Trial Outcomes & Findings for A Study of Lu AF82422 in Participants With Multiple System Atrophy (NCT NCT05104476)

Last Updated: 2026-01-29

Results Overview

The primary endpoint assessed disease progression by a Bayesian repeated measures model on UMSARS TS. Reported here is the estimated slowing (%) of clinical progression in participants receiving Lu AF82422 relative to those receiving placebo. UMSARS is a combined clinician and patient-reported outcome assessment developed to provide a surrogate measure of disease progression in multiple system atrophy (MSA). UMSARS TS was obtained by the sum of the items from Part I and Part II. Part I assesses historical information on symptoms and activities of daily living over the past 2 weeks and Part II consists of a clinical examination of key MSA motor signs and symptoms. UMSARS TS score was the sum of all items and ranged from 0 (no impairment) to 104 (severe impairment). A higher score indicated greater impairment.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE2

Target enrollment

64 participants

Primary outcome timeframe

Baseline up to Week 72

Results posted on

2026-01-29

Participant Flow

This study included a Placebo-controlled Double-blind Period (DBP) (48 weeks up to 72 weeks) and an Optional Open-label Extension (OLE) Period (96 weeks). Individual participant End of Trial (EOT) DBP will vary from 48 to 72 weeks. Once the last participant reaches week 48, the remaining participants will have their next scheduled visit converted to EOT DBP.

The data for DBP has been reported. The optional OLE period data will be reported after study completion.

Participant milestones

Participant milestones
Measure	Placebo Participants received Lu AF82422 matching placebo IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.	Lu AF82422 Participants received Lu AF82422 IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.
Overall Study STARTED	22	42
Overall Study Received at Least 1 Dose of Study Drug	21	40
Overall Study COMPLETED	16	32
Overall Study NOT COMPLETED	6	10

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants received Lu AF82422 matching placebo IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.	Lu AF82422 Participants received Lu AF82422 IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.
Overall Study Randomized But Not Treated	1	2
Overall Study Adverse Event	2	2
Overall Study Withdrawal by Subject	3	3
Overall Study Other Than Specified	0	3

Baseline Characteristics

A Study of Lu AF82422 in Participants With Multiple System Atrophy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=21 Participants Participants received Lu AF82422 matching placebo IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.	Lu AF82422 n=40 Participants Participants received Lu AF82422 IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.	Total n=61 Participants Total of all reporting groups
Age, Continuous	59.8 years STANDARD_DEVIATION 6.85 • n=35 Participants	61.4 years STANDARD_DEVIATION 8.09 • n=4328 Participants	60.8 years STANDARD_DEVIATION 7.67 • n=8687 Participants
Sex: Female, Male Female	10 Participants n=35 Participants	19 Participants n=4328 Participants	29 Participants n=8687 Participants
Sex: Female, Male Male	11 Participants n=35 Participants	21 Participants n=4328 Participants	32 Participants n=8687 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=35 Participants	0 Participants n=4328 Participants	0 Participants n=8687 Participants
Race (NIH/OMB) Asian	5 Participants n=35 Participants	12 Participants n=4328 Participants	17 Participants n=8687 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=35 Participants	0 Participants n=4328 Participants	0 Participants n=8687 Participants
Race (NIH/OMB) Black or African American	1 Participants n=35 Participants	1 Participants n=4328 Participants	2 Participants n=8687 Participants
Race (NIH/OMB) White	15 Participants n=35 Participants	26 Participants n=4328 Participants	41 Participants n=8687 Participants
Race (NIH/OMB) More than one race	0 Participants n=35 Participants	0 Participants n=4328 Participants	0 Participants n=8687 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=35 Participants	1 Participants n=4328 Participants	1 Participants n=8687 Participants
Unified Multiple System Atrophy Rating Scale (UMSARS) Part I and Part II Total Score (UMSARS TS)	37 units on a scale STANDARD_DEVIATION 7.77 • n=35 Participants	34.8 units on a scale STANDARD_DEVIATION 9 • n=4328 Participants	35.5 units on a scale STANDARD_DEVIATION 8.59 • n=8687 Participants

PRIMARY outcome

Timeframe: Baseline up to Week 72

Population: Full analysis set (FAS) included all randomized participants who received at least 1 dose of double-blind IMP and had a valid baseline assessment and at least 1 valid post-baseline assessment of the UMSARS TS, prior to, or at withdrawal from treatment.

Outcome measures

Outcome measures
Measure	Lu AF82422 or Placebo n=61 Participants Participants received Lu AF82422 or Placebo IV infusion Q4W from Baseline for a minimum of 48 weeks up to a maximum 72 weeks in the DB period.	Lu AF82422 Participants received Lu AF82422 IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.
Percentage Slowing of Clinical Progression Based on Change From Baseline in the UMSARS TS at the End of Treatment (EOT) DB Period (DBP)	19 Percentage Slowing of Clin. Progression	—

SECONDARY outcome

Timeframe: Baseline, Weeks 48 and 72

Population: FAS included all randomized participants who received at least 1 dose of double-blind IMP and had a valid baseline assessment and at least 1 valid post-baseline assessment of the UMSARS TS, prior to, or at withdrawal from treatment. 'Overall number of participants analyzed' = participants evaluable for this outcome measure. 'Number analyzed' = participants evaluable at specified timepoint.

UMSARS is a combined clinician and patient-reported scale to assess motor impairment in MSA participants. UMSARS TS was obtained by the sum of the items from Part I and Part II. Part I assesses historical information on symptoms and activities of daily living over the past 2 weeks (12 items) rated on a scale ranging from 0 = not affected to 4 = unable to do the activity. Part I total score ranged between 0 to 48 (higher score indicated greater impairment). Part II consists of a clinical examination of key MSA motor signs and symptoms (14 items) rated on a scale ranging from 0 = normal to 4 = marked/severe impairment. Part II total score ranged between 0 and 56 (higher score indicated greater impairment). UMSARS TS score was the sum of all 26 items and ranged from 0 (no impairment) to 104 (severe impairment). A higher score indicated greater impairment. LS mean and SE were calculated using MMRM.

Outcome measures

Outcome measures
Measure	Lu AF82422 or Placebo n=16 Participants Participants received Lu AF82422 or Placebo IV infusion Q4W from Baseline for a minimum of 48 weeks up to a maximum 72 weeks in the DB period.	Lu AF82422 n=37 Participants Participants received Lu AF82422 IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.
Change From Baseline in the UMSARS TS at the End of Treatment (EOT) DBP Change at Week 48	13.93 units on a scale Standard Error 3.42	13.32 units on a scale Standard Error 2.86
Change From Baseline in the UMSARS TS at the End of Treatment (EOT) DBP Change at Week 72	19.13 units on a scale Standard Error 3.74	15.10 units on a scale Standard Error 3.00

SECONDARY outcome

Timeframe: Baseline, Weeks 48 and 72

UMSARS Part 1 assesses historical information on symptoms and activities of daily living over the past 2 weeks as reported by participants and caregivers (12 items) rated on a scale ranging from 0 to 4; with 0 = not affected/normal 1= mildly affected/impaired, 2= moderately affected/impaired, 3= severely affected/impaired, and 4 = helpless or entirely affected/impaired. The modified UMSARS part I (mUMSARS) score was derived by collapsing the response option 0 and 1 within each item (0 \& 1 =1). Hence, the mUMSARS score ranged from 12 to 48 (higher score indicated greater impairment). LS mean and SE were calculated using MMRM.

Outcome measures

Outcome measures
Measure	Lu AF82422 or Placebo n=17 Participants Participants received Lu AF82422 or Placebo IV infusion Q4W from Baseline for a minimum of 48 weeks up to a maximum 72 weeks in the DB period.	Lu AF82422 n=38 Participants Participants received Lu AF82422 IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.
Change From Baseline in the Modified UMSARS Part I (mUMSARS) Score at the EOT DBP Change at Week 48	7.07 units on a scale Standard Error 1.62	6.48 units on a scale Standard Error 1.33
Change From Baseline in the Modified UMSARS Part I (mUMSARS) Score at the EOT DBP Change at Week 72	8.40 units on a scale Standard Error 2.00	8.77 units on a scale Standard Error 1.44

SECONDARY outcome

Timeframe: Baseline, Weeks 48 and 72

UMSARS Part 1 assesses historical information on symptoms and activities of daily living over the past 2 weeks as reported by participants and caregivers (12 items: speech, swallowing, handwriting, cutting food and handling utensils, dressing, hygiene, walking, falling, orthostatic symptoms, urinary function, sexual function, and bowel function) each rated on a scale ranging from 0 to 4; with 0 = not affected/normal 1= mildly affected/impaired, 2= moderately affected/impaired, 3= severely affected/impaired, and 4 = helpless or entirely affected/impaired. Part I total score ranged between 0 to 48 (higher score indicated greater impairment). LS mean and SE were calculated using MMRM.

Outcome measures

Outcome measures
Measure	Lu AF82422 or Placebo n=17 Participants Participants received Lu AF82422 or Placebo IV infusion Q4W from Baseline for a minimum of 48 weeks up to a maximum 72 weeks in the DB period.	Lu AF82422 n=38 Participants Participants received Lu AF82422 IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.
Change From Baseline in the UMSARS Part I Scores at the EOT DBP Change at Week 48	7.64 units on a scale Standard Error 1.92	6.98 units on a scale Standard Error 1.59
Change From Baseline in the UMSARS Part I Scores at the EOT DBP Change at Week 72	8.49 units on a scale Standard Error 2.21	10.23 units on a scale Standard Error 1.65

SECONDARY outcome

Timeframe: Baseline, Weeks 48 and 72

UMSARS Part II consists of a clinical examination of key MSA motor signs and symptoms (14 items: facial expression, speech, ocular motor dysfunction, tremor at rest, action tremor, increased tone, rapid alternating movements of hands, finger taps, leg agility, heel-knee-shin test, arising from chair, posture, body sway, gait) each rated on a scale ranging from 0 to 4; with 0 = not affected/normal 1= mildly affected/impaired, 2= moderately affected/impaired, 3= severely affected/impaired, and 4 = helpless or entirely affected/impaired. Part II total score ranged between 0 and 56 (higher score indicated greater impairment). LS mean and SE were calculated using MMRM.

Outcome measures

Outcome measures
Measure	Lu AF82422 or Placebo n=16 Participants Participants received Lu AF82422 or Placebo IV infusion Q4W from Baseline for a minimum of 48 weeks up to a maximum 72 weeks in the DB period.	Lu AF82422 n=37 Participants Participants received Lu AF82422 IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.
Change From Baseline in the UMSARS Part II Scores at the EOT DBP Change at Week 48	7.16 units on a scale Standard Error 2.15	6.76 units on a scale Standard Error 1.83
Change From Baseline in the UMSARS Part II Scores at the EOT DBP Change at Week 72	10.24 units on a scale Standard Error 2.38	7.10 units on a scale Standard Error 1.93

SECONDARY outcome

Timeframe: Baseline, Week 48

The SE-ADL is a combined participant- and clinician-reported scale to assess participants physical functioning in activities in daily living to grade functional status. For this study, only the clinician-rated part was administered. The SE-ADL scale uses percentages to represent how much effort and dependence on others, participants need to complete daily chores. The SE-ADL scale ranged from 0% indicating worst possible function (fully dependent) to 100% indicating no impairment (completely independent). LS mean and SE were calculated using MMRM.

Outcome measures

Outcome measures
Measure	Lu AF82422 or Placebo n=16 Participants Participants received Lu AF82422 or Placebo IV infusion Q4W from Baseline for a minimum of 48 weeks up to a maximum 72 weeks in the DB period.	Lu AF82422 n=36 Participants Participants received Lu AF82422 IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.
Change From Baseline in Schwab and England Activities of Daily Living (SE-ADL) Score at Week 48 in the DBP	-23.56 units on a scale Standard Error 7.40	-20.82 units on a scale Standard Error 6.52

SECONDARY outcome

Timeframe: Baseline, Week 48

The CGI-S was administered by an experienced neurologist familiar with MSA participants to make an expert clinical global judgement about the severity of the disease across various time points. The rating was based upon observed and reported symptoms, behaviour, and function in the past seven days. The CGI-S was rated on a scale ranging from 0 to 4 (whereas the 0 = normal, not impaired; 1 = mildly impaired; 2 = moderately impaired; 3 = severely impaired; 4 = extremely impaired). LS mean and SE were calculated using MMRM.

Outcome measures

Outcome measures
Measure	Lu AF82422 or Placebo n=16 Participants Participants received Lu AF82422 or Placebo IV infusion Q4W from Baseline for a minimum of 48 weeks up to a maximum 72 weeks in the DB period.	Lu AF82422 n=36 Participants Participants received Lu AF82422 IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.
Change From Baseline in Clinical Global Impression - Severity of Illness (CGI-S) Score at Week 48 in the DBP	0.58 units on a scale Standard Error 0.17	0.34 units on a scale Standard Error 0.14

SECONDARY outcome

Timeframe: Baseline, Week 48

The PGI-S is a self-reported single item to evaluate all aspects of participants' MSA symptoms. Participants were asked to choose the response that best described the severity of their MSA symptoms over the past week. The question was rated on a 5-point scale ranging from 0 to 4 (0 = none; 1 = minor; 2 = moderate; 3 = severe; 4 = very severe). LS mean and SE were calculated using MMRM.

Outcome measures

Outcome measures
Measure	Lu AF82422 or Placebo n=16 Participants Participants received Lu AF82422 or Placebo IV infusion Q4W from Baseline for a minimum of 48 weeks up to a maximum 72 weeks in the DB period.	Lu AF82422 n=36 Participants Participants received Lu AF82422 IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.
Change From Baseline in Patient Global Impression - Severity of Illness (PGI-S) Score at Week 48 in the DBP	-0.07 units on a scale Standard Error 0.21	0.18 units on a scale Standard Error 0.18

SECONDARY outcome

Timeframe: Baseline, Week 48

The OGI-S is a single-question carer/observer-reported outcome to evaluate all aspects of participants' MSA symptoms. Carer/observers were asked to choose the response that best described the observed severity of MSA symptoms in the person they care for over the past week. The question was rated on a 5-point scale ranging from 0 to 4 (0 = none; 1 = minor; 2 = moderate; 3 = severe; 4 = very severe). LS mean and SE were calculated using MMRM.

Outcome measures

Outcome measures
Measure	Lu AF82422 or Placebo n=11 Participants Participants received Lu AF82422 or Placebo IV infusion Q4W from Baseline for a minimum of 48 weeks up to a maximum 72 weeks in the DB period.	Lu AF82422 n=16 Participants Participants received Lu AF82422 IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.
Change From Baseline in Observer-Reported Global Impression - Severity of Illness (OGI-S) Score at Week 48 in the DBP	0.36 units on a scale Standard Error 0.22	0.20 units on a scale Standard Error 0.18

SECONDARY outcome

Timeframe: Week 48

The COMPASS Select, a participant-reported scale, consists of a subset of 36 items derived from the original COMPASS, to assess severity of autonomic symptoms in MSA during the last year. The COMPASS Select includes 3 domains related to blood pressure control: syncope, orthostatic intolerance, and vasomotor symptoms; and 3 domains focused on symptoms of disturbed secretomotor, bladder, and sleep function. The COMPASS Select Change is a derivate of COMPASS Select, consisting of 16 items in which participants were asked to score their change in autonomic symptoms since their last visit. The scoring algorithm of COMPASS was highly complicated and required computer analysis for score generation. COMPASS Change Select score ranged from -150 to 150. A higher score indicated greater autonomic symptom severity.

Outcome measures

Outcome measures
Measure	Lu AF82422 or Placebo n=17 Participants Participants received Lu AF82422 or Placebo IV infusion Q4W from Baseline for a minimum of 48 weeks up to a maximum 72 weeks in the DB period.	Lu AF82422 n=38 Participants Participants received Lu AF82422 IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.
Composite Autonomic Symptom Score Select Change (COMPASS Select Change) Total Score at Week 48 in the DBP	18.79 units on a scale Standard Deviation 41.98	34.28 units on a scale Standard Deviation 26.86

SECONDARY outcome

Timeframe: Baseline, Week 48

The UMSARS part IV comprised a global disability scale ranging from 1-5, with 1 = 'Completely independent. Able to do all chores with minimal difficulty or impairment. Essentially normal. Unaware of any difficulty'; 2 = 'Not completely independent. Needs help with some chores'; 3 = 'More dependent. Help with half of chores. Spends a large part of the day with chores'; 4 = 'Very dependent. Now and then does a few chores alone or begins alone. Much help needed'; and 5 = 'Totally dependent and helpless. Bedridden'. LS mean and SE were calculated using MMRM.

Outcome measures

Outcome measures
Measure	Lu AF82422 or Placebo n=17 Participants Participants received Lu AF82422 or Placebo IV infusion Q4W from Baseline for a minimum of 48 weeks up to a maximum 72 weeks in the DB period.	Lu AF82422 n=38 Participants Participants received Lu AF82422 IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.
Change From Baseline in UMSARS Part IV Score at Week 48 in the DBP	1.35 units on a scale Standard Error 0.35	1.13 units on a scale Standard Error 0.30

SECONDARY outcome

Timeframe: Baseline, Week 48

UMSARS Part I assesses historical information on symptoms and activities of daily living over the past 2 weeks as reported by participants and caregivers (12 items: speech, swallowing, handwriting, cutting food and handling utensils, dressing, hygiene, walking, falling, orthostatic symptoms, urinary function, sexual function, and bowel function) each rated on a scale ranging from 0 to 4; with 0 = not affected/normal 1= mildly affected/impaired, 2= moderately affected/impaired, 3= severely affected/impaired, and 4 = helpless or entirely affected/impaired. LS mean and SE were calculated using MMRM.

Outcome measures

Outcome measures
Measure	Lu AF82422 or Placebo n=17 Participants Participants received Lu AF82422 or Placebo IV infusion Q4W from Baseline for a minimum of 48 weeks up to a maximum 72 weeks in the DB period.	Lu AF82422 n=38 Participants Participants received Lu AF82422 IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.
Change From Baseline in Speech, Swallowing, Falls, and Walking, as Assessed by the UMSARS Part I Item Scores at Week 48 in the DBP Speech	0.61 units on a scale Standard Error 0.26	0.19 units on a scale Standard Error 0.21
Change From Baseline in Speech, Swallowing, Falls, and Walking, as Assessed by the UMSARS Part I Item Scores at Week 48 in the DBP Swallowing	0.57 units on a scale Standard Error 0.30	0.91 units on a scale Standard Error 0.25
Change From Baseline in Speech, Swallowing, Falls, and Walking, as Assessed by the UMSARS Part I Item Scores at Week 48 in the DBP Falls	0.36 units on a scale Standard Error 0.42	0.22 units on a scale Standard Error 0.36
Change From Baseline in Speech, Swallowing, Falls, and Walking, as Assessed by the UMSARS Part I Item Scores at Week 48 in the DBP Walking	1.02 units on a scale Standard Error 0.27	0.86 units on a scale Standard Error 0.23

SECONDARY outcome

Timeframe: Baseline, Weeks 44 to 48

Fall Diary period was defined as the period between the two visits where the diary was filled out according to the protocol. LS mean and SE were calculated using MMRM.

Outcome measures

Outcome measures
Measure	Lu AF82422 or Placebo n=15 Participants Participants received Lu AF82422 or Placebo IV infusion Q4W from Baseline for a minimum of 48 weeks up to a maximum 72 weeks in the DB period.	Lu AF82422 n=33 Participants Participants received Lu AF82422 IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.
Change From Baseline in Number of Falls, as Assessed by the Fall Diary Periods (Weeks 44 to 48) in the DBP	-0.18 falls Standard Error 0.05	-0.16 falls Standard Error 0.04

SECONDARY outcome

Timeframe: Baseline, Week 48

The EQ-5D-5L is a participant-reported assessment designed to measure the participant's wellbeing. It consisted of 5 descriptive items (mobility, self-care, usual activities, pain/discomfort, and depression/anxiety) and a visual analogue scale (VAS) of the overall health state. Each descriptive item was rated on a 5-point index ranging from 1 (no problems) to 5 (extreme problems). The VAS ranged from 0 (worst imaginable health state) to 100 (best imaginable health state). LS mean and SE were calculated using MMRM.

Outcome measures

Outcome measures
Measure	Lu AF82422 or Placebo n=16 Participants Participants received Lu AF82422 or Placebo IV infusion Q4W from Baseline for a minimum of 48 weeks up to a maximum 72 weeks in the DB period.	Lu AF82422 n=35 Participants Participants received Lu AF82422 IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.
Change From Baseline in EuroQol 5-Dimension, 5-Level (EQ-5D-5L) Score at Week 48 in the DBP Usual Activities Score	0.50 units on a scale Standard Error 0.39	0.87 units on a scale Standard Error 0.34
Change From Baseline in EuroQol 5-Dimension, 5-Level (EQ-5D-5L) Score at Week 48 in the DBP Mobility Score	0.75 units on a scale Standard Error 0.32	0.49 units on a scale Standard Error 0.28
Change From Baseline in EuroQol 5-Dimension, 5-Level (EQ-5D-5L) Score at Week 48 in the DBP Self Care Score	0.80 units on a scale Standard Error 0.38	0.74 units on a scale Standard Error 0.32
Change From Baseline in EuroQol 5-Dimension, 5-Level (EQ-5D-5L) Score at Week 48 in the DBP Pain/Discomfort Score	-0.06 units on a scale Standard Error 0.38	0.22 units on a scale Standard Error 0.33
Change From Baseline in EuroQol 5-Dimension, 5-Level (EQ-5D-5L) Score at Week 48 in the DBP Anxiety/Depression Score	0.05 units on a scale Standard Error 0.29	0.34 units on a scale Standard Error 0.25
Change From Baseline in EuroQol 5-Dimension, 5-Level (EQ-5D-5L) Score at Week 48 in the DBP VAS Score	-13.16 units on a scale Standard Error 6.46	-13.80 units on a scale Standard Error 5.74

SECONDARY outcome

Timeframe: Baseline, Week 48

LS mean and SE were calculated using MMRM.

Outcome measures

Outcome measures
Measure	Lu AF82422 or Placebo n=16 Participants Participants received Lu AF82422 or Placebo IV infusion Q4W from Baseline for a minimum of 48 weeks up to a maximum 72 weeks in the DB period.	Lu AF82422 n=37 Participants Participants received Lu AF82422 IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.
Percent Change From Baseline in Brain Volume With Ventricles, as Measured by Volumetric MRI (vMRI) at Week 48 in the DBP	-1.14 percent change Standard Error 0.39	-0.81 percent change Standard Error 0.33

SECONDARY outcome

Timeframe: Baseline, Week 48

LS mean and SE were calculated using MMRM.

Outcome measures

Outcome measures
Measure	Lu AF82422 or Placebo n=16 Participants Participants received Lu AF82422 or Placebo IV infusion Q4W from Baseline for a minimum of 48 weeks up to a maximum 72 weeks in the DB period.	Lu AF82422 n=36 Participants Participants received Lu AF82422 IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.
Percent Change From Baseline in P-Neurofilament Light Chain (NfL) Protein Concentration at Week 48 in the DBP	10.37 percent change Standard Error 11.60	6.81 percent change Standard Error 10.01

SECONDARY outcome

Timeframe: Weeks 0, 4, 6, 8, 12, 24, 36, 48, 60, 72, 88

Population: APTS included all randomized participants who received at least 1 dose of double-blind IMP. 'Number analyzed' = participants evaluable at specified timepoint.

Outcome measures

Outcome measures
Measure	Lu AF82422 or Placebo n=40 Participants Participants received Lu AF82422 or Placebo IV infusion Q4W from Baseline for a minimum of 48 weeks up to a maximum 72 weeks in the DB period.	Lu AF82422 Participants received Lu AF82422 IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.
Lu AF82422 Plasma Concentration in the DBP Safety Follow Up (Week 88)	42425 nanograms (ng)/milliliter (mL) Standard Deviation 18372	—
Lu AF82422 Plasma Concentration in the DBP Week 0	NA nanograms (ng)/milliliter (mL) Standard Deviation NA All observations at Week 0 were below the lower limit of quantification	—
Lu AF82422 Plasma Concentration in the DBP Week 4	186754 nanograms (ng)/milliliter (mL) Standard Deviation 63989	—
Lu AF82422 Plasma Concentration in the DBP Week 6	408806 nanograms (ng)/milliliter (mL) Standard Deviation 148195	—
Lu AF82422 Plasma Concentration in the DBP Week 8	285079 nanograms (ng)/milliliter (mL) Standard Deviation 170320	—
Lu AF82422 Plasma Concentration in the DBP Week 12	312451 nanograms (ng)/milliliter (mL) Standard Deviation 128006	—
Lu AF82422 Plasma Concentration in the DBP Week 24	418385 nanograms (ng)/milliliter (mL) Standard Deviation 349787	—
Lu AF82422 Plasma Concentration in the DBP Week 36	417758 nanograms (ng)/milliliter (mL) Standard Deviation 170012	—
Lu AF82422 Plasma Concentration in the DBP Week 48	390751 nanograms (ng)/milliliter (mL) Standard Deviation 181489	—
Lu AF82422 Plasma Concentration in the DBP Week 60	526706 nanograms (ng)/milliliter (mL) Standard Deviation 312743	—
Lu AF82422 Plasma Concentration in the DBP Week 72	544071 nanograms (ng)/milliliter (mL) Standard Deviation 355696	—

SECONDARY outcome

Timeframe: Weeks 0 and 48

Population: APTS included all randomized participants who received at least 1 dose of double-blind IMP. 'Overall number of participants analyzed' = participants evaluable for this outcome measure. 'Number analyzed' = participants evaluable at specified timepoint.

Outcome measures

Outcome measures
Measure	Lu AF82422 or Placebo n=28 Participants Participants received Lu AF82422 or Placebo IV infusion Q4W from Baseline for a minimum of 48 weeks up to a maximum 72 weeks in the DB period.	Lu AF82422 Participants received Lu AF82422 IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.
Lu AF82422 Cerebrospinal Fluid (CSF) Concentrations in the DBP Week 0	5 ng/mL Standard Deviation 0	—
Lu AF82422 Cerebrospinal Fluid (CSF) Concentrations in the DBP Week 48	1531 ng/mL Standard Deviation 886	—

SECONDARY outcome

Timeframe: Weeks 0 and 48

Outcome measures

Outcome measures
Measure	Lu AF82422 or Placebo n=28 Participants Participants received Lu AF82422 or Placebo IV infusion Q4W from Baseline for a minimum of 48 weeks up to a maximum 72 weeks in the DB period.	Lu AF82422 Participants received Lu AF82422 IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.
Lu AF82422 CSF/Plasma Concentration Ratio in the DBP Week 0	25.00 ratio Standard Deviation 0.00	—
Lu AF82422 CSF/Plasma Concentration Ratio in the DBP Week 48	0.40 ratio Standard Deviation 0.21	—

Adverse Events

Placebo

Serious events: 7 serious events

Other events: 14 other events

Deaths: 2 deaths

Lu AF82422

Serious events: 12 serious events

Other events: 34 other events

Deaths: 2 deaths

Serious adverse events

Other adverse events

Additional Information

Email contact via

H. Lundbeck A/S

Phone: +4536301311

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Placebo n=21 participants at risk Participants received Lu AF82422 matching placebo IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.	Lu AF82422 n=40 participants at risk Participants received Lu AF82422 IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.
Cardiac disorders Cardiac failure congestive	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	2.5% 1/40 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Cardiac disorders Cardio-respiratory arrest	4.8% 1/21 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	0.00% 0/40 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Cardiac disorders Cardiopulmonary failure	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	2.5% 1/40 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Cardiac disorders Dilated cardiomyopathy	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	2.5% 1/40 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	2.5% 1/40 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	2.5% 1/40 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
General disorders Asthenia	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	2.5% 1/40 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Infections and infestations COVID-19	4.8% 1/21 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	2.5% 1/40 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Infections and infestations Cellulitis	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	2.5% 1/40 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Infections and infestations Escherichia sepsis	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	2.5% 1/40 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Infections and infestations Pneumonia aspiration	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	2.5% 1/40 • Number of events 2 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Infections and infestations Sepsis	4.8% 1/21 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	0.00% 0/40 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Infections and infestations Urinary tract infection	4.8% 1/21 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	2.5% 1/40 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Infections and infestations Urosepsis	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	5.0% 2/40 • Number of events 5 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Injury, poisoning and procedural complications Fall	4.8% 1/21 • Number of events 2 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	2.5% 1/40 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Injury, poisoning and procedural complications Femoral neck fracture	4.8% 1/21 • Number of events 2 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	0.00% 0/40 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Injury, poisoning and procedural complications Pelvic fracture	4.8% 1/21 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	0.00% 0/40 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Musculoskeletal and connective tissue disorders Back pain	4.8% 1/21 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	0.00% 0/40 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Musculoskeletal and connective tissue disorders Facet joint syndrome	4.8% 1/21 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	0.00% 0/40 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Musculoskeletal and connective tissue disorders Muscular weakness	4.8% 1/21 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	2.5% 1/40 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Respiratory, thoracic and mediastinal disorders Asphyxia	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	2.5% 1/40 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	2.5% 1/40 • Number of events 2 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	2.5% 1/40 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.

Measure	Placebo n=21 participants at risk Participants received Lu AF82422 matching placebo IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.	Lu AF82422 n=40 participants at risk Participants received Lu AF82422 IV infusion Q4W from Baseline for a minimum 48 weeks up to a maximum 72 weeks in the DB period.
General disorders Chest pain	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	5.0% 2/40 • Number of events 2 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
General disorders Fatigue	9.5% 2/21 • Number of events 2 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	7.5% 3/40 • Number of events 3 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Gastrointestinal disorders Constipation	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	5.0% 2/40 • Number of events 2 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Gastrointestinal disorders Gastrooesophageal reflux disease	9.5% 2/21 • Number of events 2 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	0.00% 0/40 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Gastrointestinal disorders Nausea	4.8% 1/21 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	7.5% 3/40 • Number of events 3 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
General disorders Injection site extravasation	9.5% 2/21 • Number of events 2 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	2.5% 1/40 • Number of events 3 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
General disorders Oedema peripheral	4.8% 1/21 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	10.0% 4/40 • Number of events 4 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Immune system disorders Seasonal allergy	9.5% 2/21 • Number of events 2 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	0.00% 0/40 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Infections and infestations COVID-19	23.8% 5/21 • Number of events 5 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	25.0% 10/40 • Number of events 10 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Infections and infestations Urinary tract infection	9.5% 2/21 • Number of events 3 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	10.0% 4/40 • Number of events 4 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Injury, poisoning and procedural complications Contusion	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	5.0% 2/40 • Number of events 3 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Investigations Blood creatine phosphokinase increased	4.8% 1/21 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	7.5% 3/40 • Number of events 3 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Investigations Blood triglycerides increased	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	5.0% 2/40 • Number of events 2 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Investigations C-reactive protein increased	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	7.5% 3/40 • Number of events 3 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Investigations Low density lipoprotein increased	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	5.0% 2/40 • Number of events 2 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Investigations Weight increased	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	5.0% 2/40 • Number of events 2 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Musculoskeletal and connective tissue disorders Arthralgia	9.5% 2/21 • Number of events 3 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	2.5% 1/40 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Musculoskeletal and connective tissue disorders Back pain	9.5% 2/21 • Number of events 2 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	15.0% 6/40 • Number of events 7 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Musculoskeletal and connective tissue disorders Muscular weakness	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	5.0% 2/40 • Number of events 2 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Musculoskeletal and connective tissue disorders Pain in extremity	9.5% 2/21 • Number of events 2 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	5.0% 2/40 • Number of events 2 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Nervous system disorders Balance disorder	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	5.0% 2/40 • Number of events 3 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Nervous system disorders Dizziness	9.5% 2/21 • Number of events 2 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	0.00% 0/40 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Nervous system disorders Headache	4.8% 1/21 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	12.5% 5/40 • Number of events 11 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	5.0% 2/40 • Number of events 2 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Skin and subcutaneous tissue disorders Eczema	4.8% 1/21 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	5.0% 2/40 • Number of events 2 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Skin and subcutaneous tissue disorders Rash	9.5% 2/21 • Number of events 3 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	2.5% 1/40 • Number of events 1 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Vascular disorders Flushing	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	7.5% 3/40 • Number of events 3 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Vascular disorders Hypertension	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	10.0% 4/40 • Number of events 4 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.
Vascular disorders Orthostatic hypotension	0.00% 0/21 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.	5.0% 2/40 • Number of events 2 • From date of first dose up to Week 88 APTS included all randomized participants who received at least 1 dose of double-blind IMP.