When the FDA approved Sanofi’s Myozyme (alglucosidase alfa) as the first treatment for Pompe disease in 2006, the 6-minute walk test (6MWT) was considered then the best primary endpoint choice. But as potential new therapies progress through the pipeline, some experts are concerned that the 6MWT could be too variable and insensitive.

The 6MWT, as the name suggests, is a measure of how far a patient can walk in six minutes. Its clinical significance is well understood among Pompe disease physicians, and many experts see the 6MWT as an all-encompassing measure of endurance and breathing capacity, ideal for registrational clinical trials.

But some experts are advocating for more holistic efficacy barometers, including coprimary measures alongside the 6MWT, for Pompe disease clinical trials. The 6MWT can be highly variable and is less effective in patients with the least mobility. Additional endpoint choices include the breathing-based lung capacity test Forced Vital Capacity (FVC), and the functional endpoint Gait, Stairs, Chair, Gower (GSCG), which requires less time and patient mobility than the 6MWT.

But experts disagree if a new primary endpoint will ultimately take precedence over the 6MWT. According to Pompe disease expert Dr Corrado Angelini, it is possible the digital health revolution could catalyse a shift towards new efficacy measures.

Overcoming 6MWT challenges for Pompe disease

“Overall, the 6MWT is more of a fatigue test than a function test,” says Angelini, who is the director of the Neuromuscular Center at the University of Padua, Italy. This metric doesn’t make sense for patients who are no longer ambulatory or who struggle to stand, so the field needs more sensitive functional endpoints, he explains.

Fatigue from travelling to clinical sites can adversely affect 6MWT scores because patient effort affects the assessment, says rare disease consultant Dr Gerald Cox. For example, patients who are more exhausted from long or overnight travel to testing centers could perform worse on the 6MWT, adding further variability to patient scores, he explains.

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However, Cox says that a strong trial design can overcome many challenges surrounding the 6MWT. With stringent trial inclusion criteria, clinical trials can enroll patients with similar baseline 6MWT scores, making it a standardised marker of quality of life, he adds.

A 6MWT of 300m, or 50m per minute, is considered the minimum score to perform basic day-to-day tasks like crossing a crosswalk, Cox says. For patients with baseline 6MWT scores around 300m, an improvement of around 30m would be highly clinically meaningful, he adds. However, this same 30m improvement would not be clinically meaningful for patients with baseline scores of around 500m, meaning a heterogeneous clinical trial population could make results harder to interpret, he notes.

Amicus’s AT-GAA (cipaglucosidase alfa/miglustat) has a PDUFA date of May 29, based on positive data from the Phase III PROPEL trial (NCT03729362). The trial recruited late-onset patients who still can walk and breathe without support. In the primary endpoint 6MWT, the 85-patient treatment arm had a baseline mean of 357.9m, with a standard deviation of 111.8m. In the 37-patient alglucosidase alfa arm, this was 351m with a standard deviation of 121.3m. AT-GAA delivered an increase of 20.8 meters from baseline at week 52, compared with 7.2m with Myozyme (p=0.072). 

“The 6MWT is still likely the best option available for Pompe disease,” Cox notes. Many Pompe disease studies have used the 6MWT as a primary endpoint, so clinicians have a good appreciation what changes are clinically meaningful, he explains.

Adding lung capacity measure welcome

Still, there are potential coprimary endpoints that can bolster the 6MWT’s clinical value. The 6MWT tests the stamina of patients, including endurance of muscles, lungs, and the respiratory system, says Dr Carlos Javier Alméciga-Díaz, a principal investigator in Pompe disease trials. But to fully assess a patient’s disease, pulmonary and cardiac assessments are necessary in addition to the 6MWT, he notes.

For Pompe disease, which is a progressive muscle weakness, both mobility and lung capacity are the most relevant endpoints, Cox says. FVC is a measure of the amount of air a patient can forcibly exhale after taking the deepest breath possible. Thus, to holistically assess an investigational drug’s effect, clinical trials should look at both the 6MWT and percent-predicted FVC as coprimary endpoints, Cox adds.

In Amicus’s PROPEL trial, along with the FVC secondary endpoint, AT-GAA patients experienced a 0.1% absolute increase in percent-predicted FVC while alglucosidase alfa patients had a 4% absolute decline over a year (p=0.006). Sanofi’s Nexviazyme (avalglucosidase alfa) was FDA-approved on August 2021 for late-onset patients, based on the Phase III COMET trial (NCT02782741) that used FVC as a primary endpoint. Nexviazyme patients had a 2.4-greater improvement in FVC percent-predicted versus alglucosidase alfa patients at week 49, meeting the noninferiority benchmark (p=0.0074).  

Among assets in earlier-phase trials, Astellas Gene Therapies’s Phase I/II FORTIS trial studying AT-845 has 6MWT and FVC as secondary endpoints, while Spark Therapeutics’s Phase I/II RESOLUTE trial studying SPK-3006 does not list any efficacy outcome measures. 

An alternative to 6MWT?

According to Angelini, the 6MWT should be replaced entirely by GSCG as the primary endpoint of choice. GSCG includes quantitative and qualitative assessments of four motor functions: walking for 10 meters, climbing four steps, performing the Gower’s maneuver, and climbing from a chair. Amicus’s PROPEL trial used GSCG as a secondary endpoint, in which AT-GAA delivered a statistically significant improvement (p<0.05). Sanofi’s COMET trial does not use this endpoint at all.

GSCG can assess motor function for a wider range of patients with Pompe disease, ranging from those who are relatively mobile to those who struggle to walk or stand, Angelini says. And, unlike the 6MWT, GSCG can be self-assessed at home, which is particularly important as the COVID-19 pandemic pushed more clinical studies toward remote designs, he adds.

A trend toward remote patient monitoring in trials should catalyse more Pompe disease clinical trials to use GSCG over 6MWT, he notes. Clinical Trials Arena recently published a data-driven analysis of the key driving forces behind clinical trial decentralisation. The companies in the table below did not respond to a comment request.

Pompe disease drug development pipeline

Clinical trialNotable endpointsMechanism of actionKey Pompe disease dates
Amicus’s Phase III PROPEL trial studying AT-GAA (cipaglucosidase alfa) (NCT03729362)6MWT as primary endpoint; FVC and GSCG included as secondary endpointsChaperone advance enzyme replacement therapyPDUFA date May 29
Sanofi’s Phase III COMET trial studying Nexviazyme (NCT02782741)FVC as primary endpoint; 6MWT included as secondary endpointEnzyme replacement therapyFDA approved August 2021; full trial completion May 2023
Astellas Gene Therapies’s Phase I/II FORTIS trial studying AT-845 (NCT04174105)Safety, pharmacokinetics as primary endpoints; 6MWT and FVC included as secondary endpointsGene replacement therapyPrimary completion December 2022
Spark Therapeutics’s Phase I/II RESOLUTE trial studying SPK-3006 (NCT04093349)Safety, pharmacokinetics as primary endpoints; ClinicalTrials.gov does not list secondary endpointsAdeno-associated virus gene therapyPrimary completion October 2023

What’s next for drug development

As experts contend with potential efficacy endpoints in Pompe disease trials, the overall disease market is expected to expand. In the US, standard newborn screening means a growing number of patients are diagnosed early on and can immediately begin treatment, explains Dr Barry Byrne, director of the Powell Gene Therapy Center at the University of Florida.

According to a GlobalData consensus forecast, Genzyme’s Myozyme and Lumizyme are expected to account for more than 90% of global Pompe disease drug sales in 2022 with $1.14 billion. But in 2027, Myozyme and Lumizyme are expected to account for just under 50% of global sales as several new therapies potentially gain market traction. Myozyme was approved in 2006 and Lumizyme, which uses the same underlying mechanism, was approved in 2010.

Amicus’s AT-GAA is a chaperone advance enzyme replacement therapy (CHART) combination, which, unlike enzyme replacement therapies (ERTs), can be administered orally. A chaperone therapy approach could benefit patients through both increased potency and through the lack of infusion reactions, Byrne says. Later in the pipeline, gene therapies ultimately hold the highest potential as they could potentially cross the blood-brain barrier for Pompe disease, Alméciga-Díaz says.

Key Takeaways:

  • The 6MWT is best suited as a primary endpoint for Pompe disease trials enrolling patients with similar baseline walking abilities and a relatively high degree of mobility.
  • But having a coprimary endpoint that measures pulmonary capacity, such as FVC, can paint a fuller efficacy picture than the 6MWT alone.
  • GSCG is an alternative motor function assessment to the 6MWT that works for decentralised or remote trials, as well as for patients with limited mobility.