Assessment of Efficacy and Safety of Zagotenemab

Abstract

Background and Objectives

Zagotenemab (LY3303560), a monoclonal antibody that preferentially targets misfolded, extracellular, aggregated tau, was assessed in the PERISCOPE-ALZ phase 2 study to determine its ability to slow cognitive and functional decline relative to placebo in early symptomatic Alzheimer disease (AD).

Methods

Participants were enrolled across 56 sites in North America and Japan. Key eligibility criteria included age of 60–85 years, Mini-Mental State Examination score of 20–28, and intermediate levels of brain tau on PET imaging. In this double-blind study, participants were equally randomized to 1,400 mg or 5,600 mg of zagotenemab, or placebo (IV infusion every 4 weeks for 100 weeks). The primary outcome was change on the Integrated AD Rating Scale (iADRS) assessed by a Bayesian Disease Progression model. Secondary measures include mixed model repeated measures analysis of additional cognitive and functional endpoints as well as biomarkers of AD pathology.

Results

A total of 360 participants (mean age = 75.4 years; female = 52.8%) were randomized, and 218 completed the treatment period. Demographics and baseline characteristics were reasonably balanced among arms. The mean disease progression ratio (proportional decline in the treated vs placebo group) with 95% credible intervals for the iADRS was 1.10 (0.959–1.265) for the zagotenemab low-dose group and 1.05 (0.907–1.209) for the high-dose, where a ratio less than 1 favors the treatment group. Secondary clinical endpoint measures failed to show a drug-placebo difference in favor of zagotenemab. No treatment effect was demonstrated by flortaucipir PET, volumetric MRI, or neurofilament light chain (NfL) analyses. A dose-related increase in plasma phosphorylated tau181 and total tau was demonstrated. Zagotenemab treatment groups reported a higher incidence of adverse events (AEs) (85.1%) compared with the placebo group (74.6%). This difference was not attributable to any specific AE or category of AEs.

Discussion

In participants with early symptomatic AD, zagotenemab failed to achieve significant slowing of clinical disease progression compared with placebo. Imaging biomarker and plasma NfL findings did not show evidence of pharmacodynamic activity or disease modification.

Trial Registration Information

ClinicalTrials.gov: NCT03518073.

Classification of Evidence

This study provides Class II evidence that for patients with early symptomatic AD, zagotenemab does not slow clinical disease progression.

Introduction

Tau, an axonal microtubule binding protein, functions to promote microtubule assembly and stability within neurons. Abnormal tau has been implicated in several neurodegenerative diseases. In Alzheimer disease (AD), when tau is hyperphosphorylated, it aggregates and accumulates as intraneuronal tangles and is believed to lead to downstream cellular toxicity and death.¹ Although pathologic tau accumulates within neurons, there is substantial evidence that propagation of aggregated tau can occur by transcellular spread throughout the brain.^2-4 In AD, tau accumulates and spreads in a predictable pattern strongly associated with progressive memory decline.⁵ Interventions targeting extracellular aggregated tau and aiming to reduce its spread can potentially slow pathologic and clinical progression.

Zagotenemab (LY3303560) is a monoclonal antibody that strongly favors binding to a tertiary conformation specific only to misfolded, pathologic tau species. N-terminus binding occurs at amino acids 7–9 of the tau protein, with additional binding in the microtubule binding region at amino acids 312–322. In preclinical mouse models, on treatment with MC-1 (a murine equivalent), tau pathology was reduced in genetic variant mice (JNPL3 mice) and blocked in models of tau seeding (P301S mice).⁶ In addition to delaying the transcellular spread of pathologic tau by binding to aggregated tau, zagotenemab was hypothesized to reduce neurofibrillary tangle formation, and subsequent neuronal loss, and thus may have the potential to slow the clinical progression of relevant tauopathies.

Two phase 1 studies were conducted to assess the safety and pharmacokinetic properties of zagotenemab. A single ascending dose study in healthy participants (NCT02754830) assessed doses ranging from 7 to 5,600 mg of zagotenemab. A multiple ascending dose study was conducted in patients with mild cognitive impairment due to AD or mild to moderate AD and included 16 weeks of multiple doses of either 70 or 210 mg zagotenemab (NCT03019536). These studies demonstrated that the pharmacokinetics of zagotenemab were typical for a monoclonal antibody and adverse events (AEs) were not dose limiting. Multiple doses above 210 mg were not examined in phase 1 and were included in the phase 2 study with a gated safety strategy as outlined in the methods.

PERISCOPE-ALZ (NCT03518073) was a multicenter phase 2 clinical trial designed to determine whether zagotenemab slows disease progression relative to placebo in early symptomatic AD. The study population was selected based on the presence of intermediate levels of tau burden, resulting in a more homogeneous trial cohort. The safety and efficacy results from this trial are presented here.

Methods

Standard Protocol Approvals, Registrations, and Patient Consents

This study was conducted according to the consensus ethical principles derived from international guidelines such as the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines including applicable International Conference on Harmonisation Good Clinical Practice guidelines, and other laws and regulations. The study protocol was approved by the appropriate ethics committee at each participating center and was open to enrolment from April 30, 2018, through August 23, 2019. This study was registered at ClinicalTrials.gov (NCT03518073). The study protocol and statistical analysis plan were published and can be found in the study documents section of the ClinicalTrials.gov site.⁷ All participants provided written informed consent.

Patients and Study Design

PERISCOPE-ALZ was a multicenter (56 academic and private centers in Canada, Japan, and the United States), randomized, double-blind, placebo-controlled phase 2 study of zagotenemab. All study participants, the sponsor study team, and all trial site staff except site pharmacist remained blinded during the conduct of the study. Eligibility criteria included patients with early symptomatic AD (patients with mild cognitive impairment or mild dementia due to AD) 60–85 years of age with gradual and progressive change in memory function for ≥6 months consistent with AD, a Mini-Mental State Examination (MMSE) score of 20–28, and biomarker evidence of AD-type tauopathy. Enrollees were required to have a study partner who was in frequent contact with the participant, provided written informed consent, and was able to accompany the participant to study visits. Participants on stable doses of approved, oral prescriptions of AD medications were allowed to enroll. Participants were excluded if they had any contraindications for imaging, a history of severe drug hypersensitivity, or other significant neurologic disease or current serious or unstable illness that could interfere with the ability to complete the study.

An intermediate tau level (based on the visual pattern and within a prespecified quantitative range) was also a requirement. At screening, flortaucipir PET scan quantification and estimation of a tau-standardized uptake value ratio (SUVR) were determined according to published methods, using an AD signature-weighted neocortical region,^8-10 and a participant-specific white matter reference region.⁹ Centralized visual reads were assessed for tau deposition patterns consistent with AD.¹¹ Patients with high tau (SUVR of more than 1.46⁹) were excluded from the trial. Participants were excluded from the study if they had a negative visual flortaucipir AD pattern or an SUVR of less than 1.10 but were included if they had an SUVR of less than 1.10 and an advanced AD pattern.¹¹

Additional biomarkers of AD including amyloid were not assessed as part of the screening process because zagotenemab is a tau-targeting antibody and the presence of an AD pattern with flortaucipir is strongly associated with a diagnosis of amyloid-positive symptomatic AD and concomitant presence of amyloid pathology consistent with a pathologic diagnosis of AD.^11-13

Participants who met inclusion criteria were randomized in a 1:1:1 ratio to receive IV infusions every 4 weeks for 100 weeks of 1,400 mg zagotenemab, 5,600 mg zagotenemab, or placebo (Figure 1, eFigure 1, links.lww.com/WNL/D389). Phase 2 doses were selected based on nonclinical and clinical pharmacokinetic/pharmacodynamic and safety findings from phase 1 studies (NCT02754830 and NCT03019536). However, since multiple repeated monthly doses of zagotenemab at 1,400 mg and 5,600 mg had not been tested before initiation of the phase 2 study, the PERISCOPE-ALZ protocol included an initial cohort of 39 participants (equally randomized across the 3 arms, with minimization using the investigative site as a factor) who received monthly IV doses of study drug for 3 months followed by a 1-month observation period during which enrolment of additional participants was paused. An external data monitoring committee review of the unblinded safety data from this initial safety cohort found nothing significant that warranted a protocol change.

Figure 1. Participant Flow for the PERISCOPE-ALZ Trial.

N = number of patients in the treatment arm; n = number of patients in the subgroup.

The initial consented version of the protocol included a total treatment period of 18 months. Approximately 1 year after the study was fully enrolled, and before any enrolled participant reached 18 months of treatment, the protocol was amended, with Internal Review Board approval and reconsenting of all participants, to add an additional 6 months (24 months total) to the blinded treatment period. This change was implemented based on new analyses of data from other trials suggesting more than 18 months may be required to show a treatment effect on clinical measures. A clinical protocol addendum and a guidance document were created to allow for remote visits, which would mitigate risks of missed visits and thus maintain integrity of the study during the coronavirus disease 2019 (COVID-19) pandemic.

Objectives/Procedures

The primary objective of this study was to determine whether zagotenemab would decrease the decline in cognition and function in patients with early symptomatic AD relative to placebo in the randomized population with at least 1 postbaseline primary endpoint measure. Outcome assessments were conducted by Lilly personnel after the completion of the blinded phase of the study (after database lock). The primary endpoint was the change in the integrated AD Rating Scale (iADRS)^14,15 score from baseline to 104 weeks (eFigure 1, links.lww.com/WNL/D389) as assessed using a Bayesian disease progression model (DPM).¹⁶ iADRS is a validated instrument that is a linear combination of its 2 components: the AD Assessment Scale–Cognitive subscale (ADAS-Cog13) and the AD Cooperative Study–Instrumental Activities of Daily Living (iADL) scale. Additional covariates include age, pooled site ID, and concomitant use of acetylcholinesterase inhibitor (AChEI) and/or memantine at baseline.

A Bayesian DPM was chosen for the primary analyses because this method incorporates all longitudinal timepoints into the estimation of treatment effect, reduces variability, and often provides improved power for detecting effect sizes. A disease progression ratio (DPR: change in treatment group over change in placebo) of less than 1 corresponds to a slowing of disease progression with zagotenemab vs placebo. To test the hypothesis of a disease progression benefit, we calculated the posterior probability of superiority of zagotenemab vs placebo where study success was predetermined as ≥51% probability of ≥25% slowing of disease progression on the iADRS (which controls the false positive rate at 2.5%). Percent slowing was calculated as (1 − DPR) × 100.

Secondary study endpoints included mixed model repeated measures (MMRM) analysis of changes in ADAS-Cog13 score, Alzheimer's Disease Cooperative Study–Instrumental Activities of Daily Living Inventory (ADCS-iADL) score, Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) score, and MMSE score.

The change from the baseline score at each planned postbaseline visit during the treatment phase was the dependent variable. The key time point for treatment comparison was at week 104. Visit was considered a categorical variable. The model for the fixed effects included pooled investigator, baseline score, age at baseline, concomitant AChEI and/or memantine use at baseline (yes/no), treatment, visit, treatment-by-visit interaction, and baseline-by-visit interaction. Both MMRM and DPM models assume that missing data are missing at random.

Fluid biomarker and imaging methods are in the eMethods section (links.lww.com/WNL/D391).

Safety

In addition to AE reporting, physical examinations, vital signs and weight monitoring, ECG monitoring, laboratory assessments, neurologic examinations, MRI assessments, immunogenicity testing, and assessments of suicidal ideation and behavior were included to facilitate a comprehensive safety evaluation. An independent external data-monitoring committee held periodic reviews of unblinded safety data.

Data Availability

Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after primary publication acceptance. For details of submitting a request, see the instructions provided at vivli.org.

Results

Patients

A total of 1,319 participants consented for screening of whom 360 participants were randomized (Figure 1). The most commonly reported reason for screen failure was not meeting flortaucipir PET requirements (n = 550 [41.7%]). The safety population (N = 360) consisted of all randomized participants who received at least 1 dose of double-blind treatment (1,400 mg [n = 126], 5,600 mg [n = 116], or placebo [n = 118]). A total of 218 participants completed treatment (1,400 mg [n = 76], 5,600 mg [n = 70], or placebo [n = 72]) (Figure 1). A total of 142 participants (39.4%) were discontinued from treatment (1,400 mg [n = 50], 5,600 mg [n = 46], or placebo [n = 46]). The most frequent reason for discontinuation was “withdrawal by subject,” reported in 93 participants (25.8%). There were 4 (3.2%), 2 (1.7%), and 2 (1.7%) discontinuations due to AEs in the 1,400 mg, 5,600 mg, and placebo arms, respectively. The effect of COVID-19 was similar in all arms.

Of the placebo, 1,400 mg, and 5,600 mg groups, 44.9%, 57.1%, and 56.0% were female; 83.1%, 84.1%, and 82.8% were White; and 72.9%, 70.2%, and 69.8% were apolipoprotein E allele 4 carriers, respectively (Table 1). The average age was 75.4 years (75.3 for placebo, 75.1 for 1,400 mg, and 75.7 years for 5,600 mg). The baseline tau levels (whole brain with white matter SUVR as measured by flortaucipir) were 1.22, 1.22, and 1.24, and the MMSE score was 23.65, 23.84, and 23.51 for the placebo, 1,400 mg, and 5,600 mg groups, respectively.

Table 1.

Demographics and Baseline Characteristics of the Population

	Placebo (N = 118)	1,400 mg (N = 126)	5,600 mg (N = 116)	Total (N = 360)
Female, n (%)	53 (44.9)	72 (57.1)	65 (56.0)	190 (52.8)
Mean age, y	75.3	75.1	75.7	75.4
AChEI or memantine use at baseline, n (%)	80 (67.8)	78 (61.9)	68 (58.6)	226 (62.8)
APOE4 carrier, n (%)	86 (72.9)	87 (70.2)	81 (69.8)	254 (70.9)
Race, n (%)
Asian	18 (5.3)	18 (4.3)	17 (14.7)	53 (14.7)
Black or African American	2 (1.7)	2 (1.6)	2 (1.7)	6 (1.7)
Native Hawaiian or other Pacific Islander	0 (0.0)	0 (0.0)	1 (0.9)	1 (0.3)
White	98 (83.1)	106 (84.1)	96 (82.8)	300 (83.3)
Ethnicity, Hispanic/Latino	4 (3.4)	3 (2.4)	3 (2.6)	10 (2.8)
Education, ≥13 y	80 (67.8)	87 (69.0)	75 (64.7)	242 (67.2)
Flortaucipir PET SUVR,a mean (SD)	1.22 (0.117)	1.22 (0.115)	1.24 (0.112)	1.23 (0.115)
Clinical assessments, scale, mean (SD)
iADRS	103.50 (13.51)	105.96 (13.34)	103.60 (11.65)	104.39 (12.90)
ADAS-Cog13	28.78 (7.82)	28.08 (8.37)	29.63 (7.23)	28.81 (7.84)
ADCS-iADL	47.28 (8.34)	49.24 (7.52)	48.25 (6.81)	48.28 (7.61)
CDR-SB	4.03 (2.23)	3.61 (1.96)	3.88 (2.04)	3.84 (2.08)
MMSE	23.65 (2.81)	23.84 (2.95)	23.51 (2.72)	23.67 (2.83)

Abbreviations: AChEI = acetylcholinesterase inhibitor; AD = Alzheimer disease; ADAS-Cog13 = Alzheimer's Disease Assessment Scale–Cognitive 13-item subscale; ADCS-ADL = Alzheimer's Disease Cooperative Study–Activities of Daily Living scale; ADCS-iADL = Alzheimer's Disease Cooperative Study–Instrumental Activities of Daily Living subscale; CDR-SB = Clinical Dementia Rating Scale–Sum of Boxes; iADRS = Integrated Alzheimer’s Disease Rating Scale; MMSE = Mini-Mental State Examination; N = number of participants in the population; n = number of participants in the specified category; SUVR = standardized uptake value ratio.

Note: n = number of participants with nonmissing data, used as a denominator in categorical data (unless specified).

^aAD signature-weighted neocortical region,^8,10 and a participant-specific white matter reference region.⁹

Clinical Assessments

Neither zagotenemab arm showed slowing in rate of clinical decline as assessed by iADRS across 104 weeks compared with placebo (Figure 2). The mean of the Bayesian posterior distribution of the DPR comparing zagotenemab 1,400 mg with placebo and 5,600 mg with placebo was 1.10 (95% credible interval [CrI] 0.96–1.27) and 1.05 (95% CrI 0.91–1.21), respectively (eTable 1, links.lww.com/WNL/D392). The corresponding predicted percent slowing compared with placebo was −10.0% (95% CrI −26.5% to 4.1%) and −5.0% (95% CrI −20.9% to 9.3%) for 1,400 mg and 5,600 mg groups, respectively (Figure 2, eTable 1), where a negative percent indicates slower progression in placebo vs the indicated treatment groups. The posterior probability of achieving ≥25% slowing of disease progression on the iADRS was less than 0.01% for each zagotenemab arm, indicating that PERISCOPE-ALZ did not meet its primary success criteria. Consistent with the primary endpoint, no meaningful slowing of clinical decline rate, compared with placebo, was observed for ADCS-iADL, ADAS-Cog13, CDR-SB, or MMSE using the DPM (Figure 2, eTable 1).

Figure 2. Percent Slowing of Disease Progression with Zagotenemab.

% slowing = (1 − DPR) × 100, where DPR = percent change of the treatment group/percent change of the placebo group. Posterior mean change from baseline and 95% credible intervals were derived using the Bayesian disease progression model. ADAS-Cog = Alzheimer's Disease Assessment Scale; ADCS-iADL = Alzheimer's Disease Cooperative Study–Instrumental Activities of Daily Living Inventory; CDR-SB = Clinical Dementia Rating–Sum of the Boxes; iADRS = Integrated Alzheimer's Disease Rating Scale; MMSE = Mini-Mental State Examination. Note: Study success predefined as 25% slowing on iADRS (bold = primary endpoint).

Similarly, no meaningful slowing in clinical decline at 104 weeks, compared with placebo, was observed for any clinical assessments using the MMRM-based analysis (Figure 3). However, the MMRM least squares mean (LSM) ADCS-iADL change from baseline at week 104 showed a nominally significant increase in clinical decline rate of the 5,600 mg arm compared with placebo. The change from baseline ± standard error (SE) was −6.29 ± 0.958 in the placebo group, −8.64 ± 0.953 in the 1,400 mg group, and −9.12 ± 0.974 in the 5,600 mg group. The LSM change difference from placebo ± SE at week 104 for the 1,400 mg and 5,600 mg groups was −2.35 ± 1.363, uncorrected p = 0.086, and −2.83 ± 1.367, uncorrected p = 0.040, respectively. Post hoc MMRM analysis of the CDR subcategory box scores of the zagotenemab treatment arms vs placebo did not demonstrate any significant groupwise differences at 104 weeks on combined cognitive (Memory, Orientation, Judgment & Problem Solving) or combined functional (Community Affairs, Home & Hobby, Personal Care) components, or by independent subcategory scores.

Figure 3. LS Mean Change of Clinical Assessments From Baseline Based on MMRM Analysis.

ADAS-Cog = Alzheimer's Disease Assessment Scale; ADCS-iADL = Alzheimer's Disease Cooperative Study–Instrumental Activities of Daily Living Inventory; CDR-SB = Clinical Dementia Rating–Sum of the Boxes; iADRS = Integrated Alzheimer's Disease Rating Scale; LS = least squares; MMSE = Mini-Mental State Examination. *Unadjusted, 2-sided p value = 0.04 vs placebo.

Aggregated Tau Deposition

There were no significant differences at week 104 on global or regional analyses with either zagotenemab dose group compared with placebo as measured by flortaucipir PET. Figure 4A shows the changes over time for the bilateral: whole-brain, frontal, parietal, and lateral temporal regions.

Figure 4. LS Mean Change of (A) Aggregated Tau Deposition (SUVR) as Determined by Flortaucipir PET and (B) Plasma Biomarkers From Baseline Based on MMRM Analysis.

LS = least squares; NfL = neurofilament light; p-tau = phosphorylated tau; SE = standard error; SUVR = standardized uptake value ratio; Wk = week. Note: Modified cerebellar grey used as a reference region.

Plasma Biomarkers

Over 104 weeks, 1,400 mg and 5,600 mg groups showed a significant increase from baseline of plasma total tau compared with placebo (p < 0.001). The LSM changes from baseline to week 104 (SE) in the placebo, 1,400 mg, and 5,600 mg groups were 13.02 (34.93) pg/mL, 266.50 (34.10) pg/mL, and 739.60 (35.15) pg/mL, respectively.

Over 104 weeks, 1,400 mg and 5,600 mg groups showed a significant increase from baseline of phosphorylated tau (p-tau)181 compared with placebo (p < 0.001). The LSM changes from baseline to week 104 (SE) in the placebo, 1,400 mg, and 5,600 mg groups were −0.84 (1.36) pg/mL, 16.49 (1.32) pg/mL, and 33.51 (1.37) pg/mL, respectively (Figure 4B).

Neither the zagotenemab-treated group resulted in significant change from baseline in neurofilament light chain (NfL) compared with the placebo group. The log-transformed LSM changes from baseline to week 104 (SE) in the placebo, 1,400 mg, and 5,600 mg groups were 0.14 (0.032) pg/mL, 0.09 (0.031) pg/mL, and 0.12 (0.032) pg/mL, respectively (Figure 4B).

Changes in Brain Volume

There were no statistically significant changes in brain volume in either of the zagotenemab dose groups compared with the placebo group in any of the 14 brain regions over 104 weeks as measured by volumetric MRI (vMRI). eFigure 2 (links.lww.com/WNL/D390) shows the changes over time for the bilateral: whole brain, cortical gray, hippocampus, and ventricles.

Safety

Serious AEs and Deaths

Four deaths occurred in the double-blind period of the study, 2 in the placebo group (1 due to respiratory distress and 1 due to COVID-19 infection) and 1 in each of the zagotenemab treatment groups (1,400 mg—due to COVID-19 infection and 5,600 mg—cause of death unknown) (Table 2). None of the deaths were judged by study investigators as likely related to study drug. A total of 54 participants (15%) reported serious AEs (SAEs): 14 (11.9%) with placebo, 22 (17.5%) with 1,400 mg, and 18 (15.5%) with 5,600 mg zagotenemab (Table 2). Syncope was the only SAE experienced by >1% of the population: 2 (1.7%), 2 (1.6%), and 1 (0.9%) in the placebo, 1,400 mg, and 5,600 mg arms, respectively. A complete list can be found on ClinicalTrials.gov.⁷ Discontinuations due to any AE were also balanced among treatment arms: 4 (3.4%) with placebo, 5 (4.0%) with 1,400 mg, and 3 (2.6%) with 5,600 mg zagotenemab. COVID-19 infection was the only AE that resulted in more than 1 discontinuation.

Table 2.

Overview of Adverse Events

	Placebo (N = 118), n (%)	1,400 mg (N = 126), n (%)	5,600 mg (N = 116), n (%)
TEAEs	88 (74.6)	105 (83.3)	101 (87.1)
Deaths	2 (1.7)	1 (0.8)	1 (0.9)
SAEs	14 (11.9)	22 (17.5)	18 (15.5)
AEs leading to discontinuation	4 (3.4)	5 (4.0)	3 (2.6)

Abbreviations: AE = adverse event; N = number of patients in the treatment arm; n = number of patients in the subgroup; SAE = serious AE; TEAE = treatment-emergent AE.

Treatment-Emergent AEs

Treatment-emergent AEs (TEAEs) were reported by 88 (74.6%) participants in the placebo group, 105 (83.3%) in the zagotenemab 1,400 mg group, and 101 (87.1%) in the zagotenemab 5,600 mg group. Of the TEAEs reported by the placebo group, 33.1% were mild, 36.4% were moderate, and 5.1% were severe. Of the TEAEs reported by the 1,400 mg and 5,600 mg groups, 30.2% and 40.5% were mild, 39.7% and 31.0% were moderate, and 13.5% and 15.5% were severe. No severe TEAEs were experienced more than once in any arm except for COVID-19, pneumonia, and hip fracture. Fall, dizziness, diarrhea, urinary tract infection, arthralgia, nasopharyngitis, skin laceration, and anxiety occurred in more than 5% of the overall population (Table 3; an expanded list can be found at ClinicalTrials.gov).⁷ Participants in the zagotenemab 1,400 mg group reported gait disturbance and rash (6 [4.8%] for both) at a higher frequency than the placebo group (0 [0%] for both). COVID-19 infection was reported by 3 (2.5%), 2 (1.6%), and 5 (4.3%) participants in the placebo, low-dose, and high-dose arms.

Table 3.

TEAEs Occurring in >5% of Total Participants

Preferred term	Placebo (N = 118)	1,400 mg (N = 126)	5,600 mg (N = 116)	Total (N = 360)	1,400 mg vs placebo OR (95% CI)	5,600 mg vs placebo OR (95% CI)
Participants with ≥1 TEAE	88 (74.6)	105 (83.3)	101 (87.1)	294 (81.7)	1.70 (0.91–3.19)	2.30 (1.16–4.54)
Fall	16 (13.6)	18 (14.3)	15 (12.9)	49 (13.6)	1.06 (0.51–2.20)	0.95 (0.44–2.02)
Dizziness	10 (8.5)	10 (7.9)	11 (9.5)	31 (8.6)	0.93 (0.37–2.32)	1.13 (0.46–2.78)
Diarrhea	5 (4.2)	10 (7.9)	11 (9.5)	26 (7.2)	1.95 (0.65–5.88)	2.37 (0.80–7.04)
Urinary tract infection	6 (5.1)	12 (9.5)	8 (6.9)	26 (7.2)	1.96 (0.71–5.42)	1.38 (0.46–4.12)
Arthralgia	9 (7.6)	7 (5.6)	9 (7.8)	25 (6.9)	0.71 (0.26–1.98)	1.02 (0.39–2.66)
Nasopharyngitis	12 (10.2)	5 (4.0)	8 (6.9)	25 (6.9)	0.37 (0.12–1.07)	0.65 (0.26–1.66)
Skin laceration	7 (5.9)	9 (7.1)	7 (6.0)	23 (6.4)	1.22 (0.44–3.39)	1.02 (0.35–3.00)
Anxiety	7 (5.9)	4 (3.2)	9 (7.8)	20 (5.6)	0.52 (0.15–1.82)	1.33 (0.48–3.71)

Abbreviations: N = number of patients in the treatment arm; OR = odds ratio; TEAE = treatment-emergent adverse event.

Anti-Drug Antibodies

Of the 241 participants across both zagotenemab arms with evaluable predose and postdose anti-drug antibody (ADA) samples, 2 from the 1,400 mg group and 1 from the 5,600 mg group showed treatment-emergent ADAs. The titer of all 3 participants was low (≤1:320) and returned to baseline at subsequent visits.

Hypersensitivity and Infusion-Related Reactions

Serious hypersensitivity reactions (moderate lip swelling and severe angioedema) occurred ∼6 and 8 months after first dose, respectively, in the same participant (1,400 mg group) and were not deemed related to study drug by the investigator. Both reactions resolved and did not reoccur with restarting of drug, and the participant completed the study.

Infusion-related reactions (IRRs) were reported by 2 other study participants: 1 mild in the 5,600 mg group and 1 serious and severe in the 1,400 mg group. Both participants continued in the study with no further IRRs reported.

Additional information, including the number of participants analyzed by country, discontinuations from study rather than treatment, and the number of participants with suicidal ideation and behaviors assessed by the Columbia Suicide Severity Rating Scale, can be found on ClinicalTrials.gov.⁷

Classification of Evidence: The primary question of the investigation was whether zagotenemab slows cognitive and functional decline in participants with early symptomatic AD. This study provides Class II evidence that for patients with early symptomatic AD, zagotenemab does not slow clinical disease progression.

Discussion

PERISCOPE-ALZ did not meet its primary objective of demonstrating a significant slowing of disease progression on the primary outcome measure, the iADRS, for those treated with zagotenemab compared with placebo. Similarly, prespecified secondary and exploratory clinical measures did not show evidence of a treatment effect on slowing of disease progression across 104 weeks. In addition, there was no evidence of disease-modifying effects seen on predefined biomarker outcome measures using tau PET, vMRI, or plasma NfL. Measures of plasma p-tau181 and total tau demonstrated a dose-related increase in plasma concentration.

Neither the primary statistical evaluation using Bayesian DPM nor the MMRM demonstrated slowing of progression associated with zagotenemab treatment on combined cognitive and functional impairment (iADRS and CDR-SB) or cognition-only (ADAS-Cog13 and MMSE) assessments. However, the MMRM analysis of the only independent measure of function collected (ADCS-iADL) showed a more rapid decline in the 5,600 mg group compared with placebo at 104 weeks (uncorrected for multiple drug arms or multiple comparison) (Figures 2 and 3, and eTable 1, links.lww.com/WNL/D392). This separation from placebo was not seen at any other timepoint. This finding of functional worsening in those treated with 5,600 mg of zagotenemab was not supported by results on the total CDR-SB scores nor by changes in the functional components of the CDR. In the course of AD, it is typical that functional decline presents after, and as a result of, notable cognitive decline, which was not clearly seen in this case.^17,18 However, we must consider the possibility that zagotenemab resulted in cumulative worsening because participants who received the low dose had, on average, numerically greater decline than those who received placebo on the iADRS, CDR-SB, ADAS-Cog13, and MMSE as well. Additional research would be required to understand whether zagotenemab had a true negative effect on function.

During the double-blind period, participants in the zagotenemab arms reported a higher incidence of TEAEs (most notably the proportion of severe TEAEs) and SAEs compared with the placebo arm. These differences were not obviously attributable to any specific AE or category of AE by the body organ system.

Consistent with the absence of positive cognitive and functional benefit of zagotenemab intervention, no biomarker evidence was found to support the hypothesis that zagotenemab reduced cortical spread of AD-related tauopathy or pathologic disease progression. Expected results in flortaucipir PET, vMRI, and NfL were demonstrated for placebo, consistent with the natural history of AD progression.^8,19,20 There was a dose-dependent increase in plasma p-tau181 and total tau, as would be expected because of antibody binding to soluble tau species in the periphery. Although zagotenemab has a high affinity for aggregated tau over monomeric tau (1,000-fold specificity),²¹ the peripheral increase in plasma tau is likely due to weak binding of peripheral monomeric tau species. Antibody binding of tau protein is expected to increase the apparent elimination half-life of tau, thereby increasing blood concentrations in a time-dependent and dose-dependent fashion, as was observed. The possibility of increased turnover of soluble tau from the CNS cannot be excluded, but no conclusion can be made from these results about central target engagement of aggregated tau.

The lack of efficacy signal from this study should be interpreted in the context of the study design and operational effectiveness, and the underlying mechanistic hypothesis for zagotenemab. Overall, this 2-year study completed successfully and was sufficiently powered to detect an efficacy signal on the predetermined outcome measures. Randomization, blinding, and longitudinal monitoring were successful in capturing and following the balanced cohorts across study arms. The placebo group behaved as expected for an early symptomatic AD population in terms of clinical measure^14,22 and biomarker progression.^23,24

The role of tau in the pathogenesis of AD is not fully understood. In this study, the lack of efficacy may arguably be attributable to the mechanism of action of zagotenemab or, alternatively, reflect a failed hypothesis about the importance of extraneuronal tau spread in the pathogenesis of AD. The proposed mechanism of clinical benefit is based on the hypothesis that extraneuronal tau spread is a key driver of pathologic and clinical progression of AD, and zagotenemab would act to neutralize extracellular tau seeds to prevent further spread. If the hypothesis of transneuronal spread-driving tau propagation is indeed true, zagotenemab, even at high doses, was not sufficient to curtail tau propagation to a degree detectable by flortaucipir PET imaging or translatable into an appreciable clinical or disease-modifying effect. Alternatively, it is possible that extraneuronal tau species are not accessible to zagotenemab if spread is occurring within exosomes, extracellular vesicles, or between cells, rather than exposed in the interstitial fluid,²⁵ or potentially, extraneuronal tau spread may simply not be a prominent mechanism by which tau pathology evolves in AD. There was no direct biomarker evidence of central tau target engagement. As we cannot claim with certainty that zagotenemab was binding to central aggregated tau, this study does not provide information about the potential therapeutic benefit of reducing extracellular tau. In addition, the disease stage of participants in this study with intermediate tau levels may in fact be too late in pathologic progression to see an effect with this mechanism of drug action. In total, these findings do not invalidate tau as an important target in AD but have yet to provide evidence that a large molecule approach to treating tauopathy is viable. PERISCOPE-ALZ is now one of several reported negative phase 2 studies assessing the efficacy of anti-tau antibodies in early AD (including but not limited to NCT02880956, NCT03289143,²⁶ and NCT03352557). Binding properties of different anti-tau molecules may result in evidence of efficacy in ongoing and future AD trials.

There are several notable strengths to this study. Dosing was believed to be sufficient to achieve acceptable brain penetrance and central target binding, as evidenced by a 0.15%–0.28% cerebral spinal fluid to serum concentration ratio in phase 1 (NCT03019536). This suggested that 1,500 mg of zagotenemab should provide an ample pharmacodynamic effect. Another strength of the study was the pathologically defined cohort with intermediate levels of brain tau burden. This homogeneous population would likely show sufficient clinical disease progression during the study. Individuals with high levels of tau pathology indicative of a later stage of tauopathy and who were not as likely to respond to a drug designed to slow further spread of cortical tau were also excluded. Furthermore, a treatment duration of 24 months most likely provided sufficient opportunity to identify an efficacy signal, compared with typical shorter duration clinical trial designs. Other unique aspects of the study intended to increase the likelihood of trial success included the use of a novel composite endpoint, the iADRS, in combination with a statistical DPM that more efficiently uses measurements throughout the study duration (rather than overly weighting the last timepoint), which has been demonstrated to have improved signal-to-noise detection compared with clinical endpoint measures that do not include combined measures of both cognition and function.¹⁵ Overall, this study successfully tested the hypothesis that zagotenemab would show clinical benefit or disease-modifying effects in an early symptomatic Alzheimer population with intermediate levels of brain tau on flortaucipir PET.

There were several limitations to this study. The small sample size of this phase 2 study was further compounded by missing data and infusions due to COVID-19 quarantines, study site staffing limitations, and dropouts. As COVID-19 infection can potentially affect cognitive abilities, it is possible to have impacted study endpoints; however, we believe that this is unlikely due to the low number of participants who reported COVID-19 infection. Competition for other clinical trials also contributed to the higher-than-expected dropout. Despite these challenges, the study treatment arms and completers remained well balanced and sufficiently powered to give confidence in the findings presented here and thus had a minimal effect on the study. Another limitation is that the selection of a homogeneous population based on intermediate tau pathology is not broadly generalizable to the entire spectrum of real-world AD population. In addition, subsequent to the launch of this study, it was demonstrated in an autopsy comparison study that flortaucipir has limited sensitivity to early stages of AD pathology and largely selects those with Braak stage V and VI tau pathology,¹¹ suggesting that even an “intermediate” stage of disease may have relatively widely distributed tau spread throughout the brain. Finally, this population was also limited in racial and ethnic diversity (Table 1), further challenging its generalizability.

In conclusion, zagotenemab did not slow clinical decline as assessed by the iADRS at 104 weeks compared with placebo. Participants in the zagotenemab arms reported a higher incidence of TEAEs compared with the placebo arm, but these differences were not attributable to any specific AE or category of AEs. Further research is needed to understand the viability of anti-tau monoclonal antibody therapy approaches to treating and preventing AD.

Glossary

AChEI

acetylcholinesterase inhibitor

AD

Alzheimer disease

ADA

anti-drug antibody

ADAS-Cog13

Alzheimer's Disease Assessment Scale–Cognitive 13-item subscale

ADCS-ADL

Alzheimer's Disease Cooperative Study–Activities of Daily Living scale

ADCS-iADL

Alzheimer's Disease Cooperative Study–Instrumental Activities of Daily Living subscale

AE

adverse event

CDR-SB

Clinical Dementia Rating Scale–Sum of Boxes

CrI

credible interval

COVID-19

coronavirus disease 2019

DPM

disease progression model

DPR

disease progression ratio

iADRS

Integrated AD Rating Scale

IRR

infusion-related reaction

LSM

least squares mean

MMRM

mixed model repeated measures

MMSE

Mini-Mental State Examination

NfL

neurofilament light chain

p-tau

phosphorylated tau

SAE

serious AE

SE

standard error

SUVR

standardized uptake value ratio

TEAE

treatment-emergent AE

vMRI

volumetric MRI

Appendix 1. Authors

Name	Location	Contribution
Adam S. Fleisher, MD, MAS	Eli Lilly and Company, Indianapolis, IN	Data acquisition, analysis, and interpretation; drafting and critical revision of the manuscript; provided final approval of the version to be published
Leanne M. Munsie, BS	Eli Lilly and Company, Indianapolis, IN	Design of the study; data acquisition, analysis, and interpretation; manuscript drafting and critical revision; provided final approval of the version to be published
David G.S. Perahia, MD	Eli Lilly and Company, Indianapolis, IN	Data interpretation; critical revision of the manuscript; provided final approval of the version to be published
Scott W. Andersen, MS	Eli Lilly and Company, Indianapolis, IN	Data analysis and interpretation; critical revision of the manuscript; provided final approval of the version to be published
Ixavier A. Higgins, PhD	Eli Lilly and Company, Indianapolis, IN	Data analysis and interpretation; drafting of the manuscript; provided final approval of the version to be published
Paula M. Hauck, PhD	Eli Lilly and Company, Indianapolis, IN	Data interpretation; drafting and critical revision of the manuscript; provided final approval of the version to be published
Albert C. Lo, MD, PhD	Eli Lilly and Company, Indianapolis, IN; Kisbee Therapeutics, Cambridge, MA	Conceptualization and design of the study; data acquisition, analysis, and interpretation; critical revision of the manuscript; provided final approval of the version to be published
John R. Sims, MD	Eli Lilly and Company, Indianapolis, IN	Conceptualization of the study; critical revision of the manuscript; provided final approval of the version to be published
Miroslaw Brys, MD, PhD	Eli Lilly and Company, Indianapolis, IN	Data interpretation; critical revision of the manuscript; provided final approval of the version to be published
Mark Mintun, MD	Eli Lilly and Company, Indianapolis, IN	Conceptualization and design of the study; data acquisition and interpretation; critical revision of the manuscript; provided final approval of the version to be published

Appendix 2. Coinvestigators

Coinvestigators are listed at links.lww.com/WNL/D393.

Study Funding

This study was supported by Eli Lilly and Company, Indianapolis, IN.

Disclosure

A.S. Fleisher is a full-time employee and minor stockholder of Eli Lilly and Company. L.M. Munsie is a full-time employee and minor stockholder of Eli Lilly and Company. D.G.S. Perahia is a full-time employee and minor stockholder of Eli Lilly and Company. S.W. Andersen is a full-time employee and minor stockholder of Eli Lilly and Company. I.A. Higgins is a full-time employee and minor stockholder of Eli Lilly and Company. P.M. Hauck is a full-time employee and minor stockholder of Eli Lilly and Company. A.C. Lo is a former full-time employee and minor stockholder of Eli Lilly and Company. J.R. Sims is a full-time employee and minor stockholder of Eli Lilly and Company. M. Brys is a full-time employee and minor stockholder of Eli Lilly and Company. M. Mintun is a full-time employee and minor stockholder of Eli Lilly and Company. Go to Neurology.org/N for full disclosures.