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

Huntington’s disease patients in England have received the first dosing of an Isis Pharmaceuticals drug, ISIS-HTT_Rx, aimed at stopping the disease at its genetic roots.

The patients displayed no immediate complications. This so far confirms expectations that the gene-silencing drug would be safe to use, although clinical trial administrators will continue to make critical observations in the coming months. Other dosings will occur. The drug’s efficacy will not be analyzed until later stages of the trial.

An announcement came October 19 that a small number of Phase I clinical trial participants at University College London (UCL), the lead site for study, had received injections via spinal cord of the Isis compound, according to a UCL news release.

“It's the beginning of quite an important journey in Huntington's disease,” Sarah Tabrizi, Ph.D., the director of UCL’s Huntington's Disease Centre and the global chief clinical investigator for the trial, told the BBC. “It is clearly very early but this is a step forward.

“The preclinical work shows that if you lower production of the mutant protein then animals recover a large amount of motor function. Huntington's is a really terrible disease that blights families. I know a mother whose husband and three children were affected. This would have a massive impact [if it works].”

Sarah Tabrizi, Ph.D. (photo from University College London website)

Slowing or preventing the disease

The news comes just three months after Isis announced the official start of the trial, the first time HD patients are receiving a substance aimed to attack the genetic causes of the disease. Isis has partnered with the Swiss-based pharmaceutical giant Roche to facilitate the clinical trial and, if it’s successful, the marketing of the drug.

Isis officials were unavailable for comment on October 19 but the main scientist spearheading the development of ISIS-HTT_Rx, which signifies a medication for HD, commented in the UCL release.

“We designed ISIS-HTT_Rx to target the huntingtin gene and reduce the production of huntingtin protein, which is the known cause of the disease,” stated Frank Bennett, Ph.D., the Isis senior vice president for research. “This approach has the potential to prevent or slow the progression of this disease. If this first-in-human trial proves the drug is safe, we look forward to continuing our successful partnership with Roche to bring the drug to market.”

Dr. Bennett has previously described the drug, scientifically known as an antisense oligonucleotide (oligo), as a “laser-guided missile” targeting a “specific messenger RNA that causes a particular disease and kill it or take it out of the body so that you don’t produce that messenger RNA.”

Isis announced the details of the trial in August 2014 (click here to read more).

Frank Bennett, Ph.D., senior vice president for research at Isis Pharmaceuticals (photo by Dr. Ed Wild)

Safety and tolerability first

The Phase I trial involves patients at UCL and also at various sites in Canada and Germany. Across all sites, a total of about 36 patients will take part. Phase I trials focus primarily on the safety and tolerability of a drug. The study will also help determine the frequency and size of dosages for eventual Phase II and Phase III trials, which measure efficacy.

All of the volunteers have early stage HD. Because of the use of spinal taps to administer the drug and the highly experimental nature of the oligos, no non-HD-affected individuals are taking part as controls.

No announcements have yet been made about dosing of patients in Canada and Germany.

According to the UCL release, the ISIS-HTT_Rx is taking place in the new Leonard Wolfson Experimental Neurology Centre, a custom-built facility designed to accelerate innovative treatments for neurodegenerative diseases.

“The administration of the first doses of ISIS-HTT_Rx marks the Centre's first use as a phase 1 'first into human' trial facility, as well as the first time that an experimental drug has been given by spinal injection in the 156-year history of the National Hospital for Neurology and Neurosurgery, part of University College London Hospitals (UCLH) NHS Foundation Trust,” the release stated.

What’s next?

“The first volunteers have been treated without any immediate complications,” the scientist-written HD research site HDBuzz observed. “The next year or so will be a period of intense study of these trial volunteers to make sure that they don’t have unexpected complications from the treatment. They’ll also be examined for a range of measures of whether or not the drug is working, which will provide critical information for planning future HD gene silencing studies.”

Depending on the pace of recruitment, Phase I most likely will end in 2017. 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.

Historically, only ten percent of clinical trials ever result in a marketable drug.

Regardless, the HD community has crossed a significant threshold. Science has yet to produce an effective treatment for HD, as well as for Alzheimer’s, Parkinson’s, and other neurological disorders. HD could be the first.

Hope is palpable.

As a carrier of the deadly HD gene who lost his mother to the disease in 2006 and has tracked the Isis project since 2007, I am thrilled that our fellow HD community members have successfully made the first step in this historic clinical trial. They deserve our enthusiastic applause for volunteering.

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

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

Isis Pharmaceuticals, Inc., based in Carlsbad, CA, has launched its long-awaited clinical trial to test a drug designed to attack Huntington’s disease at its genetic roots.

In a July 21 press release, Isis said it had initiated a Phase I human clinical study of ISIS-HTT_Rx, its compound aimed at diminishing the symptoms of HD. HTT_Rx signifies a medication for HD. The disease is caused by a defect in both the huntingtin gene and protein, which are symbolized by the letters htt.

“ISIS- HTT_RX is the first therapy to enter clinical development that is designed to directly target the cause of the disease by reducing the production of the protein responsible for HD,” the release stated.

In partnership with Roche, the Switzerland-based pharmaceutical giant sharing costs of the typically expensive clinical trial, Isis thus becomes the first entity to use a gene-silencing technique in the attempt to stop HD.

“Although the toxic protein produced from the huntingtin (HTT) gene in HD patients has been a target of interest for many years, no therapies have advanced to clinical trials to treat the underlying cause of the disease,” Frank Bennett, Ph.D., Isis’s senior vice president of research, stated . “Our antisense technology has enabled us to discover and develop ISIS-HTT_Rx, the first therapeutic approach designed to treat the genetic cause of HD."

Frank Bennett, Ph.D., of Isis Pharmaceuticals (photo by Dr. Ed Wild)

A ‘significant milestone’

HTT_Rx is an antisense oligonucleotide, an artificial strand of DNA created by Isis to block the action of the RNA molecules that translate the huntingtin genetic code to make the huntingtin protein.

Involving about 36 early-stage HD patients at about six sites in Europe and Canada, the Phase I trial focuses on the safety and tolerability of HTT_Rx. According to an Isis spokesperson, the sites will start recruiting participants as early as in a few weeks.

Depending on the pace of recruitment, Phase I most likely will end in 2017. If Phase I is successful, a larger Phase II trial to test efficacy likely would take place in 2018. A successful Phase II trial would be followed by a Phase III trial. Together all three phases of a clinical trial program typically take at least five years.

Last August, scientists from Isis and CHDI Foundation, Inc., the nonprofit virtual biotech firm that funded the early stages of the Isis research starting in 2007, provided extensive details about the plans for the trial. (Click here to read more.).

“The initial development of this antisense drug for Huntington’s disease came out of a longstanding productive partnership between Isis and CHDI, and its advancement now to clinical trial is testament to Isis’ perseverance and scientific expertise,” CHDI president Robi Blumenstein stated in the press release. “It’s exciting that therapeutic candidates grounded in the biology of Huntington’s disease are finally making their way to clinical trial.”

“The initiation of the ISIS-HTTRx study is a significant milestone in the history of Huntington's disease research as this marks the first time a drug designed specifically for Huntington's patients has transitioned into the clinic,” George Yohrling, Ph.D., senior director for mission and scientific affairs for the Huntington’s Disease Society of America (HDSA), wrote in an e-mail. “My hope is that this study not only shows that the drug is safe, but serves as an informative beacon for all future huntingtin-lowering trials.”

Martha Nance, M.D., the director of the HDSA Center of Excellence at Hennepin County Medical Center in Minneapolis and a member of the executive committee of the Huntington Study Group, said that “it would be impossible to overstate the importance of this trial.”

“I am old enough to have grown up in the 1960s, swept up as a young child with the excitement of space exploration, and I remember, almost as clearly and importantly as the Apollo 11 mission that actually LANDED on the moon, the Apollo 8 mission over Christmas 1968, during which William Anders took the iconic picture of the earthrise over the moon,” Dr. Nance wrote in an e-mail. “There were several more steps, several more Apollo missions, before Neil Armstrong could jump off the ladder onto the moon. The ISIS study is the HD equivalent of the Apollo 8 mission.”

LaVonne Goodman, M.D., the founder of Huntington's Disease Drug Works, said that there are "high hopes and expectations" about the trial. "We celebrate those individuals with HD, heroes who are selflessly participating in this trial and all others, 'taking one for the team,'" she wrote in an e-mail.

“We’re very enthusiastic about the drug,” Dr. Bennett said in a 2014 interview.

As he put it previously, 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.”

The Isis-Roche partnership

According to the press release, with the initiation of the clinical trial, Isis – a small company – earned a $22 million milestone payment from Roche. To date, Isis has earned $52 million in upfront and milestone payments from the partnership. It can earn more as the project progresses, as well as royalties on potential sales.

Roche can exercise the option to license ISIS- HTT_Rx from Isis through the completion of the Phase 1 trial. If so, Roche will assume responsibility for global development, the acquisition of regulatory approvals, and marketing the drug.

The partnership is critical. Isis cannot alone afford to carry out a clinical trial. Drugs usually cost hundreds of millions of dollars to develop.

According to the press release, Isis’s drug projects include 38 drugs aimed at treating a wide range of diseases, among them cardiovascular disease, metabolic disorders, cancer, and severe and rare diseases, including neurological disorders such as HD.

A huge dose of hope

The announcement of the historic trial’s launch provides a huge dose of hope for the HD community.

Since the discovery of the huntingtin gene in 1993, scientists have published thousands of research papers on HD and identified hundreds of potential “targets” for treatments.

In recent years, scientists and drug companies have initiated an increasing number of clinical trials in the quest for effective treatments. However, to date none has proven successful in halting the disease.

A necessary leap

As seen in animal studies, the infusion of HTT_Rx into the brain has led to the disappearance of the HD-like symptoms.

Scientists warn that it’s a still a huge leap from animals to humans when it comes to testing drugs. Also, only about one in ten clinical trials results in a drug reaching the market.

Earlier this year prominent HD specialist Bernhard Landwehrmeyer, M.D., Ph.D., cautioned that it could still take decades for the gene-silencing approach to play an effective part in managing the disease.

“We should all be extremely excited and hopeful, but remember that there is a lot of work ahead for researchers, doctors, patients, and families before we will get to our moon, and no guarantee of success,” wrote Dr. Nance.

Nevertheless, the Isis-Roche trial is a major step. At a minimum, it will help answer key questions about the gene-silencing approach.

If it is successful in ameliorating symptoms, it could mean the beginning of the end of Huntington’s disease as a threat to the tens of thousands of families affected worldwide.

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Below see links to previous reports on Isis.

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

Also see coverage at HDBuzz by clicking here.

(Disclaimer: I hold a symbolic number of Isis shares.)