Windfall Week for Trial Data: Papers on Crenezumab, Neflamapimod, Tofersen

A trio of papers this week describe in detail the outcomes of efficacy trials of three different experimental therapies. The first paper fills in the picture of the Aβ antibody crenezumab’s Phase 3 effort, which was scrapped early for lack of a discernable effect. The results for the kinase inhibitor neflamapimod and the antisense oligomer tofersen closely follow the contours of previously covered presentations at meetings, or press releases. All three drugs are still being evaluated.

Results of two large Phase 3 trials of crenezumab, Roche’s monoclonal antibody to Aβ oligomers, appear in the September 20 JAMA Neurology (Ostrowitzki et al., 2022). Roche stopped the two CREAD trials, in more than 1,600 participants with prodromal to mild Alzheimer’s disease, early in 2019, when an interim analysis found no evidence that the treatment was effective. As previously reported, crenezumab was well-tolerated but changed neither the rate of cognitive loss, nor disease biomarkers (Jan 2019 news).

This antibody is also the subject of the ongoing Alzheimer's Prevention Initiative trial in Colombia. That trial earlier this year posted negative data, with cognitive and biomarker trends favoring the drug (Jun 2022 news; Aug 2022 conference news). The API trial is slated to finish in December.

EIP Pharma first reported positive Phase 2 results for neflamapimod in dementia with Lewy bodies at the 2020 Alzheimer’s Association International Conference (Nov 2020 conference news). Participants who got three doses daily of this p38MAP kinase inhibitor for half a year improved on cognitive and motor endpoints; twice-daily dosing had no effect. The company now presents the complete data in the September 21 Nature Communications (Jiang et al., 2022). 

This paper also contains new preclinical work suggesting neflamapimod acts by restoring lysosomal function and preserving basal forebrain cholinergic neurons. These neurons are the main source of acetylcholine in the brain, and their degeneration with age or disease contributes to cognitive decline in Alzheimer’s and other dementias (April 2020 news). A confirmatory Phase 2 trial is in the works, the company said (press release).

Last year, Biogen announced its antisense therapy tofersen had missed its primary clinical endpoint in the Phase 3 VALOR trial for adults with ALS caused by mutations in the SOD1 gene (October 2021 news). Tofersen hit its target, successfully reducing SOD1 protein levels in CSF, but did not significantly stanch decline on the ALS Functional Rating Scale as compared to placebo in 72 people dosed for 28 weeks.

Nonetheless, the company, with its partner Ionis Pharmaceuticals, forged ahead and applied to the FDA for accelerated approval. This is based on change in the fluid biomarker neurofilament light and a numerical slowing of decline in patients in the long-term extension (press release). Now, the study team formally report VALOR’s findings in the September 22 New England Journal of Medicine (Miller et al., 2022). The FDA will render its decision by the end of January 2023.—Pat McCaffrey 

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References

Therapeutics Citations

  1. Crenezumab
  2. Neflamapimod
  3. QALSODY™

News Citations

  1. Roche Pulls Plug on Two Phase 3 Trials of Crenezumab
  2. API Colombian Trial of Crenezumab Missed Primary Endpoints
  3. Crenezumab Secondaries Negative; Gantenerumab OLE Hints at Efficacy
  4. In Phase 2 Trial, Neflamapimod Aids Cognition in Lewy Body Dementia
  5. Does Alzheimer’s Start in the Heart of the Cholinergic System?
  6. Antisense ALS Drug Nudges Outcomes, But Misses Primary

External Citations

  1. press release
  2. press release

Further Reading

No Available Further Reading

Primary Papers

  1. Ostrowitzki S, Bittner T, Sink KM, Mackey H, Rabe C, Honig LS, Cassetta E, Woodward M, Boada M, van Dyck CH, Grimmer T, Selkoe DJ, Schneider A, Blondeau K, Hu N, Quartino A, Clayton D, Dolton M, Dang Y, Ostaszewski B, Sanabria-Bohórquez SM, Rabbia M, Toth B, Eichenlaub U, Smith J, Honigberg LA, Doody RS. Evaluating the Safety and Efficacy of Crenezumab vs Placebo in Adults With Early Alzheimer Disease: Two Phase 3 Randomized Placebo-Controlled Trials. JAMA Neurol. 2022 Nov 1;79(11):1113-1121. PubMed.
  2. Jiang Y, Alam JJ, Gomperts SN, Maruff P, Lemstra AW, Germann UA, Stavrides PH, Darji S, Malampati S, Peddy J, Bleiwas C, Pawlik M, Pensalfini A, Yang DS, Subbanna S, Basavarajappa BS, Smiley JF, Gardner A, Blackburn K, Chu HM, Prins ND, Teunissen CE, Harrison JE, Scheltens P, Nixon RA. Preclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration. Nat Commun. 2022 Sep 21;13(1):5308. PubMed.
  3. Miller TM, Cudkowicz ME, Genge A, Shaw PJ, Sobue G, Bucelli RC, Chiò A, Van Damme P, Ludolph AC, Glass JD, Andrews JA, Babu S, Benatar M, McDermott CJ, Cochrane T, Chary S, Chew S, Zhu H, Wu F, Nestorov I, Graham D, Sun P, McNeill M, Fanning L, Ferguson TA, Fradette S, VALOR and OLE Working Group. Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2022 Sep 22;387(12):1099-1110. PubMed.

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