A new study is now enrolling patients ages 4 and up to determine the safety and efficacy of Diazoxide Choline Controlled Release (DCCR) for the treatment of hyperphagia in PWS. A live webinar was conducted on February 26th sharing details of the study, what you can expect if you choose to participate, and eligibility criteria for participation. The presentation is about 15 minutes, followed by 15 minutes of Q&A. You can watch the complete presentation by clicking on the embedded video. In case you don't have time to watch the full video, we've included a full transcript below
Susan Hedstrom, FPWR:
Welcome everyone to today’s webinar. This webinar is the second in our series of clinical trial webinars and I am happy to have you joining us today. As you know, there are many clinical trials currently enrolling PWS patients for their studies. Some of these trials are investigational drugs, others are behavioral interventions. A list of trials is available on FPWR.org and I encourage you to visit the site to learn more about the opportunities that are available.
Our community has been waiting a long time for these treatment opportunities and we are fortunate to have so many opportunities available to us this year. I know you are joining us today because you want treatments for your loved one and these trials are the first step. In order to bring any treatment to market, we need to enroll these trials so that they can collect the data necessary to show efficacy for the FDA. It will require the effort of the entire PWS Community to help complete these trials and encourage you to learn more about these opportunities and to determine which opportunity may be right for your family and your loved one with PWS.
Today's guest presenters are from Soleno Therapeutics and they'll be sharing more information with you regarding their Phase 3 study of DCCR which stands for Diazoxide Choline Controlled Release tablets. We will be collecting questions from the audience throughout the webinar and will answer all of your questions after their short presentation. Without further delay, I give you the team from Soleno Therapeutics.
Anish Bhatnagar, Soleno Therapeutics:
Thank you, Susan for inviting us to provide an overview of our DESTINY PWS study to members of the PWS community. I am Anish Bhatnagar, CEO of Soleno Therapeutics, which is a biotech company located in Redwood City, California. We are focused on the development and commercialization of novel therapeutics for the treatment of rare diseases. Our lead candidate is Diazoxide Choline Controlled-Release or DCCR, which is a once-daily oral tablet for the treatment of PWS. Our ongoing Phase III study is, DESTINY PWS, which stands for DCCR Efficacy and Safety Trial IN Young children and adults with PWS.
I am joined by my colleagues, Dr. Neil Cowen, Senior Vice President of Drug Development and Kristen Yen, Head of Clinical Operations, as well as Dr. Parisa Salehi, Principal Investigator at Seattle Children’s Hospital.
Neil Cowen will provide some background on DCCR.
Neil Cowen, Soleno Therapeutics:
Thank you, Anish. I would like to provide you with some background on DCCR. Appetite is controlled by 2 sets of neurons in a region of the brain called the hypothalamus which controls certain metabolic processes in the body. The NPY/AgRP neurons increase appetite. POMC neurons decrease appetite.
Research shows that, due to the deletion of SNORD116, one of the genes in the Prader-Willi critical region, the function of neurons involved in stimulating appetite is increased in PWS. These increases are likely what drives hyperphagia. The neurons that increase appetite and decrease appetite have channels, called KATP channels. DCCR opens the KATP channels in these neurons, thereby reducing appetite and hyperphagia.
DCCR is a once daily tablet formulation of diazoxide choline, which is a choline salt of diazoxide and breaks down into diazoxide and is then absorbed in the gut. Diazoxide has a long history of safe use. It was approved by the FDA in 1976, and has been in use since then in patients for which it is approved, so the safety profile of diazoxide is well known. It is used for treatment of low blood sugar due to increased insulin levels in infants, children and adults in very rare conditions known as hyperinsulinism and insulinoma. The oral suspension is usually taken 2-3 times per day and normally at daily doses up to several times higher than the doses that are being evaluated in PWS.
In the development of DCCR, there have been no new safety findings, compared with diazoxide. The most common adverse effects include increase blood sugar and peripheral swelling – both of which can be managed by your doctor. It is worth noting that the doses of DCCR used in this study are at the low end or below the range used for diazoxide.
DCCR has pre-clinical and clinical data supporting its safety. To date, 8 clinical trials have been conducted using DCCR. Over 210 healthy volunteers and subjects with obesity, hypertriglyceridemia and Prader-Willi syndrome patients participated in these studies.
A study of DCCR in 13 overweight and obese PWS patients aged 10-22, was conducted at University of California at Irvine. In this study, the subjects treated with DCCR showed significant improvements in hyperphagia. In addition, there was a significant decrease in body fat mass and waist circumference, consistent with a loss of visceral fat, and a significant increase in lean body mass. There was also a significant reduction in aggressive behaviors. It is worth noting that subjects who were treated at the higher doses showed greater beneficial effects such as improvements in hyperphagia, decreases in body fat and an increase in lean body (muscle) mass. The adverse events reported in this study were consistent with the adverse events that would be expected with diazoxide. This pilot study helped drive the design of the DCCR development program.
Dr. Parisa Salehi, Principal Investigator:
Thank you, Anish. Thank you to the FPWR for inviting me to speak about the DESTINY PWS study. It is nice to see a potential option for PWS patients which not only may affect hyperphagia but also may have an effect on other aspects of this disease. This program consists of two studies, C601, the DESTINY PWS Study, which is a multi-center, randomized, double-blind, placebo-controlled, parallel arm study in patients with PWS (Phase III) and C602, an open-label safety extension study.
In the C601 study, the plan is to enroll approximately 100 patients at approximately 25 sites. Eligible subjects will be in this study for approximately 15 weeks. This is a double-blind study. It is also a placebo-controlled study which means that some subjects will not receive DCCR but placebo, which means that the tablet does not contain any drug. The assignment to DCCR or placebo is random, like rolling a die or flipping a coin. Subjects have a 2 out of 3 chance in being assigned to DCCR and a 1 out of 3 chance of being assigned to placebo. Subjects will undergo a titration phase during which their doses will be increased every two weeks until they reach their maintenance dose. In total, there are 7 visits in this study where the first 6 visits are every two weeks then there are 5 weeks in between the last two visits. At the End of Study Visit, subjects who successfully complete C601 are eligible to enroll into C602. C602 is a 9-month open-label safety study. In C602, all subjects will receive DCCR.
The primary objective of this study is to evaluate the effects of DCCR compared to placebo on hyperphagia in PWS patients. This is being evaluated using a Hyperphagia Questionnaire.
One of the secondary objectives is to evaluate changes in body fat mass. The body fat mass will be measured using a DXA scanner, which is an X-ray procedure to measure body fat mass and lean body mass (or muscle).
Two other secondary objectives are to evaluate the Clinical Global Impression of Improvement (CGI-I), and Caregiver Global Impression of Change (GI-C). The Clinical Global Impression of Improvement is a question that the Study Doctor will answer. The Caregiver Global Impression of Change is a question that the Caregiver will answer.
Additional objectives of this study are to assess safety as well as the effect of DCCR compared to placebo on body composition parameters, BMI, waist circumference, lipid parameters, subject’s health related quality of life, caregiver burden, and PWS behaviors.
What are the Key Eligibility criteria for this study?
Key Inclusion Criteria
- Provide voluntary, written informed consent (parent(s) / legal guardian(s) of patient); provide voluntary, written assent (patients, as appropriate)
- Have genetically-confirmed Prader-Willi syndrome and be hyperphagic
- Be 4 years of age and older
- Be in a stable care setting for at least 6 months prior to Visit 1
- Be on stable regimens of medications for at least 3 months prior to Visit 1
Key Exclusion Criteria
- Weigh < 30kg or ≥ 135 kg (<66 lbs or ≥ 297 lbs)
- Have participated in another interventional clinical study within 3 months of Visit 1 (this will be within 60 days of Visit 1 in the next protocol amendment)
- Have any history of allergic reaction to diazoxide, thiazides, sulfonamides
- Have a history of blood clots
- Use of any of the prohibited medications within 3 months of Visit 1
- – Drugs that effect weight loss or any study endpoints
- – Systemic steroids
- – Insulin
- – Medications that affect metabolism of the study drug
- – Any investigational drugs
The duration of participation is 15 weeks with 7 visits. Visits 1 - 6 are two weeks apart. Visit 6 and 7 are 5 weeks apart.
At every visit, to monitor for safety, subjects will have a physical exam, which will include a peripheral edema assessment and a thromboembolic assessment. Subjects will need to fast for at least 8 hours prior to every visit for fasting blood tests.
At some visits, there will be questionnaires for the caregiver to complete, an ECG at Visits 1, 6, and 7, a DXA scan at Visits 2 and 7, urine test at Visit 2, 4, 6 and 7 as well as a Diet, Physical Activity and Sleep Assessment at Visits 2 – 7.
This map shows where the sites are in the US. There are 12 sites that are currently recruiting subjects and 4 sites that will soon be recruiting. There will be more sites coming soon.
Clinicaltrials.gov as well as the FPWR website lists the sites that are actively recruiting subjects. If you have any questions about sites or if your do not see a site in your area, please contact the Soleno Project Manager at the phone number or email provided.
Webinar attendees were invited to ask questions of the panelists. Below are the questions presented and the responses.
Q: Is there any documentation that shows that DCCR works?
A: Yes, in fact there are there has been a pilot study in patients with PWS which was conducted at UC Irvine Medical Center. And in that study DCCR showed significant improvements in hyperphagia, significant decreases and body fat mass and waist circumference, consistent with the loss of visceral fat, and also a significant increase in lean body mass, this is based on DEXA scanning. A number of posters and presentations have been done at national and international conferences that describe the safety and potential effectiveness of dccr in patients with PWS and a number of these are available on our website at www.soleno.life.
Q: How have subjects been doing so far in this study? Have you seen any improvements?
A: As we noted earlier the ongoing Destiny PWS study is a double-blind placebo-controlled study with a third of patients receiving placebo. We do not know which patients are on DCCR and which are on placebo so we are not really able to say whether improvements have been seen or not at this time.
Q: How is this DCCR different from the Diazoxide that's already available?
A: That's a really good question. Diazoxide Choline Controlled Release (or DCCR) is not the same as diazoxide. Diazoxide Choline is a crystalized salt form of Diazoxide which allows it to be made into a tablet form, which in turn allows for a slow release of Diazoxide Choline and absorption of diazoxide. Think of it as a tablet that releases small amounts of a diazoxide choline over 24 hours in the gut. In contrast, the currently available diazoxide formulation is an immediate release formulation. Meaning that it is more rapidly absorbed and then cleared
From the body so it needs to be taken 2 or 3 times a day. DCCR is an extended release formulation so it is absorbed over a longer time and it allows us to dose the medication once daily. The DCCR tablets also allow for consistent dosing which is difficult to achieve with an oral suspension diazoxide. We expect that DCCR may be safer and may have a lower number and severity of side effects due to the ability of being able to dose at lower levels while still achieving a therapeutic effect. That, however, needs to be confirmed in the clinical trial we are now conducting.
Q: What side effects might participants need to be watching for?
A: The most common side effects that have been seen in previous studies on the use of diazoxide in its current indication are increased blood sugar and edema, think of it as fluid retention or swelling. In most cases, we expect these to be short term. If needed, the doctor can lower the DCCR or stop treatment temporarily to treat those, but we expect that to be infrequent. We have seen that in the past that when diazoxide is used without titration, which means that we directly dose with a high dose of diazoxide, there used to be more side effects. With the current dosing, DCCR is much better tolerated.
Q: Does this medication interact with a person's blood sugar? Does it increase or decrease those levels and if so, is this monitored during the 15 week trial?
A: Theoretically, it can impact blood sugar because it does decrease the insulin secretion temporarily. However, what we have seen so far is that these effects tend to be temporary. In the study we are conducting, we allow either patients that are not diabetic or patients who are diabetic on treatment without insulin to be admitted into the study. What we have seen so far and what we expect to see, is that they may be a transient increase in glucose but over time with continued dosing of DCCR, the levels should come back to normal. And that's kind of our expectation with DCCR.
Q: How long will trial visits lasts and what are some of the tests that will be completed at the visits?
A: So in total, there are 7 visits within the15 weeks in the study and most of these visits are lasting two and a half hours on average. However the screening and randomization and end of study visits may last up to about four hours.
Some of the evaluations Dr. Salehi was talking about, like a DEXA scan, think of it as a simple x-ray of the whole body that takes just a few minutes and doesn't require any particular involvement from the patient. A number of the other evaluations are just questionnaires, typically filled out by the caregiver who is accompanying the patient or the physician. There is blood work to be done and it varies by which visit in some visits there is more blood work and others there's less.
Q: In regards to the blood work, fasting is needed to take place for 8 hours prior, are these appointments scheduled for the morning so that fasting can take place overnight?
A: All the sites will make an attempt to schedule the visits as early as possible in the morning to ensure that the fasting blood can be obtained. And I also wanted to complete an answer from a question which was asked earlier: Is blood pressure evaluated on a regular basis for these 15 weeks, and the answer is yes, blood sugar is carefully evaluated for these 15 weeks.
Q: Is there an open label extension with access to drug after the 15 week study period?
A: As Dr. Salehi mentioned, once the patient completes the three-month randomized double-blind placebo-controlled study, they have the ability to enroll into a 9-month safety extension study. This is a study in which everyone will get drug. So the total duration of treatment could be as much as one yea.
Q: Could you provide more information on what the monitoring looks like during that open-label 9-month period?
A: Think of it more as a safety extension study. So we don't do such extensive evaluation in the study. It's a simpler version of the randomized double-blind version of the study. After the first few weeks, the visits are much less frequent and the number of evaluations are much less as well. We are working on simplifying the protocol further and we expect to see the number of visits to be quite infrequent after the first few weeks in that protocol.
Q: My child is old enough to participate but weighs less than 30kg and he clearly has hyperphagia. Why can my child not enroll?
A: The answer is because the optimal dose of DCCR is in a certain range based on body weight. Think of it as a milligram per kilogram. We currently have specific tablet strengths that are available which could make the dose too high for patients who are lighter than 30kg. We are working on lower dose strength right now and we plan to update the protocol once those are available. And conversely, if the patient is above 135 kg, the challenges are such that would make the dose is too low for patients or have a heavier than 135kg. In addition, on the higher end we want to limit the dose to what has been used in studies so far. So that we continue to be comfortable with the safety of DCCR in the study.
Q: If my child’s height and weight are normal, is he or she still eligible?
A: There's no exclusion for anyone with normal height or weight. The exclusion really is that the patient must weigh either above 30 kg or below 135 kg to be eligible. And obviously they must meet the other eligibility criteria as well. Patients do not need to be obese or have a high BMI to be enrolled in the study.
Q: You showed us a list of clinical trial sites that are currently enrolling, or preparing to enroll. One of our audience members would like a site near Chicago. Will additional sites be opened or are the travel funds to help patients get to existing sites?
A: We are actively trying to recruit more sites who are interested in participating so I would actually encourage anyone who is a seeing a physician in the Chicago area to ask if their interested. We're happy to open a site in the area, however until such time, we would be happy to support the travel of anyone who would want to go to the nearest site which is not in their area.
Q: What is covered when you facilitate travel? Does this cover transportation or lodging expenses?
A: Yes, there is reimbursement available for each visit and it does cover lodging and other travel expenses as well as meals.
Q: If there is not a trial site near you, how does a person select a site?
A: It may be easiest to pick the geographically closest site and call the contact information that's listed at clinicaltrials.gov. The study coordinators are very responsive and they will be able to talk you through how to best do it. If you have any problems with that, the Soleno project manager is always available to help you and that contact information is also one of the slides.
Q: Do you have a timeline for when more sites may be made available?
A: We are active at 12 sites right now, and those are listed on the side,s and I believe there's four or five additional sites that we are hoping to start in the next few weeks. As I said, if there are specific geographies, we're happy to look at them for other sites. However remember the time to get to site up and running, so it may be most practical for someone to actually look at their closest site graphically and be enrolled there. As Kristen mentioned we do provide to travel assistance Etc so that should be able to facilitate the participation.
Q: Does being on growth hormone preclude someone from participating in the study?
A: It does not. Patients in our prior study, a good proportion of them, where on growth hormone as well and we do not expect to have any detrimental effects of DCCR on growth hormone or vice versa.
Q: How big is this tablet and have patients had any problem taking it?
A: We have not had any concerns expressed by patients or sites to date.This was a topic of conversation as we designed the study. There are two strengths of tablets available, the smaller one is probably the size of an advil and the larger one is probably about two times that or so. So these are not large tablets and like I said we have not heard any concerns so far from patients in terms of swallowing them. Just a reminder, these tablets do need to be swallowed whole. They should not be chewed because this is an extended-release product and it's important that they be swallowed.
Q: Does DCCR impact any specific organs like the kidneys or liver?
A: There is no evidence to suggest that DCCR has any detrimental effects on the liver or kidney etc, however we are studying that, we are closely following that. The reason we do this blood work is to insure that that is the case, but there's no evidence of that it detrimentally impacts any of the vital organs.
Q: Speaking of long term use, is there any data so far that supports this drug continues to work after 3 or 6 months?
A: Thats a very good question as is probably all of this to you, DCCR has not been studied for long-term treatment in PWS patients however, there is an interesting data set that can be looked at to see if patients developed tolerance or not. This drug was first approved in 1976 for the treatment of rare conditions and is currently used for treating hyperinsulinism and patients with insulinoma. These are patients that stay on diazoxde for a very long time, years at a time and it remains a standard of care for many of those patients. So if that is any gauge, we should not expect to see tolerance develop but we do not have this specific data in PWS at this time.
Q: Let’s talk about anxiety. A lot of our community members, their loved ones experience high levels of anxiety. Have you seen or measured any changes in anxiety with DCCR?
A: As part of this study we are measuring a number of behaviors. As you know the FPWR has a very substantial series of questions that are asked as part of the PWS profile questionnaire and that will be administered as part of this study. so we don't have any definitive data on the effect on anxiety at this time. What we saw in the earlier study was an effect on aggressive and destructive behaviors but we hope to know a lot more at the end of this study.
Q: Will all participants start at the same time or will there be open enrollment so that patients can enroll whenever they are ready?
A: Its the latter, so it is a rolling enrollment in the sense that not all patients will start at the same time. There are several who have started and we expect that patients will continue to enroll over the next handful of months.
Q: Is there a deadline for when people need to be enrolled by?
A: We don't have a definitive date for completion of enrollment but we are currently enrolling at 12 different sites and new sites are coming onboard quite rapidly so I expect that we should be completing enrollment in the not-too-distant future I would encourage patients to reach out to their closest sites as soon.
Additional information on this study, as well as others, can be found on the FPWR.org web site as well as clinicaltrials.gov. We do have more upcoming trial webinars and these are all listed on the FPWR website. We hope you will continue to join us and learn more about these important opportunities.