I observed this process in person earlier this month at the Fifth Annual HD Therapeutics Conference and a Clinical Workshop sponsored by CHDI Management, Inc., the multi-million-dollar “cure Huntington’s disease initiative.” More than 200 people from around the world attended the workshop at the Parker Palm Springs hotel in Palm Springs, California, from February 8-11.
On February 14, I reported my initial impressions of the event, describing the immense progress that scientists have made since the discovery of the HD gene in 1993. The conference included 31 presentations and 59 posters on the latest work done in Huntington’s research labs.
As I concluded, the challenge today is not a lack of possibilities, but a plethora of fronts on which the disease could potentially be fought. Researchers now must select the correct targets among many and find a way to administer them safely and effectively in humans.
In this report I provide an overview of the first part of the event and the hope that it brought for the HD-afflicted, premanifest (gene-positive, asymptomatic) individuals such as myself, and untested at-risk people.
From labs to clinics
Appropriately for an effort geared towards moving targets into clinical trials, the CHDI event started with a clinical workshop on February 8. Titled “Engaging the Field: New Clinical Approaches to Disease Modification in Huntington’s Disease,” the workshop addressed the question of how to design safe and useful trials.
The workshop indicated that the HD research community is now highly focused on moving potential treatments from the labs into the clinic. This gathering was not a theoretical exercise for the benefit of pure science, but a practical approach to helping HD-affected and premanifest individuals as quickly and as safely as possible.
In the morning, workshop participants heard eight presentations relevant to designing trials in humans. These presentations provided both an overview of some of the crucial areas of clinically-driven HD research and examples of strategies that might be used.
Attacking HD’s genetic roots
The first two presentations dealt with attempts to halt the disease at its genetic roots.
Neil Aronin, M.D., of the University of Massachusetts Hospital described the advantages and pitfalls of trying to directly combat the defects wrought in brain cells by the mutated huntingtin gene through the use of antisense oligonucleotides (oligos or ASOs) and RNA interference (RNAi). These valuable, cutting-edge techniques go to the root of HD’s causes, but they also could produce unforeseen consequences in the cell.
Current use of oligos, for example, targets the harmful effects of the mutated huntingtin gene in brain cells, but it also could prevent the proper operation of normal huntingtin, which is essential for life. Scientists are looking for ways to keep good huntingtin functioning while blocking out only the effects of the bad. Continued research is needed.
Other presentations later in the conference, as well as several of the posters, addressed these techniques in greater detail.
(I wish to thank Doug Macdonald, Ph.D., and Simon Noble, Ph.D., both of CHDI Management, Inc., for their assistance with this article. Next time: a report on the second part of the CHDI meeting, the 5th Annual HD Therapeutics Conference.)
A poster demonstrating experiments with antisense oligonucleotides, also used to target the huntingtin gene (photo by Gene Veritas)
Timothy Miller, M.D., Ph.D., of the Hope Center for Neurological Disorders at Washington University in St. Louis, reported on the successful use of an oligo manufactured by Isis Pharmaceuticals, Inc., of Carlsbad, California, to ameliorate amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) in transgenic rats carrying specific traits of the disease.
The Isis oligo was targeted at SOD1, a gene that, when mutated, causes ALS. The oligo slowed down the onset of the disease and doubled the survival time of the animals. The oligo was found to be safe in rhesus monkeys. The next step in this project is a Phase I trial in humans to test for the safety of the oligo in the human body.
It will take place at six sites: Washington University in St. Louis; Massachusetts General Hospital in Boston; Johns Hopkins University in Baltimore; the Carolinas Medical Center in Charlotte, North Carolina; the Methodist Neurological Institute in Houston; and the Center for Neurological Study at the Scripps Institute in San Diego. This project is highly important for HD research, because Isis is currently testing oligos for Huntington’s. These studies may show the way forward in the search for HD treatments and a cure.
Drains on energy
The next two presentations focused on energy usage in HD. They specifically addressed one of the most controversial and difficult questions in the science of HD: whether the failure of the mitochondria, the powerhouses of our cells, is a cause of the disease.
Bernhard Landwehrmeyer, M.D., of Ulm University in Germany, explained that the brain relies heavily on energy. While the brain accounts for only two percent of our body weight, it represents 20 percent of the oxygen consumed in the body and 25 percent of our glucose utilization. The mitochondria of the brain are responsible for this immense energy usage.
Regarding the connection between Huntington’s disease and mitochondrial dysfunction, the big question resembles the classic one about the chicken and the egg: is the dysfunction the cause or the effect of HD?
For the most part HD researchers have assumed the former. As Dr. Landwehrmeyer explained, HD presents motor, cognitive, psychiatric, and metabolic (energy-related) symptoms. The body’s muscles and brain work harder, consuming more energy. Many HD patients lose weight. Research demonstrates that glucose uptake (absorption) diminishes in HD-affected brains. Biopsies of HD-affected brains reveal abnormal mitochondria. Additional evidence suggests that a gene (PGC-1 alpha) regulating energy metabolism affects the age of onset in HD and might play a role in mitochondrial dysfunction.
Other evidence suggests that HD is not causing dysfunction. The genetic defect of HD, for instance, does not directly cause mitochondrial dysfunction.
Dr. Landwehrmeyer concluded that more studies are needed to clarify the role of this dysfunction in HD patients.
Bernhard Landwehrmeyer (right) converses with Rodrigo Osorio of the Chilean Huntington's association (photo by Gene Veritas).
Ronald Haller, M.D., of the University of Texas Southwestern Medical Center agreed that there is “no definitive smoking gun of mitochondrial defect” in Huntington’s disease. Dr. Haller presented his ongoing research on mitochondria in the muscles of HD patients whom he studies as they ride stationary bicycles.
Such exercises allow for an excellent measure of oxygen usage. In contrast with healthy individuals, Dr. Haller discovered, HD patients experience a striking impairment of oxygen flow. They must use more oxygen and a larger mass of muscle to carry out the same tasks. So far, however, he has found no link to mitochondrial dysfunction.
As general advice, Dr. Haller recommended that people with or facing HD remain active. Excessive rest, he stated, reduces mitochondrial capacity.
Understanding changes in patients
The final four presenters discussed ways of understanding changes in HD patients (disease modification).
Yaning Wang, Ph.D., of the of Office of Pharmacology of the Food and Drug Administration (FDA) spoke via a webinar about the agency’s study of disease modeling and modification in Parkinson’s disease. Dr. Wang pointed out that several companies are investing in Parkinson’s drugs aimed at attacking the underlying disease, as opposed to just the symptoms. An FDA working group is encouraging the collection of biomarkers (indications of disease symptoms) in the early and late phase clinical trials as well as information about the effects of the trials. Understanding clinical endpoints (a disease symptom occurring in a trial) is important for exploring useful biomarkers, Dr. Wang explained.
The FDA plans to establish a similar working group for HD in the near future.
Doug Langbehn, M.D., Ph.D., of the University of Iowa, affirmed the need to develop mathematical models for better measurement of disease progression and the effectiveness of clinical trials.
Dr. Langbehn, who studies premanifest and early manifest HD patients, emphasized that the concept of “diagnosis” is tricky in Huntington’s disease. With most diseases, progression of the disease is measured from the start of the diagnosis by a physician. In HD, however, difficulties imperceptible to the patient occur years before an official clinical diagnosis is possible.
Medical researchers still have very little data about the disease over its full course – ranging from 15 to 30 years – in a patient. Dr. Langbehn stated that the first changes in a patient probably begin as early as 15 years before onset. As people near onset, it’s possible that various biomarkers converge and accelerate their progression to produce the disease.
Without taking these complexities into account, drug trials could go awry and produce very ambiguous results, Dr. Langbehn explained. A complete disease model should include comparisons between clinical observations and results of brain imaging, he added.
Doug Langbehn with Dr. Lavonne Goodman of Huntington's Disease Drug Works (photo by Gene Veritas)
Sarah Tabrizi, M.D., Ph.D., of the Institute of Neurology at University College London, explained that long-term studies of large groups of HD patients are producing increasingly detailed information about symptoms earlier and earlier in the disease process, including premanifest individuals. Improved testing also has permitted better measurement of short-term changes in the disease.
Dr. Tabrizi analyzed the results of observations on 363 individuals – 123 “control” individuals unaffected by HD, 120 premanifest individuals, and 120 HD patients. These people took part in a large observational study known as TRACK-HD.
In one premanifest person, changes in the brain began 14 years before the onset of the disease. Overall, considerable changes took place in the brains of both manifest and premanifest individuals in short periods of time. Manifest patients suffered an annual loss of brain cells (atrophy) of 1.9 percent of their brains, while the premanifest individuals lost 0.7 percent.
Other tests included measures of atrophy of the caudate (a region of the brain); subjects’ eye movements; individuals’ ability to perform finger-tapping (a highly useful measure); functioning of the sense of smell; slowed reaction time on a task; and the motor functions of the UHDRS (Unified Huntington’s Disease Rating Scale).
Eye tests, for example, measured how precisely an individual looked at a target and detected significant changes in just one year.
Researchers are also developing psychiatric markers for the disease such as temper, judgment, and irritability. The nearer to diagnosis, the more those with HD show increased temper and irritability and impaired judgment, Dr. Tabrizi stated.
Scientists have further observed “cortical thinning” in HD subjects, she added. The outermost region of the brain, the cortex plays an important role in cognitive functions. Scientists are seeking to measure subjects’ ability to probe and make spatial perceptions.
To properly utilize the growing variety of biomarkers and tests for measuring them, a new HD functional scale for premanifest and early manifest individuals is needed, Dr. Tabrizi concluded. The new scale will help validate the usefulness of the biomarkers in the clinic and clinical trials. CHDI is currently developing such a scale.
Cristina Sampaio, M.D., Ph.D., a professor of clinical pharmacology and therapeutics at the University of Lisbon, is a member of the European Medicines Evaluation Agency (EMEA), the European equivalent to the FDA.
Dr. Sampaio stressed the need for accurate clinical diagnoses of HD and outcome measures for the clinical trials. Relevant data are important for providing the best drugs possible. HD’s status as an orphan disease does not mean that researchers should settle for anything less than the best, she said.
Treatments must prove effective over decades, she added, and clinical trials should be held for both manifest and premanifest individuals. Debates such as the one over mitochondrial dysfunction may be irrelevant as long as the treatment works.
Tackling big issues in drug discovery
After the presentations, the CHDI organizers broke up the participants into six small groups placed in separate rooms. Each discussed a specific question about HD drug discovery.
CHDI placed me in Group 2. It tasked us with determining which segments of people in the HD population would be included in particular kinds of clinical trials. We also had to consider the inclusion of premanifest individuals. Yet another concern centered on differences in drug safety for each segment.
For 90 minutes I observed as the scientists, physicians, pharmaceutical representatives, and others reviewed the main issues involved in HD drug discovery and formulated specific recommendations.
Several issues became clear.
First was safety. One person suggested the standard approach of beginning a trial with only symptomatic individuals. Clinicians would study this segment to determine drug safety. Later, others could be included in testing the drug for efficacy.
Another issue first involved the possible lack of a sufficient number of patients and premanifest people to carry out clinical studies. One scientist stated that 1,000-2,000 individuals would be required for a single trial. That is a very large percentage of HD-affected population, estimated at around 30,000 in the U.S.
In addition, only certain segments might be useful in a particular phase of a study. One participant pointed out that there is a “sweet spot” population of early- to mid-manifest patients who are ambulatory and in a stable relationship and therefore able to take part in studies. Other patients might be too ill to participate. Once a patient can no longer go to the clinic, he or she would be dropped from the study.
A potentially large number of premanifest individuals could participate, but their lack of classic symptoms makes it difficult to measure the effects of a trial on them. Within the premanifest segment, various subgroups face different periods of time before onset begins.
Another factor concerned the degree and risk of side effects. Premanifest people might not be as tolerant of uncomfortable side effects, whereas a diseased person likely would be willing to take greater risks and endure greater side effects. Examples would include trials requiring surgery, spinal taps, or the taking of a drug with immunosuppressive side effects.
As one individual observed, patients with advanced disease are in huge need and desperate for help. They are likely to die of HD in just a few years.
The group – and other activities at the CHDI meeting – also noted that the FDA does not currently accept brain defects that appear in imaging as confirmation of neurological disease. A person must have symptoms. In this respect, the agency seems far behind the scientists, who have used imaging to demonstrate profound changes in the brain. Nevertheless, clinical researchers still face the challenge of linking the particular results of imaging studies to actual symptoms and later to actual improvements in symptoms.
All in all, the group agreed that a trial should start with one segment and, once the drug proved effective, proceed to the general HD population. People also seemed to agree that premanifest individuals should be included in the more general trial.
Debates on clinical trials
After the six groups returned to the main conference hall, each one presented its conclusions.
Mutant huntingtin and “repurposing”
We learned from Group 1 that a drug created to reduce the effects of the mutant huntingtin gene should, in order to be effective, cut the actions of the gene by at least 35 percent. Group 1 also noted that already existing drugs used in other conditions could be “repurposed” to combat HD.
Charged with designing a Phase III trial, Group 3 stirred debate by including the use of so-called secondary effects (or secondary endpoints) of the disease: behavioral and psychiatric symptoms. These symptoms could be measured by what the group described as a “quality of life” scale, as opposed to a “total functional capacity” (TFC) scale.
To make their point, Group 3 noted that functions such as finger-tapping or extending the tongue – scientifically very useful and highly indicative of disease – do not always have much meaning for the patients themselves. Patients, the group affirmed, don’t complain about their capacity to tap but about their cognitive functions declining.
In addition, clinical researchers have the additional burden of convincing FDA regulators that tongue extension and finger-tapping are meaningful in the drug discovery process.
As the debate over these issues made clear, nobody has yet discovered the best way for measuring what happens in HD. The very definition of Huntington’s disease could change in the coming years. But ultimately measures must be quantitative and sensitive to changes in the disease.
The usefulness of MRI
Tasked with discussing ways to see the meaningful effects of a drug in a Phase III (final) trial, Group 4 pointed to the need to examine the cerebrospinal fluid and brain plasma, measure the activity of non-neuronal brain cells (glial activation), and utilize various techniques for tracking changes in the brain, including MRI.
Although MRIs are helpful, Group 4 noted that scientists don’t really know why the brain shrinks in HD. Loss of brain volume could result from cell body shrinkage or from changes in the synapses, the communication lines that allow one brain cell to pass a signal to another. In either case, this kind of damage is potentially reversible.
Group 4 concluded that, although not a perfect measure of disease, imaging is the most reliable instrument that scientists have for examining the HD-affected brain.
Late-stage and truly premanifest individuals
Group 5 considered the limitations of both those in the late stages of the disease and the “truly premanifest,” who show no symptoms at all.
Both groups for the time being can't be included in trials. Late-stage patients are in such compromised conditions that it's extremely difficult for any kind of measurement to take place. According to Group 5, the premanifest should not run the risk that any clinical trial poses.
Patient attitudes and FDA regulations
Group 6 focused on the design of study necessary in a Phase III trial and raised a set of interesting issues related to patient attitudes and FDA regulations.
The group proposed a flexible trial design in order to have the ability to shift gears in the middle of the experiment. This kind of trial is more easily done in Europe than in the U.S, the group noted.
The ideal study does not always meet with FDA approval. But the group advocated a design unrestricted by current FDA guidelines. Within a trial, clinicians need to think actively and utilize various parallel methods simultaneously in order to account for all possible useful biomarkers.
Further, Group 6 proposed the idea of Huntington’s as a continuum of disease – not just one, simple diagnosis. (See my earlier entry on this topic.) This interpretation of HD would open up broader possibilities for FDA approval of drugs. Along these lines, the group observed that some patients may not want to be “diagnosed,” while others may want to be proactive and test early and therefore receive early treatment.
Group 6 further noted that some drugs may help only the very early symptomatic patients and premanifest individuals, as clinicians are observing with the use of antibodies to combat Alzheimer’s disease.
Group 6 concluded that, although drug approval might occur more easily in Europe, it was necessary to obtain the more stringent FDA approval in order to secure international markets for the drugs. Areas such as Asia could be important in the marketing of the drugs.
Progress is being made
The challenges in potential HD clinical trials are daunting, but the HD research community has assembled some of the best minds in science to meet them.
For a long time, scientists have thought that HD would require treatment on many fronts. By holding clinical workshops such as the one in Palm Springs, CHDI is gearing up to fight on many of those fronts simultaneously.
Today scientists offer not just hope to the HD community; they are developing a practical plan for turning that hope into the first real medicines for alleviating Huntington’s disease.