09.2018 | THE SCIENTIST 65za’s original developer, to test an ASO tar-
geting SOD1 in ALS.
The SOD1 ASO avoids many of the
pitfalls of previously proposed ALS treat-
ments: “ You know your target, you know
your mutation, you have a drug that works
at your mutation, and you actually have
readouts,” explains Jeffrey Rothstein,
director of the Robert Packard Center
for ALS Research at Johns Hopkins Uni-
versity. In mutant SOD1 mice, the ASO
knocks down overall protein levels and
improves survival and muscle strength;
currently, a Phase 1 multiple dosing trial
seeks to discern a similar effect in people.
“It could be the first domino to fall,” says
ALS TDI’s Perrin, potentially making way
for the development of ASOs for other ALS
targets. Biogen and WAVE Life Sciences
are developing C9orf72-targeting antisense
oligonucleotides that are expected to enter
clinical trials soon.
Another promising approach, gene
therapy, also received a boost in the ther-
apeutics industry, following the 2009 dis-
covery that the viral vector adeno-associated
virus 9 (AAV9), unlike most vehicles, could
cross the blood-brain barrier (Nat Biotech,
27:59–65). Gene-therapy company AveXis,
recently acquired by Novartis, pairs AAV9
with short hairpin RNAs targeting SOD1 in
its ALS therapy AVXS-301. Like the SOD1
ASO, AVXS-301 extends life and improves
motor function in SOD1 mice. It’s cur-
rently in preclinical safety testing, and
AveXis plans to file an investigational new
drug application (IND) by early 2019, says
CSO Brian Kaspar. He says he hopes that
it might even be useful in patients without
SOD1 mutations who nevertheless have
abnormal levels of the protein, and that, if
successful, AAV9 could become the basis
for ALS therapies targeting other genes.
Rather than altering genes, the cell ther-
apy NurOwn, developed by New York City–
based BrainStorm Cell Therapeutics, consists
of cells differentiated from patients’ own bone
marrow-derived mesenchymal stem cells
(MSCs). These MSCs are thought to produce
protective neurotrophic factors and immuno-
modulatory molecules that both help main-
tain motor neuron function and reduce
inflammation, explains Chief Medical Offi-
cer and COO Ralph Kern. A Phase 3 trial
aims to enroll 200 patients, half of whom will
receive three spinal injections of these cells
at two-month intervals; results are expected
in early 2020. However, despite positive
reported results to date, some remain skep-
tical. “The hype about stem cells is masking
the unbelievable ignorance about the biol-
ogy of these cells,” says Rothstein, who argues
that it would be better to administer specific
growth factors. Kern counters that the mix of
factors provided by the cells is critical for tar-
geting different types of neurons and differ-
ent patient groups.Designing better trials
Both Kern and Jean Hubble, VP of medical
affairs at Mitsubishi Tanabe Pharma Amer-
ica, the maker of the recently approved eda-
ravone, point to a new strategy to develop
promising ALS therapies: restricting clini-
cal trials to patients with rapidly progress-
ing disease, which allows scientists to more
easily determine the therapy’s impact. That
approach might lead to disappointment for
some patients in the short term, but MGH’s
Cudkowicz thinks that more-carefully tar-
geted trials are ultimately more likely to
identify effective drugs for a broader swath
of patients (see “Clinical Matchmaker,” The
Scientist, June 2015).
To get there, some ALS researchers are
pursuing large-scale studies to develop bet-
ter ways to stratify their patients and quan-
titatively track disease progress. For exam-
ple, through its precision medicine program,
which has enrolled 700 patients, ALS TDI
uses data from accelerometers strapped to
patients’ limbs to monitor disease progres-
sion, says Perrin. The initiative also col-
lects standard Functional Rating Scale–
Revised results, voice recordings, full genome
sequences, and RNA and protein biomark-
ers, which are made available to each patient
through a secure online portal. A separate,
multi-institution effort, Answer ALS, is
beginning to spot key differences betweenpatient groups based on the 8 billion data
points (on motor function, breathing, speech,
speed of thought, and molecular profiles of
individualized iPS cells) collected from each
of the 780 patients enrolled so far, says Roth-
stein, who is involved in the program.
Both efforts rely on partnerships
with big-data experts: ALS TDI is work-
ing with Google and the Broad Institute,
while Answer ALS links multiple medi-
cal centers, IBM Watson, and research-
ers at MIT. The breadth and scale of
these alliances highlight another new
trend: the rise of large collaborative
teams in ALS spanning basic research,
the clinic, and nonprofits. “There’s much
more cohesion, and the academic-industry
partnerships are extremely vibrant,” says
Lucie Bruijn, chief scientist of the ALS
Association, a nonprofit aimed at eradi-
cating the disease.
That’s not to say there won’t be fail-
ures. In the past year, those include Cyto-
kinetics’s tirasemtiv, a small-molecule
no longer in development after a Phase 3
trial failed due to tolerability issues and lack
of efficacy; Neuraltus’s NP001, a proprie-
tary formulation of sodium chlorite, which
missed clinical endpoints for efficacy in
Phase 2 trials; and AB Science’s masitinib,
an anti-inflammatory, small-molecule tyro-
sine kinase inhibitor, which was rejected by
European regulators on the basis of uncon-
vincing trial data.
Overall, however, the explosion of
biological and technical advances in
the ALS therapy field—as well as grow-
ing connections between the players—
have led to general optimism that future
drug development might finally be able
to avoid past pitfalls.
“ALS has been labeled incurable, but
I think it will be curable with the right
strategy,” says the University of Arkan-
sas’s Kiaei. Steve Perrin agrees: “Many of
the things that are in clinical development
today are better shots on goal than they
were a decade ago.” gJenny Rood is a freelance writer in Cam-
bridge, Massachusetts, and the senior
development writer at the Broad Institute
of MIT and Harvard.I think it will be curable with
the right strategy.
—Mahmoud Kiaei, University of Arkansas