Thursday, May 21, 2020

In the pandemic, we need to rediscover patience and grasp our responsibility

In this time of pandemic, the virtue of patience is paramount. So is the need to grasp our impact on the history of the planet and its effect on our lives. We who are afflicted with rare diseases have already had to learn many hard life lessons, which apply to the vital efforts to confront the coronavirus. 

As we mark Huntington’s Disease Awareness Month, we recall how many in the HD and other neurological and rare disease communities have demonstrated great fortitude and also patience as we await effective treatments. Since learning of my mother’s diagnosis with HD in 1995 and my positive test for the mutation in 1999, I have worried about the inevitable onset of symptoms and yearned for a successful clinical trial to produce a drug to stave off the disease or ameliorate it.

“HD warriors” like my mother and caregiver father (both deceased) have had to confront the disease on a daily basis for a decade or longer. 

Drugs like tominersen, the gene-silencing compound now in a historical Phase 3 clinical trial run by Roche, require painstaking development and often well over a decade to reach the market.

The tominersen project began in 2007, and Roche expects to analyze Phase 3 data in 2022. (Tominersen was previously known as RG6042 and, before that, as IONIS-HTTRx.)

The best-case scenarios for an effective and safe COVID-19 vaccine for the general public point to some time in 2021. 

“What people don’t realize is that normally vaccine development takes many years, sometimes decades,” Dan Barouch, M.D., a virologist at Beth Israel Deaconess Medical Center in Boston, stated in a news report. “And so trying to compress the whole vaccine process into 12 to 18 months is really unheard-of.”

A vaccine might never be found; after decades of intense research, science still has not developed one for AIDS.

Drug development requires precision and patience.

Possible hope from new drug development approaches

That said, by dint of biomedical progress (but lacking overall preparedness for a pandemic), the current worldwide effort could take place more rapidly than previous drug-development work.

With positive results in the very early stage of its vaccine program, drug maker Moderna, Inc., is using an RNA-based approach to attempt to block the actions of the coronavirus.

Ionis Pharmaceuticals, Inc., the developer of tominersen, is also looking into ways its drug technology “could benefit COVID-19 patients, first by looking at our existing pipeline to see if any clinical or preclinical drugs would have a use in treatment in either the disease, or more likely the complications of the disease arising from the acute respiratory syndrome,” Eric Swayze, Ph.D., the firm’s senior vice president of research, wrote in an e-mail to me on May 8. Ionis designs drugs using antisense oligonucleotides (artificial strands of DNA), a form of gene silencing technology.

“In the 2002/2003 SARS epidemic we did done some work with ASOs targeting both the coronavirus itself as well as host factors, and had preliminary hints of activity [effect],” Swayze added. “Because of this, we are making newer generation ASOs targeted to the SARS-CoV-2 [COVID-19] virus as well as host factors that contribute to the infection and disease. 

“We plan to work with collaborators who have the capability to test our lead ASOs in virus cultures. We believe that our recent pulmonary program advances position us to quickly move forward, provided that our drugs look promising. However, we feel this remains a high-risk discovery project, with many challenges ahead.”

Behind the reaction against lockdowns

However, despite the need for a long-term fight against COVID-19, only a few weeks after lockdowns began, tiny groups of purported “protestors” appeared demanding to “open up” states. They were egged on by President Donald Trump, who has declined to marshal national resources against the virus, and organized by conservative groups.

I have wondered: What if Americans had wanted to give up only three weeks after the 1941 attack on Pearl Harbor?

The initial impatience about COVID-19 was clearly politically motivated. Since then, some criticism of lockdowns results from growing economic hardship: with a 14.7 percent unemployment rate, the U.S. has lost the greatest number of jobs since the Great Depression of the 1930s. In addition, many small business owners have had to curtail their work or even shut down completely.

The pain hits professors and students

The economic pain has hit American universities such as my employer, the University of San Diego (USD), which switched to remote, online instruction in mid-March. Confronting an unexpected deficit, the president has announced a 50 percent cut in retirement benefits and a salary and hiring freeze.

There is no consensus nationally on how to resume classes in the fall, with leaders of different campuses struggling with uncertainty. The nation’s largest public university, California State University, for example, has announced, that its campuses will move nearly all instruction online.

With USD’s dependence on tuition for institutional survival and its reputation for high-quality instruction in relatively small classes in small classrooms, the administration has launched a still inchoate plan to reopen for the fall semester early, in mid-August. According to administrators, because of the loss in student fees, going remote again would extend losses by tens of millions of dollars, forcing possible layoffs and furloughs of some instructors and employees, an increased teaching load for the main faculty, and other types of cutbacks.

Many professors, including myself, fear returning to campus so soon; in normal times, packed dorms, classrooms, and other facilities (and student parties administrators can’t control) provide ideal conditions for a virus to spread. Though young people are less likely to suffer from coronavirus symptoms, some do get serious cases, and asymptomatic people can of course spread the virus to others more vulnerable.

Universities and their employees will seek to implement social distancing, testing for COVID-19, and other measures. Ultimately, depending on the course of the pandemic, many might have to resort again to remote learning.

We cannot return to ‘normal’

In fact, three in four Americans have supported social distancing and wearing masks.

Without good health, we are restricted economically, as the HD community knows so well.

I believe that the impatience comes in part from our culture of instant gratification, epitomized by online shopping and overnight delivery. Another part relates to political orientation, with Republicans favoring a more rapid opening than Democrats (for one analysis, click here).

I think many people – myself included – wrongly thought that, after a month or two of lockdown, we would return to “normal.”

However, as New York Governor  Andrew Cuomo put it on April 1, “I don’t think we get back to normal. We get to a new normal.” As a result of the crisis, society will undergo a “transformation,” and we must assure that it be “positive and not negative,” Cuomo urged.

“I fear that the resumption of normality would signal a failure to learn,” commented Pulitzer-Prize-winning medical writer Siddhartha Mukherjee, M.D. “We need to think not about resumption but about revision.”

He added, with reference to how the drive for instant success has exacerbated the pain of the pandemic: “To what extent did the market-driven, efficiency-obsessed culture of hospital administration contribute to the crisis?”

The perspective of Big History

Cuomo echoed the point that professional historians like me make to students and readers of our books: history is ever-changing, often with great progress, but also devastating setbacks, including world wars, plagues, and inhumane practices like slavery.

I teach a course called “Big History: From Cosmos to Cannibals,” which begins with the start of the universe and ends with the dawn of the modern era: Europeans' conquest of the Americas, beginning in the late 1400s and quickly causing epidemics of Old World diseases in which tens of millions of native Americans died in the hemisphere – a very poignant point of comparison with the pandemic this past semester. A field that has emerged recently, Big History embraces the idea that human development must be understood in the context of physics, biology, evolution, and the transition from small bands of hunter-gatherers to cities with millions of people.

Over the past several years, my classes have focused on how we now live in the Anthropocene, an era in which humans have taken control of the earth’s systems (atmosphere, oceans, land, life, and others).

Human agency has led to global warming, probably a more daunting challenge to humankind than coronaviruses, and many other threatening phenomena.

Human control has contributed to the crisis

In fact, some commentators have asserted that the pandemic has resulted from the humans’ super-control of the earth and our encroachment on the last vestiges of nature in areas such as the Amazon rainforest (for some examples, click here, here, and here).

Deforestation (for cash crops and cattle), mining, a growing population, and the expansion of urban areas have put the environment and the species therein under greater stress, making them more susceptible to viruses and zoonosis (jumping of a virus from one species to another, including humans).

Human domination of the planet has intensified over the past several decades. I witnessed the devastation firsthand of the Amazon in 1988 and 1990, during my time in Brazil as a graduate student. I saw gold prospectors who penetrated the deepest recesses of the forest, using clandestine airstrips. I also viewed up close how many square miles of trees had been cut down.

Above, using modern equipment, men prospect for gold by excavating the floor of the Amazon rainforest in Brazil, 1988 (photo by Gene Veritas, aka Kenneth P. Serbin). Below, Gene Veritas (wearing sunglasses) with workers at the mining site (personal photo).

Reconnecting with ourselves, and the planet

In my Big History course just concluded this semester, we were all deeply saddened by the onset of the pandemic. However, in the context of history, a devastating viral outbreak was highly likely. Leading scientists have also warned the world for decades.

The pandemic serves as a global alarm. The Earth is a system, and it is crying out against our dangerous intrusions into rainforests and other attacks on the environment. Ironically, with the decrease in vehicle traffic, the vast reduction in pollution gives us a glimpse of the air quality we once had and must achieve again to stem the tide.

A key lesson of my Big History course is that the modern world led humans to think they were separate from nature, but, in reality, we are ever more interconnected. The pandemic will perhaps force humanity to rediscover our identity (for some, a spirituality) of being one with nature. We are part of the Earth, not over and above it.

As Dr. Mukherjee pointed out, the virus has laid bare many things, such as the inequality of our health system. It has also laid bare our impatience. To overcome the virus, we need to regain patience and, along with it, humility and respect for the planet.

As Dr. Mukherjee and others have urged, we also need to learn from this crisis and make better policy choices for future threats of all types.

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

Thursday, April 23, 2020

Combatting the pandemic, Roche also forges ahead with critical Phase 3 Huntington’s disease clinical trial

Using its expertise to combat a coronavirus pandemic that has left more than 180,000 people dead worldwide and a third of the earth’s people on lockdown, pharmaceutical giant Roche is also forging ahead with its Phase 3 clinical trial for the Huntington’s disease gene silencing drug RG6042, now known by the generic name tominersen.

The final step in a clinical trial program, Phase 3 tests the efficacy of a drug. A successful Phase 3 allows a pharmaceutical company to apply to regulatory agencies for permission to market the drug. In a time of “social distancing” and a shutdown of normal life, Roche and HD clinical trial administrators are seeking to mitigate the risks associated with the spread of COVID-19, the disease caused by the coronavirus.

In an April 20 letter to the global HD community, Roche announced that it had completed recruitment for the trial, GENERATION HD1. A total of 791 symptomatic volunteers across 18 countries have been enrolled, just ten fewer people than Roche projected after the trial got under way last year – almost 99 percent of the target.

“This achievement is a result of the HD community’s commitment from the beginning, and we are very grateful to all trial participants, their families, the clinical trial sites and staff, and the broader HD community who have supported the design, initiation and recruitment phases of the study,” Roche global patient partnership directors David West and Mai-Lise Nguyen stated in the letter.

West and Nguyen reassured the community that “tominersen studies are ongoing at clinical trial sites around the world,” and, in collaboration with local health authorities, “ensuring patient safety and data integrity throughout the studies given the ongoing impact of COVID-19.”

On February 27, Roche announced the generic name for its HD gene-silencing drug candidate RG6042, formerly known as IONIS-HTTRx, developed by Ionis Pharmaceuticals, Inc. With assistance from Roche, Ionis ran the successful Phase 1/2a trial for the compound, shown to be safe and tolerable in trial participants. It also lowered the amount of mutant huntingtin protein, a major suspect in the disease, in volunteers’ cerebrospinal fluid. (Slide courtesy of Roche.) 

Aiming to analyze data in 2022

“Given the dynamic situation with COVID-19, we decided to close recruitment at 791 participants globally in order to avoid additional pressure on clinical trial sites who were screening potential participants,” they added, noting that the number of participants is “sufficient” to assess tominersen’s efficacy.

Roche is “working closely with the research teams, trial sites and local authorities to reduce any new risks posed by COVID-19 and ensure the trial can continue as long as it is safe to do so,” the letter stated. Roche advises participants to “discuss individual circumstances with their respective study sites.”

“Where patients and families can no longer go into [the] hospital to receive treatment or assessments, research teams will be in close contact over the phone to monitor their health and discuss any potential adverse events or any other issues,” the letter added.

Roche expects to complete the trial and start analyzing data by 2022, after each of the volunteers has completed the 25-month program involving intrathecal (spinal) injections of tominersen or a placebo, tests, medical evaluations, and digital monitoring, West and Nguyen stated.

If tominersen demonstrates efficacy and safety, Roche will submit applications to national health authorities to obtain approval as a treatment.

“During these exceptional times, we continue to consider how we can best support the community and welcome any suggestions,” the letter concluded.

In an April 21 e-mail to me, West noted that GENERATION HD1 recruitment was “completed within expected timelines,” unaffected by the COVID-19 crisis. In line with plans announced last October, Roche will also extend the study to China “as soon as possible,” West added.

Combatting COVID-19

The April 20 statement on GENERATION HD1 followed a general statement by Roche on March 19 discussing the March 11 announcement of the pandemic by the World Health Organization and the company’s efforts to combat it.

“We recognise that the public and private sectors across the globe need to work together to help effectively manage this developing situation,” said the statement, noting that Roche was engaged in developing a COVID-19 “diagnostics test which was granted Emergency Use Authorization by the U.S. Food and Drug Administration.”

Scientists, physicians, and public officials have stated repeatedly that vastly increased testing for the virus is needed in the battle against the pandemic.

Roche also confirmed initiation of COVACTA, a global Phase 3 clinical trial to evaluate the safety and efficacy of its rheumatoid arthritis drug Actemra/RoActemra in treating patients with severe COVID-19 pneumonia. The study started to enroll patients on April 3, with a target of 330 globally, including the U.S., Canada, and Europe.

Roche is also examining other drugs in its portfolio for potential testing to treat COVID-19.

(Click here to read more on Roche’s efforts against the coronavirus.)

A key supplementary trial

The February 27 announcement of the generic name tominersen took place at the 15th Annual Huntington’s Disease Therapeutics Conference, sponsored by CHDI Foundation, Inc., in Palm Springs, CA. (For an overview of the conference, click here.)

Scott Schobel, M.D., M.Sc., Roche’s associate group medical director and medical leader of the GENERATION HD1 effort, introduced the name when presenting the preliminary results of the so-called open label extension study (OLE) study of the compound. For 15 months, Roche continued to give the drug to all of the 46 participants of the successful Ionis trial, completed in December 2017. That same day, Roche posted the slides of Dr. Schobel’s presentation on its website.

The OLE reinforced the findings of the Phase 1/2a trial, which showed tominersen to be safe and tolerable in trial participants. Tominersen also lowered the amount of mutant huntingtin protein, a major suspect in the disease, in volunteers’ cerebrospinal fluid.

Also, when still in progress in early 2019, the OLE led Roche to temporarily halt GENERATION HD1 to redesign it in line with the OLE’s promising early data. 

In the original GENERATION HD1 design, participants would undergo monthly spinal tap (lumbar puncture) procedures over 25 months. One-third of participants would receive tominersen each month and one-third every other month. Another third would get a placebo.

In the updated trial, which resumed in June 2019, Roche decreased lumbar punctures to once every other month over the same period of time. In this revised design, one-third of participants are receiving tominersen every other month and one-third every four months. Another third will receive a placebo every other month. (Click here to read more.)

Less frequent dosing eases the burden on participants, their families, and clinical trial administrators.

The OLE also investigated potential biomarkers (signs of the disease and drug efficacy) for use in GENERATION HD1.

The OLE formed part of Roche’s strategy for skipping the usual Phase 2 trial to test efficacy and entering directly into Phase 3 to confirm efficacy in a larger population (click here to read more).

Scott Schobel, M.D., M.Sc., presenting open label extension study data for tominersen at the 15th Annual HD Therapeutics Conference (photo by Gene Veritas)

The ‘ultimate’ question: efficacy

After his presentation, Dr. Schobel met briefly with HD advocates to discuss his presentation and GENERATION HD1.

For the HD community, the takeaway message was the OLE’s confirmation of a less frequent dosage, and its helpful data for GENERATION HD1. Except for one person who decided to drop out to take a trip around the world, all of the OLE participants had continued taking the drug, putting them now at 20 months of follow-up, he explained.

Roche has great “confidence” in the sufficiency of the less frequent dosing in GENERATION HD1, Dr. Schobel emphasized.

With the OLE, Roche has “been able to learn” and apply it directly to GENERATION HD1 “in a way that we couldn’t have done if did a more traditional drug development path, which we feel great about,” he said.

What remains is the “ultimate” question: will tominersen be an effective treatment?

“We’re well-positioned with GENERATION HD1 to answer that question,” Dr. Schobel concluded.

If the trial is successful, tominersen will become the first treatment to slow, halt, and perhaps even reverse the symptoms of Huntington’s disease. 

(I hope to report soon on other ways in which COVID-19 has impacted the HD community and research.)

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

Tuesday, March 31, 2020

Giving back during the COVID-19 pandemic

Many advocates for Huntington’s and other rare diseases work passionately and selflessly for their causes.

Now, as the coronavirus pandemic rages, more and more people around the globe want to give back. 

We are all witnessing the testimonies of the doctors, nurses, and other healthcare workers who offer front-line care for the patients hit with COVID-19, the disease caused by the virus.

As a Huntington’s gene carrier who lost his mother to the malady, I, too, want to help – in part because the crisis has postponed or forced online so many aspects of the HD cause (more on this in an upcoming article).

HD activists can and should do their part to help alleviate this crisis!

Preparing for a surge of patients

Worried about the flood of reports about shortages of personal protective equipment (PPE), I reached out to Yale University class of 1982 colleague and freshman roommate Peter S. Kieffer, M.D., an emergency room pediatrician, to see if I could help, perhaps by organizing an online campaign to support him and his institution. Dr. Kieffer works at HSHS St. John’s Hospital in Springfield, IL. An assistant professor at the Southern Illinois University School of Medicine, he also advocates for the chronically mentally ill through Independence Center

In 2014, after decades out of touch, Dr. Kieffer wrote in an e-mail that he had discovered this blog and my family’s struggle against HD.

“My heart goes out to you and your family as I have been long aware of the challenges of Huntington's disease, its genetic transmission, and the implications of early testing but have never known anyone personally with the diagnosis,” Dr. Kieffer wrote.

Since then, he and his family have donated generously to the Serbin Family Team in the annual Hope Walk of the San Diego Chapter of the Huntington’s Disease Society of America (HDSA). Several years ago, they visited us during their vacation in the area.

In his response to my March 28 e-mail, Dr. Kieffer explained that “physicians in rural Illinois have had more time to prepare for COVID-19 than our colleagues in big cities.”

“Numbers were small, now cases are becoming more frequent, and we are preparing for a surge in the next few weeks which could very easily surpass the ICU bed and ventilator capacity of our two hospitals,” he wrote. “However, Governor [J. B.] Pritzker's early shutdown may help blunt that curve. Although COVID-19 typically sickens children with less severity, they could still pass it to a white-haired pediatrician like myself! Fortunately, we still have enough PPE for what we need.”

So far, Dr. Kieffer has treated a young child who was a “Patient Under Investigation,” although tests have not yet confirmed COVID-19 in any of his patients, he wrote in an e-mail today.

Dr. Kieffer agreed to contact me should his institution need aid. I know that I personally cannot send PPE or medical equipment, but raising awareness about the local predicament and raising funds could be a way to assist.

Peter S. Kieffer, M.D. (photo by Southern Illinois University School of Medicine)

Donating critically needed blood

There are other ways I - and you - can help now.

After seeing an American Red Cross blood drive appeal on TV a couple weeks ago, I scheduled a donation for March 30. 

Last week, I suspended my minimal meat diet to raise the iron levels in my blood, as recommended by a Red Cross employee, who set me up for a “power red” donation (double the number of red blood cells).

That employee also told me of a critical shortage of blood, as reported by the Red Cross and in the media (click here to read more).

At the donation center, an employee took my temperature at the door, to make sure I had no fever and, therefore, possible COVID-19 symptoms. Donors were spaced about eight feet apart, to avoid contamination, and the nurses and other workers wore not only the typical gloves, but also masks.

Unfortunately, in a pre-donation pin-prick blood test, I fell just shy of the necessary iron level for a power red.

However, I was able to make a simple “whole blood” donation.

Gene Veritas, aka Kenneth P. Serbin, at an American Red Cross blood donation center in San Diego (photo by Gene Veritas)

Running risks for the common good

On the way home I thought: in any public place, we all run the potential risk of contracting the coronavirus, even at a facility like the Red Cross. 

I washed my hands very thoroughly, twice at the facility, then again at home. None of the donors, nor I, wore a mask. However, I may on future trips to public places, given the increasing number of reports about their effectiveness in blocking droplets that might contain the virus.

Like so many other HD gene carriers, I’ve spent many moments monitoring myself for symptoms. Now, I’ve started doing that for the virus.

However, physicians like Dr. Kieffer, first responders, grocery store workers, and so many others risk their health daily for the common good.

We all need to embrace the spirit of Dr. Kieffer’s words to me, echoing one of the signs at the Red Cross: “Thanks so much for your life-giving donation!”

Above, Gene Veritas' blood pack, and below, Gene Veritas in a donor chair at the American Red Cross (photos by Gene Veritas)

Sunday, March 15, 2020

In times of crisis, Huntington’s and other chronic disease communities provide examples of fortitude

For individuals and families facing Huntington’s and other chronic diseases, daily living often seems like nonstop crisis. These communities, including selfless caregivers, have demonstrated great fortitude.

The current coronavirus pandemic adds another giant, unknown layer to the kind of challenges and suffering many in these communities are already accustomed to.

The country’s reaction to the pandemic and the shutdown of daily routines starkly reminded me of the national climate in the months following the September 11, 2001, terrorist attacks on New York City and Washington, D.C. Resulting in 3,000 deaths, 9/11 led to a temporary grounding of all domestic flights, the fear of subsequent attacks (including nuclear), and panic regarding other, unrelated terrorist threats such as the deliberate spread of highly dangerous anthrax bacteria. The economy also suffered serious long-term effects.

Members of the San Diego Chapter of the Huntington’s Disease Society of America (HDSA), in the bewildering days after 9/11, held a previously planned fundraiser and got ready to hold its first Celebration of Hope Gala.

With so many other, urgent demands on potential donors, we feared people might not remember our needs.

Later that fall, in an editorial in Conquest, our chapter newsletter, I wrote the following:

On September 20, less than two weeks after the crisis, members of the public and local organizations participated in the Third Annual Indy Go-Kart Challenge to raise funds for the cure of HD. Then, on October 11, the one-month anniversary of the attack, several hundred San Diegans took part in the Celebration of Hope Dinner to assist the Center of Excellence for Family Services and Research at the University of California, San Diego. We raised tens of thousands of dollars at these events. Elsewhere in the country other HDSA events went on as planned.

In this manner HDSA and its supporters have sent a resounding message that generosity and compassion are far stronger than the hateful politics of terror. We will move ahead, no matter what the odds are against us. This is the American spirit.

Unprecedented impact on daily life

So far, the coronavirus pandemic has had an unprecedented impact on the United States, with schools, universities, and many other institutions closing or switching to remote, online operations. As of March 15, at least 65 people had died in the U.S., with worst-case scenarios projecting 200,000 to 1.7 million deaths.

The pandemic has changed my workplace unlike any earlier tragedy. After 9/11, no classes were cancelled by my employer, the University of San Diego (USD). In 2003, the devastating Cedar Fire in San Diego County left 15 dead, destroyed 2,820 buildings, and charred more than 280,000 acres. In response, USD shut down for just two weeks and finished the semester normally, with everybody back on campus.

Now, because of the virus, USD has cancelled classes this week and will finish the semester (eight more weeks, plus final exams) online. The University of Pennsylvania, where my HD-free daughter Bianca studies, will do the same. My wife and I are worried that Bianca will not be able to make it home in time before potential travel restrictions.

Each hour, we learn of more victims of the virus and further curtailment of life as we know it.

Impact on the HD community

The global crisis has also impacted the mission of HDSA and individual HD families.

On March 13, HDSA CEO Louise Vetter sent an e-mail to “friends of HDSA” announcing that the organization “holds the well-being of our families, volunteers and staff as our top priority” and will therefore postpone “ALL local HDSA events (educational & fundraising) nationwide” until April 30. That complies with public health recommendations to curtail public gatherings to slow the spread of the coronavirus.

According to Vetter, HDSA still plans to hold its 35th Annual Convention in New Orleans, June 4-6, but will continue to follow the guidance from the Centers for Disease Control, World Health Organization, and state and local health agencies.

HDSA’s national headquarters in New York City is closed. However, the entire staff is working remotely and has the resources “to continue the uninterrupted support of our mission during this time,” Vetter assured.

The Huntington’s Disease Youth Organization postponed its May 2020 international congress in Glasgow, Scotland, to March 2021.

I have accepted an invitation to deliver the keynote address at the 37th National Conference of the Huntington Society of Canada in November, but have been told to hold off on reserving flights until the pandemic’s long-term effects become clear.

Visiting the afflicted

For one HD community member and blogger, Mandi, 33, the pandemic meant that on March 12 she could not visit her 58-year-old HD-stricken father, Danny, at the Missouri nursing home where he resides.

“They are locking all doors for the safety of people there,” wrote Mandi, a dedicated caregiver and herself at risk, but untested, for HD. “Was my first reaction sad I couldn’t see my dad? Sure, but I immediately checked myself. I realized my own selfish want to see my dad was tiny in comparison to keeping the people in the nursing home safe because who knew if I was a carrier since you can have it for over a week and not show symptoms.”

Mandi pointed out how the nursing home’s restriction is “terrifying for those of us with possibilities of losing family.” She wants “to do everything in my power to protect him as I always have.”

However, she concluded: “Until we really know what we are dealing with let’s just take the precautions seriously.”

Danny (left) and Mandi (family photo)

Especially resilient

With the coronavirus pandemic, the world can learn from the example of the HD community and our generous supporters.

We in the HD community, and other neurological disease groups, face relentless adversity. HD grinds down the brain, leaving the affected like my late mother unable to walk, talk, or care for themselves. Caregivers like Mandi and my late father are true “HD warriors.” 

However, because of this, we have developed a very realistic view of life.

“We are all in a race to death, but people at risk for life-shortening diseases know that their time to the finish line is painfully fast and troubled,” I wrote in 2009 in an article titled “HD: hurtling towards death.”

At the same time, we also have a special appreciation for the “preciousness of life.”

Confronting HD makes us especially resilient. I am hopeful that the HD community will successfully meet the challenges of the coronavirus pandemic and, as in facing past challenges, become even stronger.

Monday, March 02, 2020

CHDI head scientist Pacifici: ‘hang on in the learning roller coaster ride of Huntington’s disease clinical trials’

With historic clinical trials now aiming for the first effective treatments for Huntington’s disease, affected individuals and their families need to clearly understand the news about these efforts and their implications.

That critical recommendation was offered by Robert Pacifici, Ph.D., the chief scientific officer of the nonprofit HD-treatment-seeking CHDI Foundation, Inc., during an interview on the last day of the organization’s 15th Annual HD Therapeutics Conference, held February 24-27 in Palm Springs, CA.

“Getting to this stage – which we’ve all so been hoping for – is still a bit of a roller coaster ride,” Dr. Pacifici told me. “You have to be able stay in our seats and weather the ups and downs. I think we’re well-poised for some great news, as some of these trials hopefully report out. Even a whisper of efficacy would be just amazing.”

However, there will also be “disappointments, where, despite our best attempts, some of the things that showed so much promise didn’t end up meeting their endpoints,” he cautioned. “But it’s going to be a learning roller coaster. So hang in there. Don’t lose hope.”

The HD-affected (and their caregivers) should keep informed about the trials by consulting their physicians, attending meetings of patient organizations such as the Huntington’s Disease Society of America (HDSA), and keeping abreast of developments in such sources as and this blog, Dr. Pacifici advised.

Become knowledgeable, he urged, “so that you are not disproportionately spooked or elated when these bits of information come out.”

Featured conference speaker Christopher Austin, M.D., the director of the National Center for Advancing Translational Sciences/National Institutes of Health, presents part of the Drug Discovery, Development and Deployment Map the research and pharmaceutical community must navigate in today's complex and challenging scientific world (photo by Gene Veritas, aka Kenneth P. Serbin).

‘Genuinely interested’ in treating HD

Dr. Pacifici began the interview noting the excitement generated by the conference and within the HD field, with a record 380 participants, overflow seating, and more than 100 people turned away. However, CHDI’s goal ultimate goal is not to host well-attended conferences, but to stop HD, he emphasized.

“There are that many people who are genuinely interested in presenting the results and learning about the incredible developments that are unfolding in Huntington’s disease drug discovery and development,” he said of the response to the conference.

Dr. Pacifici also noted the very high quality of the presentations, in comparison with the early years of the event. 

“We’re batting 1,000 this time – every single talk very relevant,” he observed.

Considered science fiction a decade ago, the new technologies applied in HD research are transforming the field and allowing for a more thorough analysis of cells in the quest to understand the disease, he added.

Dr. Pacifici cited the example of whole-genome sequencing on individual brain cells, which permits the reading of the DNA sequence of “every single gene in there, and doing that thousands of times.” 

You can watch my interview with Dr. Pacifici in the video below. For my video album of the conference, please click here (and check back in the coming days as I add videos).

New understanding of the protein

Dr. Pacifici also discussed new research into the huntingtin protein presented at the conference. Such research suggests that the protein might have a key role in maintaining the integrity of the huntingtin gene and also in the way the gene expands over time (known as somatic expansion), which researchers now see as a key driver of the disease (click here to read more).

With this potential new finding, a single drug might be developed to counteract the mutant protein by both reducing its quantity and preventing it from causing somatic expansion, he speculated.

He pointed in particular to the presentation by Jeffrey Carroll, Ph.D.

A possible key biomarker

Dr. Pacifici also commented on the discussion around phosphodiesterase-10 (PDE-10). A PDE inhibitor was seen as a potential “Viagra for the brain” but ultimately showed no improvement in a clinical trial run by the drug giant Pfizer.

However, PDE-10 might still play a role for the HD community as a biomarker (sign of disease and/or effect of a treatment), Dr. Pacifici said.

“It is pretty uniquely expressed in the neurons that we know are affected by Huntington’s disease, the medium spiny neurons,” he explained. 

If PDE-10 decreases in HD because the gene is shut down or cells die or some combination of both, and “if you had a molecule that bound to PDE10 and sent out a signal, then you could know how much PDE10 was in that brain, and if it was declining, that would mean that the disease was progressing.” Similarly, with an effective therapy, “you would see PDE10 levels going up,” Dr. Pacifici added.

The U.S. Food and Drug Administration is unlikely to approve a drug based solely on evidence from a biomarker, because it needs to see actual clinical benefits in patients, Dr. Pacifici said. However, the biomarker could give a drug maker the “confidence” that the “intervention is doing its job biologically and now it’s worth waiting for the clinically meaning outcome.”

(The presentation by Steven A. McCarroll, Ph.D., of the Harvard Medical School, included discussion of the role of PDE-10.)

Above, Dr. Steven McCarroll answers a question from the audience after his presentation on single-cell analysis of HD biology. Below, McCarroll lab researchers Nora Reed (left) and Christopher Mullally with the lab's poster on single-cell analysis, which took second prize in the poster competition (photos by Gene Veritas).

The terrifying truth about drug development

Dr. Pacifici reflected on the in-depth talk by the conference’s featured speaker, Christopher Austin, M.D., the director of the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health. NCATS, founded in 2011, aims to speed the development of treatments and cures.

I asked Dr. Pacifici to comment on the phrase that struck me from Dr. Austin’s presentation: “The hard work that nobody else wants to do.”

Scientific research is “unsexy” and “difficult to understand,” but Dr. Austin challenged the field to forge ahead, I observed.

“He painted a pretty bleak picture of how we’re sadly finding diminishing returns on our investment,” Dr. Pacifici said regarding drug investigation in general. “In other words, he kind of flipped around Moore’s law. Instead of things getting better and faster, the more money we spend, the fewer treatments we see coming out, especially for the harder neurological diseases.”

Dr. Austin presented to the audience what he called a “truly terrifying fact”: “The number of new drugs approved per billion dollars spent, inflation-adjusted, has gone down by half every nine years, since 1950.”

You can learn why this is so – and its very serious implications for HD – by watching Dr. Austin’s presentation by clicking here.

The HD field hopes to be the exception and the model

Dr. Pacifici pointed to the difficult and complex challenges involved in drug discovery, as illustrated by Dr. Austin.

Everybody wants to be the “star” that “made the compound that turned out to be the cure,” Dr. Pacifici said. But imagine: the compound is there, but no patients are available to do the clinical trial. Or patients participate, but researchers lacked the “outcome measures to see whether people were actually getting better.” Or, antibodies and assays needed to measure the samples derived from patients weren’t there.

Those things are the not-so “sexy” but need to get done, he said.

The HD field will need to overcome the inertia of diminishing returns, Dr. Austin emphasized. Deeply familiar with HD science, he believes that HD as a monogenetic disease has the potential to do so and could serve as the model for treating other, more common neurological disorders.

Dr. Pacifici agreed. He praised the HD research and biotech community not only for its commitment to make sure that key elements of the drug-hunting process are “proactively put in place,” but the “selflessness with which they are shared, so that those don’t represent competitive advantages for one company or another. I think everybody has come to the realization that this is a really hard problem. It’s no use competing with each other. We’re going to have to help each other.”

At the start of his talk on huntingtin-lowering strategies, Ignacio Muñoz-Sanjuán, Ph.D., a CHDI scientist and the co-founder of Factor-H, reminded the audience of the goal of the HD cause: to help individuals like Anyervi (in cap) and Brenda, two youths from South America with juvenile HD (photo by Gene Veritas).