Breakthrough Clinical Results
Soleno Therapeutics announced poster presentations on its VYKAT XR (diazoxide choline) extended-release tablets at the Pediatric Endocrine Society (PES) Meeting 2025. VYKAT XR is approved for treating hyperphagia in adults and pediatric patients (4 years and older) with Prader-Willi syndrome (PWS). The presentations will cover long-term administration effects on lean body mass and the impact of resuming treatment after a withdrawal period. PWS is a rare disorder characterized by hyperphagia, leading to significant health risks. VYKAT XR offers a once-daily oral treatment option for this debilitating symptom.
Key Highlights
- Poster presentations on VYKAT XR (diazoxide choline) at PES 2025 will cover long-term administration and treatment resumption after withdrawal.
- VYKAT XR is approved for treating hyperphagia associated with Prader-Willi syndrome (PWS).
- PWS is a rare disorder with hyperphagia as a hallmark symptom, posing significant health risks.
- VYKAT XR is a once-daily oral treatment commercially available in the US.
Incidence and Prevalence
Incidence:
The incidence of Prader-Willi syndrome (PWS) is estimated to be between 1 in 10,000 and 1 in 30,000 live births globally. Several studies have reported varying incidence rates:
- A study in France estimated the birth incidence of PWS at 1/21,000 births in 2013.
- A study in Victoria, Australia, estimated the birth prevalence for individuals with a molecular diagnosis of PWS to be 1:15,830 for the period 2003-2012.
- A study in Flanders estimated the birth incidence for the period 1993-2001 at 1:26,676.
- A study in Estonia estimated the minimum live birth prevalence for PWS at 1:30,439 for the period 1984-2004.
- A study in the San-in district of Japan estimated the incidence among live births at 1 in 15,060 for the period 1980-1989.
Prevalence:
The prevalence of PWS is difficult to determine precisely due to factors such as underdiagnosis, variations in diagnostic criteria, and mortality. Several studies have reported varying prevalence rates:
- A study in Flanders estimated the minimum prevalence of PWS at 1:76,574 on December 31, 2001.
- A study in the San-in district of Japan estimated the prevalence at 1 in 17,483 in patients under 15 years old.
Factors Affecting Incidence and Prevalence:
Several factors can influence the reported incidence and prevalence of PWS:
- Advances in diagnostic techniques: The availability of molecular genetic testing has improved the accuracy and timeliness of diagnosis, potentially leading to higher reported rates in recent years.
- Increased awareness: Greater awareness of PWS among healthcare professionals may also contribute to higher detection rates.
- Geographic variations: Incidence and prevalence may vary across different regions and populations due to genetic and environmental factors.
- Maternal age: Some studies have suggested a possible link between advanced maternal age and an increased risk of PWS, particularly for the maternal uniparental disomy subtype.
- Mortality: The mortality rate in individuals with PWS is higher than in the general population, which can affect prevalence estimates, especially in older age groups.
It is important to note that these are estimates, and the actual incidence and prevalence of PWS may vary. Further research is needed to obtain more precise and globally representative data.
Risk Factors and Comorbidities
Prader-Willi syndrome (PWS) is not caused by risk factors in the traditional sense, but rather by genetic mechanisms. The primary "causes" are genetic errors affecting the paternal copy of chromosome 15. It's important to distinguish between risk factors for a condition (things that increase the likelihood of developing it) and the actual underlying causes. Here's a breakdown:
Underlying Genetic Causes of PWS:
- Paternal Deletion (DEL): About 70% of PWS cases are due to a deletion of a specific region (15q11-q13) on the paternally inherited chromosome 15. This is the most common cause.
- Maternal Uniparental Disomy (UPD): Approximately 20-30% of cases result from inheriting two copies of chromosome 15 from the mother and no copy from the father.
- Imprinting Defect: A small percentage (1-3%) of cases are caused by errors in the imprinting process. Imprinting is a normal mechanism where certain genes are expressed depending on whether they are inherited from the mother or father. In PWS, an imprinting defect disrupts the normal paternal gene expression in the 15q11-q13 region.
Factors Potentially Associated with Increased Risk of Specific PWS Genetic Subtypes:
While the genetic errors causing PWS are generally random, some factors have been suggested as potentially increasing the risk of specific subtypes, particularly UPD:
- Advanced Maternal Age: Some studies have suggested a possible link between advanced maternal age and an increased risk of maternal UPD, although this is not a strong risk factor like it is for some other chromosomal abnormalities (e.g., Down syndrome).
- Assisted Reproductive Technology (ART): While some initial studies suggested a possible link between ART and PWS, larger studies have not confirmed this association. There may be a slightly higher proportion of UPD cases in PWS individuals born after ART, but the overall incidence of PWS is not higher in the ART population.
It's crucial to emphasize that these are not risk factors for PWS in general, but rather potential associations with specific genetic subtypes. The vast majority of PWS cases occur spontaneously, regardless of parental age or use of ART.
Comorbidities Associated with PWS:
Comorbidities are conditions that frequently occur alongside PWS. These are not causes of PWS, but rather health problems that individuals with PWS are more likely to experience:
- Obesity: The hallmark of PWS is hyperphagia (excessive hunger) leading to severe obesity if food intake is not strictly controlled. This is a direct consequence of the genetic defect and not a risk factor for developing PWS.
- Type 2 Diabetes Mellitus: Due to obesity, individuals with PWS are at significantly increased risk of developing type 2 diabetes.
- Obstructive Sleep Apnea (OSA): OSA is very common in PWS, likely due to a combination of obesity, hypotonia (low muscle tone), and central breathing abnormalities.
- Scoliosis: Spinal curvature (scoliosis) is frequently seen in PWS, possibly related to hypotonia and low muscle mass.
- Osteoporosis: Low bone density (osteoporosis) is more common in PWS, potentially due to multiple factors including hormonal imbalances, low physical activity, and nutritional deficiencies.
- Mental Health Conditions: Individuals with PWS are at increased risk for various mental health problems, including anxiety, obsessive-compulsive disorder (OCD), and psychosis.
- Other Endocrine Problems: PWS can involve several hormonal imbalances, including growth hormone deficiency, hypogonadism (underactive sex glands), and hypothyroidism (underactive thyroid).
These comorbidities are important to consider in the management of PWS, as they can significantly impact an individual's health and well-being.
Recent Studies
Several studies have investigated different interventions for Prader-Willi syndrome (PWS), focusing on various aspects of the condition, including hyperphagia, behavioral problems, and growth. Here's a summary of a few recent studies, including their interventions and key outcomes:
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GLWL-01 for Hyperphagia:
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Study Name: Phase 2 crossover study of GLWL-01 in PWS
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Intervention: GLWL-01 (450 mg twice daily), a selective ghrelin O-acyltransferase (GOAT) inhibitor.
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Efficacy Outcomes: While GLWL-01 significantly reduced plasma acylated ghrelin (AG) levels, it did not significantly reduce hyperphagia-related behavior or change global clinical endpoints.
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Safety Outcomes: GLWL-01 was found to be safe and well-tolerated, with less than half of patients reporting treatment-emergent adverse events. No serious adverse events were reported.
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Diazoxide Choline Extended-Release (DCCR) for Hyperphagia and Behavioral Problems:
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Study Name: DESTINY PWS Phase 3 study
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Intervention: DCCR tablets administered for up to 52 weeks.
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Efficacy Outcomes: DCCR significantly improved hyperphagia scores (Hyperphagia Questionnaire for Clinical Trials) and showed improvements in aggression, anxiety, and compulsivity. Reductions in leptin, insulin, and insulin resistance were observed, along with an increase in adiponectin and lean body mass.
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Safety Outcomes: DCCR was generally well-tolerated, with common adverse events including hypertrichosis, peripheral edema, and hyperglycemia. Adverse events infrequently led to discontinuation (7.2%).
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Telehealth Intervention for Social-Cognitive Abilities:
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Study Name: Telehealth pretend play intervention for PWS
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Intervention: Six-week remote pretend play intervention delivered via telehealth.
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Efficacy Outcomes: Children demonstrated significantly improved cognitive and affective processes in pretend play and general cognitive flexibility.
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Safety Outcomes: The study did not specifically report on safety outcomes, but the feasibility study mentioned good acceptability and satisfaction with the telehealth approach.
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High-Fiber Intervention for Hyperphagia and Metabolic Health:
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Study Name: Fiber intervention study in PWS
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Intervention: High-dose fiber intervention (35 g/day) for 3 weeks, followed by a control period and then a crossover to the other treatment.
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Efficacy Outcomes: The fiber intervention did not significantly alter hyperphagia or key metabolic markers.
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Safety Outcomes: Participants reported high tolerance to the fiber intervention.
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Goal Attainment Scaling (GAS) with Pitolisant for Narcolepsy-like Features:
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Study Name: Case report of GAS with Pitolisant in PWS
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Intervention: Pitolisant, a medication for excessive daytime sleepiness, combined with GAS framework for goal setting.
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Efficacy Outcomes: Overall improvements in most symptoms were observed during a 6-month follow-up, as captured by the individualized GAS framework.
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Safety Outcomes: The case report did not specifically mention safety outcomes related to Pitolisant.
These studies highlight the ongoing efforts to develop and evaluate interventions for PWS. While some interventions show promise, further research is needed to confirm their efficacy and long-term effects.
Drug used in other indications
VYKAT XR (diazoxide choline controlled-release tablet, DCCR) is primarily known for its trials in Prader-Willi syndrome (PWS). However, diazoxide, the active component, has been explored and used in various other conditions. While the provided text doesn't explicitly mention other ongoing trials for VYKAT XR specifically, it does detail uses of diazoxide in other conditions, which could suggest potential future trial avenues for the controlled-release formulation. Here's a summary of diazoxide's uses and related information, which may inform potential future trials of VYKAT XR:
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Hyperinsulinism (HI): Diazoxide is FDA-approved for treating neonatal hypoglycemia caused by HI. It acts by opening ATP-sensitive potassium (KATP) channels in pancreatic beta cells, inhibiting insulin release. The provided texts discuss dosing, monitoring, and adverse events associated with diazoxide use in HI. This suggests that VYKAT XR, with its extended-release profile, could be explored as a potential treatment option for HI beyond the neonatal period, offering improved convenience and adherence.
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Insulinoma: Diazoxide is used in the management of insulinoma, a tumor of the pancreas that causes excessive insulin production and hypoglycemia. The texts describe its effectiveness in controlling hypoglycemia in patients not cured by surgery or unsuitable for it. VYKAT XR could potentially offer advantages in insulinoma management due to its extended-release properties.
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Hypoglycemia in Chronic Kidney Disease (CKD): Diazoxide has been reported to be effective in treating hypoglycemia in patients with CKD, where impaired renal function can contribute to low blood sugar. This suggests another potential application for VYKAT XR.
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Dumping Syndrome: A case report describes the successful use of diazoxide in treating hypoglycemia secondary to dumping syndrome in a child. VYKAT XR's extended-release formulation might be beneficial in managing the postprandial hypoglycemia associated with this condition.
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Hypertension: Diazoxide has been historically used to treat hypertensive crises, although its use is now limited due to potential side effects. The controlled-release formulation might offer a safer and more manageable approach to hypertension treatment, warranting further investigation.
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Obesity and Hyperinsulinemia: Studies have explored the use of high-dose diazoxide in combination with lifestyle interventions for weight loss in obese, hyperinsulinemic individuals. VYKAT XR could be further investigated in this context, potentially offering a more convenient dosing regimen.
Intervention Models in Potential Trials:
Based on the described uses of diazoxide, potential trials of VYKAT XR in these conditions could employ the following intervention models:
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Randomized Controlled Trials (RCTs): The gold standard for evaluating drug efficacy, RCTs would compare VYKAT XR to placebo or standard treatments. Blinding, randomization, and appropriate outcome measures would be crucial for robust results.
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Crossover Studies: These studies would allow each participant to receive both VYKAT XR and the comparator treatment, reducing variability and increasing statistical power.
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Dose-Finding Studies: These studies would determine the optimal dose of VYKAT XR for different indications, considering efficacy, safety, and tolerability.
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Long-Term Extension Studies: These studies would follow patients treated with VYKAT XR for extended periods to assess long-term efficacy, safety, and durability of response.
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Real-World Evidence Studies: These studies would collect data on VYKAT XR use in routine clinical practice to assess its effectiveness and safety in a broader patient population.
It's important to note that the specific intervention model and trial design would depend on the indication being investigated, the patient population, and the research question being addressed.