Background
Given the interest around the use of stem cells in ALS, the ENCALS neurologists from across Europe have reviewed the published evidence around the Brainstorm Therapeutics treatment, NurOwn (debamestrocel), and discussed this at a meeting on 13 July 2023.
On 10 December 2021, Brainstorm Therapeutics published the results of their Phase 3 clinical trial. The therapy is an intrathecal infusion of autologous mesenchymal stem cells given on three occasions. The trial did not meet its primary endpoint of a response at 28 weeks. A post-hoc analysis (analysis performed after the initial results are known, but not previously planned) subsequently showed that in a subset of participants with initially higher ALSFRS-R scores, there was possibly a trend toward efficacy. Further post-hoc analysis showed an approximately 11% reduction in NFL, statistically significant after adjustment on baseline variables.
What is known about the effect of NurOwn?
Researchers from six institutions in the USA, working with Brainstorm Therapeutics took part in a 28-week double-blind placebo-controlled Phase 3 trial of NurOwn. The trial included about 200 participants, randomized 1:1 to active therapy or placebo. Results of the double-blind study have been presented. These showed no difference between treatment arms in the primary responder analysis endpoint, and no difference between treatment arms in the secondary endpoints. Following this initial result, the Brainstorm statisticians examined the data, and found that in some cases, subscores of the ALSFRS-R were at zero, and therefore could not show further deterioration. A post-hoc analysis was done in the patients with a total ALSFRS-R score above 25. This re-analysis, which was not previously planned, suggested a possible benefit of NurOwn. A further post-hoc analysis showed a response of NFL and other biomarkers to NurOwn when adjusted on baseline variables.
Comment
ENCALS neurologists note that other trials have enrolled people with zero scores on individual ALSFRS-R items, and have been able to demonstrate efficacy nonetheless. In addition, evaluation of changes in ALSFRS-R in both placebo and active treatment arms do not show a reduction in apparent slope at later time points in the study. Thus, this so-called “floor effect”, while taken as an explanation for the negative results, does not obviate the possibility of perceiving an efficacy signal.
Political pressure through advocacy
Because of the enormity of a diagnosis of ALS and the lack of general effective therapy, there is pressure for approval for new drugs. For NurOwn, this pressure has been unprecedented, and fuelled by anecdotal social media reports suggesting dramatic improvement in some participants, although their treatment status remains blinded, and whether any improvement was transient remains unknown.
The opinion of the ENCALS neurologists
The effect of NurOwn is currently unclear. There are interesting changes in biomarkers, but no statistically significant clinical benefit in any a priori functional outcome measure. The established scientific opinion is that post-hoc analysis is not an appropriate method on which to base policy. The reason for this is statistical: if enough tests are performed, some will show a positive result by chance, rather than because of a real effect. It is not therefore possible on current evidence to show a benefit of NurOwn therapy, since the only positive results are from post-hoc analyses. A further Phase 3 trial, designed to confirm the post-hoc analysis, is required, and will provide the only valid evidence of benefit. To provide a treatment that imposes a significant burden on the patient and on the system requires stringent adherence to drug development principles and an obligation to complete a formal registration trial. Furthermore, we strongly counsel against advocacy as a substitute for robust science, or we set a bad precedent for future studies to identify much-needed therapies for ALS. ENCALS is firmly committed to the search for more effective treatments for this devastating disease.
Signatories:
- UK: Ammar Al-Chalabi, Christopher McDermott, Martin Turner, Sharon Abrahams, Carolyn Young, John Ealing, Suresh Chhetri, Clemens Oliver Hanemann, Thomas Lambert, Andrea Malaspina, Nicola Watson, Amina Chaouch, Suresh Chhetri
- Netherlands: Leonard van den Berg
- Belgium: Philip Van Damme
- Germany: Albert Ludolph, Annekathrin Roediger, Susanne Petri, Joachim Wolf, Torsten Grehl, Thomas Meyer, Patrick Weydt, Andreas Hermann, Andre Maier, Joachim Wolf, Jochen Weishaupt, Julian Grosskreutz
- France: Phillipe Corcia, Philippe Couratier, Marie-Hélène Soriani, Gaëlle Bruneteau, Francois Salachas, David Devos, Shahram Attarian, Annie Verschueren, Serge Lumbroso, Claude Desnuelle, Véronique Danel Brunaud, Florence Esselin
- Switzerland: Markus Weber, Kathi Schweikert, Annemarie Hübers, Magdalini Polymenidou
- Czech Republic: Lenka Šlachtová
- Austria: Hakan Cetin
- Italy: Adriano Chio, Vincenzo Silani, Christian Lunetta, Nilo Riva, Massimiliano Filosto, Alberto Albanese, Fabiola De Marchi, Pilar Ferraro, Jessica Mandrioli, Gianni Sorarù, Gioacchino Tedeschi, Francesca Trojisi
- Ireland: Orla Hardiman
- Iceland: Björn Logi Þórarinsson
- Norway: Geir Bråthen, Trygve Holmøy, Ole-Bjørn Tysnes, Angelina Maniaol, Helle Høyer
- Denmark: Kirsten Svenstrup, Mia Heintzelmann
- Sweden: Peter Andersen, Caroline Ingre
- Spain: Juan Francisco Vázquez Costa, Jesus Esteban, Luis Varona, Alberto Garcia Redondo, Miguel Angel Rubio Perez, Rosario Osta Pinzolas, Adolfo López de Munain, Julio Pardo, Jose Luis Muñoz-Blanco, Monica Povedano, Javier Mascias, Jesus Mora
- Portugal: Mamede de Carvalho
- Poland: Jakub Antczak, Magdalena Kuzma
- Croatia: Ervina Bilic, Mira Bučuk
- Greece: Elisabeth Chroni
- Serbia: Zorica Stevic
- Slovenia: Blaz Koritnik
- Bosnia and Herzegovina: Srdjan Mavija
- Bulgeria: Stayko Sarafov
- Israel: Stanislav Engel, Eran Hornstein, Adrian Israelson