Adaptive Platform Trials to Transform Amyotrophic Lateral Sclerosis Therapy Development

Paganoni, Sabrina; Berry, James; Quintana, Melanie; Macklin, Eric A.; Saville, Benjamin R.; Detry, Michelle A.; Chase, Marianne; Sherman, Alex; Yu, Hong; Drake, Kristin; Andrews, Jinsy; Shefner, Jeremy M.; Chibnik, Lori B.; Vestrucci, Matteo; Cudkowicz, Merit; Saville, Ben; Bind, Marie‐Abèle; Chan, James; Locatelli, Eduardo; Alameda, Gustavo; McCaffrey, Alexandra; Babu, Suma; Nicholson, Katie; Scalia, Jennifer; Simmons, Zachary; Grogan, James; Su, Xiaowei; Mamarabadi, Mansoureh; Heitzman, Daragh; Nasri, Mohamad Asaad; Katz, Jonathan; Jenkins, Liberty; Felice, Kevin J.; Whitaker, Charles H.; Ajroud‐Driss, Senda; Quick, Adam; Kolb, Stephen J.; Heintzman, Sarah; Appel, Stanley H.; Greene, Ericka; Thonhoff, Jason R.; Shroff, Sheetal; Liao, Bing; Goutman, Stephen A.; Feldman, Eva L.; Miller, Timothy M.; Malcolm, Amber; Newman, Daniel S.; Arcila‐Londono, Ximena; Steijlen, Kara; Owegi, Margaret; Brown, Robert H.; Ghasemi, Mehdi; Fernandes, Joseph Americo M.; Piccione, E; Thaisetthawatkul, Pariwat; Weiss, Michael D.; Rad, Nassim; Ilieva, Hristelina; Pasinelli, Piera; Guarnieri, Judith; Ladha, Shafeeq; Jacobsen, Bill; Bowser, Robert; Foster, Laura A.; Jackson, Carlayne E.; Rosenfeld, Jeffrey; Bhuvaneswaran, Karthikeyan; Elman, Lauren; Quinn, Colin; Yasek, Julia E.; Fee, Dominic B.; Heiman‐Patterson, Terry; Deboo, Anahita; Swenson, Andrea; Nance, Christopher; Vu, Tuan; Suresh, Niraja; Farias, Jerrica; Caress, Jim; Cartwright, Michael S.; Rezania, Kourosh; Elliott, Matthew; Rutkove, Seward B.; McIlduff, Courtney; Cohen, Jeffrey A.; Stommel, Elijah W.; Glass, Jonathan D.; Fournier, Christina; Young, Eufrosina

doi:10.1002/ana.26285

Cited by 57 publications

(33 citation statements)

References 42 publications

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“…This enables ineffective treatment arms to be discontinued and studies with a positive signal to seamlessly graduate to the next trial phase. Platform trial designs (for example, Healey ALS Platform Trial and MND-SMART) have emerged to allow more rapid assessments and inclusivity for patients, and more efficient deployment of a pooled placebo arm 233,234 . at the individual level, which preceded the onset of symptoms and elevations in neurofilament levels 303 .…”

Section: Advances In Als Clinical Trialsmentioning

confidence: 99%

Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation

Mead

Shan²,

Reiser³

et al. 2022

Nat Rev Drug Discov

201

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Amyotrophic lateral sclerosis (ALS) is a devastating disease caused by degeneration of motor neurons. As with all major neurodegenerative disorders, development of disease-modifying therapies has proven challenging for multiple reasons. Nevertheless, ALS is one of the few neurodegenerative diseases for which disease-modifying therapies are approved. Significant discoveries and advances have been made in ALS preclinical models, genetics, pathology, biomarkers, imaging and clinical readouts over the last 10–15 years. At the same time, novel therapeutic paradigms are being applied in areas of high unmet medical need, including neurodegenerative disorders. These developments have evolved our knowledge base, allowing identification of targeted candidate therapies for ALS with diverse mechanisms of action. In this Review, we discuss how this advanced knowledge, aligned with new approaches, can enable effective translation of therapeutic agents from preclinical studies through to clinical benefit for patients with ALS. We anticipate that this approach in ALS will also positively impact the field of drug discovery for neurodegenerative disorders more broadly.

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Section: Advances In Als Clinical Trialsmentioning

confidence: 99%

Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation

Mead

Shan²,

Reiser³

et al. 2022

Nat Rev Drug Discov

201

View full text Add to dashboard Cite

show abstract

“…Recently, an innovative platform trial (NCT04297683) approach has been launched for ALS [ 92 ]. This trial creates a shared ongoing clinical trial infrastructure where different ALS drugs can be tested on an ongoing basis using a shared protocol.…”

Section: Statistical Enrichmentmentioning

confidence: 99%

Considerations for Amyotrophic Lateral Sclerosis (ALS) Clinical Trial Design

Fournier

2022

Neurotherapeutics

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Thoughtful clinical trial design is critical for efficient therapeutic development, particularly in the field of amyotrophic lateral sclerosis (ALS), where trials often aim to detect modest treatment effects among a population with heterogeneous disease progression. Appropriate outcome measure selection is necessary for trials to provide decisive and informative results. Investigators must consider the outcome measure’s reliability, responsiveness to detect change when change has actually occurred, clinical relevance, and psychometric performance. ALS clinical trials can also be performed more efficiently by utilizing statistical enrichment techniques. Innovations in ALS prediction models allow for selection of participants with less heterogeneity in disease progression rates without requiring a lead-in period, or participants can be stratified according to predicted progression. Statistical enrichment can reduce the needed sample size and improve study power, but investigators must find a balance between optimizing statistical efficiency and retaining generalizability of study findings to the broader ALS population. Additional progress is still needed for biomarker development and validation to confirm target engagement in ALS treatment trials. Selection of an appropriate biofluid biomarker depends on the treatment mechanism of interest, and biomarker studies should be incorporated into early phase trials. Inclusion of patients with ALS as advisors and advocates can strengthen clinical trial design and study retention, but more engagement efforts are needed to improve diversity and equity in ALS research studies. Another challenge for ALS therapeutic development is identifying ways to respect patient autonomy and improve access to experimental treatment, something that is strongly desired by many patients with ALS and ALS advocacy organizations. Expanded access programs that run concurrently to well-designed and adequately powered randomized controlled trials may provide an opportunity to broaden access to promising therapeutics without compromising scientific integrity or rushing regulatory approval of therapies without adequate proof of efficacy. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-022-01271-2.

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“…Concordantly, different S1R modulators such as pridopidine, N-n-propyl-3-(3-hydroxyphenyl) piperidine (3-PPP), and AF710B (ANAVEX 3-71) displayed neuroprotective properties in animal models of AD, reviewed in Ryskamp D. et al (2019). Several ongoing trials for HD such as PROOF-HD (Phase 3) (Reilmann et al, 2021) and HEALEY ALS (Phase 2-3) (Paganoni et al, 2022) have been spurred by promising results of pridopidine in vitro and in vivo. AD pridopidine itself is not currently being tested; nonetheless, other S1R agonists including blarcamesine (phase II/III) (Hampel et al, 2020), edonerpic (phase II) (Schneider et al, 2019), dextromethorphan formulations AVP-786 (phase III) (Cummings et al, 2015), AVP-923 (phase IV) (Fralick et al, 2019), and AXS-05 (phase II-III) (Wilkinson and Sanacora, 2019) are undergoing clinical trial validation.…”

Section: Therapeutic Potential In Alzheimer's Disease and Clinical Tr...mentioning

confidence: 99%

The Potential of Small Molecules to Modulate the Mitochondria–Endoplasmic Reticulum Interplay in Alzheimer’s Disease

Dentoni

Castro-Aldrete

Naia

et al. 2022

Front. Cell Dev. Biol.

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Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting a growing number of elderly individuals. No disease-modifying drugs have yet been identified despite over 30 years of research on the topic, showing the need for further research on this multifactorial disease. In addition to the accumulation of amyloid β-peptide (Aβ) and hyperphosphorylated tau (p-tau), several other alterations have been associated with AD such as calcium (Ca2+) signaling, glucose-, fatty acid-, cholesterol-, and phospholipid metabolism, inflammation, and mitochondrial dysfunction. Interestingly, all these processes have been associated with the mitochondria–endoplasmic reticulum (ER) contact site (MERCS) signaling hub. We and others have hypothesized that the dysregulated MERCS function may be one of the main pathogenic pathways driving AD pathology. Due to the variety of biological processes overseen at the MERCS, we believe that they constitute unique therapeutic targets to boost the neuronal function and recover neuronal homeostasis. Thus, developing molecules with the capacity to correct and/or modulate the MERCS interplay can unleash unique therapeutic opportunities for AD. The potential pharmacological intervention using MERCS modulators in different models of AD is currently under investigation. Here, we survey small molecules with the potential to modulate MERCS structures and functions and restore neuronal homeostasis in AD. We will focus on recently reported examples and provide an overview of the current challenges and future perspectives to develop MERCS modulators in the context of translational research.

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Adaptive Platform Trials to Transform Amyotrophic Lateral Sclerosis Therapy Development

Cited by 57 publications

References 42 publications

Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation

Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation

Considerations for Amyotrophic Lateral Sclerosis (ALS) Clinical Trial Design

The Potential of Small Molecules to Modulate the Mitochondria–Endoplasmic Reticulum Interplay in Alzheimer’s Disease

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