FDA Approves Diazoxide Choline Extended-Release Tablets for Hyperphagia in Prader-Willi Syndrome

Jennifer Miller, MD

(Credit: University of Florida)

According to a new announcement, the FDA has approved Soleno Therapeutics' diazoxide choline (DCCR) extended-release tablets, marketed as Vykat XR, for the treatment of Prader-Willi syndrome (PWS) for patients 4 years and older who have hyperphagia. Thus, DCCR, a novel, proprietary extended-release dosage form containing diazoxide choline — the crystalline salt of diazoxide — is administered once daily and becomes the first therapy to treat hyperphagia in PWS.¹

In November 2024, the FDA extended its review period for the new drug application (NDA) of DCCR extended-release tablets for PWS.² The extension was triggered by recent responses to the agency's information requests, which were classified as a major amendment to the NDA. As a result, the PDUFA goal date was pushed back by 3 months to allow the FDA sufficient time to complete its review, including the newly submitted data. Notably, the agency did not highlight any concerns related to safety, efficacy, or manufacturing in its correspondence.

“My immediate reaction was relief - I have been working with PWS for [over] 25 years to try to find an answer to the life-limiting issue of hyperphagia in this syndrome, so I was grateful that we now have an effective medication. I was one of the [principal investigators] for the study and had 33 patients on trial at my site, so got to see firsthand how well this medication worked for patients,” Jennifer Miller, MD, professor of pediatric endocrinology at the University of Florida, told NeurologyLive^® in a recent interview. "I think it will change the treatment landscape by offering hope to patients and families with this condition. The concept of having a starving child and not being able to feed them is devastating for parents to contemplate. For physicians it offers the possibility of treatment in a space where there is currently none. That is huge."

The NDA is supported by data from the phase 3 DESTINY-PWS trial (NCT03440814) of DCCR tablets in PWS, which did not achieve its primary end point of significantly improving hyperphagia compared with placebo. However, notable improvements were observed in patients with severe baseline hyperphagia and in a pre-COVID analysis.³

The 13-week, randomized, double-blind, placebo-controlled trial included 127 participants aged 4 years and older with PWS and hyperphagia. The primary outcome measured changes from baseline in hyperphagia using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Secondary end points assessed global impression scores, body composition, behaviors, and hormone changes.

DCCR treatment did not yield a statistically significant reduction in hyperphagia in the overall population (least-square mean [LSmean] [SE]: -5.94 [0.879] vs -4.27 [1.145]; P = .198). However, in participants with severe hyperphagia, DCCR demonstrated a significant reduction (LSmean [SE]: -9.67 [1.429] vs -4.26 [1.896]; P = .012). Two of the 3 secondary end points showed positive results, including improvements in the Clinical Global Impression of Improvement (CGI-I; P = .029) and reductions in fat mass (P = .023).

Importantly, a pre-COVID analysis revealed statistically significant improvements across all primary and secondary end points, including hyperphagia (P = .037), CGI-I (P = .015), caregiver-reported global change (P = .031), and fat mass (P = .003). DCCR was generally well-tolerated, with 83.3% of participants in the DCCR group experiencing a treatment-emergent adverse event (TEAE) compared with 73.8% in the placebo group — a difference that was not statistically significant.

Additional efficacy was confirmed during the 16-week randomized withdrawal phase of Study 2-RWP (NCT03714373), a phase 3 multicenter, double-blind, placebo-controlled trial.¹ Participants who were switched to a placebo experienced a statistically significant increase in hyperphagia compared with those who continued taking DCCR. Before entering the randomized withdrawal phase, all participants had received DCCR in either a double-blind or open-label setting for an average of 3.3 years.

Soleno submitted its NDA to the FDA on June 27, 2024, which was accepted with priority review in August 2024. In the Untied States, diazoxide choline has received breakthrough and fast track designations, along with orphan drug designation in both the U.S. and E.U. for the treatment of PWS. The company noted that it anticipates DCCR to be available in the U.S. beginning in April 2025.¹

"The data was always positive from my perspective (even though did not reach statistical significance initially due to COVID interrupting the trial) -watching it was remarkable," Miller said. "I have been involved in basically every clinical trial in PWS and have never seen anything like this in terms of efficacy and duration of efficacy. Remarkable! In terms of [adverse] effects - this is a huge message I want the community to know! The drug reduces insulin release from the beta cells of the pancreas so for people with PWS who are older and obese and have insulin resistance or pre-diabetes there is a huge risk for development of type 2 diabetes."

Building on previous data from the 13-week DESTINY PWS trial, a 1-year analysis of DCCR administration further supported its potential to address key complications of PWS.⁴ This extended study included 125 participants aged 4 years and older who were enrolled in the original phase 3 trial and its open-label extension, receiving DCCR for up to 52 weeks. The primary end point, change in hyperphagia measured b HQ-CT, showed a significant reduction (mean [SE]: -9.9 [0.77]; P < .0001). Notably, patients with more severe baseline hyperphagia (HQ-CT > 22) experienced even greater improvements.

Beyond hyperphagia, DCCR administration led to marked reductions in aggression, anxiety, and compulsivity (all, P < .0001). Metabolic parameters also improved, with significant decreases in leptin, insulin, and insulin resistance, alongside a rise in adiponectin levels (all, P < .004). Additionally, lean body mass increased significantly (P < .0001), reflecting positive changes in body composition.

Clinician and caregiver assessments indicated a meaningful reduction in overall disease severity (both, P < .0001), suggesting DCCR may ease the burden on families managing the complex symptoms of PWS. Common TEAEs included hypertrichosis, peripheral edema, and hyperglycemia, though only 7.2% of participants discontinued because of adverse events.

Following promising results from the DESTINY PWS trial and its open-label extension, a comparative analysis offered additional evidence that long-term administration of DCCR tablets could lead to meaningful improvements in PWS symptoms.⁵ In this study, participants from the phase 3 and open-label extension DCCR trials were compared with a matched cohort from the PATH for PWS natural history study to better understand how DCCR impacts the progression of the syndrome over time.

The analysis included participants aged 5 years and older with similar baseline characteristics, focusing on changes in hyperphagia as measured by the HQ-CT (range 0–36). At 26 weeks, the DCCR-treated group showed a significantly greater reduction in hyperphagia scores compared to the natural history cohort (LSmean [SE]: -8.3 [0.75] vs -2.5 [0.43]; P < .001). This difference remained significant at 52 weeks (LSmean [SE]: -9.2 [0.77] vs -3.4 [0.47]; P < .001), even under a worst-case sensitivity analysis where missing scores were imputed with the highest possible value.

Behavioral improvements extended beyond hyperphagia. Using the Prader-Willi Syndrome Profile questionnaire (PWSP), significant reductions were observed across all measured domains at both 26 weeks (P < .001) and 52 weeks (P ≤ .003) in the DCCR-treated cohort compared to the natural history group. These findings suggested that DCCR may positively influence aggression, anxiety, compulsivity, and overall disease burden.

REFERENCES
1. Soleno Therapeutics Announces U.S. FDA Approval of VYKAT(TM) XR to Treat Hyperphagia in Prader-Willi Syndrome. News Release. Soleno Therapeutics. Published March 26, 2025. Accessed March 27, 2025. https://investors.soleno.life/news-releases/news-release-details/soleno-therapeutics-announces-us-fda-approval-vykattm-xr-treat
2. Soleno Therapeutics Announces FDA Extension of Review Period for DCCR (Diazoxide Choline) Extended-Release Tablets in Prader-Willi Syndrome. News Release. Soleno Therapeutics. Published November 26, 2024. Accessed March 26, 2025. https://investors.soleno.life/news-releases/news-release-details/soleno-therapeutics-announces-fda-extension-review-period-dccr
3. Miller JL, Gevers E, Bridges N, et al. Diazoxide Choline Extended-Release Tablet in People With Prader-Willi Syndrome: A Double-Blind, Placebo-Controlled Trial. J Clin Endocrinol Metab. 2023;108(7):1676-1685. doi:10.1210/clinem/dgad014
4. Miller JL, Gevers E, Bridges N, et al. Diazoxide choline extended-release tablet in people with Prader-Willi syndrome: results from long-term open-label study. Obesity (Silver Spring). 2024;32(2):252-261. doi:10.1002/oby.23928
5. Strong TV, Miller JL, McCandless SE, et al. Behavioral changes in patients with Prader-Willi syndrome receiving diazoxide choline extended-release tablets compared to the PATH for PWS natural history study. J Neurodev Disord. 2024;16(1):22. Published 2024 Apr 26. doi:10.1186/s11689-024-09536-x