Development of high sustained anti-drug antibody titers and corresponding clinical decline in a late-onset Pompe disease patient after 11+ years on enzyme replacement therapy

Kim, Katherine H.; Desai, Ankit K.; Vucko, Erika; Boggs, Tracy; Kishnani, Priya S.; Burton, Barbara K.

doi:10.1016/j.ymgmr.2023.100981

Cited by 4 publications

(7 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The efficacy of therapeutic ITI in LOPD remains debated due to the uncertain impact of ADA on treatment outcomes ( 28 , 29 ). However, recent studies have shown promising results of therapeutic ITI in LOPD patients with HSAT ( 30 , 31 ). In our study, three LOPD patients exhibited diverse responses to ITI.…”

Section: Discussionmentioning

confidence: 99%

“…For the younger subjects (Subject B2-B5), ITI was initiated swiftly upon the detection of elevated ADA titers, thereby minimizing the duration of high ADA exposure and potentially mitigating its impact. Recent reports have also addressed the importance of regular monitoring of ADA titers across both IOPD and LOPD patients ( 24 , 30 ). Secondly, our study’s reliance on conventional clinical outcome measures, such as the 6MWT and FVC, may not be sensitive enough to discern subtle improvements within the six-month study duration.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy

Chen,

Hsu,

Fang

et al. 2024

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

IntroductionPompe disease, a lysosomal storage disorder, is characterized by acid α-glucosidase (GAA) deficiency and categorized into two main subtypes: infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). The primary treatment, enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), faces challenges due to immunogenic responses, including the production of anti-drug antibody (ADA), which can diminish therapeutic efficacy. This study aims to assess the effectiveness of immune tolerance induction (ITI) therapy in cross-reactive immunologic material (CRIM)-positive Pompe disease patients with established high ADA levels.MethodIn a single-center, open-label prospective study, we assessed ITI therapy’s efficacy in Pompe disease patients, both IOPD and LOPD, with persistently elevated ADA titers (≥1:12,800) and clinical decline. The ITI regimen comprised bortezomib, rituximab, methotrexate, and intravenous immunoglobulin. Biochemical data, biomarkers, ADA titers, immune status, and respiratory and motor function were monitored over six months before and after ITI.ResultsThis study enrolled eight patients (5 IOPD and 3 LOPD). After a 6-month ITI course, median ADA titers significantly decreased from 1:12,800 (range 1:12,800-1:51,200) to 1:1,600 (range 1:400-1:12,800), with sustained immune tolerance persisting up to 4.5 years in some cases. Serum CK levels were mostly stable or decreased, stable urinary glucose tetrasaccharide levels were maintained in four patients, and no notable deterioration in respiratory or ambulatory status was noted. Adverse events included two treatable infection episodes and transient symptoms like numbness and diarrhea.ConclusionITI therapy effectively reduces ADA levels in CRIM-positive Pompe disease patients with established high ADA titers, underscoring the importance of ADA monitoring and timely ITI initiation. The findings advocate for personalized immunogenicity risk assessments to enhance clinical outcomes. In some cases, prolonged immune suppression may be necessary, highlighting the need for further studies to optimize ITI strategies for Pompe disease treatment. ClinicalTrials.gov NCT02525172; https://clinicaltrials.gov/study/NCT02525172.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy

Chen,

Hsu,

Fang

et al. 2024

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…These have long been associated with worse outcomes in IOPD, including declines in muscle strength, pulmonary function, and overall survival. There have also been reports of clinical decline in LOPD (de Vries et al, 2010;Desai et al, 2019;Kim et al, 2023). In general, persistent titers greater than or equal to 12,800 are viewed as clinically significant.…”

Section: Introductionmentioning

confidence: 99%

“…In general, persistent titers greater than or equal to 12,800 are viewed as clinically significant. Titers are monitored regularly, and patients with high and persistent titers often require immunomodulation (Sanofi Genzyme, 2010;Desai et al, 2019;Sanofi Genzyme, 2021;Kim et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

Real-world outcomes from a series of patients with late onset Pompe disease who switched from alglucosidase alfa to avalglucosidase alfa

Carter,

Boggs,

Case

et al. 2024

Front. Genet.

Self Cite

View full text Add to dashboard Cite

Introduction: Pompe disease is an inherited, progressive neuromuscular disorder caused by deficiency of lysosomal acid α-glucosidase and accumulation of glycogen in tissues, resulting in cellular dysfunction, muscle damage, and functional disabilities. Enzyme replacement therapy with alglucosidase alfa (Myozyme/Lumizyme) has led to better outcomes, but many patients have plateaued or declined despite treatment. The second-generation ERT avalglucosidase alfa (Nexviazyme) was designed to have enhanced cellular uptake via the conjugation of additional bis-mannose-6-phosphate residues. There have been trials comparing the efficacy of alglucosidase and avalglucosidase, but there remains a need for more real-world data on patients who switched from alglucosidase to avalglucosidase.Methods: A chart review was conducted on n = 15 patients with late-onset Pompe disease followed at a single center who switched from alglucosidase to avalglucosidase and continued for at least 6 months.Results: A total of n = 8/15 patients received alglucosidase for more than 3 years prior to switching, and n = 7/15 received it for more than 5 years prior to switching. There were statistically significant improvements in CK, Hex4, and AST with mean differences of −104.8 U/L, −3.0 mmol/molCr, and −14.7 U/L, respectively, post-switch. 6-Minute Walk Test; comfortable gait speed; Gait, Stairs, Gower, Chair; and Quick Motor Function Test scores improved or stabilized in most patients post-switch (n = 8/12, n = 11/12, n = 9/12, n =7/11, respectively). Of n = 7 patients with pulmonary function testing, n = 4/7 had improved upright FVC. Patient-reported outcomes revealed improvements in dyspnea (n = 4/4), physical function (n = 3/4), fatigue (n = 2/3), and lower back pain (n = 3/3). Avalglucosidase was well tolerated without infusion-associated reactions, and all n = 7 patients on home infusions continued receiving ERT at home. Anti-drug antibodies were seen in n = 9/10 of patients on alglucosidase and n = 8/13 of those on avalglucosidase, with titers below 12,800 in a majority of patients. We also present the first outcome data for a patient with LOPD who is non-ambulatory and a full-time wheelchair user; she demonstrated meaningful improvements in quality of life and motor function with the switch.Discussion: In summary, improved outcomes were seen in most patients, with a subset whose decline persisted. This study presents evidence that switching from alglucosidase to avalglucosidase may be associated with improved outcomes in certain patients with LOPD.

show abstract

“…In this article, we summarize the lessons learned from patients previously reported who received a bortezomib-based ITI regimen and report on two new CRIM-positive IOPD patients who developed high antibody titers (14, [16][17][18][19]. Both newly reported patients failed to achieve durable immune tolerance despite routine immune modulation with TLD-MTX in the ERT-naïve setting.…”

Section: Introductionmentioning

confidence: 99%

An updated management approach of Pompe disease patients with high-sustained anti-rhGAA IgG antibody titers: experience with bortezomib-based immunomodulation

Desai,

Shrivastava,

Grant

et al. 2024

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

IntroductionHigh sustained anti-rhGAA antibody titers (HSAT; ≥12,800) are directly linked to reduced efficacy of enzyme replacement therapy (ERT) and subsequent clinical deterioration in infantile-onset Pompe disease (IOPD). We have previously demonstrated the safety and effectiveness of a bortezomib-based immune-tolerance induction (ITI) regimen (bortezomib, rituximab, methotrexate, and IVIG) in eliminating HSAT.MethodsHere, we describe two IOPD cases (patients 6 and 8) who developed HSAT at 8 and 10 weeks on ERT despite transient low-dose methotrexate ITI administration in the ERT-naïve setting and were treated with a bortezomib-based ITI regimen, and we compare their courses to a series of six historical patients (patients 1-5, and 7) with a similar presentation who exemplify our evolving approach to treatment.ResultsIn total, patients 6 and 8 received 16 and 8 doses of bortezomib (4 doses=1 cycle) respectively reducing titers from 25,600 to seronegative, but differences in the course of their therapy were instructive regarding the optimal approach to initial treatment of HSAT; specifically, patient 6 was treated initially with only a single course of bortezomib rescue therapy, while patient 8 received two back-to-back courses. Patient 8 received IVIG therapy throughout the immunosuppression whereas patient 6 received IVIG therapy and was switched to subcutaneous IgG replacement. Patient 6 had a transient reduction in anti-rhGAA antibodies, after receiving a single initial cycle of bortezomib, but had a recurrence of high anti-rhGAA antibody titer after 160 weeks that required 3 additional cycles of bortezomib to ultimately achieve tolerance. In contrast, patient 8 achieved tolerance after being given two consecutive cycles of bortezomib during their initial treatment and had B cell recovery by week 54. Since the reduction in anti-rhGAA antibodies, both patients are doing well clinically, and have decreasing ALT, AST, and CK. No major infections leading to interruption of treatment were observed in either patient. The bortezomib-based ITI was safe and well-tolerated, and patients continue to receive ERT at 40 mg/kg/week.DiscussionThese case studies and our previous experience suggest that to achieve an effective reduction of anti-rhGAA antibodies in the setting of HSAT, bortezomib should be initiated at the earliest sign of high anti-rhGAA antibodies with a minimum of two consecutive cycles as shown in the case of patient 8. It is important to note that, despite initiation of ERT at age 2.3 weeks, patient 8 quickly developed HSAT. We recommend close monitoring of anti-rhGAA antibodies and early intervention with ITI as soon as significantly elevated anti-rhGAA antibody titers are noted.

show abstract

Development of high sustained anti-drug antibody titers and corresponding clinical decline in a late-onset Pompe disease patient after 11+ years on enzyme replacement therapy

Cited by 4 publications

References 22 publications

Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy

Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy

Real-world outcomes from a series of patients with late onset Pompe disease who switched from alglucosidase alfa to avalglucosidase alfa

An updated management approach of Pompe disease patients with high-sustained anti-rhGAA IgG antibody titers: experience with bortezomib-based immunomodulation

Contact Info

Product

Resources

About