Thursday, December 20, 2018
Pharmaceutical firm Roche has announced 26 planned sites in the U.S. and Canada for its historic Phase 3 clinical trial of a gene-silencing drug to slow, halt, or perhaps even reverse the progression of Huntington’s disease.
Called GENERATION HD1, the greatly anticipated trial will test the efficacy of the drug, RG6042. Roche expects to start enrolling volunteers in early 2019.
The announcement comes one year after the successful completion of the Phase 1/2a trial to measure the safety and tolerability of RG6042, developed by Ionis Pharmaceuticals, Inc.
RG6042 dramatically reduced the amount of mutant huntingtin protein in the cerebrospinal fluid (CSF) of trial participants. As a result, Roche took the unusual step of skipping a Phase 2 trial (testing efficacy for the first time) and going directly to a Phase 3 (confirming efficacy in hundreds of participants, or more).
In a statement released December 19 to the Huntington’s Disease Society of America (HDSA) and other patient groups, Roche announced the sites listed below, grouped by province/state.
Alberta, Edmonton – University of Alberta
British Columbia, Vancouver – University of British Columbia
Ontario, Ottawa – Ottawa Hospital
Ontario, Toronto – Centre for Movement Disorders
Nova Scotia, Halifax – Queen Elizabeth II Health Sciences Centre
Quebec, Montreal – Centre Hospitalier de l’Université de Montréal
Alabama, Birmingham – University of Alabama
Arizona, Phoenix – Barrow Neurological Clinic
California, Davis – University of California, Davis
California, Palo Alto – Stanford University
California, Pasadena – Arcadia Neurology Center
California, San Diego – University of California, San Diego
Colorado, Englewood – Rocky Mountain Movement Disorders Center
District of Columbia, Washington – Georgetown University
Florida, Tampa – University of South Florida
Illinois, Evanston – Northwestern University
Maryland, Baltimore – Johns Hopkins University
Massachusetts, Boston – Beth Israel Deaconess Medical Center
Missouri, St. Louis – Washington University in St. Louis
New York, Amherst – Dent Institute
New York, New York – Columbia University
Pennsylvania, Pittsburgh – University of Pittsburgh Medical Center
Tennessee, Nashville – Vanderbilt University Medical Center
Texas, Houston – University of Texas Health Science Center
Utah, Salt Lake City – University of Utah
Washington, Kirkland – Evergreen Health
Roche plans to announce sites in approximately 13 additional countries in the coming months. It hopes to enroll a global total of 660 volunteers with early HD symptoms at 80 to 90 sites. Each participant will receive the drug or placebo monthly over 25 months through a lumbar puncture (spinal tap), the way into the CSF.
The CSF bathes the brain. Because biopsies of the brain are currently not possible, measuring the effect of the drug in the CSF gives researchers a window onto the effects of the drug.
Moving as ‘quickly as possible’
“It is important to note that these sites are not fully activated nor recruiting yet,” the Roche announcement stated. “We hope to complete the final steps as quickly as possible.”
According to the statement, Roche selected sites based on a variety of factors, including prior experience with HD studies, clinic infrastructure capacity, ability to run the study as quickly and completely as possible, patient population, and geographic location.
The news follows Roche’s announcement last month of 16 sites for the HD Natural History Study, an arm of the RG6042 program to involve 100 observational study volunteers in Canada, Germany, the United Kingdom, and the United States.
The HD Natural History Study will seek to deepen understanding of the natural progression of HD, the role of the mutant huntingtin protein in the disorder, and the assessment of biomarkers (signs of the disease measured in patients) and their efficacy in predicting the effects of the drug. The volunteers will undergo four lumbar punctures to examine their CSF, but receive no drug.
Click here for the full text of Roche’s December 19 statement.
In the U.S. and Canada, HD families can contact Roche/Genentech about the trial at 888-662-6728. Information about the trial is also available at ClinicalTrials.gov.
For additional background on GENERATION HD1, click here.
If effective, RG6042 would be the first treatment to affect the progression of Huntington's.
Stay tuned to this blog for future updates on GENERATION HD1.
Sunday, December 09, 2018
Building solidarity in disease communities’ quest for better care and treatments: a conversation with a young tennis award-winner
In disease communities, it’s easy for affected individuals and their families to become insular as they struggle with the many challenges posed by their particular illness. To attract the attention and funds needed to combat a disease, sometimes they even portray their condition as more devastating than others.
In the Huntington’s disease community, we refer to HD as “the devil of all diseases,” like a combination of Alzheimer’s, Parkinson’s, and psychiatric and behavioral disorders, including a high suicide rate. There is no treatment for stopping disease progression.
However, in the quest to treat difficult chronic illnesses, disease communities need to build solidarity and learn valuable lessons from one another. Also, although the causes and symptoms of diseases vary widely, the different communities share the common cause of overcoming the limits diseases place on people’s lives.
I had a reawakening about solidarity a year ago this week. At the University of San Diego (USD), where I’m in my 26th year in the Department of History, a new advisee, 20-year-old sophomore Garrett Kurtz, sat in my office as he began to recount his own battle to live with type 1 diabetes.
Suddenly, Garrett untucked the left side of his shirt to reveal a device about the size of a small smartphone attached to his waist. He explained that it was a pump that gave him injections of insulin, which helps convert sugar in the blood so that it can enter the cells and allow them to use energy. Type 1 diabetics cannot produce this essential hormone.
I felt an immediate bond with Garrett. I shared a bit of my family’s fight against HD, including my HD-afflicted mother’s death and my condition as a gene carrier.
Remarkably, I learned, despite his potentially limiting condition, Garrett has played competitive tennis since he was seven and a half. By 12, he was ranked in the top 50 male players in the nation, and in the top ten in Southern California. He now plays for USD’s men’s team, a top 35 National Collegiate Athletic Association (NCAA) Division I team.
As Garrett explained, few prominent athletes have diabetes. Choosing the rare but ingenious combination of a history major and chemistry minor, he aims to work for a biotech or similar firm with the goal of helping physically active people, including athletes, better manage their diabetes.
For his efforts, in July Garrett was named one of two 2018 Novo Nordisk Donnelly Award national winners. The award includes a one-time $7,500 scholarship towards education, tennis development, and/or medical care. These and smaller awards go to male and female athletes ages 14-21 who are in good academic standing, manage diabetes, and play tennis competitively in tournaments or on their school team.
Garrett received the award from all-time tennis great Billie Jean King, a type 2 diabetic.
Garrett Kurtz and Billie Jean King (photo from @USDmtennis)
The inspiration of Billie Jean King
“To receive an award from someone like her was absolutely incredible, and I’m extremely honored,” Garrett said in a November 14 interview with me at USD, recalling King as a “trailblazer” in women’s sports, gender equality, and LGBTQ advocacy.
After speaking with King for an hour, Garrett was inspired by her personality and positive attitude.
“She was very direct,” he said. “She had an aura of self-confidence. She talked about how having self-confidence and a vision is something so important to people of all ages, but especially young people, wherever they may be in society.”
The awards take their name from Diane Donnelly Stone and Tracey Donnelly Maltby, two sisters who became college tennis stars and have lived successfully with type 1 diabetes since childhood. Novo Nordisk, a Denmark-based global healthcare firm with a focus on diabetes, became the award’s title sponsor in 2002.
“They want to highlight specifically tennis players who are type 1 diabetics and basically give them a voice or recognition for what they go through every day, the struggles that they have to deal with,” Garrett commented.
You can watch my interview with Garrett in the video below.
Diagnosed with type 1 diabetes
Garrett and his parents discovered that he had type 1 diabetes when he was seven, just around the same time he started playing tennis in his hometown of Newport Beach, CA.
“I was extremely thirsty and dehydrated,” he recalled. “I also had lost some weight. One of the unrelated members of my family had type 1 diabetes and we had a spare blood sugar test kit in my house. My mom took my blood sugar and I was extremely high and that was a strong indicator of what was happening. I was taken to the hospital and diagnosed pretty soon afterwards.”
Other type 1 symptoms include fatigue and weakness, frequent urination, extreme hunger, irritability and other mood changes, and blurred vision.
“I think diabetes is a very unique disease, because you cannot take a medication and just be good for the day,” Garrett said. “It’s a 24/7/365 type of disease where everything that I do – whether it be studying, exercising, eating, the anticipation of waiting for something, being happy – diabetes affects it.”
With vigilant management of the disease, today his symptoms are under control.
Understanding type 1 and type 2
In 2015, more than 30 million Americans had diabetes, 1.25 million with type 1 and the rest with type 2.
Type 1 was previously known as “juvenile diabetes” but actually affects more adults than children. It occurs in all ages and ethnic groups.
Garrett explained the differences between the two types.
“Type 1 is an autoimmune disease, which basically means your immune system attacks part of your body, whereas type 2 comes from your lifestyle, what you eat, and it’s not necessarily hereditary,” he said. “There’s a whole host of autoimmune diseases.”
His father has ankylosing spondylitis, believed by some researchers to also be an autoimmune disease. It has the same genetic marker as type 1 diabetes, but the doctors “don’t know if there’s a link between that and my diabetes,” Garrett said.
“Type 1 is something that you cannot control,” Garrett continued. “Basically what happens with a type 1 diabetic is that your immune system – and this is the great mystery with type 1 diabetes, whether it’s your environment or something you eat or it’s just how your body works – attacks all of your beta cells, which are produced by your pancreas.”
Beta cells produce insulin, Garrett explained. Insulin breaks food, especially carbohydrates, down into glucose, which is the blood sugar that diabetics measure by pricking their fingers.
“Insulin attaches itself to the sugar and allows it to get transferred to the individual cells and allows them to use the energy, for you to function and exercise,” he said.
Type 1 diabetics must “manually administer” their insulin via injection or a pump such as Garrett’s.
Type 2 diabetes generally results from an unhealthy lifestyle, including obesity, lack of exercise, and poor diet.
“A type 2 diabetic is different in the sense that they become insulin-resistant,” Garrett explained. “You become so used to consuming so much, that your body keeps producing more and more insulin. It becomes a point where it’s like taking too much of a drug. It’s like becoming addicted. You need more and more and more until the point where the insulin just doesn’t become effective.”
Unhampered on the court
From 2012 to 2015, another unexpected, painful, episodic condition hit Garrett, this time sidelining him from competitive tennis. After consulting with nearly a dozen sports orthopedic specialists and undergoing many MRI scans, he learned that he had a rare physical abnormality: a blood vessel was sitting on the nerves of his inner right elbow. In late summer 2015, he underwent a successful surgery to relieve the pain, enabling him to return to the court.
In 2016, after another tennis player recommended Garrett, USD head tennis coach Ryan Keckley recruited him for the team.
“With the understanding that he was a top ten player, and understanding his character, his family, and his love for the game, we decided to offer him an opportunity to play for USD,” Keckley told me. Since his arrival, Garrett has played in several important matches for USD. Keckley said he expects Garrett to compete in the upcoming spring 2019 season.
Receiving the Novo Nordisk Donnelly Award was “really a testament of his character and his work ethic,” added Keckley, a top player while a student at the University of Notre Dame. “There are very few athletes that have been able to manage what he manages, and are successful at it. This gives him an edge in seeking to go into the field of studying diabetes.”
Given Garrett’s small stature for tennis – 5-7, 150 lbs. – “he needs to be the little engine that could,” Keckley observed. “He has learned how to be tougher than his opponents, which is ultimately why he was one of the ten best players in the country in the 14 and unders.”
Because of Garrett’s careful management of his diabetes, the condition has not hampered his play, Keckley added.
“If you didn’t know Garrett, you wouldn’t know it was something he dealt with,” he said.
Garrett Kurtz at practice (photo courtesy USD Men's Tennis Team)
The hope of managing HD
I told Garrett that we in the HD community hope for the breakthrough that allows patients to manage the disease in a way not unlike how he controls his diabetes with his pump. HD is also a 24/7/365 disease. HD patients, I speculated, might tweak their own administration of drug the way he does.
Still, to affect HD, a drug must cross the highly protective blood-brain barrier, a monumental task for drug researchers.
HD drug developers have discussed the possibility of using pumps to deliver a drug. In 2008, in my first visit to the former Isis Pharmaceuticals, Inc., now Ionis Pharmaceuticals, Inc., the company’s senior vice president, Frank Bennett, Ph.D., explained how the company used this approach. (Click here to read my 2008 report.)
Ionis researchers inserted pumps under the skin of mice, then, for each mouse, ran a tube into the brain to deliver an experimental gene-silencing drug. At that time, researchers were considering the use of a hockey puck-sized pump placed in the abdomen of HD patients, which would pump the drug through a tube carefully inserted into the brain.
In our discussion, Dr. Bennett pointed out that people with a number of conditions such as chronic back pain or diabetes already used commercially approved pumps. Doctors could use infrared signals to program the pumps and control the flow of medication and could inject a new supply into the pump through a port just under the skin.
“It’s obviously not ideal, but considering the severity of this disease, it’s well worth the inconvenience that these pumps produce,” Dr. Bennett observed in 2008. “Once patients acclimatize to them, they’re really not that bothersome.”
A pump instead of spinal taps?
Indeed, Ionis was exploring the possibility of pumping an HD drug into the cerebrospinal fluid (CSF), which bathes the brain, via pump. It had already used one of its drugs to reduce the effects of Lou Gehrig’s disease in test rodents using this method.
So far, such pumps aren’t being used in HD clinical trial. In its historic, highly successful Phase 1/2a clinical trial, completed in December 2017, Ionis injected the drug via lumbar puncture (spinal tap) four times into the CSF of 46 volunteers, without any serious side effects.
The follow-up Phase 3 trial, to be run by Swiss-based Roche starting in early 2019, will involve 25 monthly lumbar punctures (click here to read more).
Delivering drugs via spinal fluid is a new procedure. There are no studies of the effects of long-term use of spinal taps. I expressed my own concerns about this.
With its current crucial focus on demonstrating efficacy in the Phase 3 trial, Roche is not yet ready to discuss the hypothetical use of a pump or other drug-delivery methods such as its proprietary “brain shuttle” technology (click here to read more).
Medtronic, the medical device and healthcare firm that makes Garrett’s pump, has conducted HD research but not initiated any clinical trials. It also makes a pump for delivering drugs into the CSF for treating conditions such as chronic pain.
A revolution in diabetic care
In our November 2018 conversation, Garrett spoke in great detail about his use of the Medtronic MiniMed 670G electronic insulin pump and its companion, linked device, a continuous glucose monitoring sensor.
The Medtronic MiniMed 670G electronic insulin pump (largest device in photo), continuous glucose monitoring sensor (small device on right), and blood sugar test kit (on the left)
“It’s like a temporary IV that you have to change every three days,” Garrett explained. “You put it on a region of subcutaneous fat [fat under the skin] so that it can absorb and go into your system.
“And the great thing about the insulin pump – and what makes it great for being a tennis player and being active – is you can give yourself insulin at any point in time during the day. I just have to press a few buttons, and I can configure how much insulin I’m giving myself. The great thing about the pump is that it allows you to give insulin in very small samples.”
That’s important, Garrett said, because the overall volume of insulin needed by a diabetic “is not very much.”
The system helps “cover carbs” consumed – plus glucose produced by normal bodily functions – with small, pre-programmed boluses (doses) of insulin.
“In a normal person, their pancreas is doing all this automatically,” he continued. “Every few minutes or every few seconds, your pancreas is giving you insulin. It also gives you a shot of adrenalin, which also bumps your blood sugar up.”
Garrett used to prick his finger up to a dozen times per day to measure his glucose. Now, with the continuous monitoring glucose sensor, he does it only twice. “My finger pads are in bit better shape now,” he observed, laughing.
The monitor is also attached to a small area of subcutaneous fat, generally on the stomach or the back of the arm or hips. It measures blood sugar every five minutes.
“For a diabetic, that’s extremely helpful for you to understand where you are and what you need to do,” Garrett said, noting that he can thus both anticipate and make adjustments and know whether he needs to consume sugar or insulin.
In this hybrid system, the pump and the sensor “talk to each other,” Garrett added. There are still technical difficulties, but “it’s revolutionary in terms of diabetic care, because it’s that first step in trying to get the artificial pancreas.”
He can also download data from the pump and sensor that allows him to analyze his blood glucose trends and insulin consumption for continual adjustments.
Feeling ‘on top of your disease’
The devices have not restricted his life in any way, Garrett said. On the contrary, as a tennis player, he can avoid having to take insulin shots during a match.
I asked Garrett what advice he would offer to drug companies working on neurological disease treatments and the potential of long-term drug delivery.
Garrett replied that he has recently been thinking more about the significance of his pump.
The system has allowed him to “fine-tune” his insulin intake, he observed.
“Having a pump kind of makes you feel empowered,” he said. “It makes me feel like I control my disease. I own the disease. The disease doesn’t own me.”
With drugs delivered via pump, people with HD and other neurological disorders could also feel “on top of their disease,” he said.
Disease communities learning from one another
Now a junior, Garrett turned 21 in October. As a history major and chemistry minor, he wants to research the history of diabetes and how medical care for the condition has evolved.
After graduation, he would like to work for a company such as Medtronic to focus on diabetic product design and sales. He is especially passionate about mentoring young athletes affected by diabetes. He also envisions starting a division at a healthcare or biotech firm focused on athletes and other physically active people with diabetes.
He’s also hoping for progress on the development of the artificial pancreas, the equivalent of a cure for diabetes.
Likewise, the HD community and other neurological disease communities anxiously await the first effective treatments.
“Time is of the essence in many of these diseases,” Garrett observed. “The faster you can bring cutting-edge technology to the patient, the better it is. Just 50 years ago for diabetes, you were taking your blood sugar by urinating in a cup. Now I wear a device that literally takes it every five minutes and beams it to a pump.”
These communities all can learn from one another, Garrett stressed.
I have already learned much from Garrett and his approach to life.
Wednesday, November 21, 2018
This Thanksgiving, I am especially grateful for good health – and all that it enables me to enjoy.
At my annual neurology checkup on October 31, the doctor told me that I remain asymptomatic for Huntington’s disease. My more extensive annual Enroll-HD examination earlier in the year also showed no symptoms.
I tested positive for the HD gene in 1999. Next month, I turn 59. At that age, my mother had already been diagnosed and was rapidly losing the ability to walk, talk, and care for herself. She died in 2006 at the age of 68 after a long struggle.
I never imagined that at this point I could still pursue my passion for writing, teach at the university, and support my family.
As I frequently tell students, colleagues, and my family, “health is first.” Without it, achieving goals and handling responsibilities can become very difficult, if not impossible.
Studying the history of the HD cause
I am putting the final touches on a book in my field of Brazilian history, scheduled to be published next June, From Revolution to Power in Brazil: How Radical Leftists Embraced Capitalism and Struggled with Power. I began the research more than two decades ago, not long after learning of my mother’s HD diagnosis. Seeing the project come to fruition is thrilling and profoundly fulfilling.
With the Brazil project complete, I will carry out my long-gestating plan to shift my main scholarly focus to the history of science, technology, and medicine. Last month I proposed a new, multi-year research project, titled “Racing Against the Genetic Clock: A Social, Scientific, and Personal History of the Huntington’s Disease Movement.”
I aim to study how key facets of the movement intertwined with major developments in the biotechnological and medical revolutions of the past 200 years. I believe that the HD cause can serve as a guidepost for other disease communities and inform key bioethical questions related to them.
I also want to help the HD community reflect on its path through history.
More than ever, my scholarly work and HD advocacy will meld. (Click here to read more.)
Seeing our daughter enter college
On a personal level, good health allowed me to join my wife Regina last August in helping our HD-free daughter Bianca set up for her first semester at the University of Pennsylvania, where she is studying in its College of Arts and Sciences.
I had always feared that HD would prevent me from experiencing this special moment – just as HD had stopped my mother from interacting with Bianca as a baby and young child.
I am more determined than ever to see Bianca graduate from college and find her way in life. I’m hoping that GENERATION HD1, the historic Roche Phase 3 clinical trial of a gene-silencing HD drug, will result in an effective treatment not only for patients, but as a preventive measure for presymptomatic gene carriers like me. Roche hopes to enroll the first volunteers starting in early 2019.
Looking ahead, I hope to retire on my own timeline – not because of HD.
Regina, Bianca, and Kenneth Serbin (aka Gene Veritas) during Penn Family Weekend, October 21, 2018 (family photo)
The preciousness of life
I’ve been extremely fortunate to reach this point without HD symptoms—or other significant health problems. Many HD brothers and sisters of my generation are struggling with symptoms.
Like so many in HD families and other difficult situations, I’ve learned to value each moment of life.
Others face different health issues. At this time last year, I lost two wonderful friends about my age, generous supporters of the HD cause, taken quickly and unexpectedly by other conditions. I’ve missed them dearly, and think about them daily as a reminder of the preciousness of life.
Tomorrow, I want to enjoy Thanksgiving.
God and nature willing, I’ll awake the next day ready to love my family, continue the fight to defeat HD, and dream of a day when a cure frees me to assist people less fortunate.
Happy Thanksgiving! And the best of health for you and yours.
Friday, November 09, 2018
Pharmaceutical firm Roche has identified nine sites in the U.S. and Canada for an observational study that will seek to answer key questions for the company’s upcoming Phase 3 trial of a gene-silencing drug to treat Huntington’s disease.
In a November 7 e-mail to the Huntington’s Disease Society of America (HDSA) and other HD groups, the Swiss-based Roche announced that it plans to carry out its HD Natural History Study, beginning by the end of this year.
The HD Natural History Study is part of Roche’s global development program for the gene-silencing drug, RG6042. The Natural History Study will provide context for GENERATION HD1, the company’s Phase 3 clinical trial of RG6042, which will start enrolling volunteers in early 2019.
The HD Natural History Study will seek to deepen understanding of the natural progression of HD, the role of the mutant huntingtin protein in the disorder, and the assessment of biomarkers (signs of the disease measured in patients) and their efficacy in predicting the effects of the drug.
Roche announced the sites listed below.
Centre for Movement Disorders, Toronto, ON
University of British Columbia, Vancouver, BC
Columbia University, New York, NY
Georgetown University, Washington, D.C.
Hereditary Neurological Disease Center, Wichita, KA
Johns Hopkins University, Baltimore, MD
Rocky Mountain Movement Disorders Center, Englewood, CO
University of California Davis, Sacramento, CA
University of Texas, Houston, TX
“These sites are not fully activated nor recruiting yet, but we hope to complete the final steps as quickly as possible,” wrote Mai-Lise Nguyen, the patient partnership director for the Roche HD team, in the e-mail.
Roche will announce a total of eight additional sites in Germany and the United Kingdom. It hopes to enroll 100 volunteers with early symptomatic (Stage I and II) HD for the 15-month study (preceded by one month of screening). Participants must be between 25 and 65 at the start of the study.
“I am pleased to share that setup has progressed well in all four countries in which the HD Natural History Study is planned,” Nguyen added.
The pivotal Phase 3 trial
In March, researchers announced the impressive results of the Phase 1/2a trial for RG6042, completed in December 2017 with 46 participants in Canada, Germany, and the United Kingdom. That trial tested primarily safety and tolerability (click here to read more). Those results led Roche to skip the usual Phase 2 trial and go directly to a pivotal Phase 3, named GENERATION HD1.
RG6042 was developed by Ionis Pharmaceuticals, Inc., which partnered with Roche in 2013. Roche now holds the license to the drug.
The GENERATION HD1 trial, to take place at 80 to 90 sites in 15 countries, will test whether RG6042 can slow, halt, and perhaps even reverse HD symptoms in 660 volunteers over 25 months.
Each month, GENERATION HD1 participants will receive the drug or placebo through a lumbar puncture. Physicians will also withdraw samples of participants’ cerebrospinal fluid (CSF) to measure the level of mutant huntingtin and other biomarkers.
Roche will announce GENERATION HD1 sites gradually in the coming months.
Why a natural history study?
Roche officials said that the HD Natural History Study will start by the end of 2018.
Participants in this observational trial will receive no drug. They will undergo four lumbar punctures, with withdrawals of CSF for analysis. They will also undergo MRI scans, blood tests, neurological examinations, and two phone checkups. Like the volunteers in GENERATION HD1, they will use digital monitoring devices.
Researchers have studied both the normal and mutant forms of the huntingtin protein since the late 1990s. However, for GENERATION HD1, Roche needs a deeper understanding of mutant huntingtin’s role in the progression of the disease. Only in recent years have researchers started examining the CSF of HD-affected individuals, so a critical question is how mutant huntingtin levels change over time naturally.
That data will provide context for researchers to interpret the GENERATION HD1 data.
Furthermore, the RG6042 program involves just one Phase 3 trial, but regulatory agencies frequently want a second. Thus, the HD Natural History Study can help with the proper interpretation of Phase 3. Roche is collecting additional data from an “open-label extension” study involving all participants in the Phase 1/2a study. Each is receiving the drug.
“We’re really trying to understand better the natural history of the disease and the predictive power of the biomarkers at baseline to predict clinical outcome,” commented Scott Schobel, M.D., M.S., Roche clinical science leader of product development, in a September 26 HDSA webinar on the RG6042 program.
Dr. Scott Schobel announces GENERATION HD1 at the European Huntington's Disease Network Meeting in Vienna, Austria, on September 16, 2018 (photo courtesy of HDBuzz.net).
Supporting GENERATION HD1
According to Frank Bennett, Ph.D., Ionis senior vice president of research and franchise leader for neurological programs, the Natural History Study aims to further understand the correlation between mutant huntingtin in the CSF and other clinical measures of HD.
“Several studies have previously described the natural history of the disease,” Dr. Bennett stated in an interview posted on the Ionis site on September 17. “Many, however, have focused on specific clinical outcome measures or changes in brain volume using imaging.”
The HD Natural History Study, he noted, will examine participants from various angles: “This study will provide high-quality, longitudinal data to help inform patients and clinicians about the course of HD, including well-validated clinical measures of HD, novel clinical outcomes, measurement of mutant huntingtin in CSF and the use of wearable devices to measure disease burden. Results from the HD Natural History study will provide valuable information in support of our Phase 3 Generation HD1 study.”
(With another scientist, Dr. Bennett recently received the $3 million Breakthrough Prize in Life Sciences. He also received the 2018 Hereditary Disease Foundation Leslie Gehry Brenner Prize for Innovation in Science.)
The Natural History Study participants could later have an opportunity to take the drug.
“For all patients who complete the HD Natural History study, an open-label extension study with the option of receiving RG6042 (no placebo control) is planned, pending approval by authorities and ethics committees/institutional review boards and if data support the continued development of RG6042,” Nguyen stated.
An HDSA FAQ
As with GENERATION HD1, Roche will not require participants to live within a certain distance of the study sites. However, a seven-page FAQ on the Roche program posted by HDSA on October 17 states that “the travel burden will likely be considered during the screening” of volunteers.
“A major move or a long-distance commitment could create additional stress on a participant and his/her loved ones,” the document continues. “Excessive travel may also make it more likely for someone to drop out of a trial, which could hamper the success of GENERATION-HD1 or the HD Natural History Study. Clinical studies are subject to international, national and local laws and regulations.
“Additionally, factors such as institutional site policies and health insurance may impact your ability to relocate and be accepted into one of the study sites. Eligibility and enrollment are ultimately decided by the study investigator at each site, who takes into account all these factors and may also wish to speak to you or your local HD specialist for more information.”
The FAQ addresses many of the hundreds of questions posed by the HD community before, during, and after the September 26 webinar (click here to read more). Topics include study eligibility requirements, the potential risks of RG6042, and the procedures, examinations, and other activities of the clinical appointments for both GENERATION HD1 and the Natural History Study.
‘Difficult to predict the outcome’
The imminence of the Natural History Study indicates that Roche is on track to carry out its plan to gradually announce GENERATION HD1 sites in the coming months and enroll the first patients in early 2019.
People can track the progress of the Natural History Study at ClinicalTrials.gov. That site and HDSA’s HDTrialFinder will also provide information on GENERATION HD1.
Regarding the duration of GENERATION HD1 and next steps if the drug works, the HDSA FAQ points out that “it’s very difficult to predict the outcome and timing of a large international drug study.[…] If the results are promising, approvals would need to move through regulatory health authorities.”
For now, the watchwords for the HD community are commitment, patience, and hope.
(Disclosure: I hold a symbolic amount of Ionis shares.)
Sunday, September 30, 2018
Pharmaceutical giant Roche’s September 16 announcement of the 2019 start of its Phase 3 Huntington’s disease clinical trial has raised great expectations about whether this drug could be the first effective treatment for this devastating disorder.
The short answer: it’s still too soon to tell.
During a September 26 Huntington’s Disease Society of America (HDSA) hour-long webinar on the trial, Roche representatives received hundreds of questions via chat from HD community members. They had time to answer only a few, with HDSA pledging to compile and post answers to unanswered questions on its website soon. (Click here to watch the webinar.)
Likewise, in response to my September 16 posting about the Roche announcement, many people in Facebook HD discussion groups have sought further information about the trial.
Roche plans to test the efficacy of RG6042, a gene-silencing drug aimed at slowing, halting, and perhaps even reversing HD symptoms, in 660 volunteers over 25 months. The test will take place at 80 to 90 sites in approximately 15 countries. Each month, participants will receive the drug or placebo through a lumbar puncture. Roche will announce the sites gradually in the coming months.
Roche has named the study GENERATION HD1 (short for Global EvaluatioN of Efficacy and safety of Roche/genentech AnTIsense OligoNucleotide for Huntington’s Disease).
Let me try to address some of the key questions about the trial from the HD community, as well as my own relationship to it as a presymptomatic HD gene carrier.
Scott Schobel, M.D., M.S. (left), Roche clinical science leader of product development, announces GENERATION HD1 at the European Huntington's Disease Network Meeting in Vienna, Austria, on September 16, 2018 (photo courtesy of HDBuzz.net).
‘How do I sign up?’
A frequent question from the community: “How do I sign up for the trial?”
During the webinar, Roche officials stressed that patients should consult with their HD doctors and families about eligibility for the trial, the pros and cons of participation, and logistics such as transportation or relocation to a trial site.
J. P. Sacksteder, of Genentech Advocacy Relations, said that Roche will announce the sites as each becomes ready to enroll patients. (Genentech, a major U.S.-based biotech firm, was acquired by the Swiss-based Roche in 2009. All U.S-based Roche personnel and products still use the name Genentech.)
“We ask for your patience and understanding as we share these trial sites,” Sacksteder said, noting that many factors influence site selection, including experience in conducting HD studies. “We understand that each of your situations is unique, so please continue to discuss your situation with your HD specialist.”
Erik Lundgren, lifecycle leader of the Roche HD program, recognized the great “desire” of HD-affected individuals to take part, but also pointed out the substantial “commitment” required in a rigorous, 25-month clinical research project.
and will provide the latest information on GENERATION HD1.
Roche officials further noted that participants could continue taking most HD-related medications, including anti-depressants as well as drugs to control involuntary movements such as Austedo and Xenazine. Excluded drugs are memantine and riluzole. Participants must start any new regimen of medicines at least three months prior to the trial’s start. Individuals cannot participate in a concurrent trial, but are not barred if they had participated in past HD trials.
For those aged 25-65
Roche will recruit volunteers who are between the ages of 25 and 65 at the start of the trial, explained Scott Schobel, M.D., M.S., Roche clinical science leader of product development.
Based on statistical studies of the HD population, people in the 25-65 age group have a more predictable progression of symptoms than younger or older groups, Dr. Schobel explained. Focusing on that cohort, he said, will furnish trial researchers with the best, most efficient way to measure whether RG6042 alleviates symptoms.
The later a person’s motor onset, the standard diagnosis of HD, the “potentially less of a progression of symptoms over time,” he added. Motor symptoms involve involuntary movements and imbalance.
Thus, including people over 65 in GENERATION HD1 would be less helpful to researchers trying to gauge the drug’s impact.
Dr. Schobel’s assertion about later motor onset reassured me a bit regarding my own potential disease progression as an HD gene carrier. At my latest HD checkup earlier this year, I had not shown such symptoms. My HD-stricken mother’s onset occurred probably in her late 40s, and by age 58 (my current age) she had full-blown HD. She died at 68.
I hope that the lack of motor symptoms at this stage means that, after my inevitable onset, I, too, will have a lesser progression of symptoms.
Healthy gene carriers excluded
However, I can’t participate in GENERATION HD1, because, at this time, presymptomatic gene carriers are ineligible. My question during the webinar requesting further details about this wasn’t answered.
In general, presymptomatic gene carriers haven’t been invited to participate in most HD clinical trials because it’s hard to measure a drug effect on an apparently healthy person.
There are also safety and ethical concerns in involving healthy individuals in a complex clinical trial like GENERATION HD1 – for example, exposing a healthy person to the potential side effects of the trial.
Regarding presymptomatic individuals and also the excluded juvenile HD population, Roche stated in its September 16 announcement: “We recognize the critical medical need for a treatment for HD, especially for people living with severe forms like juvenile onset HD. In consultation with HD community experts, our team will explore the potential use of RG6042 in populations beyond manifest [symptomatic] HD once there is sufficient scientific and safety rationale.”
At the September 16 announcement of GENERATION HD1, Dr. Schobel pointed out that the drug might act differently in the still developing brains of children and young people.
The ultimate goal of researchers is to develop a preventive treatment.
Concerns about frequent spinal taps
Even if eligible, I would have to seriously consider the risks of undergoing the lumbar punctures. The punctures, also known as spinal taps, introduce the drug into an individual’s cerebral spinal fluid (CSF) and allow researchers to withdraw some CSF for analysis.
Lumbar punctures are routine and generally safe procedures, although they can cause side effects such as headaches and bleeding. The 46 subjects in the Phase 1/2a trial of RG6042, completed in December 2017, had few side effects. Ed Wild, M.D., Ph.D., who conducts research on the CSF in HD, underwent the procedure as a demonstration for the HD community
Still, I’m personally concerned about the lumbar puncture, which, if a medicine is approved, would likely be the initial pathway for it to be administered.
In 1977, at age 17, I suffered two herniated disks in my lower spine while shoveling heavy snow in my hometown of Mentor, Ohio. Ever since, I have struggled with low back pain.
An MRI (magnetic resonance imaging) scan ten years ago revealed that the disks mainly healed, but I suffer daily with muscular pain, or myofascial pain syndrome. Occasionally, severe flareups prevent me from walking and performing some daily activities.
Since that MRI, I’ve consulted regularly with pain management specialists. I’ve also worked with physical therapists to incorporate other exercises into my morning stretching routine to strengthen my core and back.
Along with daily aerobic exercises, I want to stay strong and flexible to help forestall my inevitable HD onset and, later, to help ameliorate symptoms.
Alternative drug delivery methods?
In 2013, as a participant in the PREDICT-HD (Neurobiological Predictors of Huntington’s Disease) research project at the University of Iowa, I considered a request to provide a sample of my CSF.
After reviewing my lower spinal MRI, a doctor at Iowa concluded that a lumbar puncture was too risky.
Also, had I suffered any complications after the procedure, I would have had to obtain medical care not in Iowa, but only after returning to my current hometown of San Diego, where I have health coverage.
I wanted to assist with the research, but ultimately believed that the potential risks outweighed the benefits.
Given these concerns, during the webinar I posed two questions regarding the spinal taps. First, what will Roche due to minimize the impact of the 25 monthly procedures? Secondly, how will Roche address the fact that many people in the U.S. suffer from lower back problems?
I look forward to hearing Roche’s ideas, including the latest research on alternatives to spinal taps such as Roche’s “brain shuttle” technology and/or devices for delivering the drug.
If back pain is part the price for an effective HD treatment, I am willing to endure it.
Timeline and cost
Another major concern of the community: if GENERATION HD1 is successful, when might drug approval come?
“I can’t ultimately commit to what that timeline looks like,” Lundgren said. “We are doing everything we can to speed it up.”
First, Roche must enroll all 660 volunteers. “That’s a big variable,” he said. “We can’t complete the study until 25 months after the last patients receive their first dose.”
Then researchers must organize and analyze the data. If the latter appear promising, then Roche must seek regulatory approval from the U.S. Food and Drug Administration and similar agencies around the world.
According to a September 17 article on the scientist-produced site HDBuzz, “Not every patient enrolls on the first day of the trial, so a trial in which each participant is involved for 25 months will take around twice that long to run, and possibly longer.”
It’s also too early to project the cost of the potential drug, Lundgren said. He added that Roche is committed to providing access to those with inadequate insurance.
Working towards the best treatments
Dr. Schobel addressed concerns about the fact that RG6042, developed by Ionis Pharmaceuticals, Inc., is designed to reduce both the harmful mutant huntingtin protein involved in HD and normal huntingtin, essential in cell function.
According to Dr. Schobel, the drug’s effect “fundamentally is partial and can reverse and is titratable [adjustable], versus those kinds of experiments that are in the scientific literature, which shut off the gene 100 percent. That is not what we’re doing, for either the mutant protein or the so-called normal or total levels of protein. We have the ability to find a sweet spot potentially where there’s benefit and less risk, or even pause dosing.”
The Roche-Ionis approach differs from the two current Phase 1b/2a clinical trials by Wave Life Sciences, whose drugs target only the harmful protein by using genetic markers present in most but not all people with HD. (Click here to watch a presentation on the trials by Wave’s Michael Panzara, M.D., MPH.)
These and other clinical trials seek to find the best approach. Scientists have said that a combination of approaches, or an “HD cocktail,” may be needed to treat this complex disease.
(I hold a symbolic amount of Ionis shares.)
The Serbin Family Team of the 2018 Hope Walk: above, from left to right, Lance Ramsey, Adi Drapkin, Alexandra Drapkin, Regina Serbin, Gene Veritas (aka Kenneth P. Serbin), Maria Ramos, Peter Kim, Yuka Kim, and Lily Kim (in stroller). Below, from left to right, Tom Johnson, Yuka Kim, Peter Kim, Lily Kim (in stroller), Judy Melville, Gene Veritas, Patrick Melville, Sean Naficy, and Sam Melville (personal photos).