What effects does enzyme replacement therapy (ERT) have on people with late-onset Pompe disease (LOPD)?

Key messages

• Late-onset Pompe disease (LOPD) is a rare condition that causes people to become more unwell over time. Enzyme replacement therapy (ERT) can help to slow disease progression.

• Alglucosidase alfa (a type of ERT) probably improves some aspects of disease progression in people with late-onset Pompe disease (LOPD) compared to placebo (an inactive or 'dummy' medicine).

• Future studies should monitor participants for as many years as possible to better understand the long-term effects of treatments.

What is late-onset Pompe disease (LOPD)?

LOPD is a rare, inherited disorder that leads to muscle weakness, breathing difficulties, and reduced life expectancy. It is caused by a deficiency of the enzyme acid alpha-glucosidase (GAA). Enzymes are proteins that help speed up chemical reactions in the body. They are essential for breathing, digesting food, muscle function, and many other processes. People of any age can start having symptoms of LOPD. People with LOPD retain some residual enzyme activity, meaning the enzymes produced by their bodies are still doing some of the work expected of them.

How is LOPD treated?

LOPD is treated by giving people a replacement enzyme called 'recombinant human acid alglucosidase alfa' via an infusion into a vein. There are two types of this enzyme replacement therapy (ERT) – alglucosidase alfa and avalglucosidase alfa – which are approved treatments. There is a third treatment – cipaglucosidase alfa with miglustat – which medicine regulators have not yet approved. The aim of ERT is to slow down disease progression.

What did we want to find out?

We wanted to discover whether ERT was better or worse than no ERT or ERT alongside other medications, in terms of:

• mobility, measured by how far someone can walk in 6 minutes (6MWT);
• breathing problems, assessed by measuring the maximum amount of air someone can blow out of their lungs (forced vital capacity or FVC);
• side effects;
• quality of life (QoL).

What did we do?

We searched for studies that compared one ERT to a placebo , or one ERT to a different ERT. We summarised their results and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We found 6 studies with a total of 358 people, each with a different ERT comparison. The longest trial lasted 78 weeks. Only one trial compared a single ERT (alglucosidase alfa) to placebo; the others compared the different ERT combinations summarised below. Drug companies funded 4 of the studies; the medicine regulator in the USA funded 1 study; and the funding source for the sixth study was unknown.

Key results

None of the studies assessed 2 of the review's outcomes of interest: people's need for breathing support and the use of a wheelchair or walking aid.

Alglucosidase alfa versus placebo: compared to placebo, alglucosidase alfa probably improves results for 6MWT and FVC. It may make little or no difference to QoL, the risk of allergic reactions, and the number of side effects.

Alglucosidase alfa with clenbuterol versus alglucosidase alfa with placebo: we are very uncertain whether this ERT plus clenbuterol (a bronchodilator, or medicine to help breathing) improve results for the 6MWT and FVC compared to the same ERT plus a placebo. This study did not report on QoL or any side effects.

Alglucosidase alfa with albuterol versus alglucosidase alfa with placebo: we are very uncertain whether this ERT plus albuterol (a bronchodilator) improves results for the 6MWT or FVC, or increases the risk of side effects when compared to the same ERT plus a placebo.

VAL-1221 versus alglucosidase alfa: we are very uncertain of the effects of VAL-1221 (an experimental ERT) on 6MWT and side effects compared to standard ERT given to people with LOPD.

Cipaglucosidase alfa plus miglustat versus alglucosidase alfa plus placebo: cipaglucosidase alfa plus miglustat may make no difference to the 6MWT, but probably improves FVC when compared to alglucosidase alfa plus placebo (although there was no difference between the 2 treatments for a second lung function measure). It may make no difference to QoL, the risk of allergic reactions, or the number of side effects.

Avalglucosidase alfa versus alglucosidase alfa: avalglucosidase alfa probably improves results of the 6MWT compared to alglucosidase alfa but probably makes no difference to FVC. There may be little or no difference between the two treatments in terms of QoL, the risk of allergic reactions, or the number of side effects.

What are the limitations of the evidene?

Only one study compared ERT to no treatment (placebo). We also had concerns about some people dropping out of the studies and influencing the results. We thought that, in some cases, only some results were reported while others were missing. The results that were reported often had large variations, which made it difficult to determine if there was a true effect of treatment.

How up to date is this evidence?

The evidence is current to 21 April 2022.

Authors' conclusions: 

One trial compared the effect of ERT to placebo in LOPD, showing that alglucosidase alfa probably improves 6MWT and respiratory function (both moderate-certainty evidence). Avalglucosidase alfa probably improves 6MWT compared with alglucosidase alfa (moderate-certainty evidence). Cipaglucosidase plus miglustat probably improves FVC compared to alglucosidase alfa plus placebo (moderate-certainty evidence). Other trials studied the adjunct effect of clenbuterol and albuterol along with alglucosidase alfa, with little to no evidence of benefit. No significant rise in adverse events was noted with all ERTs.

The impact of ERT on some outcomes remains unclear, and longer RCTs are needed to generate relevant information due to the progressive nature of LOPD. Alternative resources, such as post-marketing registries, could capture some of this information.

Read the full abstract...
Background: 

Pompe disease is caused by a deficiency of the enzyme acid alpha-glucosidase (GAA). People with infantile-onset disease have either a complete or a near-complete enzyme deficiency; people with late-onset Pompe disease (LOPD) retain some residual enzyme activity. GAA deficiency is treated with an intravenous infusion of recombinant human acid alglucosidase alfa, an enzyme replacement therapy (ERT). Alglucosidase alfa and avalglucosidase alfa are approved treatments, but cipaglucosidase alfa with miglustat is not yet approved.

Objectives: 

To assess the effects of enzyme replacement therapies in people with late-onset Pompe disease.

Search strategy: 

We searched the Cochrane Inborn Errors of Metabolism Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched MEDLINE OvidSP, clinical trial registries, and the reference lists of relevant articles and reviews.

Date of last search: 21 April 2022.

Selection criteria: 

We included randomised controlled trials (RCTs) of ERT in people with LOPD of any age.

Data collection and analysis: 

Two review authors independently assessed trial eligibility, extracted data, assessed the risk of bias and the certainty of the evidence (using GRADE). We resolved disagreements through discussion and by consulting a third author.

Main results: 

We included six trials (358 randomised participants) lasting from 12 to 78 weeks. A single trial reported on each comparison listed below. None of the included trials assessed two of our secondary outcomes: need for respiratory support and use of a walking aid or wheelchair. Certainty of evidence was most commonly downgraded for selective reporting bias.

Alglucosidase alfa versus placebo (90 participants)

After 78 weeks, alglucosidase alfa probably improves the six-minute walk test (6MWT) distance compared to placebo (mean difference (MD) 30.95 metres, 95% confidence interval (CI) 7.98 to 53.92; moderate-certainty evidence) and probably improves respiratory function, measured as the change in per cent (%) predicted forced vital capacity (FVC) (MD 3.55, 95% CI 1.46 to 5.64; moderate-certainty evidence).

There may be little or no difference between the groups in occurrence of infusion reactions (risk ratio (RR) 1.21, 95% CI 0.57 to 2.61; low-certainty evidence), quality of life physical component score (MD -1.36 points, 95% CI -5.59 to 2.87; low-certainty evidence), or adverse events (RR 0.94, 95% CI 0.64 to 1.39; low-certainty evidence).

Alglucosidase alfa plus clenbuterol versus alglucosidase alfa plus placebo (13 participants)

The evidence is very uncertain about the effect of alglucosidase alfa plus clenbuterol compared to alglucosidase alfa plus placebo on: change in 6MWT distance after 52 weeks (MD 34.55 metres, 95% CI-10.11 to 79.21; very low-certainty evidence) and change in % predicted FVC (MD -13.51%, 95% CI -32.44 to 5.41; very low-certainty evidence).

This study did not measure infusion reactions, quality of life, and adverse events.

Alglucosidase alfa plus albuterol versus alglucosidase alfa plus placebo (13 participants)

The evidence is very uncertain about the effect of alglucosidase alfa plus albuterol compared to alglucosidase alfa plus placebo on: change in 6MWT distance after 52 weeks (MD 30.00 metres, 95% CI 0.55 to 59.45; very low-certainty evidence), change in % predicted FVC (MD -4.30%, 95% CI -14.87 to 6.27; very low-certainty evidence), and risk of adverse events (RR 0.67, 95% CI 0.38 to 1.18; very low-certainty evidence).

This study did not measure infusion reactions and quality of life.

VAL-1221 versus alglucosidase alfa (12 participants)

Insufficient information was available about this trial to generate effect estimates measured at one year or later. Compared to alglucosidase alfa, VAL-1221 may increase or reduce infusion-associated reactions at three months, but the evidence is very uncertain (RR 2.80, 95% CI 0.18 to 42.80).

This study did not measure quality of life and adverse events.

Cipaglucosidase alfa plus miglustat versus alglucosidase alfa plus placebo (125 participants)

Compared to alglucosidase alfa plus placebo, cipaglucosidase alfa plus miglustat may make little or no difference to: 6MWT distance at 52 weeks (MD 13.60 metres, 95% CI -2.26 to 29.46); infusion reactions (RR 0.94, 95% CI 0.49 to 1.80); quality of life scores for physical function (MD 1.70, 95% CI -2.13 to 5.53) and fatigue (MD -0.30, 95% CI -2.76 to 2.16); and adverse effects potentially related to treatment (RR 0.83, 95% CI 0.49 to 1.40) (all low-certainty evidence).

Cipaglucosidase alfa plus miglustat probably improves % predicted FVC compared to alglucosidase alfa plus placebo (MD 3.10%, 95% CI 1.04 to 5.16; moderate-certainty evidence); however, it may make little or no change in % predicted sniff nasal inspiratory pressure (MD -0.06%, 95% CI -8.91 to 7.71; low-certainty evidence).

Avalglucosidase alfa versus alglucosidase alfa (100 participants)

After 49 weeks, avalglucosidase alfa probably improves 6MWT compared to alglucosidase alfa (MD 30.02 metres, 95% CI 1.84 to 58.20; moderate-certainty evidence).

Avalglucosidase alfa probably makes little or no difference to % predicted FVC compared to alglucosidase alfa (MD 2.43%, 95% CI -0.08 to 4.94; moderate-certainty evidence). Avalglucosidase alfa may make little or no difference to infusion reactions (RR 0.78, 95% CI 0.42 to 1.45), quality of life (MD 0.77, 95% CI -2.09 to 3.63), or treatment-related adverse events (RR 0.92, 95% CI 0.61 to 1.40), all low-certainty evidence.