well educated about avoiding this dangerous adverse effect.

CHAPTERS
Introduction 00:00
Primary IGF-1 Deficiency Overview 00:44
Severe IGF-1 Deficiency 3:32
Diagnosis in Children 4:42
Treatment for Severe IGF-1 Deficiency 5:29
Safety Considerations 8:07
Unmet Needs 8:56
Take Home Message 9:36

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Robert Rapaport, MD, Professor of Pediatric Endocrinology, and Director of the Comprehensive Growth Center at the Icahn School of Medicine, Mount Sinai Medical Center, New York City, discussed the differences between severe, primary IGF-1 deficiency and growth hormone (GH) deficiency in patients with short stature.

In young patients with short stature, GH deficiency is the most common cause. However, in a small subset of patients, the underlying problem is not GH deficiency but an abnormality in insulin-like growth factor-1 (IGF-1) levels. This peptide hormone was first discovered 50 years ago, and IGF-1 deficiency has been found to be caused by mutations in the GH receptor and defects in the IGF-1 gene. In patients with a specific subtype of severe, primary IGF-1 deficiency (SPIGF1D) called Laron syndrome, the specific cause is GH-receptor mutations.

Severe, primary IGF-1 deficiency is generally associated with the following patient characteristics: severe postnatal growth failure, short limb length, typical facial features (e.g., small forehead), and delays in sexual development and skeletal maturation. Crucially, affected children do not respond to a GH stimulation test.

Patients who have abnormally low GH levels can also be considered IGF-1 deficient. On the other hand, if the patient has normal GH levels, IGF-1 concentrations may still be abnormally low. According to Dr. Rapaport, patients with IGF-1 deficiency may be found to have abnormal IGF-1 levels across a spectrum from borderline low to extremely low, the latter of which represents the main feature of SPIGF1D (IGF-1 levels are 5–6 standard deviations below the mean for healthy individuals).

The only effective treatment for SPIGF1D is IGF-1 supplementation, with mecasermin, a human recombinant IGF-1 preparation. Although mecasermin is proven to increase patients’ growth velocity, patients taking the product are expected to attain “near normal” adult height only. It is given twice daily, and it does carry a risk of hypoglycemia, as IGF-1 lowers blood glucose levels. It is thus important that patients and their caregivers are well educated about avoiding this dangerous adverse effect.

0 0

Robert Rapaport, MD, Professor of Pediatric Endocrinology, and Director of the Comprehensive Growth Center at the Icahn School of Medicine, Mount Sinai Medical Center, New York City, discussed the differences between severe, primary IGF-1 deficiency and growth hormone (GH) deficiency in patients with short stature.

In young patients with short stature, GH deficiency is the most common cause. However, in a small subset of patients, the underlying problem is not GH deficiency but an abnormality in insulin-like growth factor-1 (IGF-1) levels. This peptide hormone was first discovered 50 years ago, and IGF-1 deficiency has been found to be caused by mutations in the GH receptor and defects in the IGF-1 gene. In patients with a specific subtype of severe, primary IGF-1 deficiency (SPIGF1D) called Laron syndrome, the specific cause is GH-receptor mutations.

Severe, primary IGF-1 deficiency is generally associated with the following patient characteristics: severe postnatal growth failure, short limb length, typical facial features (e.g., small forehead), and delays in sexual development and skeletal maturation. Crucially, affected children do not respond to a GH stimulation test.

Patients who have abnormally low GH levels can also be considered IGF-1 deficient. On the other hand, if the patient has normal GH levels, IGF-1 concentrations may still be abnormally low. According to Dr. Rapaport, patients with IGF-1 deficiency may be found to have abnormal IGF-1 levels across a spectrum from borderline low to extremely low, the latter of which represents the main feature of SPIGF1D (IGF-1 levels are 5–6 standard deviations below the mean for healthy individuals).

The only effective treatment for SPIGF1D is IGF-1 supplementation, with mecasermin, a human recombinant IGF-1 preparation. Although mecasermin is proven to increase patients’ growth velocity, patients taking the product are expected to attain “near normal” adult height only. It is given twice daily, and it does carry a risk of hypoglycemia, as IGF-1 lowers blood glucose levels. It is thus important that patients and their caregivers are well educated about avoiding this dangerous adverse effect.

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