Immunomodulatory Regimen Provides Long-term Tolerance to ERT in Children With Pompe, Study Shows

Adding a preventive short-course immunomodulatory regimen — rituximab, methotrexate, and intravenous immunoglobulins (IVIG) — to enzyme replacement therapy (ERT) safely provides long-term protection from antibodies that can block ERT’s effectiveness in children with classic infantile Pompe disease, a study found.

These findings highlight that the benefits of adding this immune tolerance induction (ITI) regimen to ERT outweigh the risks in the youngest group of Pompe patients reported so far, regardless of their cross-reactive immunologic material (CRIM) status. CRIM status determines a patient’s risk to develop high and sustained levels of neutralizing antibodies against ERT.

The study, “Benefits of Prophylactic Short-Course Immune Tolerance Induction in Patients With Infantile Pompe Disease: Demonstration of Long-Term Safety and Efficacy in an Expanded Cohort,” was published in the journal Frontiers in Immunology.

Alglucosidase alfa, an ERT that delivers a lab-made version of the enzyme missing in people with Pompe disease, is the only approved treatment for this condition. It is marketed by Sanofi Genzyme as Lumizyme in the U.S., and Myozyme in the European Union.

While ERT has led to significant clinical benefits in these patients, not all respond equally well. This is determined by several factors, including the development of antibodies against ERT, neutralizing its effect.

Notably, patients classified as CRIM-negative carry the highest risk of producing high levels of neutralizing antibodies and subsequently responding poorly to treatment.

To prevent or lessen this immune response and provide tolerance to ERT, several immunomodulatory approaches have been combined with ERT.

A previous study showed that a five-week course of rituximab, low-dose methotrexate, with or without IVIG successfully induced tolerance to ERT in CRIM-negative patients with infantile Pompe disease, the most severe form of the disease.

Rituximab and methotrexate are intended to target several immune cells (B-cells and T-cells), preventing the development of anti-ERT antibodies, while IVIG provides passive immunity until the pool of B-cells is reconstituted after treatment.

However, the long-term safety of this strategy has not been evaluated, and safety results of immunomodulation with rituximab are limited.

Importantly, data from several disease settings suggest that rituximab can cause long-term impairment of the immune system (particularly B-cells) and adversely impact vaccine responses.

Here, a team of researchers at Duke University Health System, in North Carolina, along with a colleague at the Center for Drug Evaluation and Research of the U.S. Food and Drug Administration, evaluated the long-term safety and effectiveness of this preventive immunomodulatory regimen in the largest and youngest group of CRIM-positive and CRIM-negative children with Pompe disease reported to date.

The study, supported by Sanofi Genzyme and the Lysosomal Disease Network, included participants enrolled in a larger Duke-sponsored observational clinical trial (NCT01665326), which is assessing ERT responses, with or without immunomodulatory treatment, in children with Pompe disease. Recruitment in this trial is still open; more details are available here.

The ITI regimen included four doses of weekly rituximab of 375 mg/m²   (milligrams per square meter) into the bloodstream and three cycles of low-dose methotrexate (0.4 mg/kg), with or without monthly IVIG, at 500 mg/kg.

The team analyzed data from 34 participants — 25 CRIM-negative and nine CRIM-positive — treated with ERT and the immunomodulatory regimen at a median age of 3.5 months and with at least six months of follow-up. As of the study’s completion, patients’ median age was nearly 6 years (maximum age 12 years).

Results showed that most (88%) patients either did not develop (16 children) or maintained low levels of anti-ERT antibodies (14 participants). As the researchers had no explanation for the poor responses seen in the remaining four CRIM-negative patients, they hypothesized that it may be due to a resistance to rituximab.

In addition, the combined treatment led to meaningful clinical improvements, including a reduced need for mechanical ventilation, a trend toward heart size normalization, improved motor ability, and prolonged survival.

Notably, three CRIM-negative children became free of invasive ventilation at the most recent follow-up, a benefit rarely seen in this patient population. In addition, the team noted that CRIM-negative participants lived significantly longer than those who received ERT only in previous clinical trials. Yet, seven CRIM-negative patients had died by study completion.

All patients showed complete B-cell reconstitution after rituximab discontinuation within a median of 17 weeks, which was maintained for at least four years. Most evaluable patients were able to receive routine vaccinations and showed mostly adequate vaccine responses.

The immunomodulatory regimen was well-tolerated, without any major side effects or treatment-related deaths. Infections were reported in five CRIM-negative patients, but were all resolved with antibiotics and did not lead to treatment discontinuation.

“To our knowledge, this [is] the largest cohort of patients with IPD [infantile Pompe disease] treated with ITI in ERT-naïve settings and the largest cohort of pediatric patients under a year of age evaluated for the safety of rituximab,” the researchers wrote.

“The addition of this ITI regimen to ERT is life-saving and our data show that the benefits of adding immune modulation (ITI regimen) outweigh the risks in this setting,” the team concluded.