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

Bioenergetic 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. To determine the effects of CNM-Au8 on ALS disease progression. CNM-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. Eligible 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. The 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. Among 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 <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%]). No benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks. ClinicalTrials.gov Identifiers: NCT04297683, NCT04414345.