Ionis Phase I Huntington’s disease trial at halfway mark: ‘No surprises so far’ means good news

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At its halfway mark, Ionis Pharmaceuticals’ historic Huntington’s disease Phase 1 gene-silencing clinical trial is on track to finish as scheduled in late 2017, company officials said in an interview on September 26.
“What we can say is that the trial is going well,” said Frank Bennett, Ph.D., Ionis senior vice president of research and the franchise leader for the company’s neurology programs.
Dr. Bennett added that no “issues” have arisen so far in the Phase 1 safety and tolerability study of its drug IONIS-HTTRx in patients with early HD. IONIS-HTTRx aims to reduce the production of huntingtin protein in brain cells. This approach, if it advances to Phases 2 and 3, may have the potential to slow, halt or perhaps even reverse the progression of HD symptoms. The trial began in September 2015, with participants in England, Germany, and Canada.
The Ionis HD team explained that the Phase 1 trial is not assessing the drug’s efficacy. Each patient in the trial receives the drug for just three months – not long enough to gauge any impact on symptoms.
Furthermore, the trial is “double-blinded”: trial participants, trial administrators, and Ionis scientists do not know who is getting the drug or a placebo. This insures that bias and other external factors don’t affect the trial results.
Nevertheless, the absence of problems is good news.
No surprises have occurred to date, commented Anne Smith, Ph.D., the Ionis director of clinical development and the individual responsible for the day-to-day management of the trial.
“It’s blissfully quiet,” Dr. Smith said. “You don’t want surprises in clinical trials. Most surprises in safety trials are bad surprises. This one is surprise-free to date.”
Also, trial participants had no difficulties with the delivery of the drug via injections into the spine (so-called intrathecal injections), added Roger Lane, M.D., the Ionis vice president for neurology clinical development and one of the designers of the trial.
Watch my reaction after the interview at Ionis headquarters on September 27 in the video below.
Phase 2 could start in 2018
“We’re continuing to enroll patients in the study,” Dr. Bennett said. A total of 36 patients divided into four cohorts – each subsequent cohort taking a higher dose of IONIS-HTTRx – will participate in the trial.
Ed Wild, M.D., Ph.D., one of the administrators of the trial at University College London, announced in June at the annual convention of the Huntington’s Disease Society of America in Baltimore that the third cohort had received permission to receive the drug. (Click here to watch a video of Dr. Wild’s presentation.)
“This is a new therapy, and we want to make sure that we’re doing no harm,” Dr. Bennett emphasized. “Everything is geared towards the safety of the drug at this stage.”screenshot-2016-10-20-10-23-40
If Phase 1 confirms safety and tolerability, a year-long Phase 2 trial to measure efficacy in a larger number of patients likely would start in 2018, Dr. Bennett said.
Infants on an Ionis SMA drug living longer
The update provided by the Ionis HD team came in the wake of further validation of the company’s scientific approach.
Ionis makes antisense oligonucleotides (ASOs, artificial strands of DNA) that alter the expression of genes and can therefore potentially serve as treatments for genetic diseases. On August 1, Ionis and its partner Biogenactually halted a Phase 3 trial of an Ionis ASO (nusinersen) in infants with spinal muscular atrophy (SMA) because the drug, which increases the level of a key protein, was working so well.
On September 27, Biogen announced that it had completed its application for priority review of nusinersen by the U.S. Food and Drug Administration (FDA).
Like HD, SMA is a genetic neurodegenerative disorder. It primarily affects children, who “end up becoming paralyzed over time,” Dr. Bennett explained, and become vulnerable to respiratory infections or other diseases. Children diagnosed with the most severe form of SMA generally live less than a year, he said. In a less severe form of SMA, children lose the ability to walk over time as they grow up, Dr. Bennett added.
“I think the surprising thing that we found – and this was evidence early in the program – was that we didn’t just stop the decline in these patients, but we actually reversed it,” Dr. Bennett said. “That was really unexpected. I should say that they’re not cured of the disease, but they’re doing much better now than expected. They are surviving longer based on the natural history of the disease.”
These results demonstrated the body’s capacity to mend once the cause of a disorder is removed, he observed.
“We’re hopeful that will also occur in Huntington’s,” Dr. Bennett affirmed. “We have to demonstrate it, but I think there’s a precedent now in these neurodegenerative diseases. If you remove the insult or the toxicity, you can recover function.”



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AICH ROMA ONLUS