CNM-Au8 in Amyotrophic Lateral Sclerosis
Authors:   Writing Committee for the HEALEY ALS Platform Trial, Hayden Douglas , Lai Po-Ying , Donahue Rachel A. , Chen Hao-Wun , Wang Jianing , Mathai Nithya , Lopes Gabriela , McCaffrey Alexandra , Scalia Jennifer , Luppino Sarah , Lagier-Tourenne Clotilde , Sadri-Vakili Ghazaleh , Kolb Stephen , Heintzman Sarah , Sufit Robert , Szymanski April , Jenkins Liberty , Martin Alan , (Simpson) Greene Ericka , Thonhoff Jason R. , Liao Bing , Whitaker Charles , Clawson Lora L. , Uchil Alpa , Riley Kristen M. , Arneklev JinAe , Grogan James , Su Xiaowei , Mamarabadi Mansoureh , Malcolm Amber , Bazan Tracy , Rad Nassim , Wang Leo H. , Feldman Eva L. , Piccione Ezequiel , Thaisetthawatkul Pariwat , Farmakidis Constantine , Jabari Duaa , Statland Jeffrey , Pasnoor Mamatha , Dimachkie Mazen , Brown Robert H. , Ghasemi Mehdi , Houmani Hajar , Douthwright Catherine , Daniello Kate , Suresh Niraja , Farias Jerrica , Chen I-Hweii A. , Pasinelli Piera , Steijlen Kara , Bhavaraju-Sanka Ratna , Jacobsen Bill , Milliard Jourdan , Bowser Robert , Deboo Anahita , Cartwright Michael S. , Nance Christopher , Gutmann Ludwig , Yasek Julia , Harms Matthew , Burford Matthew , Diaz Frank , Shrilla David , Rakocevic Goran , Jones Sarah , Solorzano Guillermo , Li Xiaoyan , Mahuwala Zabeen , Kumaraswamy Vishakhadatta (Vish) Mathur , Quinn Colin , Baer Michael , Borg David , Bhuvaneswaran Karthikeyan , Kaur Jasdeep , Maiser Sam , Rutkove Seward B. , Mundwiler Andrew , Meyer Jenny A. , Rao Pooja , Roos Raymond , Habib Ali A. , Mozaffar Tahseen , Korb Manisha Kak , Mullen Jeffrey , Robbins Nathaniel M , Carberry Nathan , Granit Volkan , Govindarajan Raghav , Fournier Christina N. , Oskarsson Bjorn , Darki Leila , Rodriguez Rodrigo , Chuguilin Miguel , McNeely Whitney , Diaz-Abad Montserrat , Jin Peter H. , Chauhan Chandana , Bobenhouse James , Staff Nathan P. , Hayat Ghazala , Arroyave Luisa , Bailey Abbey , Bailey Jesse , Barlow Victoria , Bulat Allison , Changkuon Genevive , Cirino Melissa , Deignan Cristina , Deirmendjian Emma , De Mattos Annette , DiStefano Sofia , Drake Kristin , Estes Michaela , Faulconer Kenneth , Figueroa-Szostek Precious , Garozzo Tessa , Hasenoehrl Meredith Gibbons , Henrique Jennifer , Henrique Natalie , Hurwitz Samuel , Igne Courtney , Irwin Liam , Jentoft Katie , Jordan Boglarka , Katsovskiy Igor , Kharakozova Olga , Kolvek Taylor , Korin Alexander , La Thuong , Li Haining , Nguyen Joey , Novak Ilya , Ortiz Ricardo , Ostrow Joe , Pagliaro Jaclyn , Palillo Jack , Patel Payal , Patterson Janae , Phan Minh , Popel Najla , Proueng Serena , Rosenthal Jesse , Small Catherine , Tarasenko Natalia , Thomas Mirna , Vigneswaran Prasha , Wahab Yusra , Whitworth Isaac , Wright Spencer , Connolly Mariah , De Santiago Diana , Felix Adrian , Garrett Karly , Hamilton Jenny , Khan Kamran , Lovett Marlee , Nelson Linda , Pabon Marissa , Rede Diana , Bolger Patrick , Fetouh Ahmed , Woodcook Joan , Kamp Cornelia , Kennedy Julie , McGarry Andrew , Torti Margherita , Berry James D. , Maragakis Nicholas J. , Macklin Eric A. , Chibnik Lori B. , Quintana Melanie , Saville Benjamin R. , Detry Michelle A. , Vestrucci Matteo , Marion Joseph , McGlothlin Anna , Stommel Elijah W. , Chase Marianne , Pothier Lindsay , Harkey Brittney A. , Yu Hong , Sherman Alex , Shefner Jeremy , Hall Meghan , Kittle Gale , Babu Suma , Andrews Jinsy , D’Agostino Derek , Tustison Eric , Scirocco Erica , Giacomelli Elisa , Alameda Gustavo , Locatelli Eduardo , Ho Doreen , Quick Adam , Ajroud-Driss Senda , Katz Jonathan , Heitzman Daragh , Appel Stanley H. , Shroff Sheetal , Felice Kevin J. , Simmons Zachary , Miller Timothy , Olney Nicholas , Weiss Michael D. , Goutman Stephen A. , Fernandes Joseph Americo , Jawdat Omar , Owegi Margaret Ayo , Foster Laura , Vu Tuan , Ilieva Hristelina , Newman Daniel S. , Arcila-Londono Ximena , Jackson Carlayne , Ladha Shafeeq , Heiman-Patterson Terry , Caress James , Swenson Andrea , Peltier Amanda , Lewis Richard , Fee Dominic , Elliott Matthew , Bedlack Richard , Kasarskis Edward J. , Elman Lauren , Rosenfeld Jeffrey , Walk David , McIlduff Courtney E. , Twydell Paul , Young Eufrosina , Johnson Kristin , Rezania Kourosh , Goyal Namita A. , Cohen Jeffrey A. , Benatar Michael , Jones Vovanti , Glass Jonathan , Shah Jaimin , Beydoun Said R. , Wymer James P. , Zilliox Lindsay , Nayar Shakti , Pattee Gary L. , Martinez-Thompson Jennifer , Rynders Austin , Evan Jacob , Evan Jeremy , Hartford Alan , Sepassi Marjan , Ho Karen S. , Glanzman Robert , Greenberg Benjamin , Hotchkin Michael T. , Paganoni Sabrina , Cudkowicz Merit E. ,   HEALEY ALS Platform Trial Study Group
Published: February 2025

ImportanceBioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD+, resulting in an increase of cellular adenosine triphosphate production.ObjectiveTo determine the effects of CNM-Au8 on ALS disease progression.Design, Setting, and ParticipantsCNM-Au8 was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind platform trial. The study was conducted at 54 sites in the US from July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n = 120) or regimen-specific placebo (n = 41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses.InterventionsEligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n = 61), CNM-Au8 30 mg daily (n = 59), or matching placebo (n = 41) for 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation.ResultsAmong 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR &amp;lt;1, 0.65) and the 3 secondary end points suggested no benefit or harm of CNM-Au8. In the active (n = 120) vs placebo (n = 163) groups, the most common adverse events were diarrhea (23 [19%] vs 12 [7%]), nausea (17 [14.2%] vs 14 [8.6%]), fatigue (12 [10.8%] vs 30 [18.4%]), and muscular weakness (24 [20%] vs 45 [27.6%]).Conclusions and RelevanceNo benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks.Trial RegistrationClinicalTrials.gov Identifiers: NCT04297683, NCT04414345