Abstract
Background
The classical complement pathway is implicated in the progression of neurodegenerative disease through its ability to drive aberrant removal of synapses, neuroinflammation, and neuronal damage. ANX005 is a humanized monoclonal antibody targeting C1q that blocks classical complement pathway activation.
Objective
The aim was to assess the safety, pharmacokinetics (PK), pharmacodynamics, and clinical activity of ANX005 in patients with Huntington's disease (HD).
Methods
ANX005‐HD‐01 (NCT04514367) was a multicenter, open‐label, phase 1b study in patients with early‐manifest HD. Primary endpoints included safety, tolerability, PK, and complement C1q and C4a/C4 levels in the serum and cerebrospinal fluid (CSF). Exploratory clinical activity endpoints included changes from baseline in composite Unified Huntington's Disease Rating Scale (cUHDRS) and component scores.
Results
All patients who received study drug (n = 28) experienced ≥1 treatment‐emergent adverse event, mostly transient infusion‐related reactions on the first dose. Three patients with elevated baseline antinuclear antibodies withdrew from the study due to treatment‐related AEs (pneumonitis) or serious AEs (systemic lupus erythematous, hemolysis). Twenty‐three patients (82.1%) received all planned ANX005 infusions. Steady‐state PK was achieved by week 6, with full saturation of ANX005 observed in serum and the CSF. Stabilization or possible improvement in cUHDRS and total functional capacity through 36 weeks was observed in a patient subgroup with higher baseline complement activity, based on baseline C4a/C4 ratio in CSF.
Conclusion
Overall, AEs with ANX005 administration were manageable, and most patients received all planned doses. Evidence of clinical improvement with ANX005 was observed in patients with higher baseline complement activity, supporting future study in patients with HD. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Keywords: ANX005, C1q, clinical trial, classical complement cascade, Huntington's disease
Complement activation is implicated in Huntington's disease; ANX005 is a potent inhibitor of component C1q. ANX005 exhibited a generally manageable safety profile with rapid reduction in C1q in the cerebrospinal fluid. Functional ability on composite Unified Huntington's Disease Rating Scale and total functional capacity was maintained, with potential for greater improvements in those with higher baseline complement.
Huntington's disease (HD) is a fatal, autosomal‐dominant progressive neurodegenerative disease caused by cytosine–adenine–guanine (CAG) trinucleotide repeat expansion in the HD gene. 1 HD is characterized by neuronal loss in the striatum and cerebral cortex. 2 Early synaptic dysfunction is a key characteristic and is manifested by dysregulated glutamate release in the striatum followed by progressive disconnection between the cortex and striatum. 3 Evidence from preclinical data, postmortem analyses, and observational studies implicates neuroinflammation, complement activation, and pathological synaptic pruning in HD progression. 4 , 5 , 6 Inhibition of C1q, the initiating molecule of the classical complement cascade, in the zQ175 mouse model of HD prevents corticostriatal synapse loss and rescues cognitive deficits associated with early HD. 4 Immunohistochemical and reverse transcription polymerase chain reaction analyses of postmortem HD brain tissue show increased expression of classical complement pathway components (C1q, C1r, C4, and C3) 4 , 5 and increased synaptic localization of complement proteins associated with corticostriatal synapse loss. 4 , 7 Finally, cerebrospinal fluid (CSF) levels of complement proteins, including C4a, have been shown to be elevated in patients with HD and to correlate with disease stage and progression rate. 4 , 6 , 8
Current treatments for HD are limited to symptom management, and there are no approved treatments that delay HD onset or slow its progression. To date, therapeutic approaches targeting the role of neuroinflammation in disease modification have not proven effective. A phase 2 study of laquinimod in patients with symptomatic HD for 52 weeks failed to show a significant effect on motor symptoms, although a reduction in the rate of caudate volume loss with laquinimod versus placebo was observed. 9 A futility analysis of a phase 3 clinical trial of minocycline failed to reject the null hypothesis for the primary and prespecified secondary outcomes. 10 Similarly, phase 2 studies of the semaphorin 4D antagonist pepinemab and of cannabinoid combination therapy failed to meet their primary efficacy endpoints. 11 , 12 Overall, these studies demonstrate the need for developing effective disease‐modifying therapies for patients with HD.
Inhibition of the classical complement cascade represents a potential novel strategy to slow HD progression by preserving synaptic function and reducing neuroinflammation and neurodegeneration. 13 ANX005, a humanized monoclonal antibody against C1q, has been shown to inhibit C1q binding, lower microglial activation, prevent pathologic synaptic pruning, and decrease neurodegeneration in nonclinical models. 4 , 14 , 15 , 16 , 17 Here, we present results from a proof‐of‐concept phase 1b study that evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and exploratory clinical activity of complement inhibition with ANX005 in patients with early‐manifest or premanifest HD.
Patients and Methods
Standard Protocol Approvals, Registrations, and Patient Consent
ANX005‐HD‐01 (Clinicaltrials.gov identifier, NCT04514367) was conducted in the United States between August 17, 2020, and January 28, 2022. This study was conducted in accordance with all International Council for Harmonization (ICH) Good Clinical Practice requirements, the Declaration of Helsinki, ICH E6, and applicable local regulations.
Study Design
ANX005‐HD‐01 was a multicenter, single‐arm, open‐label, phase 1b study evaluating ANX005 in individuals with early‐manifest or premanifest HD, aged ≥18 years, with a total CAG‐age product score >400 and a Unified Huntington's Disease Rating Scale (UHDRS) 18 independence score greater than or equal to 80%. Participants with premanifest HD were confirmed by genetic testing. Complete inclusion and exclusion criteria are provided in the online supplement. After initial doses of ANX005 (75 mg/kg) on days 1 and 5/6, all patients received maintenance doses of ANX005 (100 mg/kg) every 2 weeks from weeks 2 to 22, with follow‐up visits on weeks 24, 28, and 36. Additional administration details are provided in the online supplement.
Outcomes and Assessments
The primary aims were to assess (1) the safety and tolerability of IV ANX005; (2) the PKs of ANX005 in serum and the CSF; and (3) the PDs of ANX005, including C1q and neurofilament light chain (NfL) levels in the CSF and plasma, and C4a levels in the CSF.
Assessment of ANX005 clinical activity was an exploratory objective and was evaluated as the mean change from baseline in the composite UHDRS (cUHDRS) and its components (total functional capacity [TFC], Symbol Digit Modalities Test [SDMT], total motor score [TMS], and Stroop Word Reading [SWR]). 18 Other exploratory endpoints included assessment of levels of complement C3 and the activated complement proteins, C3a and C4, in CSF.
NfL levels in the plasma and CSF were analyzed using the Simoa NF‐light Advantage kit (Quanterix, Billerica, MA) and were assessed as the percentage change from baseline (screening or day 1 visit). Complement proteins C4, C3, and C3a in the blood and/or CSF were quantified using sandwich enzyme‐linked immunosorbent assay (ELISA). Complement protein C4a was quantified by competition ELISA using biotinylated C4a and avidin‐alkaline phosphatase detection antibodies. A summary of the complement proteins and ELISA assays is presented in Table S1.
Detailed clinical assessment methods are provided in the online supplement.
Statistical Analysis
The study sample size was determined using practical clinical methods rather than statistical considerations, and reflects the goals of assessing clinical activity, safety, and tolerability in a cohort that balances resources and meaningful data collection. The safety population included all patients who received any amount of ANX005. The PK population included patients who received any ANX005 and had evaluable ANX005 concentration data. PD and clinical activity analyses were conducted on the full analysis set, which included all patients with one or more completed infusion of ANX005 and one or more postinfusion assessments. Demographics, primary safety, PK, PD, immunogenicity, and exploratory clinical endpoints were summarized using descriptive statistics. Post hoc analyses in subgroups of patients were performed to determine if response to ANX005 was associated with complement activity at baseline. Levels of C4 and its activation products are subject to individual variability. 19 Therefore, C4a was routinely expressed as the C4a/C4 ratio in CSF. Patients with higher versus lower complement activity were defined as having baseline C4a/C4 ratio > median versus C4a/C4 ratio < median, respectively. Clinical activity at week 24 was assessed parametrically using a mixed‐effects model for repeated measures with baseline complement activity, visit, and their interactions as independent variables without additional covariates. An additional nonparametric clinical activity analysis at weeks 24 and 36 in the two subgroups was performed using a Wilcoxon–Mann‐Whitney test. Patients, investigators, and the sponsor were blinded to baseline C4a/C4 ratio. Nominal P‐values for between‐group differences were calculated without adjustment for multiple comparisons.
Results
Baseline Demographics and Disease Characteristics
In total, 34 patients were screened, and 28 were included in the study (Fig. S1). All 28 patients were included in the safety and PK analyses, and 23 were included in the clinical activity and PD analyses (Fig. S1; Table 1).
TABLE 1.
Demographics and baseline characteristics
| Characteristic | Safety population (N = 28) a | Per‐protocol population (n = 23) | TRACK‐HD b (N = 123) |
|---|---|---|---|
| Age (yr), mean (SD) | 49.7 (12.5) | 48.5 (13.3) | 48.8 (9.8) |
| Female, n (%) | 12 (42.9) | 8 (34.8) | (45) |
| CAG repeat length, mean (SD) | 44.6 (3.5) | 45.1 (3.7) | 43.7 (3.0) |
| CAP score, mean (SD) | 505.7 (57.9) | 512.2 (60.4) | NR |
| Manifest HD, n (%) | 25 (89) | 21 (91) | 123 (100) |
| CH50 (U/mL), mean (SD) | 266.7 (40.9) | 260.7 (36.5) | NR |
| Serum C1q (μg/mL), mean (SD) | 85.6 (14.0) | 83.4 (12.7) | NR |
| CSF C1q (μg/mL), mean (SD) | 0.2 (0.6) | 0.2 (0.1) | NR |
| CSF C4a (μg/L), mean (SD) | 14.5 (5.8) | 15.2 (6.1) | NR |
| Plasma NfL (ng/L), mean (SD) | 37.3 (12.3) | 39.5 (11.7) | NR |
| CSF NfL (ng/L), mean (SD) | 3104.2 (810.8) | 3236.1 (816.7) | NR |
| cUHDRS, mean (SD) | 10.4 (3.2) | 10.1 (2.9) | 11.7 (2.9) |
| TFC, mean (SD) | 10.6 (2.2) | 10.4 (2.3) | 10.9 (2.0) |
| TMS, mean (SD) | 21.6 (12.6) | 22.3 (11.4) | 23.7 (10.8) |
| SDMT, mean (SD) | 29.7 (11.3) | 28.8 (11.0) | 33.6 (10.2) |
| Stroop Word Reading Test, mean (SD) | 59.0 (18.7) | 56.7 (16.7) | 78.3 (19.5) |
The safety population included all patients who received any amount of ANX005. The per‐protocol population included those patients who completed all infusions and do not have major protocol violations.
Based on the TRACK‐HD natural history study. 18 For illustrative purposes only—differences in patient demographics, study designs, and other factors exist, and caution should be exercised when comparing data across studies.
Abbreviations: SD, standard deviation; CAG, cytosine–adenine–guanine; CAP, CAG age product; NR, not reported; HD, Huntington's disease; CH50, 50% complement hemolytic activity; CSF, cerebrospinal fluid; NfL, neurofilament light chain; cUHDRS, composite Unified Huntington's Disease Rating Scale; TFC, total functional capacity; TMS, total motor score; SDMT, Symbol Digit Modalities Test.
Safety and Tolerability
All patients experienced one or more treatment‐emergent adverse events (TEAE), the majority of which were grade 1 or 2 (92.3%, 193/209 TEAEs). The most common TEAEs were signs and symptoms of infusion‐related reactions (IRR) (eg, rash, maculopapular rash, and pruritus) and were considered related to the study drug by the reporting physician (Table 2). Twelve patients (42.9%) reported 16 grade 3 TEAEs (7.7%, 16/209), with the related events of rash, maculopapular rash, and pruritic rash being the most common (2 patients each, 7.1%). There were no grade 4 events and no deaths during the study. Five patients (17.9%) withdrew from the study and did not receive all planned study infusions: 3 (10.7%) reported drug‐related serious adverse events (SAE) or TEAEs (1 due to a TEAE of hemolytic anemia and 2 due to SAEs of systemic lupus erythematous [SLE] or pneumonitis), 1 (3.6%) reported an unrelated TEAE (COVID‐19), and 1 (3.6%) withdrew for unspecified reasons. The 1 patient with SLE presented with a rash and oral ulcers after the ninth dose of ANX005 (~12 weeks of dosing). Their symptoms progressed to an SLE‐like syndrome; therefore, ANX005 dosing was stopped after the 10th dose, and prednisone and hydroxychloroquine were administered; these symptoms resolved over time, and the patient was monitored for safety, but ANX005 was not resumed.
TABLE 2.
Incidence of treatment‐emergent adverse events
| Adverse event a | Safety population (n = 28) | |
|---|---|---|
| ALL TEAEs | TEAEs related to study drug | |
| Total number of TEAEs, n | 209 | 105 |
| Patients with ≥1 TEAE, n (%) | 28 (100) | 28 (100) |
| Most common TEAEs (≥10%), n (%) | ||
| Rash | 15 (53.6) | 14 (50.0) |
| Rash maculopapular | 10 (35.7) | 10 (35.7) |
| Pruritus | 8 (28.6) | 8 (28.6) |
| Dizziness | 6 (21.4) | 1 (3.6) |
| Headache | 5 (17.9) | 2 (7.1) |
| Nausea | 5 (17.9) | 0 |
| COVID‐19 | 4 (14.3) | 0 |
| Tachycardia | 4 (14.3) | 3 (10.7) |
| Vomiting | 4 (14.3) | 0 |
| Fall | 3 (10.7) | 0 |
| Fatigue | 3 (10.7) | 1 (3.6) |
| Flushing | 3 (10.7) | 3 (10.7) |
| Irritability | 3 (10.7) | 0 |
| Puncture site pain | 3 (10.7) | 0 |
| Rash macular | 3 (10.7) | 3 (10.7) |
| Rash pruritic | 3 (10.7) | 2 (7.1) |
| Urinary tract infection | 3 (10.7) | 0 |
| Grade 3 TEAEs, n (%) | ||
| Infusion‐related reaction | 8 (28.6) | 8 (28.6) |
| Rash pruritic | 2 (7.1) | 1 (3.6) |
| Hypokalemia | 1 (3.6) | 1 (3.6) |
| Mental status changes | 1 (3.6) | 1 (3.6) |
| Neutropenia b | 1 (3.6) | 1 (3.6) |
| Pneumonitis c | 1 (3.6) | 1 (3.6) |
| Systemic lupus erythematosus d | 1 (3.6) | 1 (3.6) |
| White blood cell count decreased | 1 (3.6) | 1 (3.6) |
| TEAEs leading to discontinuation of ANX005, n (%) | ||
| COVID‐19 | 1 (3.6) | 0 |
| Hemolysis | 1 (3.6) | 1 (3.6) |
| Molluscum contagiosum d | 1 (3.6) | 0 |
| Pneumonitis c | 1 (3.6) | 1 (3.6) |
| Systemic lupus erythematosus d | 1 (3.6) | 1 (3.6) |
| SAEs, n (%) | ||
| Pneumonitis c | 1 (3.6) | 1 (3.6) |
| Self‐injurious behavior | 1 (3.6) | 0 |
| Suicidal ideation | 1 (3.6) | 0 |
| Systemic lupus erythematosus d | 1 (3.6) | 1 (3.6) |
Abbreviations: TEAE, treatment‐emergent adverse event; SAE, serious adverse event.
Adverse events were coded by system organ class and preferred term using MedDRA, version 23.1, and graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
One event of grade 3 neutropenia considered related to ANX005 not leading to discontinuation of ANX005 or early study withdrawal.
One event of pneumonitis occurred, which was counted as a grade 3 event, an SAE, and a TEAE leading to discontinuation.
One event of systemic lupus erythematosus occurred, which was counted as a grade 3 event, an SAE, and a TEAE leading to discontinuation. The same patient had an event of molluscum contagiosum, which was also counted as a TEAE leading to discontinuation.
All patients experienced transient IRRs of rash, pruritus, tachycardia, and flushing during the first infusion of ANX005. Temporary interruptions to study drug infusion occurred 26 times in 15 patients (53.6%), with 21 of these (80.7%) secondary to one or more IRRs (9 grade 3, 8 grade 2, 4 categorized as “other signs of IRR”). Interruptions due to IRRs were rare after day 1 (1/28 participants, 3.6%). One interruption was due to time spent changing the infusion bags, and another was according to IRR infusion instructions. Interruptions were temporary, and infusion was resumed and completed in all cases. Per protocol, all participants received prophylactic treatment with corticosteroid (methylprednisolone), antihistamine (famotidine and cetirizine or loratadine), and acetaminophen ≤2 hours prior to the start of the first infusion of ANX005. During the first infusion, cetirizine or loratadine was administered approximately every 8 hours and famotidine 24 hours after the start of the infusion unless there were relative contraindications to doing so (eg, antihistamine side effects). Diphenhydramine was permitted as needed for pruritus and was received by 75% at some point during the study. Modification to the recommended medication guideline was acceptable based on individual participant medical condition and investigator discretion, and repeat prophylaxis for subsequent infusion was permitted. The majority of participants were given prophylactic treatment for the second infusion, which was supported by a review of the data listings; however, the use tapered off over the subsequent doses.
No patients with normal baseline antinuclear antibody (ANA) titers developed treatment‐related TEAEs or SAEs, resulting in study discontinuation. The 3 patients who withdrew from the study due to drug‐related SAEs or TEAEs had mildly elevated baseline ANA levels. Detailed narratives for these 3 patients are provided in the online supplement.
Pharmacokinetics
Free ANX005 steady state was achieved by week 6 in serum and the CSF Free ANX005 was undetectable by weeks 28 to 36 (6–14 weeks after the last dose; Fig. 1). Full target engagement of C1q was observed in both the serum and CSF for the entire 24‐week period (last dose administered at week 22).
FIG. 1.
Mean (±SD [standard deviation]) free ANX005 concentrations (PK population) and C1q concentrations (full analysis set) over time in (A) serum and (B) CSF. The PK population (n = 23) consisted of all patients who received one or more dose of ANX005 and had evaluable PK data. The full analysis set (n = 23) consisted of all patients who received one or more completed infusion of ANX005 and had one or more postinfusion assessments. CSF, cerebrospinal fluid; PK, pharmacokinetic.
Free ANX005 T max in serum after IV dosing was observed near the end of infusion in all patients. The mean (standard deviation [SD]) day 1 C max and AUC0–5/6day values were 1800 (345) μg/mL and 4330 (774) day · μg/mL, respectively. Exposure based on mean C max and AUC0–5/6day was approximately two to threefold higher at week 22 than on day 1. The mean (SD) week 22 C max and AUC0–5/6day values were 4050 (633) μg/mL and 12,700 (2100) day · μg/mL, respectively. The mean (SD) t 1/2 of free ANX005 after the week 22 100‐mg/kg dose was 10.3 (3.53) days. Detectable free ANX005 in serum and the CSF is an indicator of saturated binding to C1q. Free ANX005 concentrations in the CSF were measurable during the dosing phase of the study and were 0.2% to 0.25% of the mean serum concentrations at the corresponding time points, which is consistent with the anticipated range for antibody penetration of the blood–brain barrier. 20
Two patients measured positive for antidrug antibodies (ADA) at the beginning of the study, but there was no further increase in titer at later time points, indicating that there was no treatment‐related increase. There was no apparent effect of ADA on ANX005 PKs in these patients, and there were no associated safety observations.
PD Biomarkers
ANX005 blockade of C1q binding to tissues prevents surface activation of downstream complement components and tissue damage. 14 However, as ANX005 approaches saturation of C1q in solution, it triggers limited solution‐phase activation with cleavage of C4 to release C4a. The amount of C4a released in this context is a PD measure of target engagement. There was a 3.7‐fold increase in CSF C4a over the 24‐week treatment period relative to baseline (Fig. S2). CSF C4a remained 2.5‐fold higher at week 36 than at baseline, suggesting extended target engagement in the CNS beyond the treatment period. Consistent with prolonged inhibition of the classical cascade by ANX005, the levels of both downstream complement C3 and its activation product C3a were reduced during the on‐treatment (−56% and −29%, respectively) and off‐treatment periods (−70% and −39%, respectively). C3 is produced locally by activated neurotoxic astrocytes, 21 and the continued reduction in C3, as well as C3a, suggests durable suppression of neuroinflammation. 22
NfL is a neuronal cytoplasmic protein highly expressed in axons 21 and is an indicator of axonal damage in many neurological disorders. 23 To evaluate the impact of ANX005 on NfL, changes were assessed only for the subset of the 23 patients who received the full 24‐week treatment. Medians and interquartile ranges (IQR) are presented in Table 3. At week 24 (2 weeks after last infusion), median levels of NfL in the CSF and plasma increased by 5.5% and decreased by 11.2%, respectively, relative to baseline. After the end of the treatment period, there appeared to be a trend of increasing NfL levels at week 36 relative to week 24, although there was considerable between‐patient variability in both the CSF and plasma NfL levels (Table 3).
TABLE 3.
Changes in CSF and plasma NfL levels
| Biomarker, % change (IQR) | Week 24 change from baseline a | Week 36 change from week 24 b |
|---|---|---|
| CSF NfL | 5.5 (−1.1, 26.1) | 0.9 (−4.1, 11.5) |
| Plasma NfL | −11.2 (−22.5, 2.3) | 12.0 (−6.8, 26.1) |
Abbreviations: CSF, cerebrospinal fluid; NfL, neurofilament light chain; IQR, interquartile range.
First follow‐up visit after the last treatment at week 22.
Last follow‐up visit.
Exploratory Clinical Activity Assessments
Twenty‐three patients completed both the 24‐week treatment period and the 12‐week off‐treatment period. Clinical disease progression as measured by the cUHDRS and TFC was stable through week 36 (Table S2). The mean (SD) cUHDRS score was 10.1 (2.9) at baseline, 10.1 (3.6) at week 24, and 9.9 (3.8) at week 36. The mean (SD) TFC score was 10.4 (2.3) at baseline, 10.6 (2.2) at week 24, and 10.1 (2.8) at week 36.
Differential Clinical Response Observed for Patients with High Versus Low Baseline C4a/C4
The C4a/C4 ratio is a biomarker of complement activation. Levels of complement activation marker C4a are increased in patients with manifest HD compared with healthy controls and may be an indicator of faster disease progression. 8 After study completion, patients were divided into high and low complement activity subgroups (n = 12 and n = 11, respectively) based on baseline CSF C4a/C4 levels (Fig. S3). Patients with higher baseline C4a/C4 exhibited clinical improvement on the cUHDRS at the end of the 24‐week treatment period, whereas those with lower baseline C4a/C4 demonstrated clinical decline similar to that estimated by interpolated data from the TRACK‐HD 18 natural history study (nominal P = 0.037) (Fig. 2A). Improvement in cUHDRS in the higher C4a/C4 subgroup was observed at week 6 and was consistently maintained throughout the 24‐week treatment period as well as the subsequent 12‐week off‐treatment period. Consistent with this finding, more patients with higher baseline C4a/C4 had stable or improved cUHDRS at week 24 than patients with lower C4a/C4 (75% vs. 36%, nominal P = 0.032), with a trend toward greater improvement in the higher C4a/C4 group also observed at week 36 (Fig. S4). A similar treatment benefit in patients with higher baseline C4a/C4 was also observed for TFC, with improvement seen at week 6 and maintained during the off‐treatment period (Fig. 2B). The rapid clinical response is consistent with early target engagement of C1q (Fig. 1B), resulting in downstream inhibition of C3a and C3 in CSF at week 6 (Fig. S2), and may reflect real‐time impact of complement removal on synaptic functional improvement. Extended clinical improvement during the off‐treatment period is also consistent with the prolonged PD effect of ANX005 on CSF complement activation markers C4a and C3a through week 36 (Fig. S2).
FIG. 2.
Mean change from baseline for (A) cUHDRS and (B) TFC in subgroups of patients with higher versus lower baseline C4a/C4 complement activation. The gray shading represents the expected decline based on interpolated natural history from the TRACK‐HD study. 18 Nominal P‐values comparing higher versus lower C4a/C4 groups at week 24 were estimated using MMRM with C4a/C4 ratio at baseline (higher vs. lower), visit, and their interactions as independent variables (n = 23). cUHDRS, composite Unified Huntington's Disease Rating Scale; LS, least squares; MMRM, mixed‐effects model for repeated measures; TFC, total functional capacity.
Treatment benefits beginning at week 6 in patients with higher baseline C4a/C4 were also observed for SDMT and TMS in a post hoc analysis, although TMS appeared to decline slightly thereafter (Fig. S5). There appeared to be no treatment benefit on SWR, with both complement activity subgroups exhibiting a decline similar to the TRACK‐HD natural history cohort.
Discussion
This open‐label phase 1b study focuses on the safety and clinical activity of ANX005, a novel inhibitor of C1q and the classical complement cascade, in patients with HD. During the first administration of ANX005, all study participants reported at least one IRR (eg, rash and pruritus), most of which were mild or moderate in severity. Twenty‐five participants completed all 36 weeks of the study, 23 of whom received all scheduled doses of ANX005. The overall safety profile was consistent with previous studies of ANX005 in patients with GBS, where the administration has been generally well tolerated, with no increase in infections and IRRs being mild to moderate and manageable. 24
Development of autoimmune diseases, particularly SLE, is known to be a risk in patients with genetic deficiency of early complement components (C1q, C1r, C1s, C2, and C4). 25 , 26 , 27 , 28 It may also be a risk in patients receiving chronic treatment with complement inhibitors. One patient in the study presented with a cutaneous lupus‐like syndrome, which was later reported as SLE; treatment with prednisone and hydroxychloroquine was provided, and their symptoms resolved. This outcome is consistent with case studies in patients with a life‐long genetic deficiency of C1q that develop lupus, although it has been reported that treatment with fresh frozen plasma as a source of exogenous C1q allows disease resolution. 28 Because the patient with SLE in the current study had a mildly elevated ANA titer prior to dosing, it is possible that elevated ANA is a risk factor for the development of autoimmune disease with strong, chronic anticomplement therapy. The current ANX005 safety monitoring plan includes additional baseline ANA measures and triggers further evaluation by a rheumatologist if a patient demonstrates elevated ANA titers or signs and symptoms of autoimmune disease during the treatment period. Importantly, signs of autoimmunity with treatment can be monitored and reversed and may be reduced with enhanced safety screening. To date, no further cases of autoimmune disease have been observed with ANX005.
Analyses of ANX005 PK and PD demonstrated full target engagement in the CSF and serum at the earliest time points assessed. Changes in the levels of the downstream classical complement proteins are consistent with the presumed mechanism of action of ANX005. Finally, the exploratory clinical activity assessments indicated that functional ability, as measured using the cUHDRS and TFC, was generally maintained in the overall cohort at 24 and 36 weeks, and post hoc analyses supported the study hypothesis that patients with higher baseline complement activity may exhibit better outcomes.
No significant increase in NfL was observed in this study, although given the observed between‐patient variability in both CSF and plasma NfL levels, the clinical significance of any apparent increase or decrease in NfL is unclear. NfL levels have been reported to be elevated in neurological diseases such as Alzheimer's disease. However, in HD clinical trials, increases in NfL may be an indicator of CNS toxicity. Furthermore, NfL is under consideration as a biomarker for diagnostic purposes. 29 The rate of increase in NfL in manifest HD is only slightly higher than that in age‐matched healthy controls (Annexon, data on file), consistent with the most rapid increase in NfL occurring during the early stages of the disease. 30 To date, reduction in NfL in neurodegenerative diseases has been observed for drug and drug candidates in patients with spinal muscular atrophy 31 and amyotrophic lateral sclerosis, 32 possibly because NfL levels are much higher in these diseases than in HD, and in multiple sclerosis where inflammatory changes are more dynamic. 33
Although this study does not assess clinical activity, the exploratory assessments provide rationale for further study. The cUHDRS was developed to provide a single, sensitive, and reliable measure of clinical HD progression based on assessments of motor, cognitive, and functional decline 18 and has been demonstrated to correlate with magnetic resonance imaging measures of CNS regional atrophy. 34 Data from HD natural history cohorts indicate that cUHDRS declines by approximately 1 point per year, and a slowing of clinical decline of approximately 20% to 30% annually on the cUHDRS is considered clinically meaningful. 18 , 35 In the current study, mean cUHDRS did not decline relative to baseline at week 24 in the full cohort, and there was only a small (<0.25 point) decline after 12 weeks off treatment. Patients with higher baseline complement activity exhibited greater improvement in the cUHDRS than patients with lower baseline complement activity in two different assessments of clinical activity, consistent with the initial hypothesis that those with higher baseline complement activation may have better response to anticomplement therapy. In contrast, our analysis of HD‐CSF cohort data demonstrated that no patients exhibited spontaneous improvement (>0.5 points) in cUHDRS at the 2‐month follow‐up, and fewer than 10% (5/60) of HD‐CSF patients improved at the 2‐year visit (Fig. S6).
The differential treatment benefit suggests that C4a/C4 may function as a predictive biomarker of ANX005 treatment response. Correlation of C4a with disease stage and UHDRS assessments in natural history studies indicates that complement activation is associated with disease pathology. 36 In particular, evidence suggests that complement‐mediated synapse elimination begins prior to symptom onset and continues throughout disease progression, correlating with functional decline (Annexon, data on file). 4 , 37 Evidence is emerging that accumulation of complement C1q may be a central factor contributing to the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. 38 If complement does play a driving role in neurodegeneration, it is possible that this process is present in all patients with HD, but elevated C4a levels, beyond age‐matched controls, are detectable only in patients with the most active involvement of this pathway. Our observation that patients with higher, not lower, baseline C4a/C4 exhibited rapid and sustained cUHDRS stabilization or improvement is consistent with the hypothesis of the role for C1q in HD progression 4 and is an encouraging finding in this study. Collectively, these results support the hypothesis that complement activity is an important driver of clinical dysfunction in HD.
The impact of ANX005 on brain volume was not investigated in this study, and it is therefore not known whether the observed clinical improvement with ANX005 is associated with regional changes in brain structure or volume. Particularly, a placebo‐controlled study of laquinimod in patients with symptomatic HD showed a meaningful reduction in the rate of caudate volume loss but no effect on clinical outcomes. 9
Limitations of the present study include its small size and single‐arm design. Larger studies over longer durations are needed to better understand the safety profile and clinical benefit of ANX005 in patients with HD. In addition, although this was an open‐label study, it is important to note that baseline levels of complement activity (C4a/C4 ratio) were not assessed until after study completion and were unknown to the investigators, patients, and sponsor during the trial. The observed response was rapid and maintained throughout the 24‐week treatment period and 12‐week off‐treatment period. This response could be explained mechanistically by the rapid, robust, and persistent observed inhibition of C1q (in this case, presumably at the synapse surface), which has been associated with the rapid return of function in other complement‐mediated disorders due to immediate blockade of ongoing complement attack. 39 , 40 , 41 , 42 Furthermore, the response paralleled changes in biomarkers of complement activation and neuroinflammation in the CSF. 43 From a functional perspective, the cUHDRS response was consistent with responses in TFC and in cognitive and motor domains, suggesting that stabilization or improvement was not driven by a large change in a single component.
In summary, the safety and preliminary clinical activity results from this phase 1b study support the continued development of ANX005 for HD treatment and may inform recruitment strategies for future studies. In addition, ANX005 has the potential to mitigate neuronal cell death by decreasing intracellular toxic insults and preserving synaptic function. Further research is warranted to determine if the effects of ANX005‐driven C1q inhibition in reducing synaptic damage in nonclinical models translate to patients with HD, further local and systemic immune‐related effects of C1q inhibition, and determine if ANX005 could work synergistically with antisense RNA‐mediated mutant huntingtin‐lowering strategies for patients with HD. 44
Author Roles
R.K.: study execution, writing/editing of the final version of the manuscript. P.A.: study execution, writing/editing of the final version of the manuscript. K.A.: study execution, writing/editing of the final version of the manuscript. D.C.: study execution, writing/editing of the final version of the manuscript. M.D.: study execution, writing/editing of the final version of the manuscript. A.D.: study execution, writing/editing of the final version of the manuscript. B.S.: study execution, writing/editing of the final version of the manuscript. A.M.: data analysis, writing/editing of the final version of the manuscript. B.H.: data analysis, writing/editing of the final version of the manuscript. P.L.: data curation, data analysis, writing/editing of the final version of the manuscript. E.C.‐M.: study conceptualization and design, data analysis, writing/editing of the final version of the manuscript. L.T.: data analysis, writing/editing of the final version of the manuscript. G.M.: data analysis, writing/editing of the final version of the manuscript. T.Y.: study conceptualization and design, data analysis, writing/editing of the final version of the manuscript. S.K.: study conceptualization and design, data analysis, writing/editing of the final version of the manuscript. H.‐A.K.: study conceptualization and design, data analysis, writing/editing of the final version of the manuscript
Full financial disclosures of all authors for the previous 12 months
R.K. has served as a consultant for and received research support from Annexon Biosciences. P.A. and M.D. have received research support from Annexon Biosciences. K.A., A.D., and B.S. report no disclosures related to the manuscript. D.C. has served as a consultant for Annexon Biosciences. A.M. and S.K. were previously employed by Annexon Biosciences. E.C.‐M. was previously employed by and holds stock/stock options in Annexon Biosciences. B.H., P.L., L.T., G.M., T.Y., and H.‐A.K. have been employed by, hold stock/stock options in, and have received stock/stock options/board of directors compensation from Annexon Biosciences. R.K. has been employed by CenExel and Research Catalyst; has served as a consultant for AbbVie, Acorda, Alexza, Annexon Biosciences, Biohaven, BioVie, Cerevel, Roche, Supernus, and Teva; has received research support from AbbVie, Addex, Annexon Biosciences, Annovis, Biogen, BioVie, Cerevel, CHDI Foundation, CND Life Sciences, Cognition Therapeutics, Eli Lilly, Enterin, Impax, Integrative Research Labs, Lundbeck, Neuraly, Neurocrine, Neuroderm, Neuron23, Pharma Two B, Praxis, Prilenia, PTC Therapeutics, Revance, Roche, Sage Therapeutics, Sanofi, Scion Neurostim, SPARK Neuro, Supernus, Takeda, Teva, Transposon, Triplet Therapeutics, and uniQure; has served on the advisory board for Impel; has served on speakers' bureaus for Acord, Kyowa, Supernus, and Teva; and has stock/stock options in CenExel and Research Catalyst. P.A. has received research support from Annexon Biosciences, Biogen, Eli Lilly, Inhibikase, The Michael J. Fox Foundation, Roche, Sun Pharma, and Supernus. K.A. has served as a consultant for 3D Communications, Atheneum, GLG, Guidepoint, Lundbeck Neurotorium Foundation, and Medscape; has served on the advisory board for Roche/Biogen and Teva; has received research support from CHDI Foundation; has received funding for travel or speaker's honoraria from Teva; and has served on the editorial board of the Journal of Huntington's Disease. D.C. has served as a consultant for Acadia, Alterity, Adamas, Annexon Biosciences, Cerevel, Lundbeck, Neurocrine, SPARK Neuro, Teva, and uniQure; has received research support from AbbVie, Acadia, Alterity, Biogen, BMS, Cerecor, Eli Lilly, Genentech‐Roche, Griffin Family Foundation, Huntington Disease Society of America, Jazz Pharmaceuticals, Lundbeck, Neurocrine, Teva, uniQure, Vaccinex, and Wave Life Sciences; and has served on the advisory board for Cerevel, Neurocrine, and Teva. M.D. has received research support from Annexon Biosciences. A.D. reports no disclosures related to the manuscript. B.S. has received research support from the CHDI Foundation, Neurocrine, and Prilenia. A.M. was previously employed by Annexon Biosciences. B.H. has been employed by and holds stock/stock options in Annexon Biosciences. P.L. has been employed by and holds stock/stock options in Annexon Biosciences. E.C.‐M. has been employed by Abata, was previously employed by Annexon Biosciences, and holds stock/stock options in Abata and Annexon Biosciences. L.T. has been employed by Annexon Biosciences. G.M. has been employed by, holds stock/stock options in, and has received stock/stock options/board of directors compensation from Annexon Biosciences. T.Y. has been employed by and holds stock/stock options in Annexon Biosciences. S.K. was previously employed by Annexon Biosciences and has served as a consultant for Alchemab, Aleta, and Nura Bio. H.‐A.K. has been employed by, holds stock/stock options in, and has received stock/stock options/board of directors compensation from Annexon Biosciences.
Financial Disclosures and Conflicts of Interest
Author disclosures are available in the Supporting Information.
Supporting information
Table S1. Detection conditions for complement biomarkers.
Table S2. Summary of exploratory efficacy endpoints: change from baseline to week 24 and to week 36 (per‐protocol population).
Figure S1. Participant disposition.
Figure S2. Changes from baseline in CSF (cerebrospinal fluid) levels of (A) C3 and C3a and (B) C4a.
Figure S3. Median baseline C4a/C4 levels in CSF (cerebrospinal fluid) used to define participants with high versus low complement activity.
Figure S4. Change from baseline in cUHDRS (composite Unified Huntington's Disease Rating Scale) for patients with low and high baseline C4a/C4 at (A) week 24 and (B) week 36.
Figure S5. Least squares mean change from baseline in the (A) SDMT (Symbol Digit Modalities Test), (B) TMS (total motor score), and (C) SWR (Stroop Word Reading) cUHDRS (composite Unified Huntington's Disease Rating Scale) components in subgroups of participants with higher versus lower baseline complement activation.
Figure S6. Changes in cUHDRS (composite Unified Huntington's Disease Rating Scale) for patients in the natural history cohort HD‐CSF (Huntington's disease‐cerebrospinal fluid).
Acknowledgments
We thank Anita Grover, PhD, for her contributions to the early development of this clinical study, and Yaisa Andrews‐Zwilling, MSc, PhD, Logan Kuhn, and Sethu Sankaranarayanan, PhD, for their work on preclinical models and assay development in support of the clinical program. We thank Drs Edward Wild and Lauren Byrne for the generous gift of samples and data derived from the HD‐CSF cohort. Medical writing support and editorial assistance were provided by Rebecca D. Miles, PhD, John Watson, PhD, Scott Bergfeld, PhD, and Anthony DiLauro, PhD, of MedVal Scientific Information Services, LLC (Princeton, NJ), and were funded by Annexon Biosciences. This manuscript was prepared according to the International Society for Medical Publication Professionals' “Good Publication Practice for Communicating Company‐Sponsored Medical Research: 2023 Update.”
Funding agency: This work was supported by Annexon Biosciences.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1. Detection conditions for complement biomarkers.
Table S2. Summary of exploratory efficacy endpoints: change from baseline to week 24 and to week 36 (per‐protocol population).
Figure S1. Participant disposition.
Figure S2. Changes from baseline in CSF (cerebrospinal fluid) levels of (A) C3 and C3a and (B) C4a.
Figure S3. Median baseline C4a/C4 levels in CSF (cerebrospinal fluid) used to define participants with high versus low complement activity.
Figure S4. Change from baseline in cUHDRS (composite Unified Huntington's Disease Rating Scale) for patients with low and high baseline C4a/C4 at (A) week 24 and (B) week 36.
Figure S5. Least squares mean change from baseline in the (A) SDMT (Symbol Digit Modalities Test), (B) TMS (total motor score), and (C) SWR (Stroop Word Reading) cUHDRS (composite Unified Huntington's Disease Rating Scale) components in subgroups of participants with higher versus lower baseline complement activation.
Figure S6. Changes in cUHDRS (composite Unified Huntington's Disease Rating Scale) for patients in the natural history cohort HD‐CSF (Huntington's disease‐cerebrospinal fluid).
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.