Merrilee Needham

Background and aims: IBM is a rare, progressive disease characterized by invasion of muscle by highly differentiated cytotoxic CD8+ T cells. Ulviprubart, a monoclonal antibody, selectively depletes cytotoxic CD8+ KLRG1+ T cells by targeting KLRG1 expressed on most IBM-muscle–infiltrating T cells. Here, we describe PK/PD and safety of ulviprubart in patients with IBM.

Methods: In this phase 1, open-label study (NCT04659031), initial patients received subcutaneous ulviprubart (0.1, 0.5, or 2.0 mg/kg) as a single dose prior to dosing every 8 weeks (Q8W) ~6−12 months later, while later patients received 2.0 mg/kg Q8W; patients received ulviprubart for up to 18 months. PK/PD and safety with ulviprubart were assessed.

Results: Nineteen patients (mean age, 66 years; 79% male) were enrolled (0.1 mg/kg: n = 3; 0.5 mg/kg: n = 3; 2.0 mg/kg: n = 13). Ulviprubart displayed a long absorption phase, slow clearance, and 21-day half-life. Peripheral CD8+ KLRG1+ and CD4+ KLRG1+ T-cell depletion was achieved, with mean CD8+ KLRG1+ T-cell maximum depletions of 69%, 97%, and 98% after single doses of 0.1, 0.5, and 2.0 mg/kg, respectively. Effector CD8+ T-cell populations (T-cell effector memory [TEM] and TEMs expressing CD45RA [TEMRA]) were depleted to the extent of their KLRG1 expression. Regulatory T cells and B cells were preserved. No serious adverse events (AEs) or discontinuations due to AEs were reported.

Conclusion: In patients with IBM, ulviprubart led to sustained selective depletion of peripheral blood CD8+ KLRG1+ T cells and had a favorable safety profile.

Disclosure: M Needham, RD Henderson, and C Liang: Abcuro, Inc. − Consultant D Soler-Ferran and HJ Wilkins: Abcuro, Inc. – Employment S Greenberg: Abcuro, Inc. – Founder; Consultant

Background. Inclusion body myositis (IBM) is the most common acquired skeletal muscle disease associated with ageing and involves both an autoimmune attack on muscle fibres as well as muscle degeneration with protein deposition. There have been multiple studies showing a relationship between exercise and improved outcomes in IBM, however only one prior trial showed a modest benefit of Oxandrolone in IBM. No studies have explored a combination of the two. We hypothesised that a combination of exercise training and testosterone treatment would improve muscle strength and physical activity in males affected by IBM, more than exercise alone.

Methods. This pilot study adopted a double-blinded, placebo-controlled, crossover design to assess whether testosterone combined with a prescribed exercise program would improve measures of muscle strength, physical activity and quality of life in men affected by IBM, over exercise alone. Treatment (exercise and placebo) and placebo (exercise only) arms were 12 weeks in duration, with a two-week wash-out period between arms. Primary outcome was quadriceps strength, measured by isokinetic dynamometer (Humac Norm). Secondary outcomes included lean body mass, functional tests and Patient Reported Outcomes (PROs). Outcome measures were collected at baseline, Week 12 and Week 26. In response to participant feedback, a 12-month Open Label Extension (OLE) was offered, with outcome measures collected at new baseline, 6-months and 12-months.

Results. The primary outcome, quadriceps extension strength the placebo and treatment arms, was non-significant. The DEXA assessment of lean body mass and other functional tests were also non-significant between the placebo and treatment arms. There was a significant reduction of peak torque extension at 60 degrees during the placebo period (p=0.04). Within the SF-36 questionnaire, the domain of ‘role limitations due to emotional problems’ demonstrated higher scores during the testosterone arm when compared to the placebo arm (p=0.044). All other domains, as well as the IBM-FRS, were non-significant. Within the OLE, the 2- minute walk test regular and fast were significant at 6 months (p=0.03 and p=0.032 respectively) but not at 12 months. The most common adverse event reported was falls which were considered a complication of IBM rather than the study. Within the OLE, 3 of the 12 participants withdrew from the study due to adverse events related to rising prostate specific antigen and haematocrit.

Conclusions. In this study comparing exercise alone to exercise in combination of testosterone supplementation, we were unable to detect a significant effect of the treatment on muscle strength, function or quality of life. However, peak torque extension at 60 degrees worsened significantly during the exercise-only arm, which could indicate that testosterone conferred some stabilisation effect during the treatment period. Individuals on testosterone also felt that their daily activities were not as limited due to the emotional problems compared with placebo, perhaps indicating that testosterone contributes to improved mood and mental health. Individuals who participated in the OLE had improved walk tests at 6 months which then declined at 12 months. This warrants further investigation in future studies, where the benefit of testosterone on walking strength may decline after a prolonged period. Finally, we note that 12 men requested the OLE due to perceived positive effects and lack of adverse effects, so potentially the benefits of testosterone require a longer period of intervention to manifest than that applied during the crossover phase.

Background. Inclusions of Sequestosome1 (SQSTM1/p62) within muscle fibers are a pathological hallmark of sporadic inclusion body myositis (sIBM) with p62 overexpression reported in patients. Mounting evidence suggests a role for p62 expression and/or variation in sIBM pathology, due to the presence of rare and potentially pathogenic missense variants (A117V, G194R, K238E, P392L). Consequently, we hypothesized that genetic modifiers of SQSTM1 may present a critical missing link for sIBM pathology and contribute to disease expres¬sion. Short structural variants (SSVs) are a class of genetic variation that can be difficult to characterized due to their highly repetitive and complex nature. Evidence that SSVs play an important role in complex diseases such as Alzhei¬mer’s Disease, Amyotrophic lateral sclerosis, Spinocerebellar Ataxia type 2, and Huntington’s disease is now confirmed and further investigations of this type of genetic variation is necessary to uncover missing heritability in complex dis¬eases. We and others have previously reported an SSV within SQSTM1 that is associated with altered expression of p62. The SSV rs60327661 is a CAAA in¬sertion/deletion within intron 5 of SQSTM1, which also confers risk for familial Amyotrophic lateral sclerosis. Due to the role of the SSV in Amyotrophic lateral sclerosis and altered p62 expression, we hypothesized the SSV rs60327661 may have disease-modifying effects in a longitudinal cohort of sIBM patients.

Methods. DNA samples from 218 sIBM patients and 242 healthy controls were received from The Institute for Immunology and Infectious Diseases, Murdoch, Western Australia, and the NINDS Repository, Coriell Institute for Medical Research, New Jersey. Genomic DNA samples were systematically assessed through polymerase chain reaction, capillary separation, and Sanger sequencing for rs60327661 allele genotyping.

Results: In the present study, when controlling for self-declared ancestry, car¬riage of the D/D genotype is associated with sIBM disease expression (p<0.05). Both the case and control groups did not violate Hardy-Weinberg equilibrium (p=0.99, p=0.98; respectively. Intriguingly, patients who were CN1A seroposi¬tive were more likely carry the D allele (n=18) when compared to patients with-out a D allele (n=3; p<0.047). Patients classified as fast progressors (n=2) carried only the D/D genotype.

Conclusion. In this study, we present the first report of an association between the SQSTM1 insertion/deletion and sIBM disease expression. We provide evi¬dence that the investigation of genetic variants outside of the HLA region is war¬ranted, and that such investigations are likely to uncover critical information for sIBM. We present the SSV rs60327661 as a novel disease modifying variant for sIBM which is functionally linked to p62 by altering protein expression. Our data adds to growing evidence that examination of SSVs may uncover novel genetic risk markers, and consequently further understanding of the pathogenic mechanisms at play.

Background. Idiopathic Inflammatory Myopathies (myositis) are a group of rare neuromuscular diseases. Conditions within this group include Dermatomyositis (DM), Necrotising Myositis (NAM), Polymyositis (PM), Overlap Myositis and the currently untreatable Inclusion Body Myositis (IBM). It is well established that patients within research-active clinical environments have better outcomes and development of effective disease-modifying treatments is dependent on translational, patient-centered research.

Aim: Establishment of a translational research programme within specialist myositis outpatient clinics at Perron Institute for Neurological and Translational Science and Murdoch University (Perth, Australia).

Methods. Facilitated through a significant patient bequest towards myositis re¬search, a laboratory and clinical research programme was founded in 2017 by Professor Merrilee Needham. Appointment of laboratory and clinical research leads supported new workflows where during clinic visits, patients meet with research nurses/coordinators and are provided the opportunity to take part in myositis research, including donating blood and urine samples that are taken directly to the on-site laboratories for analysis. Consented patients are also enrolled in the team’s emerging observational Myositis Registry, and natural history data is collected via questionnaires and outcome measures through our team physiotherapist. At their clinic visit, patients are kept up to date with clinical trial opportunities and research news. For those actively taking part in clinical trials, re¬search visits are often aligned with clinic appointments, increasing convenience and ease of participation. Within our laboratory programme, Lead Scientist Dr Jerome Coudert and his team are characterising the immune profiles, underlying pathways and mechanisms, genetic and metabolic changes of patients over time, as well as performing detailed analyses on blood, urine and muscle samples. A critical element of the research clinic model is keeping patients actively engaged with the research programme. Our patients are kept up to date with current and upcoming projects, advise us of what is important to study next, and are actively participating in project design and review. In recent years, our group has been complimented by an increasing number of higher degree students as well as medical students, across both the clinical and laboratory arms of the programme.

Results. At time of submission, we have over 400 active patients and disease-control participants, with over 2,000 samples collected and biobanked. Our ethical approvals support invitation of participants to take part in future studies based on genotype or phenotype of interest. Our programme has supported five Investigator-Initiated clinical trials over the last 3 years and four commercial clinical trials in myositis. Our highly collaborative approach sees growing national and international collaborative projects and grant applications. In 2020 we received a $1.8M grant from the Australian Government to lead an international, multi-site, Phase 3 trial of Sirolimus in IBM.

Conclusions. Research allows us to offer our patients hope and to partner with them on the journey to finding new treatments and improving quality of life. Our translational programme features a direct and bi-directional pipeline between laboratory and clinical research, built on a solid foundation of observational research projects designed to facilitate future research and treatment trials in myositis.

Background. B mode ultrasound (US) and shear wave elastography (SWE) are easily accessible clinician lead imaging tools for idiopathic inflammatory myo¬pathies (IIM) but require further validation against standard diagnostic proce¬dures such as MRI and muscle biopsy. Our study aims to validate muscle B mode ultrasound (US) and shear wave elastography (SWE) in idiopathic inflammatory myopathies (IIM) against MRI and muscle biopsy findings.

Methods. In this prospective cross-sectional study, we compared US findings to MRI and muscle pathology in a group of 20 IIM patients seen in the clinic. US domains (echogenicity, fascial thickness, muscle bulk, shear wave speed and power doppler) in the deltoid and vastus lateralis were compared to MRI domains (muscle oedema, fatty infiltration, and atrophy) and muscle biopsy findings (in¬flammatory infiltrates, myonecrosis, atrophy and fibro-fatty infiltration) in the same muscle. A composite index score (1-4) was used as an arbitrary indicator of overall muscle pathology in biopsies.

Results. Increased echogenicity was significantly associated with the presence of fatty infiltration/atrophy on MRI (p=0.047) in the vastus lateralis and showed a non-significant association with muscle inflammation, myonecrosis, fibrosis, and fatty infiltration/atrophy (p>0.333). High echogenicity also had a non-significant association with a higher composite biopsy index score in the vastus lateralis (p=0.380). SWS and US measures of fascial thickness and muscle bulk showed poor discrimination in differentiating between pathologies on MRI or muscle biopsy. Power Doppler showed no statistical association with oedema on MRI or inflammation or fatty infiltration on biopsy. Overall, the US was very sensitive in detecting the presence of muscle pathology shown on MRI (67-100%) and showed reasonable specificity (75-100%). Increased echogenicity showed good sensitivity in detecting muscle pathology (83-100%) but lacked specificity in dif¬ferentiating pathological muscle changes specific to IIM (0%).

Conclusion. Our findings show that muscle echogenicity has a high sensitivity but low specificity for detecting muscle pathologies specific to IIM. Traditional visual grading scores are not IIM-specific and require further refinement and validation. Future studies should focus on developing a feasible scoring system that is reliable and allows translation to clinical practice.

Background. The Myositis Discovery Programme (MDP) based in Perth, West¬ern Australia works closely with consumers to provide direction and guidance in their research endeavours. Together with the Myositis Association Australia, a Myositis Research Consumer Panel was established. Comments from members of the Panel during meetings revealed that they felt they learn more about Assis¬tive Technology (AT) from their peers than from health professionals. As a result of this discussion, a study was initiated to investigate usage and perceived value of AT used by people with myositis.

Methods. Based on literature review, therapist advice and input from the Myositis Research Consumer Panel, an online survey (Qualtrics) was designed to capture information regarding AT use and value, as well as information regarding demo¬graphics, health status and quality of life, including via validated questionnaires. Members of the Myositis Association Australia and patients of the MDP (Perth, Australia) were invited to participate. Participants were asked to rate the ‘useful¬ness’ of items of AT that they use and were asked to complete health status informa-tion via the Neuromuscular Symptom Score (NSS) as well as well-being status via the ‘Patient Health Questionnaire (PHQ-9)’ and ‘Personal Wellbeing Index (PWI)’.

Results. 102 myositis patients completed the survey, with majority of respond¬ents diagnosed with IBM (n=80). 100 participants owned at least one AT device with an average of 14 items owned. The most used assistive devices pertained to bathroom and mobility. Participants rated AT devices relating to environmental support, sleeping, seating and body support as most useful. There was a correla¬tion between disease severity and numbers of devices used. Additionally, it was found that most people with myositis self-funded their own AT. It was hypoth¬esised that items which aided mobility would be most valued, however this was not found to be the case, with items that help patients to retain their independence rather than simply provide physical assistance (e.g. smart phones, tablets, modi¬fied driving controls) rated most valuable.

Conclusions. As expected, AT device usage is high among people with myosi¬tis, particularly those with more severe or disabling disease. Most items were deemed to be of value, however, AT devices that support people with myositis to retain independence were found to be of higher value than AT devices that provide physical support alone.

Objectives. Inclusion body myositis (IBM) is a progressive inflammatory and degenerative disease of the skeletal muscles that affects individuals over the age of 45 and leads to a gradual loss of mobility. It has been widely reported that a subgroup of 33 to 72% of IBM patients produce self-reactive antibodies that bind cytosolic 5’-nucleotidase 1A (NT5C1A) within the muscles and possibly exacerbate the disease severity. A genetic association between immune-related genes with IBM has been described. This study aimed to deepen our knowledge about the human leukocyte antigen (HLA) genes that alter the risk to develop IBM and to investigate whether specific HLA alleles may contribute to the occurrence of NT5C1A-directed antibodies.

Methods. In this study, we used Illumina next-generation sequencing to resolve the high resolution HLA haplotype of 102 Caucasian IBM patients from the Western Australian cohort. We then compared the frequency and carriage of the identified alleles within the IBM cohort to reference databases of Caucasian cohorts. We additionally compared the HLA allele carriage within the genotypes of anti-NT5C1A-positive and-negative patients within our IBM cohort.

Results. Our results confirmed the previously identified association risk of the 8.1 MHC ancestral haplotype with IBM. We also lifted ambiguities and clarified the identity of the risk-associated alleles that have been previously reported at a lower level of resolution. Additionally, we identified previously unreported risk allele associations with IBM. Furthermore, our analysis validated previously reported protective HLA alleles, and also revealed reduced carriage frequency of additional alleles, suggesting their protective role in the disease. Lastly, our study revealed two alleles, which carriage are associated with anti-NT5C1A antibody production.

Conclusions. Our findings refine and expand on the knowledge of the HLA genetic background of IBM. Stratifying patients based on their HLA genotype provides a genetic basis for new therapeutic intervention strategies early in the disease process to slow down symptom development.

Background. Over the past decade, the OMERACT Myositis Working Group (MWG) conducted several focus groups and international consensus studies with adult idiopathic inflammatory myopathy (IIM) patients, and identified pain, fatigue and physical activity (later operationalized as physical function based on focus groups) as the most important domains to assess. There is a lack of reliable and valid patient-reported outcome measures (PROMs) assessing these domains that are also available in multiple languages. A systematic literature review and discussions with patient research partners resulted in identification of three Patient Reported Outcome Information System (PROMIS) scales assessing pain interference (6a v1.0), fatigue (7a v1.0) and physical function (8b v2.0) as candidate PROMs. The objective of this study was to evaluate the construct validity and test-retest reliability of the PROMIS pain interference, fatigue, and physical function forms in adult IIM.

Methods. PROMs were deployed to adult IIM patients (excluding inclusion body myositis) from the OMERACT MWG international clinic sites (Australia, Canada, the Netherlands, South Korea, Sweden, UK, USA). For construct validity, data was analyzed from the OMERACT MWG 2019 Survey of Content Validity and Feasibility and 2021 Survey of Construct Validity and Reliability. In addition to the three candidate PROMs, Functional Assessment of Chronic Illness Therapy-Fatigue, Pain Disability Index, International Physical Activity Questionnaire, Myositis Activities Profile, numeric pain rating scale, PROMIS anxiety (4a v1.0), depression, sleep disturbance, and social participation were obtained. For construct validity, a total of 14 a priori hypotheses were generated based on consensus (>75% agreement by MWG members). Pearson correlation was calculated to assess the correlations between instruments for each hypothesis. For test-retest reliability, PROMIS instruments were administered at time zero and 7 days later with numeric pain rating scale as anchor. Test-retest reliability was assessed using both Pearson correlation and intra-class correlation coefficient (ICC) (considered strong if ICC or r >0.75). Internal consistency was assessed using Cronbach-α (considered good if ≥0.8, and excellent if ≥0.9). Floor and ceiling effects were determined based on histograms of each instrument.

Results. Of 368 participants who received a survey link, 161 (44%) completed ≥1 PROM and 263 completed test-retest questionnaire. Average age of participants was 60 (SD 11) with 73% female: 80% were from USA (n=129), followed by Australia (n=8, 5%), the UK (n=7, 4%), Canada (n=5, 3%), the Netherlands (n=2, 1%), and Sweden (n=2, 1%). For construct validity, 11 out of 14 a priori hypotheses were met supporting construct validity of the three PROMIS instruments (3/5 for pain interference, 4/4 for fatigue, and 4/5 for physical function) (Figure). Test-retest reliability was strong for all three PROMIS instruments with ICCs (95%CI) of 0.93 (0.91-0.95) for pain interference, 0.94 (0.91-0.95) for fatigue, and 0.97 (0.96-0.98) for physical function. All three PROMIS instruments demonstrated good/excellent internal consistency with Cronbach-α ranging from 0.89 to 0.97. None of the measures demonstrated any ceiling or floor effects with the exception of a significant ceiling effect in the pain interference scale (31%).

Conclusions. This study provides reliability and validity evidence for application of the PROMIS pain interference (6a v1.0), fatigue (7a v1.0), and physical function (8b v2.0) instruments in a large international cohort of adult patients with IIM. Internal consistency of these instruments was good to excellent. Both fatigue and physical function instruments did not show any ceiling or floor effect supporting their ability to capture the full spectrum of constructs. However, significant ceiling effect noted in the pain interference instrument raises concern about its use in patients with minimal/no pain. Further longitudinal studies to assess the responsiveness of these measures are currently ongoing in multiple countries.

Background. Inclusion body myositis (IBM) is the most common inflammatory muscle diseases that primarily affects the elderly. It is characterised by autoim¬mune aggression and degeneration of skeletal muscles, which leads to severe disability over time. Although the aetiology of IBM is uncertain, numerous lines of evidence point to T cells playing a pathogenic key role. One of the major ques¬tions that remains unsolved regarding IBM muscle-invading T cells is the nature of the antigen that drives their autoreactivity. We hypothesised that the analysis of T cells’ T cell receptor (TCR) repertoire will give insights into their specific¬ity. We used high-throughput sequencing of TCRβ chains in T cells isolated from muscle biopsies and matched blood samples to compare T cell clonal profiles within the inflammation-affected muscle tissues and systemically.

Methods. Blood and muscle samples were collected on the same days for each of the four donors. Muscle-invading T cells were isolated as bulk while peripheral blood mononuclear cells were subjected to CD4+ and CD8+ T cell separation. The TCRβ sequencing was performed using the high-throughput Illumina Miseq platform. Downstream data analysis of TCRβ repertoires was performed using in-house VGAS tool, Immunarch R package and VDJtools. HLA haplotype of each donor was determined by high resolution typing of HLA class I and II al¬leles using Illumina Miseq platform in an American Society for Histocompat¬ibility and Immunogenetics (ASHI)-accredited laboratory.

Results. Analysis of muscle-T cells for TCR repertoire overlap revealed shared clonotypes between patients. A unique TCRβ sequence was shared between pa¬tients 1, 3, and 4, while in patient 2, although this sequence was not found in the muscle, it ranked as a predominant clone in the blood. The patients 1 and 3 displayed nine sequences in common, as well as their top three TCRβ sequences. Furthermore, analysis of TCR repertoire usage in the corresponding blood sam¬ples showed common clonotypes between muscle and blood, but at higher fre¬quency in muscles indicating that a preferential expansion occurred in this tissue. Moreover, querying the top five dominant TCRβ CDR3 sequences of muscle from each patient in a curated database of TCR identified multiple highly similar sequences with known specificity for antigens derived from virus and muscle proteins, especially in the CD8+ T cell subset. In patient 1 and 3, the topmost clone showed a high level of similarity with a CDR3 specific for CMV-derived antigen as well as self-antigens derived from protein phosphatase 1F (PPM1F) and A-kinase anchor protein 9 (AKAP9). The HLA alleles reported to present these autoantigens matched with the HLA haplotype of patient 3. On the other hand, for patient 2, we identified a clone bearing high CDR3 similarity with known sequences documented to be associated with HIV-1 and EBV-derived an¬tigens, and another CDR3 that exactly matched a sequence specific for a gluten-derived peptide. Interestingly, this patient carries HLA-DQ9 which is a reported risk factor for celiac disease.

Conclusions. Our findings identified public TCRs in IBM muscle, and the pres¬ence of expanded T cell clones harbouring TCR sequences with striking similari¬ties between virus and muscle-derived antigens, suggesting that an underlying molecular mimicry mechanism may generate autoreactive T cells.

Background. Inclusion body myositis (IBM), a relentlessly progressive auto¬immune skeletal muscle disease, has no effective available pharmacological therapy. A prominent feature of IBM on microscopy is CD8+ highly cytotoxic T (Tc) cells invading non-necrotic myofibers (1, 2). These cells include T effector memory (TEM) and terminally differentiated T effector cells (TEMRA), known to be relatively resistant to apoptosis, and express markers including killer cell lectin-like receptor G1 (KLRG1) (3). ABC008, a first-in-class humanized, afucosylated monoclonal antibody (mAb) specific for KLRG1, was developed to selectively deplete these CD8+ Tc cells while sparing other cell populations, e.g., naïve, central memory, and regulatory T cells and B cells. ABC008 has been designed to treat diseases mediated by Tc cells such as IBM and T-cell large granular lymphocytic leukemia (T-LGLL). IBM overlaps clinically with T-LGLL (2) and shares similar expansions of large granular lymphocytes, which also express KLRG1. We report here preliminary data from our ongoing first-in-human trial of ABC008 in IBM (NCT04659031).

Methods. In this open label, single ascending dose trial with 3+3 design evaluating ABC008 administered subcutaneously (SC), eligible participants must have clinicopathologically defined, clinically defined, or probable IBM according to the European Neuromuscular Centre 2011 research diagnostic criteria (3) and an IBM Functional Rating Scale (IBMFRS) score <38. Four dose cohorts are planned: ABC008 0.1, 0.5, 2.0, and 5.0 mg/kg. Pharmacodynamics (PD), pharmacokinetics (PK), safety, and disease severity assessments are performed pre-dose (Day 0) and during the 6 month follow-up period.

Results. As of 12 February 2022, Cohorts 1 (C1) and 2 (C2) have received 0.1 and 0.5 mg/kg of ABC008 SC and completed 168 and 56 days of follow-up, respectively. Cohort 3 evaluating ABC008 2.0 mg/kg is enrolling. Across C1 and C2, mean baseline age is 65.7 years, IBM disease duration 6.8 years, and IBMFRS score 27.5. Maximum depletion of CD8+KLRG1+ cells in C1 and C2 ranged from 46-96% and 98-99%, respectively, with depletion evident within 24 hours (first time point assessed) (Figure). Recovery in C1 began at Day 84 with Day 168 depletion at 29-71%. Deep depletion was also present in other relevant pathogenic populations including CD4+KLRG1+, CD8+CD57+ (LGLs), CD8+ TEM, and CD8+ TEMRA cells. Protective populations of immune cells were preserved, including B cells, regulatory T cells that protect against autoimmunity, and central memory T cells that protect against infection (Figure). ABC008 SC displays a long absorption phase and slow clearance properties typical of mAb therapies. No severe adverse events (AEs) or discontinuations due to AEs have been reported. One unrelated serious AE of fall with muscle tear occurred in a participant with a prior history of falls.

Conclusions. In study participants with IBM, single SC doses of 0.1 and 0.5 mg/kg of ABC008 resulted in dose dependent depletion of CD8+KLRG1+ cells, CD8+CD57+ LGLs, and other highly cytotoxic populations, while sparing protective populations of immune cells, without apparent safety signals. Additional cohort dosing is ongoing, and a multi-ascending dose phase of the study is planned.