Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Biogen, Eisai Co., Ltd.
BAN2401 is the humanized IgG1 version of the mouse monoclonal antibody mAb158, which selectively binds to large, soluble Aβ protofibrils. The therapeutic antibody was originally developed at the biotech company BioArctic Neuroscience following the discovery of the “Arctic” mutation in APP, which leads to a form of clinically typical Alzheimer's disease that is marked by particularly high levels of Aβ protofibrils and relative absence of amyloid plaques (see Nilsberth et al., 2001). mAB158 was found to reduce Aβ protofibrils in brain and CSF of tgArc-Swe mice (Tucker et al., 2015). Subsequent studies in mouse neuron-glial co-cultures showed that mAb158 may protect neurons, i.e., reduce Aβ protofibril toxicity, by counteracting the pathological accumulation of these protofibrils in astrocytes (Söllvander et al., 2018).
BAN2401 was licensed to Eisai, which in March 2014 signed a collaboration agreement with Biogen for joint development of this therapeutic antibody.
A multicenter Phase 1 trial tested the safety, tolerability, and pharmacokinetics of a single and multiple ascending intravenous doses of BAN2401 in 80 people with mild to moderate AD. Changes in Aβ levels were also measured. BAN2401 was well-tolerated at all doses tested, up to 10mg/kg every two weeks for four months, with amyloid-related imaging abnormalities (ARIA-E, ARIA-H) occurring at the same rate in both placebo and BAN2401. The antibody entered the CSF and showed dose-dependent exposure, though with a short serum elimination half-life of seven days and no clear effect on CSF biomarkers. Results were formally published (Logovinsky et al., 2016).
A Phase 2, 18-month U.S. trial is testing five different intravenous doses of BAN2401 in a Bayesian adaptive design. Allocation of subsequent enrollees to different groups was adjusted in response to frequent interim analyses, the first to be done in late 2015 after the first 196 patients had entered the trial, and again every time 50 more people had enrolled (for detailed description of this innovative trial design see Satlin et al., 2016). This trial is enrolling up to 800 people who either have early stage AD as defined by the proposed NIA-AA diagnostic criteria of mild cognitive impairment due to AD, or who meet NIA-AA criteria for probable AD and whose diagnosis is confirmed by a positive amyloid PET scan. As primary outcomes, the trial measured 12-month change from baseline in the new ADCOMS composite of cognitive tests (Wang et al., 2016), and safety.
In 2017 the sponsors announced that BAN2401 had shown no cognitive benefit at this 12-month time point. However, futility conditions had not been met either at the 17 interim analyses conducted until then. Therefore the trial continued to full enrollment of 856 participants, and out to the full treatment period of 18 months (Dec 2017 news). In February 2018, the trial protocol was amended to offer up to five years of additional treatment in an open-label extension phase, in which change on the ADCOMS will be measured at each visit. Results of the blinded 18-month treatment phase are expected by end of 2018.
For all clinical trials of BAN2401, see clinicaltrials.gov
Clinical Trial Timeline
Last Updated: 18 May 2018
- Logovinsky V, Satlin A, Lai R, Swanson C, Kaplow J, Osswald G, Basun H, Lannfelt L. Safety and tolerability of BAN2401--a clinical study in Alzheimer's disease with a protofibril selective Aβ antibody. Alzheimers Res Ther. 2016 Apr 6;8(1):14. PubMed.
- Satlin A, Wang J, Logovinsky V, Berry S, Swanson C, Dhadda S, Berry DA. Design of a Bayesian adaptive phase 2 proof-of-concept trial for BAN2401, a putative disease-modifying monoclonal antibody for the treatment of Alzheimer's disease. Alzheimers Dement (N Y). 2016 Jan;2(1):1-12. Epub 2016 Feb 4 PubMed.
- Wang J, Logovinsky V, Hendrix SB, Stanworth SH, Perdomo C, Xu L, Dhadda S, Do I, Rabe M, Luthman J, Cummings J, Satlin A. ADCOMS: a composite clinical outcome for prodromal Alzheimer's disease trials. J Neurol Neurosurg Psychiatry. 2016 Sep;87(9):993-9. Epub 2016 Mar 23 PubMed.
- Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, Stenh C, Luthman J, Teplow DB, Younkin SG, Näslund J, Lannfelt L. The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. Nat Neurosci. 2001 Sep;4(9):887-93. PubMed.
- Tucker S, Möller C, Tegerstedt K, Lord A, Laudon H, Sjödahl J, Söderberg L, Spens E, Sahlin C, Waara ER, Satlin A, Gellerfors P, Osswald G, Lannfelt L. The murine version of BAN2401 (mAb158) selectively reduces amyloid-β protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice. J Alzheimers Dis. 2015;43(2):575-88. PubMed.
- Söllvander S, Nikitidou E, Gallasch L, Zyśk M, Söderberg L, Sehlin D, Lannfelt L, Erlandsson A. The Aβ protofibril selective antibody mAb158 prevents accumulation of Aβ in astrocytes and rescues neurons from Aβ-induced cell death. J Neuroinflammation. 2018 Mar 28;15(1):98. PubMed.
- Philipson O, Hammarström P, Nilsson KP, Portelius E, Olofsson T, Ingelsson M, Hyman BT, Blennow K, Lannfelt L, Kalimo H, Nilsson LN. A highly insoluble state of Abeta similar to that of Alzheimer's disease brain is found in Arctic APP transgenic mice. Neurobiol Aging. 2009 Sep;30(9):1393-405. PubMed.
- Lannfelt L, Möller C, Basun H, Osswald G, Sehlin D, Satlin A, Logovinsky V, Gellerfors P. Perspectives on future Alzheimer therapies: amyloid-β protofibrils - a new target for immunotherapy with BAN2401 in Alzheimer's disease. Alzheimers Res Ther. 2014;6(2):16. Epub 2014 Mar 24 PubMed.