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

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

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

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

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

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

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

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

Checking movements and cognitive loss

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

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

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

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

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

Larger, longer studies needed

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

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

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

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

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

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

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

A 'hint of clinical benefits'

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

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

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

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

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

* * *

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

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

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

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

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

‘Darkness replaced by hope and light’: taking stock of Huntington’s disease research

As the Huntington’s disease community in 2015 enters a promising phase of clinical trials for remedies that might slow or halt the progression of the disease, one of the world’s leading HD scientists recently took stock of the significant progress made over the past several decades.

“The horizons for therapy were very far away,” Michael Hayden, M.D., Ph.D., the President of Global Research and Development and Chief Scientific Officer of Israel-based Teva Pharmaceuticals, said during a February 10, 2015, presentation about his company’s latest efforts to defeat HD.

Dr. Hayden recalled how, 40 years ago, HD was virtually unknown in his native South Africa and many other countries. HD-afflicted people faced stigma and were left to cope with their disease “in isolation and despair,” Dr. Hayden remembered of his first contact with the disease as a young medical student.

“It was just a dream then that there would be pharmaceutical companies interested in Huntington disease,” he said. (In some countries HD is referred to as “Huntington,” not “Huntington’s.”)

However, as Teva and other companies work towards HD treatments, the outlook has changed dramatically.

“We are now in a place of really tremendous hope,” Dr. Hayden declared enthusiastically. “The darkness is replaced by hope and light. At the end of the tunnel we are seeing this light now, not only with this [Teva’s] drug but other trials you are hearing about.”

Dr. Michael Hayden (photo by Gene Veritas)

Reexamining a promising drug candidate

Dr. Hayden offered these remarks during a Huntington’s Disease Society of America (HDSA) research webinar titled “Pride-HD: a dose finding, safety and efficacy study of pridopidine in HD patients.” (Click here to watch the webinar.)

Pridopidine was first tested in two clinical trials – in Europe and North America – by the Danish pharmaceutical company Neurosearch. The company, although it observed some interesting effects, did not achieve sufficiently positive results to bring the drug to market.

That’s because the chosen “endpoint” in the study, the way of measuring the drug’s effects, didn’t show a result significant enough for obtaining regulatory approval, Dr. Hayden explained. Neurosearch chose only a subset of motor symptoms as the study endpoint.

But some researchers still believed pridopidine had potential as an HD drug. Dr. Hayden and Teva studied the overall impact of pridopidine and, after obtaining the license for the drug from Neurosearch, have decided to run an additional clinical trial, called Pride-HD (Pridopidine Dose Escalation in HD). Teva is using a different endpoint, the so-called total motor score, a measurement of all the motor symptoms.

Dr. Hayden observed that patients in the earlier pridopidine studies actually showed improvement in motor symptoms caused by HD such as chorea, or involuntary movements. Pridopidine also improved eye movement substantially, he said. It also stabilized levels of dopamine, a neurotransmitter and hormone involved in movement control, mood, and motivation.

Patients’ depression, another telltale HD symptom, also did not worsen, Dr. Hayden noted.

Aiming for broader impact

“There may be some broader affect on other features of Huntington disease,” he added. Additional studies of pridopidine in animals have indicated that it brings about changes in the brain, might be “neuroprotective,” and might help with improving thinking and feeling, he explained.

Therefore, Teva will add other key endpoints to the Pride-HD study: cognition, mood, and quality of life. The study also will assess the effect of dosages of pridopidine higher than those given patients in the earlier trials.

Pridopidine “could theoretically have some effect to change the course of the illness,” Dr. Hayden observed. “And wouldn’t that be exciting?”

Pride-HD enrolled its first patient in April 2014 and will continue throughout 2015. Teva aims to enroll 400 patients at 54 sites in North America, Europe, and Australia. If the results are favorable, Teva could seek regulatory approval for the drug in late 2016, Dr. Hayden said.

As HD specialist Dr. LaVonne Goodman noted in her February 18 commentary on the potential of pridopidine, “recruitment is not going well for Pride-HD.[...] The bottom line is that finding new drugs for HD takes a lot of work, good trials and a long-term commitment from HD families and investigators. If we don't join this or other trials, we will never have new drugs for HD: not for ourselves or the next generation."

To learn more about Pride-HD and how to participate, refer to the above-mentioned link to the webinar or call HDSA at 800-345-4372.

Teva is also conducting a clinical trial of the drug laquinomod for use in HD, Dr. Hayden noted. Laquinomod is thought to reduce the inflammation of the brain in neurological disorders. Click here to learn more about the trial.

Another historic moment

As a carrier of the HD gene mutation, I listened to Dr. Hayden’s comments on the long-term progress of HD research with great hope.

Scientists have observed that managing HD effectively likely will require a cocktail of drugs. Pridopidine is yet another potential element in the mix. (I have reported on many of the elements in this blog over the past ten years. Click here and here to see recent examples.)

Having tracked the HD movement for nearly 20 years, I also appreciated Dr. Hayden’s important reminder that the quest for effective treatments is a lengthy process. Science and clinical trials require time and investments of money and intellect.

I wrote this article in Palm Springs, CA, just before the start of yet another historic mark in the HD movement: the 10^th Annual HD Therapeutics Conference, sponsored by the CHDI Foundation, Inc., at the Parker Palm Springs hotel February 23-26. In the past I have referred to this event as the "Super Bowl" of HD research.

In Palm Springs, I will listen to other scientists take stock of the search for HD treatments.

I also expect to witness yet further examples of researchers replacing the darkness of Huntington’s disease with hope and light.

For yet more perspective, watch my interview with Dr. Hayden at the 2011 HD Therapeutics Conference in the video below.

Gene Veritas interviews Huntington's disease expert Michael Hayden from Gene Veritas on Vimeo.