Sunday, September 30, 2018

Unpacking GENERATION HD1, the Roche Phase 3 Huntington’s disease clinical trial

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

‘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.)

This article is dedicated to the many donors and walkers who supported the Serbin Family Team in the 2018 HDSA-San Diego Team Hope Walk, held today. See photos below. Thanks to you, we raised over $4,000 towards the care and cure of HD! You can still donate by clicking here.

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).

Sunday, September 16, 2018

Roche Phase 3 clinical trial for Huntington’s disease gene-silencing drug to enroll volunteers in early 2019

The major drug company Roche expects to start enrolling subjects worldwide (including the U.S.) in early 2019 in its historic Phase 3 clinical trial of RG6042, a gene-silencing drug aimed at slowing, halting, and perhaps even reversing the symptoms of Huntington’s disease.

Roche made the announcement today at the bi-annual plenary meeting of the European Huntington’s Disease Network in Vienna, Austria, and issued a statement to the global HD community providing details (click here for the statement).

Designed by Roche partner Ionis Pharmaceuticals, Inc., and previously known as IONIS-HTTRx, RG6042 demonstrated impressive results in the Phase 1/2a trial completed by Ionis in December 2017.

On March 1, at CHDI Foundation's 13th Annual Huntington’s Disease Therapeutics Conference, researchers revealed that RG6042 caused Phase 1/2a trial volunteers to experience a drop of 40 to 60 percent in the harmful mutant huntingtin protein in their cerebral spinal fluid (CSF). According to the researchers, projecting from tests in animals, that corresponds to as much as an 85 percent decrease in the cortex of the brain. However, this trial did not measure actual efficacy – only safety and tolerability. (Click here to read more.)

Scientists have identified mutant huntingtin protein, resulting from a defective huntingtin gene inherited by HD patients and carried by presymptomatic individuals like me, as a principal cause of HD.

Because of the solid Phase 1/2a results, Roche has taken the unusual step of skipping a Phase 2 trial (testing efficacy for the first time) and going directly to a robust Phase 3, where researchers hope to test efficacy in 660 volunteers over 25 months at 80 to 90 sites in approximately 15 countries, to be announced gradually in the coming months. Phase 1/2a involved only 46 individuals, who received the drug over just three months at nine sites in Canada, Germany, and the United Kingdom.

In a detailed interview at the CHDI meeting, Roche officials confirmed that U.S. sites would take part in Phase 3 (click here to read more).  

GENERATION HD1: can it stop or slow HD?

“Following the completion of the Phase I/IIa first-in-human study of RG6042 in December, there are several important questions that still need to be answered before this investigational medicine can potentially be approved by Health Authorities in countries around the world,” said today’s Roche statement, signed by Mai-Lise Nguyen, the patient partnership director for the firm’s HD program.

Roche has named the study GENERATION HD1. 

As outlined by Nguyen, GENERATION HD1 will gauge the effects of reducing mutant huntingtin and whether RG6042 can “slow or stop the progression of HD.” It will also further examine the drug’s safety in a larger group of people over more time.

Members of the Roche HD clinical trial team watch the presentation of the RG6042 Phase 1/2a results at the 13th Annual HD Therapeutics Conference in Palm Springs, CA, March 1, 2018. From left to right, Scott Schobel, M.D., M.S., clinical science leader of product development; Lauren Boak, Ph.D., global development team leader; Erik Lundgren, lifecycle leader of the HD program; and Mai-Lise Nguyen, patient partner director (photo by Gene Veritas).

The trial will also study whether less than a monthly dose, which was used in Phase 1/2a, can prove effective. One third of participants will receive monthly doses of 120 mg, one third a bi-monthly dose of 120 mg, and another third a placebo dose monthly. As in the Phase 1/2a trial, participants will receive the drug via a lumbar puncture (a so-called intrathecal injection). 

To assure objectivity, the study will be “double-blinded” – neither the participants nor the researchers or site staff will know which dosage is administered. To reinforce objectivity, even the bi-monthly recipients (who won’t know they’re in this group) will take part monthly; they'll get the placebo every other month. Site information will be posted on the site

Today’s statement underscored the “urgency” felt by Roche to conduct GENERATION HD1 but pointed out that not all patients and research clinics will be able to participate. “Please understand the studies are designed to provide Authorities with the required data so that the benefit-risk of RG6042 can be determined as quickly as possible,” it stated.

For now, because Roche needs to demonstrate the efficacy and safety of RG6042, the firm will offer access to the drug only through participation in clinical trials. This means patients cannot make early access (prior to regulatory approval), so-called compassionate use, or “right to try” requests.

At this time, presymptomatic gene carriers and juvenile HD patients are ineligible for GENERATION HD1.

Additional studies

In addition, Roche will conduct a second, 15-month observational study – without a drug – called The HD Natural History Study. Starting towards the end of this year, it will gauge the natural progression of the disease in up to 100 participants with early-stage HD at up to 17 sites in Canada, Germany, the United Kingdom, and the U.S.

By seeking to deepen understanding of the role of the mutant huntingtin protein in HD, the Natural History Study will provide context for GENERATION HD1. Participants will undergo four lumbar punctures, plus MRI scans, blood tests, and neurological examinations. Like the volunteers in GENERATION HD1, they will use digital monitoring devices.

Meanwhile, all 46 participants in the Phase I/IIa study continue to receive RG6042 as part of an “open-label extension” study run by Ionis to assess the safety and tolerability of longer use of the drug. Those who got placebo originally now get the medicine.

Fast-tracking drug evaluation

The EHDN update comes in the wake of an August 2 announcement by Ionis and Roche that RG6042 received “PRIME” (PRIority MEdicine) status from the European Medicines Agency (EMA), a regulatory body similar to the U.S. Food and Drug Administration (FDA).

“We are very pleased that the European Medicines Agency has granted PRIME designation for RG6042, as there is an urgent medical need to find treatment options for families affected by Huntington’s disease,” Sandra Horning, M.D., Roche’s chief medical officer and head of global product development, stated in a press release.

According to the EMA, firms benefitting from PRIME “can expect to be eligible for accelerated assessment” in the drug approval process, reducing the standard timeframe of 210 days to 150 days.

A major step, but not the last

In March, after witnessing the revelation that RG6042 successfully lowered mutant huntingtin protein in the CSF, I wrote: “It’s the best news the HD community has received since the publication of the research confirming the discovery of the gene 25 years ago this month. As scientists have observed, it’s also a major step for disease and drug research in general.”

The August 24 issue of the magazine Science published a balanced article about the Ionis-Roche clinical trials titled “Daring to Hope,” including the struggles of Canadian woman and Phase 1/2a trial and open-label extension participant Michelle Dardengo. She describes some improvements in her symptoms – although doctors caution that her situation is merely anecdotal and not proof of actual drug effectiveness.

Michelle’s 27-year-old son Joel has also tested positive for HD. He was more skeptical about her apparent improvement.

“I do wish for the best,” Joel states in the article. “At the same time, I do prepare for the worst.”

Like all of the HD community, Michelle, Joel, and I must wait for the completion of GENERATION HD1 early in the next decade to see if RG6042 can help save us from HD.

For discussion of the Roche announcement at the EHDN meeting, see the HDBuzz Twitter feed for September 16, 2018.

(Disclosure: I hold a symbolic amount of Ionis shares.)

Saturday, July 07, 2018

In Harriet’s tragic death, the vulnerability caused by Huntington’s disease – but also the story of a beautiful soul

On the morning of April 8, while out for her cherished daily walk, 71-year-old Huntington’s disease patient Harriet Hartl died tragically after being struck by an Amtrak train at a pedestrian crossing near her apartment in Del Mar, CA, in San Diego County.

The story of Harriet’s death encapsulates the fear of all Huntington’s families – indeed, the family of any individual suffering from diseases that hamper perceptions and mobility. HD, Alzheimer’s, Parkinson’s, and other such disorders make people extremely vulnerable to the world.

Harriet’s passing further highlights the need to find effective treatments for these conditions, which scientists have found especially difficult to fathom.

However, the shock of Harriet’s death should not overshadow the beautiful, beloved soul she represented for her family, friends, and fellow members of the San Diego-area HD community, including the monthly support group she loved to attend.

That’s where I met her: she always had a smile and kind words for others. She participated in the breakout group for the affected, separate from the untested at-risk and presymptomatic gene carriers like me.

We got to know each other better through this blog, which Harriet read regularly. She sometimes responded with encouraging e-mails regarding my family’s struggles with HD. She also shared some of her journey with the disease.

Brett Hartl holding photo of mother Harriet (photo by Gene Veritas, aka Kenneth P. Serbin) (To enlarge a photo, just click on the image.)

‘Bad things can happen’ to HD people

On May 17, I spoke with Harriet’s only child and caregiver Brett Hartl at their Del Mar residence, just a few yards from the train track and the Pacific Ocean.

“It was a tough blow when she died, because it was sudden, and sort of an accident, in the sense that it wasn’t the down-the-road thing that would have come eventually,” said Brett, 39, an attorney for the Center for Biological Diversity. “It’s been relatively easy for me to wrap my head around it and process it, because frankly I know enough about HD to understand that bad things can happen. It’s difficult for people with HD to deal with complex tasks that we take for granted.

“At her age, when she would take her walk, that would take all of her focus. I can just totally envision her focusing on walking and tuning out the rest of the world.”

The morning of April 8, a Sunday, Brett went out for a run. Noting that Harriet had been out longer than usual, he checked her GPS location on his smartphone and saw that she was nearby. He expected to meet up with her as she returned home.

However, as Brett neared the railroad pedestrian crossing, he noticed a train stopped on the tracks and many police cars.

“I started to get a little bit of that feeling,” Brett recalled sadly.

He returned to the apartment, hoping to find his mother. Instead, checking her GPS location again, he saw that she was located right on the track.

Fearing the worst, Brett drove to the scene. He saw her body, which the police had covered. Because the officers had Harriet’s smartphone, driver’s license, and Huntington’s disease identification card, they quickly confirmed her identification with Brett.

Brett observes the scene of the accident. The official pedestrian crossing is located at the sidewalk on the far side side of the street (photo by Gene Veritas).

Crossing the tracks

How, some wondered, could a person not notice an oncoming train?

“People don’t realize all the little things that just don’t quite work right in someone’s mind with Huntington’s,” he explained. “When she was focusing on exercise and walking, that was it. That was probably all she could comprehend at one time.”

Brett, who is still awaiting an official accident report from Amtrak, said the train was traveling at about 50 miles per hour, a standard speed for that stretch. He believes she was killed instantly.

“It was not a glancing blow,” he observed. “I doubt she even noticed.”

To complicate matters, the crossing is located just around a bend in the track, at a busy traffic intersection, and just a few yards from the ocean. The surf, vehicle traffic, and other noise probably obscured the train’s advance, Brett said. In that area the train rarely uses its klaxon (horn), he added.

“Here in Southern California, everybody crosses the railroad tracks illegally,” Brett continued, recalling that another individual was killed on the tracks recently. In other words, they don’t use the legal pedestrian crossings.

As we observed the crossing, we noted the posted suicide prevention sign. We saw a number of people go through the crossing without looking down the tracks.

“She had a route,” Brett remembered. “Sometimes she would say, ‘I took the shortcut. I crossed the tracks.’ I said, ‘Don’t do that. Only cross at the crossing station [the legal pedestrian crossing] down there. It’s too dangerous. What if you fall and can’t get up?’”

‘A terrible confluence of events’

The weakened sense of one’s surroundings caused by HD surely exacerbated the situation, he said.

“You’d have to almost turn around over your shoulder to look – which, again, normal people can do,” Brett said. “She was walking in the same direction as the train, so it came up behind her, and the train was in reverse. So the engine was in the back, so it’s extra quiet until it’s actually passed. It was just a terrible confluence of events.”

Brett is not angry at Amtrak. He asked administrators there to tell the employees on the train that they were not responsible for Harriet’s death.

“HD is in my mind was responsible for her death, because she couldn’t handle the normal things that we take for granted,” he said. “In this case, it was crossing the train tracks.”

A passion for travel

Harriet Potash was born in New York City in 1947 and grew up in the area. She studied sociology at Monmouth University in New Jersey. Around that time, she met future husband, Larry Hartl.

Harriet worked as a travel agent, in advertising, and as a teacher. Larry became a producer for the ABC-TV newsmagazine 20/20. He also worked at NBC-TV.

His job took him and Harriet to dozens of countries, including the former Soviet Union, a closed Communist regime.

“Travel was one of her big passions,” Brett remembered. “She’d been to over 50 countries. Even after her diagnosis, in 2011 [at age 64], she didn’t let that stop her from traveling. We did a trip together to Japan in 2013. Then we did the trip to see the polar bears just this last November up in Canada, which was hard for someone for HD.”

Before HD struck, Harriet and Brett also did challenging hikes such as a 15-mile trek in Montana’s Glacier Park.

Brett reflected: “I think people sometimes forget that people with HD used to be completely capable and healthy and active.”

Above, Harriet in Moscow, 1973. Below, in Ecuador in the mid-2000s (family photos).

Confronting HD

Not long after Larry died, Harriet in 2003 moved to the San Diego area to escape the harsh East Coast winters. 

In 2010, she started falling a lot. Brett recommended that she see a neurologist. That led to testing for HD, a disease unknown to the family.

Now, however, it became clear that Harriet’s father had also had HD and passed it down to her: he had emotional outbursts and chorea (involuntary movements), two typical symptoms of HD. His apparent onset – without testing – came very late. He died at 90.

Both Harriet and Brett took a proactive approach to HD.

“I got tested also, in 2011,” Brett said, disclosing that the result was negative. “Most of the immediate family did. My approach, just being who I am, was that I wanted to learn everything I could about it and understand it, the consequences.”

Most people in Brett’s situation postpone or avoid testing.

“For me it was: ‘Well, better to learn now than finding out 30 years from now,’” he said. “It’s not fun. But in the long run it was a good choice.”

So far, none of Harriet’s father’s siblings or her cousins have tested positive, Brett said. He knows of only one other relative with HD.

Harriet’s approach

Harriet regularly attended the San Diego support group of the Huntington’s Disease Society of America (HDSA).

“Having a strong community of other folks going through that was very helpful to her,” Brett said. “She really enjoyed those other people a lot.”

Harriet also participated in research studies and clinical trials aimed at understanding HD and finding treatments.

She also hoped to participate in the Phase 3 trial of IONIS-HTTRx, developed by Ionis Pharmaceuticals, Inc., in nearby Carlsbad, CA. The drug lowered the amount of the disease-causing mutant huntingtin protein in patients’ cerebral spinal fluid in Ionis’s historic Phase 1/2a trial.

Swiss pharmaceutical giant Roche, which now holds the license to the drug, renamed RG6042, has not yet announced the Phase 3 timeline but has confirmed that trial sites in the U.S. will be included. (The Phase 1/2a trial was not open to U.S. residents.)

“She had something to look forward to,” Brett said. “She was very excited about the Phase 3 for that next drug. She wanted to make sure that she got in the study.”

Harriet had also just started taking Austedo, another drug developed in San Diego that controls chorea more effectively and with fewer side effects than a similar but older drug, Xenazine (click here and here to read more). Xenazine and Austedo are the only drugs approved for HD in the U.S.

“I think it made a difference,” Brett said of Austedo. “It calmed down some of the movements. She liked it. It helped her sleep better at night. She wasn’t as restless.”

In addition to daily walks, Harriet also worked with a physical therapist and practiced yoga, Brett noted.

“She really got a lot out of daily exercise,” he said. “That was one of her greatest joys and things to plan her day around.”

Just weeks before Harriet’s death, she had decided to donate her brain for HD research. Sadly, the damage from the accident made that impossible, Brett said.

‘A very friendly lady’

Although HD impedes speech, Harriet could still communicate. She kept mentally active and reached out to the community. After her diagnosis, she continued to teach herself Spanish, a skill that allowed her to do volunteer tutoring at a school for underprivileged children. She also volunteered at the San Diego Botanic Garden.

Family, friends, and acquaintances remembered Harriet as outgoing and kind. During a trip to Costa Rica, she started talking with children on a beach. “She just struck up a conversation in Spanish with them,” Brett recalled.

“She was very, very outgoing and open with people,” Brett commented. “She cared a lot about their own personal issues. Even just the other day, at the pizza place down the street, I told some of the folks what happened. They always recognized her as ‘the very friendly lady.’ It didn’t really matter if she knew you for a minute, or a year.” 

Remembering Harriet’s whole life

There was no religious service for Harriet. According to her wishes, her body was cremated.

However, three weeks after her death, Brett and Harriet’s San Diego-area friends held a small remembrance of her at the beach.

Later this summer, Brett and friends and family will scatter her ashes in the Atlantic Ocean near Jones Beach, Long Island, where husband Larry’s ashes were spread.

“She loved both oceans,” Brett said.

He also encourages people to view the online memorial photo album he posted:

“It’s a better story than I could actually tell,” he said of the album. “She sure did a lot. She shouldn’t be remembered just in her HD state.”

Brett also set up a donation page in Harriet's honor to support HDSA-San Diego.

Monday, May 21, 2018

Free from the threat of Huntington’s disease, our ‘miracle baby’ turns 18

I dedicate this article to my daughter Bianca Serbin.

In June, our “miracle baby,” who tested negative in the womb for Huntington’s disease in 2000, will graduate from high school and turn 18. In August, she will enter the University of Pennsylvania, to study in its College of Arts and Sciences.

It is a watershed moment, a milestone I once feared I would not reach, and a sign—though hardly a final one—that our daughter is on the road to adulthood with her family intact.

Because I inherited the HD gene from my mother, who died of the disease in 2006 at age 68, I will inevitably develop symptoms. At 58, I’m well beyond my mother’s age of onset. Each day of health is a blessing and a privilege, as I witness so many of my affected “HD brothers and sisters” struggle with the disabling symptoms.

Scientists strive to understand why people like my mother and me, with the same degree of genetic defect, become symptomatic at different ages. Although there is no scientific proof, doctors and scientists have told me that leading an enriching life – and treating my health carefully – has helped me stay healthy.

I agree. Watching HD rob my mother’s ability to walk, talk, and care for herself, I could not imagine reaching this point free of the disease’s classic symptoms. Joining my wife Regina in guiding Bianca to adulthood has provided me with a deep sense of purpose, enjoyment, and pride.

With Bianca, we have also faced crises: being HD-free is no guarantee of perfect health or a worry-free life for her. As a result, we have become closer as a family, and Bianca has matured.

Now, as Bianca prepares to enter the next stage of life, I am deeply relieved.

I had feared not being able to watch her graduate from high school. As educator parents valuing quality schooling, we sacrificed financially to put her in a top private high school to give her the best chance to succeed in life. I had worried that, if disabled by HD, I could not help pay the bills and save for college.

I also feel a deep sense of pride, satisfaction, and accomplishment: I have fulfilled some key responsibilities as a father, handing Bianca the baton of life.

Bianca Serbin (family photo)

Because of the psychological trauma of testing Bianca in the womb, Regina and I decided against further children. Raised as an only child, Bianca needed to overcome shyness and social isolation. Her high school’s strong emphasis on academics and leadership helped her blossom in these areas.

Bianca and her generation will face immense challenges beyond the first-order responsibilities of learning, growing, and finding their place in the world. They are bequeathed such daunting social problems as gun violence, inequality, anti-democratic political movements at home and abroad, global warming, and nuclear proliferation – challenges my generation has failed to adequately address. They will need to exercise great leadership and form new social movements.

I believe they will. I am impressed with, and proud of, young people such as the Parkland, Florida, shooting survivors who have organized politically, refusing to accept the tiresome and dangerous status quo on gun violence. Their movement has the potential to impact society the way the civil rights and anti-war movements of the 1960s did. Bianca and her schoolmates joined students around the country in the local-level protests against the violence.

Raising a daughter in the era of #MeToo produces great angst. Bianca will need to be strong and independent as she navigates new challenges and, as in the fight against HD, she will need to find allies.

I’m confident that, no matter what path she chooses, Bianca will help make the world a better place.

Gene Veritas (aka Kenneth P. Serbin) with daughter Bianca (family photo)

Previous generations did not have our options. After the discovery of the HD gene in 1993, Regina and I became part of the first wave of couples testing babies in the womb, and later using preimplantation genetic diagnosis, to safeguard our children from the disease.

Regina and I were especially adamant about testing because, in a cruel twist of HD, men can pass on an even greater level of genetic defect, leading some children to develop the juvenile form of the disease.

Our generation of HD families have also become more outspoken about HD, a disease so terribly hidden and stigmatized in the past. It’s still that way for many families here and around the world.

I’ve always answered Bianca’s questions about HD, wanting her to learn about the topic with full transparency, to prevent the harmful effects of denial. She was first exposed to HD at the age of two by learning that her grandmother was ill with a “boo-boo on her brain.” At age nine, she learned that I carried the gene – but also that she did not.

Since childhood, Bianca has participated in HD fundraisers and other events. Recently, she has also volunteered for the local chapter of the Huntington’s Disease Society of America.

Bianca reads this blog regularly, a way for her to deepen her understanding of HD and to tighten her bond with me. I know that she loves me and is deeply concerned about my risk for HD.

Bianca, San Diego Chargers tight end Antonio Gates, and Gene Veritas at an HDSA-San Diego fundraiser, 2008 (family photo)

Throughout Bianca’s senior year, Regina and I have begun to brace ourselves for the empty nest syndrome.

At the same time, we’re very excited for Bianca. I’m looking forward to our family trip to Philadelphia to install her at Penn and help her transition to this new phase in her life.

Meanwhile, on the HD front, much work remains to be done: along with thousands of other Americans, I still face the threat of HD. We need to realize the dream of effective treatments – perhaps even a cure – that would allow me to live to a ripe old age and, with Regina, continue to enjoy the next stages of Bianca’s life.

Kenneth, Bianca, and Regina Serbin after Bianca's induction into the Cum Laude Society (family photo)

Thursday, April 26, 2018

New Ionis data show positive trends in clinical measures of Huntington’s disease drug trial volunteers

Exploratory analysis of new data showed positive trends in several clinical signs of Huntington’s disease in the recently concluded Ionis Pharmaceuticals, Inc., gene-silencing Phase 1/2a clinical trial, the company announced April 24.

“Results from exploratory analyses of data from the study demonstrated correlations between reductions in mutant huntingtin (mHTT), the disease-causing protein, and improvements in clinical measures of Huntington's disease,” an Ionis press release stated about its drug IONIS-HTTRx.

Initiated in September 2015 and completed in December 2017, the trial tested the drug in 46 symptomatic volunteers at nine sites in Canada, Germany, and the United Kingdom.

Because of the very limited size, duration, and scope of the Phase 1/2a trial, the newly studied clinical signals have only statistical importance. They do not demonstrate whether an individual patient got better, or by how much a person did better on a particular test.

However, they provide hope for the HD community because they showed an association between reducing, or lowering, mHTT, and the improved scores. The new data will help pave the way for the planned Phase 3 trial to test efficacy.

“These important clinical results further demonstrate that targeting the reduction of the toxic mutant huntingtin protein with IONIS-HTTRx has the potential to be disease-modifying,” Frank Bennett, Ph.D., Ionis senior vice president of research and franchise leader for neurological programs, stated in the release.

Sarah Tabrizi, FRCP, Ph.D., of University College London, the lead investigator of the Phase 1/2a trial, also presented the new information on April 24 at the annual meeting of the American Academy of Neurology (AAN) in Los Angeles. Out of more than 3,000 submissions, the talk was one of four selected for the top-featured session at the meeting, which drew more than 12,000 professionals.

Checking movements and cognitive loss

On March 1, at the 13th Annual HD Therapeutics Conference in Palm Springs, CA, Dr. Tabrizi revealed that the drop of 40-60 percent in mutant protein observed in the cerebral spinal fluid (CSF). Based on numerous animal studies done by Ionis, that corresponds to to a decrease of 55-85 percent in the cortex of the brain. The cortex is the most developed area of the brain and the source of thought and language, abilities severely hampered by HD. In the caudate – which helps control movement, another critical problem in HD – the corresponding decrease (based on animal data) ranged from 20-50 percent.

The new data demonstrate associations between reduction in mHTT (measured in CSF) and improvement on two clinical tests commonly used in HD clinical studies: the total motor score test (measuring impairments in movements) and the symbol digit modalities test (measuring cognitive loss).

The press release further noted a significant correlation between huntingtin reduction and an improved score on the Composite Unified Huntington's Disease Rating Scale (cUHDRS), which measures decline in patients.

Two tests showed neutral results: the stroop word reading (checking for cognitive loss) and the total functional capacity (assessing ability to perform daily tasks).

A slide from Dr. Tabrizi's talk at the AAN meeting illustrating improved scores in two clinical tests (top two graphs) and neutral scores in two others (bottom graphs) (slide courtesy of Ionis)

Larger, longer studies needed

At the AAN meeting, Dr. Tabrizi emphasized that the three-month Phase 1/2a trial was not designed to measure a true clinical benefit from IONIS-HTTRx. It sought primarily to gauge safety and tolerability of the drug.

The researchers used so-called “exploratory post-hoc analysis.”

As explained by Ionis officials in an e-mail, post-hoc means that Ionis did not predefine the analyses in the clinical trial protocol. Such analyses cannot provide conclusive proof of a drug effect. These analyses are common in early-stage clinical trials, where drug companies look for interesting signals worthy of careful evaluation in later-stage trials.

The officials also pointed out that, in analyzing the data using the gold-standard technique for demonstrating effect - comparing clinical test results of drug-treated participants with those on placebo - no improvements were found. This was not a surprise, given the limited scope of a Phase 1/2a trial.

In fact, they added, the trial planners included the clinical tests primarily to monitor for unexpected worsening.

The Ionis officials described the relationship between mHTT-lowering and potential clinical benefit as "subtle."

They emphasized the need for larger and longer trials to demonstrate efficacy.

A 'hint of clinical benefits'

“The measurements were done during the trial, but these statistical analyses were not pre-specified, and so we say that they are post-hoc and exploratory,” Jody Corey-Bloom, M.D., Ph.D., the director of the Huntington’s Disease Society of America (HDSA) Center of Excellence for Family Services and Research (COE) in San Diego, explained in an e-mail.

Dr. Corey-Bloom described the correlations between the clinical measurements and the reduction in the huntingtin protein as “positive but weak. This is very welcome news and clearly in the right direction! We will obviously need larger and longer studies to really confirm a potential clinical benefit, though.”

Swiss pharmaceutical giant Roche, which now holds the license to the Ionis drug, has confirmed that it will take the unusual step of skipping a Phase 2 trial and going directly to Phase 3. Phases 2 and 3 measure a drug’s efficacy. Roche, which renamed the drug RG6042, does not yet have a timeline. (Click here to read more about Roche’s plans.)

"Though press releases and post-hoc analysis can be problematic, the reported improvement in clinical measures in this early clinical trial, if borne out by subsequent study, is a ‘wow’ for the HD community,” LaVonne Goodman, M.D., the founder of Huntington’s Disease Drug Works, commented in an e-mail. “So I look forward to seeing the full data set in a peer-reviewed article. If results from this first trial are borne out in the larger Phase 3 trial, this drug is a game changer for HD. And also great, if results are similar to the present trial, it might take less than the earlier predicted three years to show it.”

“It is quite exciting to see any hint of clinical benefits,” Martha Nance, M.D., the director of the Minneapolis COE, wrote via e-mail. “It is important to know that these clinical results are not definitive, but this report adds to the growing list of favorable results from this groundbreaking trial of gene silencing in HD. The HD community has every right to be excited about these results!”

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For additional coverage of the Ionis news, click here and here.

For HDSA's Q & A on the news, click here.

For background on the development of clinical tests for HD, click here.

(Disclosure: I hold a symbolic amount of Ionis shares.)

(This article was updated on April 27, 2018, to include additional comments on the clinical trial analyses by Ionis officials.)