Potential PWS Therapy DCCR May Provide Safe, Long-lasting Benefits, Clinical Studies Show

Potential PWS Therapy DCCR May Provide Safe, Long-lasting Benefits, Clinical Studies Show

Treatment candidate diazoxide chloride controlled release (DCCR) may cause fewer and milder side effects than approved medication Proglycem (diazoxide suspension) in treating low blood sugar in Prader-Willi syndrome patients, as well as providing consistent benefits, according to Soleno Therapeutics’ clinical studies.

The findings showed that DCCR temporarily raises glucose (sugar) levels in PWS patients.

Two presentations on the company’s lead product candidate will be given Sept. 29 in the late breaking 2 poster session at the 57th Annual European Society for Paediatric Endocrinology Meeting Sept. 27-29 in Athens, Greece, Soleno announced in a press release.

These presentations will include data from studies of the pharmacokinetics — drug absorption, distribution, metabolism, and excretion — and glucose impact of long-term DCCR use in PWS patients.

DCCR is an oral, extended-release formulation of diazoxide — a potassium channel opener — designed for once-daily dosing. It was shown to significantly decrease fat mass and increase lean body mass in a preclinical study and a Phase 1/2 clinical trial (NCT02034071) called PC025 with 13 PWS patients. In this trial, DCCR also significantly decreased hyperphagia — an abnormally increased appetite — a hallmark PWS symptom.

The first poster, “Pharmacokinetics of Diazoxide Choline Controlled-Release Tablet, a Once Daily Treatment Being Evaluated for Patients with Prader Willi Syndrome,” will present details on the pharmacokinetics and food effects of DCCR across five clinical studies.

The pharmacokinetics of single-dose DCCR were compared to Proglycem in a study in obese subjects called PK001. Steady-state pharmacokinetics were also assessed in four studies in both obese individuals and those at a healthy weight, as well as obese PWS patients: PK008 (NCT00688857), PK015 (NCT01211860), TR002, and PC025.

Food effects of diazoxide — the main byproduct of diazoxide choline — were evaluated in healthy volunteers in the PK008 study, while the therapy’s pharmacokinetics were assessed in PK015, also using healthy participants. In the PC025 study, blood levels at steady state — the lowest concentration of a medication before the next dose is administered — were determined in 11 PWS patients receiving a range of DCCR doses.

With a single dose, the time at which maximum concentration (Cmax) was achieved, known as Tmax, was 6.5 hours for Proglycem and 22 hours for DCCR. At 13.32 mcg/ml, Proglycem’s Cmax was 47% higher than that of DCCR, which was 9.07 mcg/ml.

DCCR and Proglycem showed comparable terminal half-life, which refers to the time required for the plasma concentration to decrease by half after reaching equilibrium — 29.2 hours for Proglycem vs. 32.4 hours for DCCR.

No food effects were noted, which suggests that the treatment can be taken with or without food, the team noted.

In addition, the results showed linear increases in steady state peak and trough circulating levels with DCCR doses between 217.5 and 507.5 mg in obese subjects. Circulating medication levels were similar between PWS patients and obese controls, indicating that results related to pharmacokinetics from people without PWS are applicable to the use of DCCR in PWS patients, the researchers said.

The data also showed that DCCR was well-tolerated and suitable for once-daily dosing in PWS patients.

Overall, the team suggested that DCCR may lower the likelihood and severity of adverse events compared with Proglycem. They also suggest that the constant circulating DCCR level “likely results in a consistent therapeutic response in treated PWS patients.”

In the second poster, “Glycemic Impact of Long Term Use of Diazoxide Choline Controlled-Release (DCCR) Tablets in Patients with Prader Willi Syndrome or with Very High Triglycerides,” Soleno will present data showing that DCCR can temporarily elevate sugar levels in PWS patients.

Diazoxide has a well-known glucose-increasing effect by suppressing insulin secretion in the pancreas. For this reason, it is approved to treat hypoglycemia, or low blood sugar, caused by certain cancers and other conditions.

To counterbalance this effect, diazoxide leads to partial inhibition of the production of glucose in the liver by activating KATP potassium channels in the central nervous system (CNS), as well as leading to marked and progressive improvements in insulin sensitivity through similar activation of these channels in the periphery.

Because PWS patients are hypoinsulinemic, or have low blood insulin levels, and are insulin-sensitive, scientists presume that changes in appetite and behavior result from diazoxide’s CNS effects.

Results showed that, in both PWS patients and those with very high triglycerides, DCCR administration caused a temporary elevation in fasting glucose, post-prandial glucose and HbA1c — an indication of average blood glucose levels — which returned to baseline, or initial levels, with long-term treatment.

Among participants completing the PC025 study, fasting glucose at 69 days was 7.9 mg/dL, 9.4% higher than baseline, regressing to initial values by the end of treatment. In a subset of patients treated with DCCR for six months, HbA1c dropped progressively toward baseline values.

“Increased glucose levels in PWS have been seen with short-term [DCCR] treatment,” the scientists wrote. However, counterbalancing effects “appear to cause normalization of glucose levels with longer-term use.”

Soleno’s potential treatment is also being evaluated in a randomized, placebo-controlled Phase 3 trial (NCT03440814) in approximately 105 PWS patients, ages 4 and older. The study assesses changes in hyperphagia and body fat mass, as well as clinical and caregiver perceptions of these changes.

The trial is now recruiting at six U.S. sites. More information about study locations and contacts can be found here.

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