Despite
the disappointing clinical trial results reported last week by Roche and
Wave Life Sciences, Huntington’s disease drug researchers see an upside: they are using the data collected to achieve new insights, offering
renewed hope of effective treatments.
The news of these setbacks produced one of
the most heartbreaking moments of the last several decades for
the HD community and researchers.
“That kind
of news, I hope it’s okay to say: it sucks!” said Robert Pacifici, Ph.D., the
chief scientific officer for CHDI Foundation, Inc., of the Roche and
Wave trial data. “All of us who hold out so much hope and recognize that there
are so many families who so desperately are waiting for much needed relief and
therapies – it knocks the wind out of you.”
The
companies made their first formal scientific presentations of their data at the
start of the CHDI-sponsored 16th Annual HD Therapeutics Conference, held
virtually from April 27-29. A nonprofit virtual biotech, CHDI focuses solely on
developing Huntington’s therapies.
Roche
confirmed that its drug tominersen failed to alleviate symptoms in its Phase 3
clinical trial; patients receiving the highest of two possible doses may have
done even slightly worse than those on placebo. Two early-stage Wave trials
failed to meet the goal of reducing the amount of mutant huntingtin protein in
the trial participants – an objective already achieved by Roche in an earlier tominersen
trial. (Click here to read more.)
Dr.
Pacifici offered his assessment of the Roche and Wave data and the state of HD
drug research in a wide-ranging, 46-minute Zoom interview with me after the
close of the event.
Dr. Robert Pacifici moderates panel discussion of huntingtin-lowering clinical trial results with Dr. Vissia Viglietta of Wave Life Sciences and Dr. Scott Schobel of Roche (screenshot by Gene Veritas, aka Kenneth P. Serbin)
Gaining
perspective
“My
reaction though, now that I’ve come back down to earth, is really not one of
surprise,” Dr. Pacifici said. “Drug discovery, as we’ve discussed many times,
is a really tough business. The probability of success on any given endeavor is
incredibly low.”
Dr.
Pacifici used a baseball metaphor to explain: “How often does the first batter
get up to the plate and hit a grand slam home run? A grand slam, never, because
you need to load up the bases with three people. Even a home run is incredibly
rare.”
The “name
of the game” in discovering effective treatments is to carry out as many trials
as necessary, “doing it well, failing, but making it a good failure that we can
learn from so that subsequent efforts have a much higher chance of success,”
Dr. Pacifici explained. “And we continue to snowball and build on that so that
we can learn the things to do better, the things that we can do differently, or
the things that we should stop doing altogether because we now have confirmed
that those are not viable lines of investigation.”
The
accumulation of experience through research and clinical trials, including the crucial
participation of patient volunteers, has produced “an incredibly positive
thing,” Dr. Pacifici observed.
“Look at
how the field has matured,” he said. In the past, scientists would have kept a
trial running for three years, waiting for patient improvement, only to
discover that “the drug really didn’t even have a chance of working” because it
hadn’t done what it was “tasked with doing, which is lowering huntingtin
levels.”
Now the
process is moving “faster” and is “better informed,” Dr. Pacifici said.
Watch the
entirety of my interview with Dr. Pacifici in the video below.
Huntington's disease drug research now a 'mature field' from Gene Veritas on Vimeo.
Huntingtin
lowering still in the running
Dr.
Pacifici commented on the critical topic of lowering (reducing) the mutant huntingtin
protein, the first strategy aimed at HD’s genetic cause. Scientists believe
that the mutant protein is a main driver of the disease. In mouse studies,
lowering that protein led to a disappearance of symptoms, and, beginning with
the Roche trial, researchers have sought to achieve similar results in humans.
Thus, until now, lowering mutant huntingtin has been seen as the potentially most promising path
to a treatment.
Both Roche
and Wave used a type of drug known as an antisense oligonucleotide (ASO), an
artificial strand of DNA. Other firms and labs are also investigating ASOs.
“When two
of those things don’t move forward simultaneously, it’s perfectly reasonable to
ask the question, ‘Well, is this one of those times where we’ve learned that
this approach is not going to work?’” Dr. Pacifici asked. “I can say
unequivocally that that’s not yet the case. There are just too many things that
factor into how a drug needs to do its job that remain unanswered.”
He said
that possible key factors affecting the outcomes of the Roche and Wave trials
include the stage of disease of the participants, the concentration of the drug
tested, and the proper distribution of the drug within the brain. The
particular characteristics of the drugs selected could have also impacted the
outcome, he added.
Another
possible explanation involves the design of the trials, the techniques for
measuring patient response, and biomarkers (signs of disease and a drug’s
effects).
In
addition, even though Roche’s tominersen reduced the level of mutant huntingtin
protein in trial volunteers’ cerebrospinal fluid, researchers still do not know
whether the samples of protein actually came from the brain and, if so, cells
relevant to HD, Dr. Pacifici cautioned. Scientists also lack other critical
details about those samples; for example, they could be fragments, he said.
Crucially,
the “interim analysis” of the Roche data at the Therapeutics conference did not
demonstrate whether lowering huntingtin can help people feel, function, or
survive better, Dr. Pacifici observed.
Even a
“whisper of efficacy” would have validated the huntingtin-lowering approach and
“prepared the path for subsequent trials with gusto and confidence,” he
continued, adding, however, that “the opposite is not true. We still have great
hopes that this is a viable mechanism of action.”
Wave plans
to start a trial of a third ASO later
this year. Roche has also stated that it will continue to explore drugs for HD.
Exploring
other avenues
Because the
effectiveness of huntingtin-lowering remains an open question for the field,
Dr. Pacifici renewed his call to redouble and diversify drug-hunting efforts.
Dr.
Pacifici noted that other potential huntingtin-lowering approaches are in the
works using non-ASO compounds, while others propose different methods of
delivery, including a pill. In the Roche and Wave trials, participants received
the drug via spinal tap.
“If we
were in a fantasy world of the 20th new treatment for Huntington’s coming, you
would worry about things like convenience: ‘I’d like to have a pill instead of
an injection,’” Dr. Pacifici said. “‘I’d like to have a pill I can take once a
day. I’d like to have a small pill that’s easy to swallow.’”
However,
Dr. Pacifici observed, “we’re not at that stage yet.” Even so, “very critical
advantages” exist in exploring different modes of delivery, he said.
Indeed, another
possibility emerged at the conference. A scientist from pharmaceutical giant
Novartis presented research on its drug branaplam, a pill used to
treat spinal muscular atrophy (SMA), which causes severe muscle weakness in
children. Novartis researchers discovered that Branaplam also reduced the
amount of the huntingtin protein in a study of SMA patients. Novartis plans a
trial of branaplam in HD patients, with details expected in the coming weeks
and over the summer (click here to read
more).
Like other
so-called small-molecule drugs, branaplam becomes distributed very evenly
across the whole body, including the brain, whereas a drug like an ASO tends to
concentrate where it is administered, Dr. Pacifici explained. He added that small-molecule
drugs can be dosed “creatively” – for example, weekly instead of daily – to
maximize the “beneficial effect” and allow the person a rest from the drug.
(I will
explore the quest to develop this type of HD drug in a future article.)
Dr. Rajeev Sivasankaran of Novartis presents data demonstrating the effect of the drug branaplam on huntingtin RNA in a study of spinal muscular atrophy patients (screenshot by Gene Veritas).
Sharing
knowledge rises all boats
Dr.
Pacifici emphasized that success in the fight against HD ultimately depends on
the sharing of scientific information – even negative research results that
private companies are loathe to reveal to protect their egos and their stock
prices.
He cited
the presentation by featured speaker Aled Edwards, Ph.D., the founder and CEO of the
Structural Genomix Consortium, which practices and advocates
for open sharing of scientific information, particularly as it applies to
protein science, chemical biology and drug discovery. Dr. Edwards spoke on “HD
drug discovery in the public domain – a model for CHDI.”
“I think
the HD field will benefit by everybody realizing how difficult this problem is,”
Dr. Pacifici concluded. “It’s not giving up a competitive advantage by being
transparent about what happened. It’s sharing data. That knowledge rises all
boats. Everybody needs to know about these things.”
Sharing of
data and other knowledge has also been one of CHDI’s trademarks as a nonprofit.
Dr. Pacifici pointed to specifics: knowledge about the disease, potential
treatments, biomarkers, and clinical outcome measures (the techniques for
measuring patient response).
With such
sharing, he asserted, everybody will have an increased chance of success.
Refusing
to do so will “doom us to the same failure we see in other neurodegenerative
fields that have outspent us and been at this a lot longer than we have.”
