"What does BAN2401 mean for Alzheimer’s disease?" by Aleks Recupero
On July 25th at the Alzheimer’s Association International Conference (AAIC), a press release regarding a Phase II clinical trial swept the nation. The press release announced positive secondary outcomes of the Alzheimer’s drug BAN2401.1 However, seven months prior, many of the primary outcome measures for BAN2401 had been reported as negative. Therefore, the standing of BAN2401 was still largely in question when the public was swarmed with a myriad of hopeful headlines in large media outlets this past summer. While the results do offer some promise, they must be closely scrutinized given the complicated effects of BAN2401 in these clinical trials.
Alzheimer’s disease (AD) is a devastating neurodegenerative disease for which there has long been a scarcity of disease-modifying therapeutics. The two pathological hallmarks of AD are extracellular senile plaques largely composed of aggregated amyloid-beta peptide and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. These aggregates and tangles in the brain ultimately lead to neuronal cell death and brain atrophy. Alzheimer’s disease is the sixth leading cause of death in the United States, and thus represents a national priority for biomedical research. Although the FDA has approved several medications that can mitigate AD symptoms, none of them alter the disease’s progression. Current research is thus geared towards altering the disease’s course and ultimately towards reversing its effects.
Such a goal has led to the emergence of BAN2401. The biotechnology company BioArctic Neuroscience began by developing a mouse monoclonal antibody mAb158 that specifically binds to amyloid-beta protofibrils, which are an intermediate species before the development of amyloid-beta plaques. In 2015, this mouse antibody was observed to reduce amyloid-beta protofibrils in the brain and cerebrospinal fluid of an AD mouse model. BAN2401 was then developed as a humanized IgG1 version of mAb158. In 2014, pharmaceutical company Eisai and biotechnology company Biogen began collaborating in the development of BAN2401.
BAN2401 then began testing in clinical trials. U.S. Food and Drug Administration Phase 1 clinical trials are implemented to measure the safety and dosage of a given drug. Different intravenous doses of BAN2401 were tested in 80 people with mild or moderate AD. All doses up to 10 mg/kg of BAN2401 were found to be safe. Exposure to BAN2401 was proportional to the dose, but no effects on cerebrospinal fluid biomarkers were observed. These results were sufficient to proceed to Phase 2 clinical trials.
According to the FDA, about 70% of drugs in Phase 1 trials proceed to the Phase 2 trials, so the entry of BAN2401 into Phase 2 trials was not particularly striking. In Phase 2 trials, a drug’s efficacy and side effects are evaluated. The Phase 2 trials of BAN2401 tested five different doses on patients with mild cognitive impairment due to AD or early AD. These participants, a total of 856 patients, also had to have amyloid pathology in the brain, which was measured via PET scan. At the end of 2017, after twelve months of the clinical trial, the researchers announced that BAN2401 showed no cognitive benefit, but the study was nonetheless continued to the eighteen month mark.
Different disease measures were tested after eighteen months to determine the efficacy of BAN2401. The amount of amyloid accumulated in the brain was measured again via PET scan to compare to pre-treatment measures. Further, clinical measures such as Alzheimer’s Disease Composite Score (ADCOMS), Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog), and Clinical Dementia Rating Sum of Boxes (CDR-SB) were used to compare the patients’ disease before and after the eighteen months of treatment. The highest doses of 10 mg/kg monthly and biweekly proved most effective with statistically significant mean reductions in amyloid load. Further, conversion from amyloid positive to amyloid negative was dependent on the dose, so 81% of patients being treated with the highest dose were amyloid negative at the end of eighteen months. Cognitive decline was also slowed in a dose-dependent manner according to ACDOMS, ADAS-Cog, and CDR-SB measures. Other observations include a dose-dependent increase of amyloid-beta in cerebrospinal fluid and a decrease in total tau in patients receiving the highest dose of BAN2401. These results together suggest that BAN2401 reduces AD pathology, a very promising outcome considering the lack of any other disease-modifying therapeutics.
Despite the excitement associated with these results, they have their limitations. First, the phase 2 clinical trial was conducted on early AD patients, who are usually difficult to diagnose or detect in the general population. Early detection of Alzheimer’s disease is currently difficult because cognitive effects are often not evident until a decade after onset. Therefore, the application of BAN2401 to early Alzheimer’s disease patients may be fairly challenging. Further, high doses of BAN2401 may also lead to complications. For example, 53.4% of the patients in the 10 mg/kg monthly treatment group and 47.2% of the patients in the 10 mg/kg biweekly treatment group faced adverse effects due to the treatment compared to only 26.5% of the patients in the placebo group. The most common among these effects were Amyloid-Related Imaging Abnormalities and infusion-related reactions, which may have been caused by the high doses of BAN2401. These considerations help put the positive results of possible disease-modifying effects of BAN2401 into perspective.
The FDA will have to carefully examine the results of the phase 2 clinical trials of BAN2401 to determine whether to proceed with additional clinical trials. Due to the lack of any other drug that modifies the pathology of Alzheimer’s disease, it is expected that the FDA will push BAN2401 through further trials. Phase 3 clinical trials focus on efficacy and adverse reactions, and phase 4 clinical trials concentrate on safety and efficacy. The AAIC press release that led to the explosion of media attention for BAN2401 did acknowledge the drug’s promise but also its limitations. The ultimate impact of BAN2401 is difficult to predict, but at the very least the press and attention that it has garnered provides hope for the millions of patients and caregivers affected by Alzheimer’s disease.
 Alzheimer’s Association. 2018. “BAN2401 Phase 2 Data Released at AAIC 2018.” Accessed September 24. https://www.alz.org/aaic/releases_2018/AAIC18-Wed-3-30-pm.asp
 National Institute on Aging. 2016. “Alzheimer’s Disease Fact Sheet.” Accessed September 24. https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet#changes
 Alzforum. 2018. “BAN2401.” Accessed September 24. https://www.alzforum.org/therapeutics/ban2401
 Tucker, S. et al. 2015. “The murine version of BAN2401 (mAb158) selectively reduces amyloid- protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice.” J Alzheimer’s Dis. 43(2):575-588.
 U.S. Food and Drug Administration. 2018. “Step 3: Clinical Research.” Accessed September 24. https://www.fda.gov/forpatients/approvals/drugs/ucm405622.htm
 Logovinsky, V. et al. 2016. “Safety and tolerability of BAN2401-a clinical study in Alzheimer’s disease with a protofibril selective A antibody.” Alzheimers Res Ther. 8(1):14.
 Eisai. 2018. “Eisai and Biogen Announce Detailed Results of Phase II clinical Study of BAN2401 in Early Alzheimer’s Disease at Alzheimer’s Association International Conference (AAIC) 2018.” Accessed September 24. https://www.eisai.com/news/2018/news201866.html