Breakthrough Clinical Results

Soleno Therapeutics announced presentations at the ISPOR 2025 meeting featuring data on VYKAT™ XR (diazoxide choline) extended-release tablets for the treatment of hyperphagia associated with Prader-Willi syndrome (PWS). The presentations include data on mortality rates from a Phase 3 trial and an examination of the burden of PWS on patients and the healthcare system. VYKAT XR, approved by the FDA on March 26, 2025, is a once-daily oral treatment for hyperphagia in adults and children 4 years and older with PWS. The press release also includes important safety information regarding hyperglycemia, fluid overload, and adverse reactions.

Incidence and Prevalence

Incidence:

• A 2013 study in France estimated the birth incidence of Prader-Willi syndrome (PWS) at 1/21,000 births. This is based on data collected from 61 infants with a molecular diagnosis of PWS born in 2012 and 2013.
• A 2005 study in Flanders, Belgium, estimated the birth incidence of PWS at 1:26,676 for the period 1993-2001.
• A 2016 study using data from the Victorian Prader-Willi Syndrome Register in Australia estimated the birth prevalence for individuals with a molecular diagnosis of PWS at 1:15,830 for the period 2003-2012.
• Several other studies mention a range of 1 in 10,000 to 30,000 live births.

Prevalence:

• The 2005 study in Flanders, Belgium, estimated the minimum prevalence of PWS at 1:76,574 at the end of 2001. This study noted a decreasing number of cases with age, possibly due to missing cases in the older population, higher neonatal mortality in the past, and increasing mortality with age.
• A 2005 study in Estonia estimated the minimum live birth prevalence of PWS in 1984-2004 at 1:30,439. The point prevalence proportion on January 1, 2005, was 1:30,606.
• A 1995 study in the western part of Japan estimated the prevalence of PWS in patients under 15 years old at 1 in 17,483.

General Observations:

• PWS is considered a rare genetic disorder.
• Early diagnosis is crucial for effective long-term management and improved quality of life.
• Growth hormone treatment is often used in PWS and may influence growth patterns and some clinical features.
• Obesity is a major concern in PWS and significantly impacts morbidity and mortality.
• There can be variations in incidence and prevalence estimates due to differences in study methodologies, populations studied, and time periods.

It is important to note that these are estimates, and the actual incidence and prevalence may vary depending on the population and diagnostic methods used.

Risk Factors and Comorbidities

Recent Studies

Several studies have investigated 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 safety and efficacy outcomes:

1. Diazoxide Choline Controlled-Release (DCCR) studies:

2. Study Name: DESTINY PWS Phase 3 study and its open-label extension.

3. Intervention: DCCR tablets.
4. Efficacy Outcomes: Significant improvements in hyperphagia (measured by Hyperphagia Questionnaire for Clinical Trials [HQ-CT]), aggression, anxiety, and compulsivity. Reductions in leptin, insulin, and insulin resistance, and a significant increase in adiponectin. Increased lean body mass and reduced disease severity.

5. Safety Outcomes: Common adverse events included hypertrichosis, peripheral edema, and hyperglycemia. Adverse events infrequently led to discontinuation (7.2%).

6. Growth Hormone (GH) studies:

7. Study Name: PWS-OZGROW database study.

8. Intervention: Low-dose GH treatment (4.5 mg/m2/week).
9. Efficacy Outcomes: Increased height SDS in both infants and toddlers. BMI SDS increased, while PWS-specific BMI SDS decreased and remained negative. Normalization of height SDS occurred sooner in infants than toddlers.

10. Safety Outcomes: Mild to severe central and/or obstructive sleep apnea observed in 40% of children before GH initiation. Eight children ceased GH due to sleep apnea, but seven resumed after adjustments or adenotonsillectomy.

11. Study Name: Multicenter longitudinal observational cohort studies (ANSWER and NordiNet IOS).

12. Intervention: GH prescribed according to local practice.
13. Efficacy Outcomes: Improved height SDS in various GH deficiency indications, including PWS.

14. Safety Outcomes: No new safety signals of concern were noted.

15. Study Name: Retrospective observational multinational study.

16. Intervention: Growth hormone (0.03-0.06 mg/kg/day) for > 12 months.
17. Efficacy Outcomes: Significant improvements in height and body composition (increased lean body mass and decreased fat mass).

18. Safety Outcomes: Scoliosis reported in 8 patients at last observation (3 at baseline). Sleep apnea recorded in 3 patients (7.3%). No other severe adverse events reported.

19. GOAT inhibitor study:

20. Study Name: Double-blind, placebo-controlled, phase 2 crossover study.

21. Intervention: GLWL-01 (ghrelin O-acyltransferase inhibitor) 450 mg twice daily.
22. Efficacy Outcomes: Statistically significant differences in plasma acylated ghrelin (AG), unacylated ghrelin (UAG), and AG/UAG ratio compared to placebo. No statistically significant reduction in hyperphagia or changes in global clinical endpoints.

23. Safety Outcomes: Less than half of patients reported treatment-emergent adverse events. No deaths, serious adverse events, or severe adverse events reported.

24. Liraglutide study:

25. Study Name: Multicenter, 52-week, placebo-controlled trial.

26. Intervention: Liraglutide 3.0 mg (or maximum tolerated dose).
27. Efficacy Outcomes: No significant difference in BMI SDS change between liraglutide and placebo in adolescents or children. No significant changes in other weight-related parameters. Lower hyperphagia total and drive scores in adolescents treated with liraglutide at week 52.

28. Safety Outcomes: Most common adverse events were gastrointestinal disorders.

29. N-acetylcysteine (NAC) study:

30. Study Name: Pilot study of NAC for skin picking.

31. Intervention: N-acetylcysteine (450-1200 mg/day).
32. Efficacy Outcomes: All 35 individuals showed improvement in skin-picking behaviors, with 25 (71%) achieving complete resolution of lesions.
33. Safety Outcomes: Not explicitly reported in the provided abstract.

These studies highlight the ongoing research efforts to find effective and safe treatments for PWS. While some interventions show promise, further research is needed to confirm their long-term efficacy and safety.

Drug used in other indications

VYKAT™ XR (diazoxide choline extended-release), also known as DCCR in research settings, is primarily known for its trials and subsequent approval for the treatment of hyperphagia associated with Prader-Willi syndrome (PWS). While PWS is the main focus, diazoxide, the active component, has been used and studied for other conditions. Based on the provided research, here's a summary of other uses and trial information related to diazoxide, not specifically the extended-release DCCR formulation:

• Hyperinsulinemic Hypoglycemia (HH): Diazoxide is used as a first-line treatment for HH, particularly in neonates and infants. It works by opening ATP-sensitive potassium (KATP) channels in pancreatic beta cells, inhibiting insulin release. Several studies confirm its efficacy, with a pooled response rate of 71% in one meta-analysis. However, side effects like hypertrichosis (45%), fluid retention (20%), and gastrointestinal reactions (13%) require careful monitoring. Trials typically involve different dosing regimens and monitoring for adverse events. Some studies have explored low-dose diazoxide (<5 mg/kg/day) for transient hyperinsulinism, showing efficacy with milder side effects. Diazoxide has also been used successfully for long-term management of inoperable insulinomas, a type of tumor causing HH.

• Hypertension: Diazoxide has been used historically as an antihypertensive drug, administered intravenously for rapid blood pressure reduction. Its effectiveness in hypertension is related to its vasodilatory properties. However, oral diazoxide produces less consistent effects on blood pressure. Studies have explored its use in severe hypertension during pregnancy, but other agents like nifedipine are often preferred.

• Neonatal Hypoglycemia: Recent trials have investigated early, low-dose oral diazoxide for severe or recurrent neonatal hypoglycemia. One study found that while it didn't significantly reduce time to resolution of hypoglycemia using a strict definition, it did reduce time to enteral feeding, weaning from IV fluids, duration of hypoglycemia, and frequency of blood glucose tests. It also significantly reduced hypoglycemia after the loading dose.

• Other potential uses: Research has explored the potential of diazoxide in other areas, including:

• Preservation of myocyte volume and contractility during cardiac stress: Studies suggest diazoxide may be cardioprotective by inhibiting succinate dehydrogenase.

• Treatment of ESRD-associated hypoglycemia: Case reports indicate diazoxide may be effective in managing hypoglycemia in patients with end-stage renal disease.

• Obesity in general: Some studies have investigated diazoxide's potential as a weight-loss agent in obese individuals with hyperinsulinemia, showing promising results in combination with lifestyle interventions. However, these studies did not specifically use the extended-release formulation (DCCR).

It's important to note that the specific formulation of diazoxide (e.g., immediate-release, extended-release, intravenous) influences its pharmacokinetics, efficacy, and safety profile. Therefore, findings from studies using one formulation may not be directly applicable to another. Additionally, while diazoxide has shown promise in various conditions, further research is needed to fully understand its potential benefits and risks beyond its established use in PWS and HH.