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-HTTRx. 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-HTTRx 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-HTTRx 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.

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.

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