Researchers revealed impressive, if not conclusive, additional information at CHDI Foundation's 13th Annual Huntington’s Disease Therapeutics Conference yesterday regarding the historic Ionis HD clinical trial: the drop in mutant protein observed in the cerebral spinal fluid (CSF) of participants corresponds to as much as an 85 percent decrease in the cortex of the brain, head physician Dr. Sarah Tabrizi announced.
It’s the
best news the HD community has received since the publication of the research
confirming the discovery of the gene 25 years ago this month. As scientists
have observed, it’s also a major step for disease and drug research in general.
“The
magnitude of mutant huntingtin [protein] reduction observed exceeds the effect
needed for disease modification in animal models,” Dr. Tabrizi, of University
College of London (the lead clinical trial site), told an audience of some 350
scientists, drug company representatives, and HD advocates at the conference in
Palm Springs, CA.
Dr. Sarah Tabrizi presenting the IONIS-HTTRx trial data on March 1, 2018 (photo by Gene Veritas, aka Kenneth P. Serbin)
Ionis
officials announced in December that the Phase 1/2a trial for the
gene-silencing drug IONIS-HTTRx “substantially exceeded our
expectations” in safely reducing the mutant
huntingtin in the CSF.
For the
first time, Dr. Tabrizi’s presentation (plus an Ionis press release)
specified the level of huntingtin reduction.
During the
clinical trial, participants received the drug via spinal injections, and doctors
measured the drug’s ability to reduce the protein by extracting CSF samples.
IONIS-HTTRx
lowered mutant huntingtin an average of 40 percent, with a maximum reduction of
60 percent. As Dr. Tabrizi explained, projecting from the numerous, painstaking
animal studies done by Ionis, the reductions in the cortex range from 55-85
percent.
Frank Bennett, Ph.D., Ionis senior vice president of research and the franchise leader for neurology programs (left) and Anne Smith, Ph.D., Ionis director of clinical development (middle), confer with Dr. Tabrizi moments before the two women's historic presentation of the IONIS-HTTRx trial data. Dr. Bennett led the Ionis efforts to develop the drug (photo by Gene Veritas).
The cortex
– along with the striatum, which is critical to motor control and managing the reward
system – is the area of the brain most affected by HD. It is the most developed area of
the brain, the source of thought and language, abilities severely hampered by
HD.
Watch Dr.
Tabrizi in the short video excerpts below explain this data and thank the 46
brave clinical trial volunteers and the many others involved in the effort. I
also recommend watching the full video – which includes further trial data and a helpful overview of the project by Anne Smith, Ph.D., of Ionis – by clicking here.
The plans for RG6042, the drug’s
new name
The presentation
by Drs. Smith and Tabrizi – the first public presentation of the trial data –
can perhaps help inspire the HD community and researchers to become engaged in
the next, crucial step: testing the drug’s efficacy.
Based
on its partnership agreement with Ionis, Swiss pharmaceutical giant Roche, which now holds the license to the drug, will carry out a longer trial
with hundreds of participants, including sites in the U.S.
The main question: will symptoms of this progressive, deadly disease stabilize, or even be reversed?
In an
interview at the conference, Roche officials told me that – as Ionis had
indicated – the company would take the unusual step of skipping a Phase 2 trial
(testing efficacy for the first time) and going directly to a Phase 3 (confirming
efficacy in hundreds, or more, participants).
They
pointed to the excellent results of the Phase 1/2a trial; Ionis’ superb
development of the drug; the nonprofit CHDI’s expertise and leadership; and the
enthusiasm from – and urgent need of – the HD community.
Roche has
officially changed the name of IONIS-HTTRx to RG6042. “R” stands for
Roche, and “G” for Genentech, a major U.S.-based pharmaceutical company
acquired by Roche in 2009 for $46.8 billion. The number 6042 is a standard drug
number assigned by the company. If Phase 3 is successful, a drug issued for commercial
sale will get a brand name.
All
U.S-based Roche personnel and products still use the name Genentech.
Roche has
not yet determined a start date or timeline for Phase 3. I will provide a
detailed report on the interview and Roche’s plans, and also my personal
reactions to the conference, in upcoming articles.
Members of the Roche HD clinical trial team watch Dr. Tabrizi's presentation. From left to right, Scott
Time for excitement, but also
caution
CHDI Chief
Scientific Officer Robert Pacifici, Ph.D., called the results of the Ionis trial
“incredibly exciting.”
However,
he also cautioned the HD community.
“Drug
discovery is a really time-consuming and inefficient process, and, sadly,
fraught with many failures,” Dr. Pacifici said. “The first time you put
something into people, no matter how prepared, you never know whether it’s
going to be safe and well-tolerated. What the initial trial showed was that at
those doses, with the route of delivery, with that population of folks, it is
indeed safe and well-tolerated. (If it wasn’t, it would stop in its tracks.) Once
you get to this stage, a lot of the uncertainty about timelines goes away.
“This is
really the time to be incredibly careful and incredibly deliberate. It’s going
to take a while now to orchestrate the Phase 3 trial. That’s the pivotal trial
that tells you whether or not the drug works.”
Everything
needs to be done “by the book” to get a really “conclusive result,” he added.
If the
trial fails, it will still provide scientists and physicians with guideposts
for future research and trials, he said.
“We owe a
huge debt of gratitude to those patients who signed up for that initial trial,”
Dr. Pacifici concluded. “It’s going to require not only more of that type of
participation, but a lot of patience.”
You can
watch my interview with Dr. Pacifici about the conference and the Ionis trial
in the video below.
* * *
Ionis
hosted a live webcast at 11 a.m. Eastern Time today. A webcast replay,
including slides with clinical trial data, are available by clicking here.
For detailed
coverage of the HD conference presentations, visit hdbuzz.net.
Visit my Vimeo album, to be periodically updated in the coming weeks, for other presentations and interviews at the conference.
(Disclosure: I hold a symbolic
amount of Ionis shares.)
1 comment:
My daughter has HD and I was wondering what the process was for her to participate in a clinical trial
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