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Disease Modeling and Model-Based Meta-Analyses to Define a New Direction for a Phase III Program of Gantenerumab in Alzheimer's Disease
Retout S, Gieschke R, Serafin D, Weber C, Frey N, Hofmann C.. Clinical pharmacology and therapeutics, 2022-02-28
Topic: Drug trials: efficacy and safety
Selecting the right dose is a significant challenge in designing clinical development programs, especially for slowly progressing diseases lacking predictive biomarkers of efficacy that may require long-term treatment to assess clinical benefit. Gantenerumab, a fully human monoclonal antibody (mAb) that binds to aggregated amyloid-beta, was tested in two 24-month phase III studies (NCT01224106, NCT02051608) in participants with prodromal and mild Alzheimer's disease (AD), respectively. Dosing in the first phase III study was suspended after a preplanned interim futility analysis in 2014. Subsequently, a dose-response relationship was observed in a subgroup of fast AD progressors that, together with contemporary aducanumab (another anti-amyloid-beta mAb) data, indicated higher doses may be needed for clinical efficacy. The gantenerumab phase III studies were therefore transformed into dose-finding, open-label extension (OLE) trials. Two exposure-response models were developed to support dose selection via simulations for the OLEs: a pharmacokinetics (PK)/PET (positron emission tomography) model describing amyloid removal using PET data from low-dose gantenerumab and high-dose aducanumab, and a PK/ARIA-E (amyloid-related imaging abnormalities-edema) model describing the occurrence of ARIA-E events leveraging an existing bapineuzumab model. Multiple regimens were designed to gradually up-titrate participants to the target dose of 1,200 mg gantenerumab every 4 weeks to mitigate the increased risk of ARIA-E events that may be associated with higher doses of anti-amyloid-beta antibodies. Favorable OLE data that matched well with model predictions supported the decision to continue the gantenerumab clinical development program and further apply model-based analytical techniques to optimize the design of new phase III studies.
Key findings
- Selecting the right dose is a significant challenge in designing clinical development programs, especially for slowly progressing diseases lacking predictive biomarkers of efficacy that may require long-term treatment to assess clinical benefit.
- Multiple regimens were designed to gradually up-titrate participants to the target dose of 1,200 mg gantenerumab every 4 weeks to mitigate the increased risk of ARIA-E events that may be associated with higher doses of anti-amyloid-beta antibodies.
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Study details
- Study designopen-label trial
- Evidence strengthLow
How this study scored 43/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 25 of the 58 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Clinical pharmacology and therapeutics) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | Design recorded as “open-label trial”, which our rubric does not rank (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2022 — within 6 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 35100444) |
| Free to read | 2 / 2 | Free to read |
| Points | 25 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 25 of the 58 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Retout, S., Gieschke, R., Serafin, D., Weber, C., Frey, N., & Hofmann, C. (2022). Disease Modeling and Model-Based Meta-Analyses to Define a New Direction for a Phase III Program of Gantenerumab in Alzheimer's Disease. Clinical pharmacology and therapeutics. https://doi.org/10.1002/cpt.2535
Vancouver
Retout S, Gieschke R, Serafin D, Weber C, Frey N, Hofmann C. Disease Modeling and Model-Based Meta-Analyses to Define a New Direction for a Phase III Program of Gantenerumab in Alzheimer's Disease. Clinical pharmacology and therapeutics. 2022. doi:10.1002/cpt.2535. PMID: 35100444.
BibTeX
@article{retout2022-35100444,
author = {Retout, S. and Gieschke, R. and Serafin, D. and Weber, C. and Frey, N. and Hofmann, C.},
title = {{Disease Modeling and Model-Based Meta-Analyses to Define a New Direction for a Phase III Program of Gantenerumab in Alzheimer's Disease}},
journal = {Clinical pharmacology and therapeutics},
year = {2022},
doi = {10.1002/cpt.2535},
pmid = {35100444},
url = {https://doi.org/10.1002/cpt.2535}
}
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