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 HDBuzz.net 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).

Hang on in the 'learning roller coaster ride' of Huntington's disease clinical trials from Gene Veritas on Vimeo.

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).

Roche announces U.S., Canada sites for Phase 3 clinical trial of Huntington’s disease drug

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.

Canada

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 

U.S.

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.

Roche announces first sites for key Huntington’s disease observational study

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.

Initial sites

Roche announced the sites listed below.

Canada

Centre for Movement Disorders, Toronto, ON

University of British Columbia, Vancouver, BC

U.S.

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.)

Ionis Huntington’s disease drug a step closer to a critical Phase 2 study

Ionis Pharmaceuticals has made two positive announcements about the historic Phase 1 clinical trial of its gene-silencing drug for Huntington’s disease: trial enrollment is complete, and the company will extend the study for all patients who complete Phase 1.

These are key steps on a multi-year path to possible Phase 2 and 3 trials that, if successful, would bring the trial drug, IONIS-HTT_Rx, to market. Typically, all three phases of a clinical trial project take at least five years, although nobody can predict the actual course of a trial.

IONIS-HTT_Rx aims to alleviate HD symptoms by reducing production of the huntingtin protein in brain cells (click here to read more). Ionis launched the Phase 1 trial in September 2015. Three dozen patents are taking part in the trial, expected to be completed by the end of 2017, at sites in Canada, Germany, and England. This first phase aims not to assess success in combating HD but rather simply whether the drug is safe and tolerable.

It marks the first time HD patients are receiving a substance aimed to attack the genetic causes of the disease. It’s also the first time they’re getting a drug via spinal injection.

“The safety and tolerability profile of IONIS-HTT_Rx in the completed cohorts of the Phase 1/2a study supports its continued development,” a June 22 Ionis news release stated. “Patients who complete the Phase 1/2a study will be eligible to participate in an open-label extension (OLE) study that Ionis plans to initiate in the next several months.”

“Open label” means all participants take the drug, in contrast with a “double-blinded” clinical trial like the current Phase 1, where half the patients receive a placebo and neither patients nor doctors know who is receiving the actual drug.

This month’s news provided the strongest indication so far that Ionis and its partner Roche, a much larger multinational pharmaceutical firm with vast clinical trial experience, will take IONIS-HTT_Rx into a larger, critical Phase 2 study, as early as 2018, to measure efficacy.

“Upon completion and full analysis of this study, the next step for this program will be to conduct a study to investigate whether decreasing mutant huntingtin protein with IONIS-HTT_Rx can slow the progression of this terrible disease," Frank Bennett, Ph.D., the Ionis senior vice president of research, said in the release.

Ionis has repeatedly indicated that a Phase 2 study would include U.S. trial sites.

Frank Bennett, Ph.D. (photo by Kristina Bowyer, Ionis)

‘Cautiously optimistic news’

The double-blinded protocol of the Phase 1 HTT_Rx trial insures that bias and other external factors don’t affect the trial results.

As noted, in an OLE each participant receives the actual drug, and usually at the highest dose tried in Phase 1. An OLE allows researchers to gather more data, examine the drug’s effects over a longer period of time, and better prepare for an eventual Phase 2. Patients also potentially benefit by receiving the drug longer.

The HD research website HDBuzz, which is produced by clinicians and scientists, described the Ionis announcements as “cautiously optimistic news.”

“News that the trial is fully recruited and the final patients are going through the procedures is a strong suggestion that even at the highest doses, the drug’s safety looks good,” the HDBuzz report observed. “Despite exhaustive safety testing before going into patients, any drug can produce unwanted effects, so that’s really the best news we could be hoping to hear at this stage.”

Regarding the open-label extension, it added, “We don’t want to read too much into a brief announcement, but running an OLE isn’t cheap for a trial sponsor, so this announcement certainly gives us optimism about the whole HTT_Rx program.”

Signs of HD in the blood

A separate research study, with results published June 7, could help Ionis and Roche researchers evaluate the results of the Phase 1 trial and plan the potential Phase 2 trial.

In what was described as a “major advance in the field of Huntington's disease and neurodegeneration in general,” a team of researchers has identified a potential blood biomarker for HD.

Biomarkers indicate a disease mechanism or drug impact. They are common for many diseases, but the complexity and inaccessibility of the brain have made it extremely difficult for researchers to find them for neurological diseases.

HD scientists have most recently focused on obtaining biomarkers from the cerebral spinal fluid (CSF). However, obtaining CSF, which requires puncturing the spine, is far riskier than drawing blood, the technique used in the new biomarker research.

Led by Ed Wild, M.D., Ph.D., one of the administrators of the IONIS-HTT_Rx trial in England, the new biomarker study demonstrated that a brain protein known as neurofilament light chain (Nfl) appears in the blood of HD patients and presymptomatic gene carriers. (Click here and here to read more.)

Dr. Ed Wild (photo from EdWild.com)

A less invasive measurement

Dr. Bennett of Ionis previously described Nfl as a protein involved in the cytoskeleton, or internal “scaffold,” of neurons. HDBuzz likened it to “the ribs of an umbrella.”

Dr. Wild’s team discovered that, the more advanced the stage of HD, the greater the amount of Nfl in the blood.

“This suggests that a blood test might be able to provide consistent information about the brain, in place of an invasive spinal tap,” HDBuzz commented. “We hope [Nfl] will be added to the arsenal of resources that are helping us to monitor HD and to develop new therapies.”

Indeed, the IONIS-HTT_Rx researchers previously noted that Nfl is one potential biomarker in the Phase 1 trial.

Further research is underway to confirm the Wild team's results and to determine to what extent Nfl can be used as a biomarker.

Pope Francis, Ionis, and the hope for a cure

The Ionis announcements about the clinical trial came as the 32nd annual convention of the Huntington’s Disease Society of America got underway in Schaumberg, IL. In addition to the news release, Ionis issued a letter to the HD community.

“We can assure you our number one goal remains our commitment to advancing IONIS-HTT_Rx development, a drug that has the potential to transform the treatment of HD,” the letter stated.

The positive news also comes in the wake of HDdennomore, the historic audience of the Huntington’s disease community with Pope Francis in Rome on May 18.

Dr. Bennett made a substantial donation to HDdennomore. He and several Ionis officials attended the audience. Dr. Bennett and his wife Paula sat in the front row along with leading HD scientists and dignitaries. They were greeted by Francis.

In his address, the pope recognized the geneticists and scientists “present here, who, for some time, sparing no energy, have dedicated themselves to studying and researching a treatment for Huntington’s disease. Clearly, there is a great deal of expectation surrounding your work: resting on your efforts are the hopes of finding the way to a definitive cure for the disease, but also of improving the living conditions of these brothers and sisters, and of accompaniment, especially in the delicate phases of diagnosis, at the onset of the first symptoms.”

If it succeeds, IONIS-HTT_Rx could fulfill those hopes and show the way to curing other neurological diseases.

Frank Bennett (left), Paula Bennett, and Gene Veritas (aka Kenneth P. Serbin) in St. Peter’s Square just before the audience with Pope Francis, May 18, 2017 (photo by Bianca Serbin)

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

(Click on the links below for past coverage of the Ionis HD project.)

Ionis Phase I Huntington's disease clinical trial at halfway mark: 'No surprises so far' means good news

Chief Huntington's disease drug hunter: 'every confidence first treatments' in the works

Huntington's disease patients get first dosing in historic Isis Pharmaceuticals' gene-silencing drug trial 

Isis Pharmaceuticals launches historic clinical trial to silence Huntington's disease gene

Moving toward a potential treatment: Isis, CHDI researchers outline upcoming Huntington's disease clinical trial

A key new ally in the search for Huntington's disease treatments

Quickening the pace towards a Huntington's disease gene-silencing clinical trial: pharma giant Roche, Isis enter partnership

Designing the best drug possible to defeat Huntington's disease

Building a 'laser-guided missile' to attack Huntington's disease

Observing the cure in progress

Chief Huntington’s disease drug hunter: ‘every confidence first treatments’ in the works

Surveying the vast progress in Huntington’s disease research and a “blitz” of clinical trials now in progress, a key scientific leader in the efforts has predicted that they will produce treatments for the incurable neurological disorder.

“I have every confidence that this batch of clinical candidates that are now being tested are going to yield the first treatments for Huntington’s,” said Robert Pacifici, Ph.D., the chief scientific officer for CHDI, the multi-million-dollar non-profit virtual HD biotech.

Dr. Pacifici’s remarks came in an interview on February 24 in Palm Springs, CA, at the organization’s 11th Annual HD Therapeutics Conference, sponsored by CHDI Foundation, Inc., the backer of the initiative.

Nobody can foretell the result of a clinical trial, and Dr. Pacifici did not specify a timeline for an effective treatment reaching the market. However, he offered examples of the immense progress towards developing treatments.

“It’s really frustrating for people, I know, to say, ‘That’s good news, that’s good news, but where’s the treatment, where are the drugs?’” Dr. Pacifici said. “The thing I would point to is that so many of the things we said were going to happen actually have happened. And so many of the things that have happened have actually yielded the outcome that we wanted.”

Dr. Pacifici cited three recent key advances: the ongoing research in biomarkers (signals) to measure the efficacy of potential drugs’ in reducing the harmful presence of abnormal huntingtin protein in brain cells; major progress in identifying modifier genes that delay or hasten disease onset; and the start of clinical trials.

The trials post the most “difficult” challenge in the process, he said.

“We want to make sure that we do things in a way that obviously is very careful,” he said, explaining the primacy of drug safety. “The last thing we want to do is harm anybody.”

Noting that the search for drugs has no guarantees, Dr. Pacifici nevertheless concluded that these are “exciting times” for the community of HD families, researchers, and supporters of the cause.

You can watch my interview with Dr. Pacifici in the video below.


'Every confidence first Huntington's disease treatments' in the works from Gene Veritas on Vimeo.

First Ionis patients safe

Until recent years, such good news seemed like a remote possibility for HD Therapeutics Conference participants and, indeed, for the entire HD community.

Because of the growing number of HD clinical trials and therefore greater hope for effective treatments, Dr. Pacifici and fellow CHDI conference organizers launched a new feature at this year’s conference, the “Clinical Trials Update Blitz.” Representatives from four different trials presented their latest news in 15-minute presentations.

The most anticipated update focused on the historic trial by Ionis Pharmaceuticals, Inc., to attack the root cause of HD via gene-silencing.

Trial principal investigator Sarah Tabrizi, M.D., Ph.D., of University College London reported that all patients in the very first cohort in the Phase 1b/2a trial – aimed at testing primarily safety and tolerability – completed the trial without incident.

Dr. Sarah Tabrizi updating the historic Ionis gene-silencing trial (photo by Gene Veritas)

The first group of participants received the first dosing of the drug, IONIS-RTT_RX, in October 2015. They received three additional doses at 28-day intervals and were monitored by trial administrators.

“We completed Cohort A, in London and Vancouver, four subjects, and the DSMB [independent data safety monitoring review board] met and allowed us to move to cohort B,” Dr. Tabrizi said. (A DSMB, a standard in all clinical trials, halts a study if patient safety is threatened.)

Administrators of the Ionis trial are currently recruiting volunteers for Cohort B, to be followed by Cohorts C and D, as outlined in the plans for the experiment. In all, 36 patients will take part in Phase 1b/2a. If all cohorts are successful, Ionis will seek approval for a full-blown, larger Phase 2 trial to test drug efficacy.

For further background on the trial, watch Dr. Tabrizi’s update in the video below.


First Patients Safe in Ionis Trial for Huntington's Disease Treatment from Gene Veritas on Vimeo

More than a disease

Drawing a record 325 participants from academia, the pharmaceutical business, and the medical field, the conference highlighted cutting-edge HD research, including the structure and function of the huntingtin protein; the huntingtin gene and the human genome; potential gene-silencing treatments; restoration of cell health; and ways to measure clinical trial outcomes.

Although highly dedicated to HD research, many of the non-physician scientists have little if any contact with HD families. This has prompted CHDI to open each conference with a keynote by a representative of the HD community to drive home the human reality of the disease and the urgent need for treatments. (I keynoted the 2011 meeting.)

This year Astri Arnesen and Svein Olaf Olsen, a married couple who have led the HD cause in their native Norway and in the European Huntington Association, delivered a powerful keynote about HD and marital commitment, denial, genetic testing, and raising a family. They titled their presentation “HD – more than a disease!”

Astri and Svein Olaf received a standing ovation.

I will explore their story and provide an overview of the key scientific findings in a second report on the conference.

Svein Olaf Olsen (left) and Astri Arnesen (photo by Gene Veritas)

An upbeat mood

As in past years, the CHDI meeting moved me profoundly.

I identified with the many difficult feelings and experiences recounted by Astri and Svein Olaf.

Once again, the scientists’ presentations reminded me of HD’s devastation of the brain – and of my vulnerability as a carrier of the HD mutation.

But this was a very upbeat conference. I had never spoken before to Dr. Tabrizi, but we hugged as if we were old friends after I congratulated her on the initial clinical trial report. The HD community has waited so long for such news!

Later, after I worked late into the evening on this article and missed the buffet dinner, Jerry Turner, the CHDI staffer in charge of conference logistics, arranged for a care plate of sumptuous leftovers from the kitchen of the Parker hotel, the gracious host of the conference.

I toasted to the success of the Ionis clinical trial and to CHDI’s commitment to the project with Doug Macdonald, Ph.D., CHDI’s director of drug discovery and development and its point man on gene-silencing.

As I told another scientist, I look forward to the day when we can all toast the discovery of an effective treatment.

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