Phenylbutyrate

Sodium Phenylbutyrate–Taurursodiol for ALS

to the editor: Paganoni et al. (Sept. 3 issue)1 report that in their trial, the benefit of sodium phenylbutyrate plus taurursodiol was not materi- ally affected by a drug-distribution error that led to the first 17 patients receiving active treatment. However, in their small trial, the error may have contributed to the improbable imbalance in edara- vone use between the sodium phenylbutyrate– taurursodiol group and the placebo group (25% and 50% of patients, respectively), because edara- vone became available only after the trial had started. In the trial, edaravone use detracted from the treatment effect of the trial drug. This could reflect a chance finding. However, the European Medicines Agency has concluded that the risks associated with edaravone infusions outweigh the benefits in patients with amyo- trophic lateral sclerosis (ALS),2 and in my opin- ion, edaravone infusions are ineffective at best and more usually harmful.3,4
For whatever reason, when edaravone use is controlled for, the results of the primary analy- sis in this trial no longer reach significance at the 0.05 level. The imbalance in edaravone use between the groups was unexpectedly large and was related in part to protocol deviation. There- fore, to temper expectations, it may be prudent to moderate the conclusions.
John Turnbull, M.D., Ph.D.
McMaster University Hamilton, ON, Canada [email protected]
No potential conflict of interest relevant to this letter was reported.
Paganoni S, Macklin EA, Hendrix S, et al. Trial of sodium phenylbutyrate–taurursodiol for amyotrophic lateral sclerosis. N Engl J Med 2020;383:919-30.
Radicava: withdrawal of the marketing authorisation appli- cation. European Medicines Agency, May 29, 2019 (https://www
.ema.europa.eu/en/medicines/human/withdrawn-applications/ radicava).
Turnbull J. Reappraisal of an ALS trial: unaccounted proce- dural risk. Lancet Neurol 2020;19:717-8.

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Correspondence

Turnbull J. Is edaravone harmful? (A placebo is not a con- trol.) Amyotroph Lateral Scler Frontotemporal Degener 2018;19: 477-82.
DOI: 10.1056/NEJMc2030710

to the editor: As Paganoni and colleagues cor- rectly state, the study by Cudkowicz et al.1 estab- lished only the safety of sodium phenylbutyrate in a 20-week trial, and no significant functional improvements in the rate of disease progression were detected. In contrast, Elia et al.2 investigat- ed the efficacy of tauroursodeoxycholic acid (TUDCA, also called taurursodiol) alone. During that 54-week trial, the same taurursodiol dose was administered as in the study by Paganoni et al. (1 g twice daily). Taurursodiol showed clin- ical benefits over placebo with respect to the rate of disease progression (as measured with the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised) that were similar to those report- ed by Paganoni et al. with a sodium phenylbuty- rate–taurursodiol combination (between-group difference in the rate of change in total score,
0.41 points per month over 54 weeks and 0.42
points per month over 24 weeks, respectively).
Could this remarkable similarity in clinical benefits alter the conclusions of the trial by Paganoni et al. and suggest that tauroursodeoxy- cholic acid is the active ingredient?
Joachim Herz, M.D. Olaf Stüve, M.D.
University of Texas Southwestern Medical Center Dallas, TX
[email protected]
No potential conflict of interest relevant to this letter was reported.
Cudkowicz ME, Andres PL, Macdonald SA, et al. Phase 2 study of sodium phenylbutyrate in ALS. Amyotroph Lateral Scler 2009;10:99-106.
Elia AE, Lalli S, Monsurrò MR, et al. Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclero- sis. Eur J Neurol 2016;23:45-52.
DOI: 10.1056/NEJMc2030710

the authors reply: In reply to Turnbull: To ad- dress the concern of whether the randomization error at the start of the trial may have resulted in the imbalance in edaravone use, we reviewed the records of the first 17 participants who were ran- domly assigned to receive sodium phenylbutyrate– taurursodiol; 47% (8 of 17) received edaravone, which is similar to the percentage of patients who received edaravone in the placebo group (50%). The use of edaravone in our trial was dependent on site practice and reimbursement procedures; the imbalance is likely to have been due to chance
rather than to the randomization issue. With re- gard to the effect of edaravone use on our findings overall, prespecified sensitivity analyses were used to assess the effect of concomitant use of riluzole, edaravone, or both on efficacy outcomes. These sensitivity analyses assess for positive or negative synergistic effects of concomitant medication use. They are not designed to provide independent, post hoc inference regarding the presence or ab- sence of an effect of sodium phenylbutyrate– taurursodiol. There was no evidence of positive or negative synergistic effects in any of these three analyses, including the analysis of edaravone use. Thus, these sensitivity analyses do not alter our finding of a significant benefit in the prespecified primary analysis.
Herz and Stüve highlight the fact that our
study was not designed to assess the contribution of the individual components of AMX0035 (sodi- um phenylbutyrate–taurursodiol). The trial by Cudkowicz et al.1 was an open-label trial with intrapatient sequential dose escalation of sodium phenylbutyrate. In the absence of a control group, the results did not provide evidence for or against clinical efficacy. Herz and Stüve also reference the clinical benefit of taurursodiol in the trial by Elia et al.2 as being consistent with the benefit of so- dium phenylbutyrate–taurursodiol seen in our trial. Several features of the trial by Elia et al. complicate a comparison with our trial, including the small sample size, the different duration of follow-up, the use of a lead-in period, the enroll- ment of a different patient population (e.g., ex- cluding patients with bulbar onset), the fact that the trial was conducted in a different country (Italy), the differing use of ALS therapies, and the use of different statistical models (analysis of vari- ance with last observation carried forward). We do not believe that a meaningful head-to-head comparison can be made between the two trials.
Sabrina Paganoni, M.D., Ph.D. Merit E. Cudkowicz, M.D.
Massachusetts General Hospital Boston, MA [email protected]
Since publication of their article, the authors report no fur- ther potential conflict of interest.
Cudkowicz ME, Andres PL, Macdonald SA, et al. Phase 2 study of sodium phenylbutyrate in ALS. Amyotroph Lateral Scler 2009;10:99-106.
Elia AE, Lalli S, Monsurrò MR, et al. Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclero- sis. Eur J Neurol 2016;23:45-52.
DOI: 10.1056/NEJMc2030710
Correspondence Copyright © 2020 Massachusetts Medical Society.

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