Soleno Therapeutics : ENDO 2022 Poster Presentation

RF24 / P441: Long-Term Safety of Diazoxide Choline Extended-Release

(DCCR) Tablets in Patients with Prader-Willi Syndrome

Kathryn Obrynba, MD1, Jennifer Miller, MD2, Eric Felner, MD MS3, Lynne Bird, MD4, Moris Angulo, MD5, Jorge Mejia Corletto, MD5, Evelien Gevers, MD PhD6, Ashley Shoemaker, MD7, Jack Yanovski, MD PhD8, Merlin Butler, MD PhD9, Parisa Salehi, MD10, David Stevenson, MD11, John Wilding, DM12, Jennifer Abuzzahab, MD13, Laura Konczal, MD14, M Guftar Shaikh, MD15, David Viskochil, MD PhD16, Anthony Goldstone, MD PhD17, Melissa Lah, MD18, Verghese Mathew, MD19, Kristen Yen, MS20, Michael Woloschak, MD20, Anish Bhatnagar, MD20

1The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA, 2University of Florida Gainesville, Gainesville, FL, USA, 3Emory Children's Center, Atlanta, GA, USA, 4Rady Children's Hospital of San Diego, San Diego, CA, USA, 5NYU Winthrop Hospital, Mineola, NY, USA, 6Queen Mary University of London, Barts Health NHS Trust, London, United Kingdom, 7Vanderbilt University, Nashville, TN, USA, 8National Institutes of Health, Bethesda, MD, USA, 9Kansas University Med Center, Kansas City, KS, USA, 10Seattle Children's, Seattle, WA, USA, 11Stanford University, Palo Alto, CA, USA, 12Aintree University Hospital NHS Foundation Trust, Liverpool, Merseyside, United Kingdom, 13Children's Minnesota, St. Paul, MN, USA, 14UH Cleveland Medical Center, Cleveland, OH, USA, 15The Queen Elizabeth University, Glasgow, Scotland, United Kingdom, 16University of Utah, Salt Lake City, UT, USA, 17Hammersmith Hospital, London, United Kingdom, 18Indiana University School of Medicine, Indianapolis, IN, USA, 19Hull and East Yorkshire Hospitals NHS Trust, Hull, Yorkshire, United Kingdom, 20Soleno Therapeutics, Inc., Redwood City, CA, USA

INTRODUCTION

Prader-Willi syndrome (PWS), a rare genetic neurobehavioral-metabolic condition, characterized by hyperphagia, accumulation of excess fat, hypotonia, and behavioral/psychological complications.1,2 Aside from growth hormone to treat short stature, there are no FDA- approved treatments to manage the significant, life- threatening aspects of PWS.

Diazoxide is a potent activator of the ATP-sensitive K+ (KATP) channel, crosses the blood-brain barrier, and activates the channel in hypothalamic neurons, thereby contributing to reductions in hyperphagia.3

DCCR is a once daily, extended-release tablet formulation of diazoxide choline, which provides for continuous release and absorption throughout the GI tract and stable plasma concentrations. DCCR is currently under investigation as a therapy to reduce hyperphagia and improve behavior in PWS.

METHODS

Participants with genetically-confirmed PWS ≥4 years old with hyperphagia were treated with oral daily DCCR in multi-center studies conducted at 29 sites in the US and the UK: a 13-week, Phase 3, double-blind, placebo- controlled study (DESTINY PWS, C601) and its long-term,open-label extension study (C602).

The safety summary was based on all safety data available following the last patient reaching 1 year of

treatment. Baseline was the last assessment prior to the first dose of DCCR.

C601/C602 SAFETY POPULATION

125 participants received at least 1 dose of DCCR; 103 participants received DCCR for 52 weeks.

RESULTS

Mean (±SD) age, weight, height and BMI of participants were 13.4 ±

6.98 years, 62.06 ± 30.15 kg, 146.7 ± 18.98 cm, 27.558 ± 9.62 kg/m2, respectively. The majority of participants were white (84.8%) and female (55.2%).

Treatment-emergent adverse events (TEAEs) occurred in 98.4% of participants with 80% experiencing at least one drug related TEAE. TEAEs infrequently resulted in discontinuation of study drug. Twenty participants experienced serious adverse events (SAEs), two of which were considered drug-related (one patient with peripheral / pulmonary oedema and another with fluid retention) but expected. There were no SAEs leading to death and no suspected, unexpected, serious adverse reactions (SUSARs) reported (Table 1).

The most common TEAEs were hypertrichosis, peripheral oedema, and hyperglycaemia (Table 2, Table 3). The majority of adverse events (AEs), (77.6%) were grade 1 or 2 severity. These results are consistent with the observed safety profile of DCCR from prior studies.

Nearly all of peripheral oedema cases resolved while treatment continued (~90%), infrequently required dose adjustment (7%), or needed for diuretic treatment (1.6%). Most cases of hypertrichosis (>80%) were mild and only once resulted in discontinuation. About 35% of cases of hypertrichosis were resolved/resolving at Week 52.

At baseline, both mean fasting glucose (FG) and mean HbA1c were in the upper end of the normal range. Consistent with the expected AE of hyperglycaemia, mean FG rose through 26 weeks (mean change from baseline ± SD mmol/L = 0.35±0.81) and returned nearly to baseline by 65 weeks (0.11±0.61) (Figure 1); mean HbA1c followed a similar pattern (Figure 2). In participants experiencing hyperglycaemia, the AE resolved with continued treatment in about half of cases and 14 (11.2%) of subjects started a new anti- hyperglycaemic agent, which in a few cases could be discontinued.

Table 1. Summary of treatment emergent adverse events

	N (%) of Subjects
Event	(n=125)
TEAE	123 (98.4%)
TEAE related to study drug	100 (80.0%)
TEAE leading to premature study discontinuation	9	(7.2%)
SAE	20	(16.0%)
SAE related to study drug	2	(1.6%)
SAE leading to premature study discontinuation	3	(2.4%)

Table 2. TEAEs related to study drug report in ≥ 5 subjects

Adverse Event (Preferred Term)	N (%) of Subjects
	(n=125)
Hypertrichosis	75 (60%)
Oedema Peripheral	38	(30.4%)
Hyperglycaemia	28	(22.4%)
Hirsutism	23	(18.4%)
Blood Glucose Increased	10 (8.0%)
Headache	9	(7.2%)

Table 3. Three most common TEAEs related to study drug, by severity

Figure 1. Mean fasting glucose over 65 weeks

GlucoseFasting mmol/L(Mean±SD)	8.0
6.0
	4.0
	2.0
	0.0
	Week 0 Week 13 Week 26 Week 39 Week 52 Week 65

Figure 2. Mean HbA1C over 65 weeks of DCCR

(Mean±SD)	8.0
7.0
4.0
	6.0
HbA1c	5.0
3.0
	2.0
	1.0
	0.0	Week 0 Week 13 Week 26 Week 39 Week 52 Week 65

CONCLUSIONS

DCCR was well tolerated in long-term use. The majority of TEAEs (77.6%) were grade 1 or 2 severity. Most common TEAEs were expected based on prior studies of DCCR. These included hypertrichosis, peripheral edema and hyperglycemia, which were typically mild and resolved without intervention in most cases. Mean fasting glucose and HbA1c levels vary minimally over 52 weeks of DCCR treatment. Overall, the safety profile of DCCR is consistent with that of diazoxide-equivalent doses and the prior DCCR use.

REFERENCES

1. Butler, MG, Miller, JL, Forster, JL. Prader-Willi syndrome - Clinical genetics, diagnosis and treatment approaches: An update. Curr Pediatr Rev 2019; 15(4):207-244.
2. Miller, JL, Lynn, CH, Driscoll, DC, et al.. Nutritional phases in Prader-Willi syndrome. Am. J. Med. Genet. Part. A 2011, 155, 1040- 1049.
3. Cowen, N, Bhatnagar, A. The potential role of activating the ATP- sensitive potassium channel in the treatment of hyperphagic obesity.
   Genes (Basel) 2020; 11(4):450.

ACKNOWLEDGEMENTS

•C601/C602 DESTINY PWS Study Investigators •Participants in the C601/C602 Studies and their families

Endo 2022

Sunday, June 12, 2022

Atlanta, GA