Moving toward a potential treatment: Isis, CHDI researchers outline upcoming Huntington’s disease gene-silencing trial

Scientific research and clinical trials aren’t glamorous, but they are the meat and potatoes of effective treatments and perhaps ultimately a cure for Huntington’s disease. The gene-silencing approach like the Isis-Roche initiative reported here August 23 has great promise.

In a two-hour interview with me at company headquarters in Carlsbad, CA, on August 22, Isis Pharmaceuticals, Inc., officials and researchers provided details about the Phase I trial of the antisense oligonucleotide (ASO) ISIS-HTT_Rx. Isis and Roche, the Swiss drug maker, plan to start the trial in Canada and Europe by mid-2015. If successful, the trial could result in a drug in five or six years, by 2021.

By attacking the disease near its genetic roots, ISIS-HTT_Rx could potentially reduce, partly reverse, and even prevent the symptoms of Huntington’s. If it works as intended, this synthetic strand of DNA will turn off the huntingtin gene messenger RNA that contains the instructions to make the huntingtin protein in brain cells.

The huntingtin gene is essential for development very early in life, but some people inherit it with an expanded length, leading to the production of faulty huntingtin messenger RNA and huntingtin protein. Carriers of genes expanded beyond a certain length develop Huntington’s disease. The most recent evidence suggests that not only the faulty protein, but also the faulty messenger RNA damages the brain.

ISIS-HTT_Rx will later receive a generic scientific name and, if marketed, a trade name from Roche. HTT stands for huntingtin, and Rx for medical treatment. Founded in 1989, Isis based its name on the Egyptian goddess known for her healing powers.

“We have a drug that is going forward into clinical development,” said Frank Bennett, Ph.D., Isis’s senior vice president for research, who has led the development of the HD project. “Assuming all goes well, our plan is to start clinical trials towards the first half of next year…. We’re very enthusiastic about the drug.”

Dr. Bennett said that Isis is currently conducting standard toxicology studies of the drug primarily in non-human primates, but also in rodents, to assure that it will not cause harm to humans. A Phase I trial tests primarily for safety and tolerability.

Dr. Frank Bennett (photo by Dr. Ed Wild)

If the toxicology studies are successful, in the first quarter of 2015 Isis and Roche will request formal authorization to start the Phase I trial from the Canadian and European country equivalents of the U.S. Food and Drug Administration (FDA).

Asked about previous delays in the clinical trial timeline and the certainty of a 2015 start, Dr. Bennett affirmed that “we’re on track.”

“What’s really different is that we now have the drug,” he said. “The rest of this is really kind of operational where we have to do additional important work, but it’s not the necessarily the same kind of research we were doing before, where there were a lot of unknowns that impacted timelines. We have to do some experiments, but we … have a lot of experience doing these toxicology studies. We aren’t anticipating any major issues associated with them.”

“It’s never been more close,” said Douglas Macdonald, Ph.D., a long-time contributor to the project. The director of drug discovery and development for CHDI Management, Inc., which carries out the day-to-day mission of the non-profit, HD drug-discovery biotech CHDI Foundation, Inc., Dr. Macdonald was its point man during the foundation’s collaboration with Isis from 2007-2013 and, along with others from CHDI, continues to advise on the project.

With a $30 million investment in Isis’s preparations for the clinical trial and the prospect of additional future payments, Roche last year acquired the rights to the drug. The deal allowed CHDI to switch to an advisory role as intended and enabled Roche to bring to bear its expertise in developing drugs and bringing them to the market. Because of the high cost of drug development, a small biotech firm such as Isis must partner with a drug manufacturer to get its remedies to patients.

Gene Veritas (aka Kenneth Serbin) at Isis headquarters in Carlsbad, CA (photo by Alex Chambers, Isis intern)

Safety and tolerability

The trial of ISIS-HTT_Rx will involve approximately 36 early-stage Huntington’s patients at four to six clinical trial sites (institutions, clinics, and/or hospitals) in Canada and Europe, said Roger Lane, M.D., M.P.H., Isis vice president of clinical development and neurology and the company’s lead organizer of the HD trial. Isis will announce the sites next year after contract signings and approval from regulators. Isis and Roche are focusing on sites with considerable experience in clinical trials in Huntington’s disease.

Dr. Lane joined Isis in January 2014 in large part to help it ramp up the ISIS-HTT_Rx trial.

He explained that the site clinical trial investigators will seek to recruit individuals who have received a medical diagnosis of HD due to their high level of motor symptoms (involuntary movements) but still in the early stages of the illness. The trial will require people with a “very high level of functioning”  with Total Functional Capacity score of 11-13 (on a rising scale of 1-13).

The patients need to be “fully capable of informed consent and able to make a determination whether they want to be in the study or not,” he said.

Although it’s widely recognized that cognitive loss and/or mood and behavioral disorders can precede motor symptoms in HD, the ISIS-HTT_Rx Phase I criteria will hone to the classic definition of motor onset, Dr. Lane indicated. The patients without a lot of motor symptoms might qualify for the eventual Phases II and III, depending on the observations made in Phase I, he said.

Recruitment will take place through physicians, without public advertisements. Patients will receive reimbursement for expenses associated with the trial.

Dr. Roger Lane (photo by Dr. Gene Hung, Isis)

“We want patients that are going to be fairly local to the site, so we don’t want patients to come from a long way,” he explained. “If there’s any complication, obviously we want them to be admitted very rapidly to the clinical facility.”

Because a Phase I study focuses on safety and tolerability, patients will receive one of four ascending doses of ISIS-HTT_Rx over three months. Although ISIS-HTT_Rx might be able to reduce the amount of huntingtin messenger RNA and protein as much as 90%, the highest dose is anticipated to achieve a reduction of 50-70%, Dr. Lane explained.

The study will help determine the frequency and size of dosages for eventual Phase II and Phase III trials. In line with the research done in animals, a successful ISIS-HTT_Rx drug in humans might require dosage only a few times per year, Dr. Lane said.

One in four patients will receive a placebo and therefore become a comparison group, a standard practice in clinical trials to allow for a more accurate understanding of the actual effect of a drug.

After the first dose, patients will undergo monitoring for at least 24 hours before heading home.

Participants will undergo periodic neurological and neuropsychiatric evaluation. The first evaluation will take place on the eve of the first dose. After the last dose, researchers will continue to evaluate the patients for six months. “We’ll be keeping a close eye on them,” Dr. Lane noted.

A spinal tap

Patients will receive the drug through a routine lumbar puncture, that is, a needle inserted into the lower spine. Experienced neurologists will first withdraw a small amount of cerebral spinal fluid (CSF), to be analyzed as part of the clinical trial research. (See more on this research below.)

Next, without withdrawing the needle, the doctors will inject a few milliliters of a solution containing ISIS-HTT_Rx.

In technical terms, introducing the drug into the spinal canal is known as an intrathecal injection. The CSF naturally travels to the brain. As in tests with rodents and non-human primates, the ISIS-HTT_Rx should flow with the CSF to the brain.

As Isis and Roche prepare for the trial, they will decide on the best position for the patients – lying on their side or drooped over a chair, for instance – to get as much of the drug as possible into the brain and minimizing complications such as post-procedure headaches.

Dr. Lane explained that the doctors will use a so-called atraumatic needle, which has a slightly more blunt point than other types of needles and produces fewer post-procedural headaches.

In all, the actual procedure will last several minutes, with patients spending no more than half an hour on this part of the trial, Dr. Lane said. A local anesthetic can be used but is avoided by doctors because it can cause swelling and make it harder to see under the skin, he added. Each trial participant will undergo the procedure five times over the course of the treatment period.

“I’ve had lumbar punctures myself, and I’ve given many lumbar punctures to other people,” Dr. Lane continued. “If you’re in the hands of a very experienced clinician who’s done them many times and who does not impart any anxiety to the patient, then it’s not an inconvenient or painful procedure. You feel a little bit of pressure perhaps in the back. If you do not have any headache after the procedure, then it’s not really that inconvenient. There is a psychological component to the thought of having a needle put into your back. It’s not an agreeable thought to people. But it’s not a painful procedure.”

Children undergoing spinal taps in an Isis clinical trial for a drug to treat spinal muscular atrophy have not suffered any serious consequences, Dr. Bennett pointed out.

For more on spinal taps and Huntington’s disease research, see Dr. Ed Wild’s account of his own lumbar puncture by clicking here.

Isis and Roche are conducting joint research on the latter’s so-called brain shuttle technology, which in the future might allow patients to take a drug such as ISIS-HTT_Rx via an intravenous or subcutaneous (under the skin) injection, Dr. Bennett said. The companies are not currently offering public comment on that research, he added.

Timeline and study sites

Depending on the pace of recruitment, Phase I most likely will end in 2017, Dr. Lane said. If Phase I is successful, Phase II could follow no sooner than nine months later. All three phases of a clinical trial program typically take at least five years.

With its large HD population and high-level medical facilities, why won’t the U.S. host the Phase I trial?

“This trial is very small,” explained Dr. Lane. “So we only need a few sites. We could have run the study in the U.S., but it didn’t make sense to run it in both the U.S. and Europe. We chose Europe.”

Dr. Lane said that the FDA’s clinical trial guidelines did not lead to the decision to conduct the experiment abroad.

Aimed at demonstrating the efficacy of ISIS-HTT_Rx, Phase II would recruit a much larger number of people and will certainly include the U.S., Dr. Lane said.

Measuring the results

The trial investigators will check for the safety and tolerability of ISIS-HTT_Rx by putting the patients through several tests and measurements, including clinical observations, behavioral and neuropsychiatric testing, cognitive testing, a motor function examination, and neuroimaging (putting the participants in a structural MRI machine and taking measures of brain volume).

The measurements will also allow the researchers to make “assessments of the disease itself,” Dr. Lane said.

“On the flip side, we can actually explore if we’re actually improving those parameters [the patients’ condition],” he added.

However, Dr. Lane warned that the short duration of the study would limit the use of such observations.

“We might not see much change, even if the drug was capable of inducing change,” he said.

Key biomarkers: CSF and PET-ligands

A key set of observations on the disease will come from the CSF. Researchers will also measure the ASO concentration in the fluid to determine the amount of drug remaining in the brain.

They will also seek to identify and study biomarkers, that is, markers of the disease and disease progression. Biomarkers can also indicate the effect of a drug.

Because ISIS-HTT_Rx  should reduce or “knock down” the huntingtin messenger RNA and protein, the scientists want to measure and interpret the amount of both normal and mutant huntingtin in the CSF. (Both types exist in HD patients because they inherit a copy of the huntingtin gene from each parent, one healthy, the other HD-affected.)

“There’s good news on that front in that we can measure huntingtin in the CSF, but we don’t know yet what that means,” Dr. Lane explained. “Where is it coming from? Is it coming from the blood? Is it coming from the brain? If it’s coming from the brain, where in the brain is it coming from?”

(For a recent scientific discussion of mutant huntingtin in the CSF and other bodily fluids, please click here.)

Isis and CHDI are collaborating to help answer these and other questions about the CSF, said Holly Kordasiewicz, Ph.D., an Isis HD team member. By studying rodents genetically modified to develop HD-like symptoms and treated with ASOs, they aim to establish a correlation between the amount of both normal and mutant huntingtin in the CSF and the brain. That will help the researchers determine the frequency and quantity of the drug’s dosage.

Dr. Holly Kordasiewicz (photo by Dr. Gene Hung, Isis)

They are also gathering data on these questions from the above-mentioned toxicology studies.

In addition to huntingtin protein, the researchers will observe other markers in the CSF such as markers of neuronal damage, inflammation, and transcriptional dysfunction (incorrect formation of proteins), Dr. Lane added.

In collaboration with Dr. Macdonald and others at CHDI, the Isis HD team is working to validate huntingtin lowering biomarkers. Beside the development of assays (investigative procedures) to measure the huntingtin protein in CSF, CHDI is also looking at PET-ligands to measure the effects of ISIS-HTT_Rx in the brain. The ligand, sometimes called a PET tracer, binds to a target or receptor in the brain, which can be measured in people using PET scan imaging.  The team has selected ligands to targets that are altered in HD; the hope is that when huntingtin is lowered the level of these targets will be restored, indicating that ISIS-HTT_Rx has a desired effect.

Dr. Macdonald offered the example of dopamine receptors. “It is well established that there is less of a receptor called the dopamine subtype 2 receptor in the brains of HD patients and animal models.  This can be measured using a specific PET tracer and we will look to see if that signal is increased after huntingin-lowering with ISIS-HTT_Rx. If that occurs this would be an indication that the drug is having the expected effect in the brain.” The procedure is non-invasive, he added.

Dr. Lane said that the PET-ligand most likely will be ready only for Phase II.

From these observations of the CSF and the PET-ligand signals, the researchers hope to draw conclusions about the effectiveness of the drug, if not in Phase I, certainly in Phases II and III.

“Biomarkers are an important aspect of any drug development program,” said Dr. Macdonald. “The fact that the Isis and Roche teams are seriously looking at what biomarkers they can use in the clinic is a very positive sign”.

Of course, the ultimate biomarker will be a healthy patient.

Dr. Douglas Macdonald (photo by Gene Veritas)

Completing the ‘missile’: ISIS-HTT_Rx  

Isis’s choice of ISIS-HTT_Rx in the first quarter of this year came after seven years of engineering and the testing of some 2,000 ASOs.

As Dr. Bennett put it in 2008, Isis technology is like a “laser-guided missile” that targets a specific, disease-causing messenger RNA and destroys it or takes it out of the body “so that you don’t produce that messenger RNA.”

In 2012, Dr. Kordasiewicz, Dr. Bennett, and other researchers published an article in the important journal Neuron demonstrating how the experimental ASOs produced stunning improvement in the health of HD-affected mice.

Some researchers referred to the improvements in symptoms and signs that persisted for a long time after the ASO treatment had finished working in the affected animals as a “Huntington’s holiday.”

Throughout 2013 and into 2014, Isis has tweaked the drug formula, aiming to improve safety and efficacy.

“It’s like you’re turning two different knobs, safety and efficacy, and sometimes they go in different directions,” Dr. Bennett explained. “You have to sort of adjust both knobs by screening a lot of different drugs that ultimately give you what you’re hoping is the candidate.

“We’re very pleased that screening shows that it’s potentially a well-tolerated drug. We wanted to make sure that it’s the most potent, most efficacious and safest drug that we could identify. This candidate fits that description.”

Isis designed ISIS-HTT_Rx to knock down both the mutant form of the huntingtin gene messenger RNA and the normal form. So far, research has not shown any negative effects of knocking down the normal gene in animals. Isis also has the technology to make mutant-gene messenger-RNA-specific ASOs, that is, types that reduce only the bad huntingtin protein.

“One of the big challenges for us was to decide whether we only inhibited the mutant gene that expresses the expanded CAG repeat or we targeted both the wild type [normal] as well as the mutant gene,” Dr. Bennett said. “There are a lot of pros and cons for doing both. Ultimately we decided that the technology with the mutant-specific compound wasn’t ready to go.”

The HD team “felt it was important to get a drug into clinical trials as quickly as we are comfortable with” in order to start evaluating the effects on the disease of knocking down the huntingtin messenger RNA and protein, he continued.

If ISIS-HTT_Rx works, the company may develop the mutant-specific ASOs as second-generation drugs. As Dr. Bennett explained, this version would require at least five different ASOs because of variations on the huntingtin gene among individuals.

(You can learn more about mutant-specific ASOs by participating in a Huntington’s Disease Society of America webinar 12-1 p.m. EDT on September 24 with Amber Southwell, Ph.D., of the University of British Columbia.)

The million-dollar question

At the close of the interview the Isis scientists assessed the clinical trial’s potential impact on patients.

“That’s the million-dollar question,” said Dr. Kordasiewicz. “We’re all very hopeful that it will work, but you just don’t know until you try it.”

“We’re going into the unknown territory now, because nobody’s really developed a therapy to treat Huntington’s disease that’s really targeting the huntingtin gene,” said Dr. Bennett. The hope is to stop disease progression and potentially reverse some symptoms. “The science would suggest we minimally could prevent the disease from progressing any further.”

Dr. Lane said that ASO technology “has a lower likelihood of failing” than traditional pharmaceutical products (so-called small molecules).

“With small molecules it’s not always clear exactly how they’re working,” he explained. “The mechanism here [ASOs targeting the messenger RNA of a specific gene] is so clear and so tied into the pathogenesis [cause] of the disorder that there’s more chance at being successful.”

(Small molecule drugs make up 90 percent of the drugs currently on the market. They are traditional, chemically manufactured drugs. Large molecules, also called biologics, are a new class of drug that is becoming increasingly important. They are proteins. ASOs represent another new technology distinct from these other two classes of drugs.)

Dr. Lane added that even though HD has been well studied, not all of the pathways of the disease – that is, the downstream biological processes flowing from the mutant gene – have been described and understood. Researchers still don’t “know for certain which are the important pathways of the disease.”

With ASOs, the downstream pathways are irrelevant, he said. “We go so early in the pathway that we should help everything.”

Asymptomatic gene carriers cannot participate in the ISIS-HTT_Rx trial.

“Obviously this mechanism has great potential to be used in individuals who have the mutant gene and are not yet symptomatic,” said Dr. Lane said.

Members of the Isis team: (from left to right) Alex Chambers, intern; Kristina Bowyer, director of communications and advocacy relations; Dr. Roger Lane; Dr. Gene Hung; and Dr. Holly Kordasiewicz (photo by Gene Veritas)

A transformation of medicine?

Isis has been making medical history.

In January 2013, the FDA approved Kynamro, a drug developed by Isis to treat a rare type of extremely high cholesterol. It was the very first systemic ASO drug to reach the market.

Shortly before that, Isis also made history with a clinical trial for an ASO drug to treat amyotrophic lateral sclerosis (ALS). The program was paused after Phase I because Isis is improving the drug for its ongoing development program using the latest ASO technology.

“The ALS trial was the first time that anybody had put an oligonucleotide drug into the intrathecal space [spinal cord], and so there were a lot of safety concerns,” Dr. Bennett said. “The ALS experience showed that intrathecal administration was very well tolerated.”

ISIS-HTT_Rx is an even more advanced ASO than the one used in the ALS trial, he added.

A gene-silencing HD treatment would not only make history but could transform medicine as the world prepares to care for tens of millions of people affected by Alzheimer’s, Parkinson’s, dementia, and other neurological conditions.

Said Gene Hung, Ph.D., a long-time member of the Isis HD team: “To date I don’t think there are any disease-modifying drugs out there in CNS [central nervous system] and neurodegenerative diseases, period.”

ISIS-HTT_Rx could be the first. But it will take several years before progress can be assessed.

See below links to previous reports on Isis.

"News flash: Isis and Roche hope to start Huntington's gene-silencing trial in first half of 2015"

"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"