In this one hour and 3‑minute video, several investigators discuss a Phase 3 Clinical Trial of DCCR, a controlled release tablet of diazoxide choline, run by Soleno Therapeutics. The session includes Q&A from participants in the 2021 FPWR Virtual Conference.
Click below to watch the video. If you're short on time, scroll down for timestamps to find the portions you're most interested in.
Presentation Summary With Timestamps
0:25 Anish Bhatnagar, CEO of Soleno Therapeutics presents
DCCR Clinical Trial Update
- Bhatnagar thanks the PWS community for its support and advocacy, including collecting 26,000 signatures, conducting virtual town halls, and sharing the stories of caregivers and subjects.
- Dr. Kathryn Stephens Obrynba, investigator in the studies at Nationwide Children’s Hospital, a high enrolling site.
- Dr. Theresa Strong of FPWR will present a comparison of long‑term data with the Path for PWS Study.
- Mindy Leffler will discuss findings from caregivers.
- Dr. Jennifer Miller, PI at the University of Florida, will discuss safety profile of DCCR.
2:19 Dr. Obrynba: What Is DCCR?
- She served as principal investigator for Levocare PWS study.
- DCCR is diazoxide choline, in a controlled‑release tablet.
- Formulated for gradual release in the gut over a 24‑hour period.
- Allows for once‑daily dosing at one‑half to one‑third of the immediate release form.
- This is important because of the practicality of dosing and potentially decreasing risk for side effects or safety concerns.
3:21 How Does DCCR Work?
- DCCR acts as a potassium ATP channel.
- It is a channel agonist, and these channels are found in many different tissues throughout the body.
- Most physicians are familiar with these potassium channels in the pancreas.
- Pancreas has beta cells where DCCR acts to decrease insulin secretion and reduces hyperinsulinemia.
- There are other direct effects of DCCR.
- It acts to reduce neuropeptide Y, a hormone that regulates hyperphagia and thereby reduces hyperphagia.
- DCCR also acts on the fat cells, or adipocytes, by reducing fatty acid biosynthesis and decreasing fat mass.
4:13 Phase 3 Clinical Program Design
- C601 (DESTINY PWS): Multi‑center, randomized, double‑blind, placebo‑controlled, parallel arm study in patients with PWS (Phase 3).
- C602: Open‑label safety extension study.
- 29 sites participated, 20 in the US and 9 in the UK.
- 127 patients were randomized, two to one, to receive DCCR vs. placebo.
- Of those 127 patients, 120 completed a 13‑week study that included 7 study visits.
- Endpoint of the study was to address change from the baseline and hyperphagia on the hyperphagia questionnaire for clinical trials at visit 7 or week 13 of the double‑blinded treatment period.
5:14 Results
- Those in the DCCR group did have a bigger decrease or change in hyperphagia compared to placebo.
- Unfortunately, this did not reach statistical significance.
- We did see that two of three key secondary endpoints did reach statistical significance: Clinical Global Impression of Improvement at Visit 7 and Mean Change or Decrease in Fat Mass (DXA).
- Data was analyzed through the spring and summer of 2020 and at the time it was hard to ignore the impact that COVID‑19 and the pandemic was having on our daily lives, especially on children with special needs that are so dependent on structure and routine.
- COVID was likely impacting the clinical research as well.
- Anticipate that these subjective endpoints, such as those being assessed in the C601 trial, were likely to be impacted by changes in daily routine.
6:09 Impact of COVID‑19 Pandemic on DESTINY PWS
- Comprehensive analyses undertaken based on published statistical guidance from the FDA and industry publications, published literature on the impact of the pandemic on childhood psychiatric conditions, and FPWR’s Global Registry Pandemic Impact Survey.
- Expected that subjective endpoints more likely to be impacted: HQ‑CT, Caregiver GI‑C, PWS Profile (PWSP), and others.
- Given these impacts, sponsor reanalyzed C601 data that was generated through March 1 of 2020.
- The result of that process is that the primary and key secondary endpoints — Mean Change From Baseline in Hyperphagia at Visit 7— reached statistical significance.
7:12 HQ‑CT Changes from Baseline Waterfall Plot through March 1, 2020
- Waterfall plot describes the results of the re‑analysis period.
- Shows bigger decrease in hyperphagia scores.
- C601 Key Secondary Endpoint: Clinical Global Impression of Improvement assesses clinician’s subjective observation regarding clinical improvement.
- Remember the clinicians were blinded so they did not know if patients were receiving DCCR or placebo.
- Clinicians more often rated those on DCCR as having clinical improvement.
9:41 Impact on Behavioral Endpoints
- Data through March 1, 2020 examined the following Behavioral Endpoints: aggressive behaviors, anxiety, rigidity/irritability, compulsivity, depression, disordered thinking.
- Saw improvements in aggression, anxiety/rigidity, and compulsivity.
- Also some improvements were observed in the external or forward‑facing behaviors, meaning how our PWS kids are able to communicate or socialize.
- Improvement in communication skills, interaction skills, and socialization in those treated with DCCR vs. placebo.
10:37 Why Are We Seeing These Improvements?
- Physiological changes including significant lowering of insulin level over the course of the 13‑week study in the DCCR group vs. placebo.
- Viewed as a biomarker for the effect of DCCR, but it’s really the downstream effects of insulin that are having an impact on these improvements in behavior.
- From a metabolic standpoint, we see lower levels of Ghrelin, the hunger hormone.
- We also see decreased Leptin, which is typically produced by fat cells.
- And we see increased Adiponectin, a cardio‑protective hormone that may indicate improved cardiovascular health in those treated with DCCR vs. placebo.
11:48 Study Participants Elect to Continue to C602
- Following C601, 115 of 120 patients elected to continue into C602, the open‑label extension study.
- This means that all study participants were knowingly on the study drug, and if patients were randomized to receive the placebo, they were transitioned to DCCR.
- Currently we have just under 100 patients that are continuing on the study drug to this day, and many patients are approaching year 3 of treatment with DCCR.
12:25 Demographics and Duration of Treatment
- Patients ranged from age 4 to 44 and mean age was around 13.
- Majority were treated with growth hormone.
- At least 100 patients completed at least one year of treatment.
13: 10 Changes in Hyperphagia
- After one year of treatment we observed a 50% reduction in the hyperphagia score.
- Average score is about 21 at entry, and after one year of treatment the average score is just below 10.
- This observation holds true to what patients, families, and investigators are seeing in real life, meaning that the improvement in clinical symptoms and hyperphagia is not something that we see immediately.
- It’s a gradual improvement over time. As one investigator stated, it’s not a sprint but a marathon.
14:03 Behavioral Changes after One Year of DCCR
- Significant improvements in all core PWS behaviors across all domains: aggressive behaviors, aggressive destructive, anxiety, compulsivity, depression, disordered thinking, and rigid irritability.
- Similar to changes in hyperphagia, participants showed gradual improvements throughout the first year.
14:35 Changes in Body Composition (C601 + C602)
- In C601 investigators did not see a change in body fat mass, but body fat mass was at least unchanged or remained stable.
- This could be for several reasons, including that the study population is still growing, and getting taller and larger.
- Lean body mass or muscle mass did decrease, and the lean body mass to fat mass ratio decreased as well.
- This is exciting because DCCR has a huge impact on the body composition of our patients after one year of treatment.
- This translates into some real‑world benefits.
- One patient, previous to DCCR, would hike one to two miles each Saturday and Sunday. After a couple of years of treatment, he’s hiking three to five miles each day on the weekend and this improved exercise capacity is likely due to his improvement in lean muscle mass.
- Another patient actually had to increase his caloric intake, likely due to increased resting energy expenditure.
16:14 Endocrine and Hormonal Parameters After One Year of DCCR
- Decreased Leptin, Increased Adiponectin, Decreased Fasting Insulin, and Decreased HOMA‑IR.
- HOMA‑IR is a scientific way to measure insulin resistance, and we saw decreased insulin resistance, which, in turn, means an increase in insulin sensitivity.
- Overall, study finds evidence of improvement in metabolic health of patients with PWS treated with DCCR.
16:44 Comments on Safety
- 100 patients treated for more than one year.
- Safety profile of DCCR consistent with known profile of diazoxide and prior experience with DCCR.
- Most common adverse events reported were hypertrichosis, peripheral edema, and hyperglycemia.
- Most events were not severe, no grade 4 or higher events.
- No serious, unexpected adverse events related to DCCR.
17: 24 Summary of C602 Data After One Year— “Safe and Effective”
- Results show statistically significant improvement across all behavioral and independent and metabolic endpoints.
- We now have years of experience with this drug and it has proven to be very safe and effective.
- Although this data is very compelling in terms of efficacy and safety, we realize that in any open‑label study where all participants are receiving the study drug, it’s important to note the risk for introduction of a “hope bias,” meaning we would all be ecstatic and very hopeful that this new drug is being beneficial to our loved ones with PWS.
- So it’s important that we continue to compare the data of our study population with external controls.
18:22 Dr. Theresa Strong, FPWR, presents Comparisons of Hyperphagia and Other Behaviors from C601‑C602 with PATH for PWS
- PATH for PWS is a 4‑year prospective study. It’s non‑interventional and observational, meant to advance the understanding of serious medical events in PWS and evaluate how PWS‑related behaviors change over time.
- Study was initiated through Zafjam, but their drug did not advance. Now it is conducted through the Global PWS Registry.
- It is a parent‑reported past medical history where every 6 months caregivers go in and complete height and weight, medications, behavior assessments, and reports on serious medical or thrombotic events.
- Importantly, the behavioral assessments are similar to behavioral assessments in 601 and 602 studies.
20:14 Importance of Natural History Studies
- Natural history of a disease is traditionally defined as the course a disease takes in the absence of intervention.
- Includes participants receiving the standard of care, provides a population of participants similar to those enrolled in a clinical study, and endpoints that can be compared with treatment in a clinical study.
21:13 PATH for PWS
- PATH for PWS initiated in late 2018 so has run contemporaneously with the Soleno study.
- Initial recruitment target was 500 individuals with PWS, but the community has been so supportive, it has more than 700 recruited, and 650 who enrolled; the largest PWS study ever conducted.
- Gives us a wealth of data to really understand how PWS normally progresses and to be able to use that information to compare to drug studies.
- Mainly US participants, but also has people from Canada, Australia, and New Zealand.
- Tried to pull in adult participants. Forty percent are over the age of 18.
- Study team members are Dr. Jennifer Miller, Dr. Shawn McCandless, and Lisa Matesvac.
22:44 Choosing the Comparison Cohort
- After examining data and scores, 114 subjects from C601/C602 and 229 subjects from PATH for PWS were selected for comparisons.
- The Methodology for Comparison looked at the HQ‑CT and PWS Profile (PWSP) and were compared at 26 weeks (6 months) and 52 weeks (1 year).
- Basically trying to match participants based on their growth hormone status and their age and HQ‑CT scores.
24: 47 Results of Comparison
- Participants who are taking DCCR have a significantly higher decrease in their HQ‑CT score. This is much improved from PATH for PWS.
- Individuals treated with DCCR showed highly significant improvements in hyperphagia scores as well as significantly greater improvements in many of the behavioral features that are most challenging for families, including aggression, anxiety, irritability, and depression.
28:02 The Significance of the Comparison
- We now have the ability to take into account the natural history of the disorder if we don’t have a treatment compared to what happens if we do have a treatment.
- It provides evidence of long‑term clinically meaningful improvements in hyperphagia with DCCR treatments.
- It also provides evidence of long‑term improvements in the most troubling PWS behaviors that families face.
- DCCR seems to provide significant improvements in PWS relative to the natural history of the disease.
29:11 Mindy Leffler on Caregiver Sub‑Study
- Explains that Kasmir, her research organization, is responding to the many studies that fail to reach statistical significance.
- Goal is to ensure that no other rare disease families are left in the position of contributing their lives to study participation and ending up without any answers.
- Worked in over 20 diseases, both rare and non, to capture data that is reflective of the caregiver and patient experience.
- This study was to consider existing functional outcomes in Prader‑Willi and take a look at the ways in which they might not fully reflect the experiences of patients.
- Inherent difference of the patient population
- Impact of longtime family food procedures on caregivers’ responses to questions
- Impact of immediate context on caregivers’ responses
- The last point addresses the impact of what’s going on when families answer questionnaires. For example, if you’re answering it around the holidays, there are additional food‑related challenges.
33:36 Interview Sub‑Study Design
- Four planned interviews conducted over a secure video conferencing link: baseline, end of double‑blind (C601), and two during open‑label period (C602).
- Interviews covered 5 sections: background, food‑related behavior, behavior, daily life, wrap‑up.
- If a caregiver indicated a change, they were prompted to indicate if the change was negative or positive, whether it had a major or minor impact on the child’s quality of life, and whether the change was meaningful to the family.
- Interviews were recorded, transcribed, coded, and analyzed by researchers.
34:31 Themes That Emerged from Interviews
- With this population, in food behavior, parents were describing their children as not so much hyperphagic as being rigid about meal timing.
- The spectrum went all the way to people who were extremely driven by food‑seeking behaviors to people that were able to self‑regulate and had a lot of self‑awareness.
- Baseline interviews underscored how different every person with Prader‑Willi is from every other person.
- Higher relative numbers of caregivers of patients on DCCR described major improvement than caregivers of patients on placebo.
36:14 The Impact of COVID on Caregivers and Patients
- COVID‑19 was a major factor affecting behavior.
- Some caregivers reported that they felt like everything was worse during pandemic lockdowns.
- Others said things like they couldn’t imagine where their child would be if they hadn’t been on the medicine.
- Many children with PWS were at home all the time; they weren’t out of their food‑secure homes. So it became more difficult to identify hyperphagic behaviors.
38:20 DCCR Treatment Resulted in Positive Change in Each Domain
- Interview study showed large numbers of caregivers reporting positive changes in food behavior (47.10%), Behavior (41.20%), and Daily Life (45.10%) compared to the placebo group.
- Caregivers are watching children closely and know exactly what to look for in terms of each family’s pain point.
- For example, someone that makes his own lunch and cooks with them and they don’t have to keep things out of reach any more, or have to lock things up any more.
- Or caregivers that report that they can go out to eat without the person having tantrums.
- Acknowledge families willing to share their experiences and Soleno for valuing families’ contribution to research.
42:13 Dr. Jennifer Miller on C601 Study Safety
- Multiple adverse events seen both in patients on DCCR and those on placebo:
- Hypertrichosis: fine downy hair growth on the body
- Peripheral Edema: swelling in lower extremities
- Hyperglycemia: high blood sugars
- Reassuring that they didn’t see any adverse events in the PWS population that were unknown with the parent molecule DCCR in the parent population.
- Some patients had to go down on DCCR dose due to high blood sugars.
45:01 C602 Data on Adverse Events
- Virtually no difference in adverse events, with top 3 being the same as C601.
- Some of the adverse events began to recede over the longer time period.
47:29 Thanks to Participants and Institutions
- Grateful to participants and families who gave up time to participate in study.
- Thanks to institutions, Soleno, and the Prader‑Willi community.
49: 54 Q & A
