Editorials
Incremental Gains in the Battle against ALS
Michael Benatar, M.D., Ph.D., and Michael P. McDermott, Ph.D.
In this issue of the Journal, Paganoni et al.1 de-
scribe the results of a well-designed, multi-
center, phase 2 trial of a fixed-dose combination
of 6 g per day of sodium phenylbutyrate and 2 g
per day of taurursodiol, also known as taurourso-
deoxycholic acid, in patients with definite amyo-
trophic lateral sclerosis (ALS) according to El
Escorial criteria who were enrolled within 18
months after symptom onset. The trial showed
a difference of 0.42 points per month between
the active-drug group and the placebo group in
the mean rate of change in the total score on the
Amyotrophic Lateral Sclerosis Functional Rating
Scale–Revised (ALSFRS-R; range, 0 to 48, with
higher scores indicating better function) over a
24-week period, representing an approximately
25% drug-associated slowing of the rate of func-
tional decline. The ALSFRS-R is the most com-
monly used clinical outcome measure in ALS
clinical trials, with patients typically declining
by approximately 1 point per month on average.2
Results regarding secondary clinical and bio-
marker outcomes, assessed in a prespecified
hierarchy (rates of decline in isometric muscle
strength, plasma phosphorylated axonal neuro-
filament H subunit [pNF-H] level, and the slow
vital capacity; the time to death, tracheostomy,
or permanent ventilation; and the time to death,
tracheostomy, permanent ventilation, or hospi-
talization), did not differ significantly between
the two groups.
The trial cohort was effectively enriched for
patients with more rapidly progressive disease,
as evidenced by the mean ALSFRS-R slope of
−1.66 points per month in the placebo group.
The strategy of focusing trial eligibility on a
more homogeneous subgroup of the population
of patients with ALS with faster progressing
disease builds on experience and lessons learned
from previous studies3,4 but also raises questions
about generalizability to the broader population
of patients with ALS.5 Although the patients who
were enrolled in the trial may not be biologically
different from the broader population of patients
with ALS, the magnitude of therapeutic effect
may be smaller in the latter.
n engl j med 383;10  nejm.org  September 3, 2020
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Negative results from many previous ALS trials
have been difficult to interpret given the lack of
informative biomarker data. This trial included
the level of pNF-H, a biomarker of axonal degen-
eration, as a secondary outcome measure. The
interpretive challenge here is the discordance
between an observed clinical benefit and the
absence of an effect on a promising biomarker
of potential pharmacodynamic effect in ALS and
other motor neuron diseases.6-8 It is unclear
whether this represents an insensitivity of the
plasma biomarker to treatment effect, the fact
that longitudinal changes in the level of pNF-H
(known to have a highly right-skewed distribu-
tion6) appear to have been modeled with the use
of raw rather than log-transformed data, or a
harbinger that sodium phenylbutyrate–taururso-
diol has limited effect on the underlying neuro-
degenerative process.
A key question is how patients with ALS and
their treating physicians should interpret these
data. The observed therapeutic effect is modest,
and although formal comparisons with previous
studies of taurursodiol9 and sodium phenylbu-
tyrate10 alone are difficult, it is unclear whether
either taurursodiol alone or sodium phenylbuty­
rate alone might yield similar benefits or wheth-
er the doses were the most effective. One ongo-
ing phase 3 trial of tauroursodeoxycholic acid
alone (ClinicalTrials.gov number, NCT03800524),
with results expected in mid-2021, may provide
partial answers. Additional uncertainty emerges
from the randomization error (an error in the
distribution of kits resulted in the first 17 par-
ticipants being assigned to receive the active
drug and the next 9 being assigned to receive
placebo, although this did not appear to affect
the results), the group imbalance in the frequency
of edaravone use, and the lack of convincing sup-
porting evidence from secondary clinical and
biomarker outcomes. We also note that approxi-
mately 19% of the patients in the active-drug
group discontinued the intervention owing to
adverse events.
In light of the residual questions about effi-
cacy and the ability of patients to continue tak-
979
 Editorials

ing the drug, we agree with the authors’ conclu- interpretation of the trial results and also in-
sion that “[l]onger and larger trials are necessary form development efforts for future therapy.
to evaluate the efficacy and safety of sodium Disclosure forms provided by the authors are available with
phenylbutyrate–taurursodiol in persons with ALS.” the full text of this editorial at NEJM.org.
We hope that the sponsors and investigators will
From the University of Miami Miller School of Medicine, Miami
follow up on these tantalizing preliminary data (M.B.); and the University of Rochester Medical Center, Roch-
with a confirmatory phase 3 trial. It would be ester, NY (M.P.M.).
valuable for future trials to have broader eligibil-
1. Paganoni S, Macklin EA, Hendrix S, et al. Trial of sodium
ity criteria but still include a prespecified pri- phenylbutyrate–taurursodiol for amyotrophic lateral sclerosis.
mary efficacy analysis in the subgroup of pa- N Engl J Med 2020;​383:919-30.
tients who met the eligibility criteria used in the 2. Daghlas I, Lever TE, Leary E. A retrospective investigation of
completed phase 2 trial. Such an approach would the relationship between baseline covariates and rate of ALSFRS-R
decline in ALS clinical trials. Amyotroph Lateral Scler Fronto-
yield a balance between scientific rigor and the temporal Degener 2018;​19:​206-11.
need to inform the generalizability of results 3. Benatar M, Wuu J, Andersen PM, et al. Randomized, double-
blind, placebo-controlled trial of arimoclomol in rapidly pro-
and would also be responsive to the patient voice gressive SOD1 ALS. Neurology 2018;​90(7):​e565-e574.
that trials be more inclusive. Of course, wide- 4. The Writing Group on behalf of the Edaravone (MCI-186)
spread adoption of this drug in the near future ALS 19 Study Group. Safety and efficacy of edaravone in well
could limit confirmatory trials, especially given defined patients with amyotrophic lateral sclerosis: a ran-
domised, double-blind, placebo-controlled trial. Lancet Neurol
the availability of both taurursodiol and sodium 2017;​16:​505-12.
phenylbutyrate as individual agents. 5. Hardiman O, van den Berg LH. Edaravone: a new treatment
There has been understandable frustration for ALS on the horizon? Lancet Neurol 2017;​16:​490-1.
6. Benatar M, Zhang L, Wang L, et al. Validation of serum neu-
with the slow pace of development of therapy for rofilaments as prognostic and potential pharmacodynamic bio-
ALS. Despite dozens of trials, few pharmaco- markers for ALS. Neurology 2020;​95(1):​e59-e69.
logic agents have emerged that affect functional 7. Miller T, Cudkowicz M, Shaw PJ, et al. Phase 1–2 trial of
antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med
decline or survival — and all only modestly so. 2020;​383:​109-19.
Although the effects of sodium phenylbutyrate– 8. Darras BT, Crawford TO, Finkel RS, et al. Neurofilament as
taurursodiol are similarly modest, the incremen- a potential biomarker for spinal muscular atrophy. Ann Clin
Transl Neurol 2019;​6:​932-44.
tal gains that they provide in the battle against 9. Elia AE, Lalli S, Monsurrò MR, et al. Tauroursodeoxycholic
ALS are a cause for hope. As we collectively work acid in the treatment of patients with amyotrophic lateral sclero-
toward the development of therapies that not sis. Eur J Neurol 2016;​23:​45-52.
10. Cudkowicz ME, Andres PL, Macdonald SA, et al. Phase 2
only slow functional decline but also affect the study of sodium phenylbutyrate in ALS. Amyotroph Lateral Scler
underlying biology of disease, valid biomarkers 2009;​10:​99-106.
of target engagement and pharmacodynamic ef- DOI: 10.1056/NEJMe2021144
fect are important, since these are likely to aid Copyright © 2020 Massachusetts Medical Society.

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