Amicus Pharmaceuticals’ Phase III AT-GAA (acid alpha-glucosidase) trial is expected to show only mild improvements over the current standard-of-care, Sanofi’s Lumizyme (alglucosidase alfa), in Pompe disease.

Pompe disease treatment

Pompe disease damages the body’s muscle and nerve cells. It is caused by an accumulation of glycogen in the lysosome due to the deficiency of the lysosomal AT-GAA enzyme.

While analyst reports note expectations for better efficacy and safety than Lumizyme – the Phase III (NCT03729362) comparator – most experts this news service interviewed said that the trial will likely not be able to show sufficient superiority on the six-minute walk test (6MWT) primary endpoint.

Lumizyme’s clinical results

The Phase I/II (NCT02675465) data released thus far are based on small sample size, and the 6MWT improvement was not big enough, they explained, pointing to Lumizyme’s clinical results. The 6MWT, which measures the distance a patient can walk in that timeframe, is often used in clinical trials to determine drug efficacy.

Additionally, though experts noted AT-GAA’s safety profile could be a key advantage based on their expectation that the data will continue to show few adverse effects, they pointed out that other efficacy measures will likely show only minor improvements compared to Lumizyme.

The Phase III Propel trial has an estimated primary completion date in October 2020, according to the website. In the meantime, data from an additional Phase I/II cohort of 10 enzyme replacement therapy (ERT)-switch patients are expected to read out in 2Q 2019, according to the company’s 3Q 2018 corporate updates. So far, Amicus has released results from the other three cohorts of ERT-naïve, ERT-switch ambulatory and ERT-switch nonambulatory patients. ERT is a medical treatment used in diseases like Pompe which replaces an enzyme that is deficient or absent in the body.

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Amicus did not respond to a request for comment. The company’s market capitalisation is $1.95 billion.

6MWT improvements considered incremental

There is by no means an expectation for AT-GAA to show superiority to Lumizyme in the Phase III trial, said Dr Deborah Marsden, Clinical Geneticist for the Division of Genetics and Genomics at the Boston Children Hospital, Massachusetts, US.

As Lumizyme achieved a mean 25-metre 6MWT improvement compared to placebo in its Phase III Pompe clinical trial, AT-GAA’s 50-metre increase shown thus far is just a slight bump, considering some patients in the Phase III Lumizyme would have had a greater improvement than 25 metres, said Dr Marsden and Dr Priya Kishnani, Professor of Paediatrics of the Division of Medical Genetics at the Duke University, North Carolina, US.

While Kishnani was hesitant to assess how the Phase III AT-GAA trial would turn out, she noted that though the Phase I/II data are impressive, the small number of patients means it must be met with cautious optimism.

Phase I/II 18-month AT-GAA data for the ERT-switch ambulatory cohort (n=10) showed a 51.7-metre increase in the 6MWT and for the ERT-naïve group (n=5) showed a 49-metre increase. Ambulatory and nonambulatory patients are often cohorts in clinical trials as diseases like Pompe can affect movement. Naïve patients have never taken ERT.

AT-GAA’s data are a moderate improvement over Lumizyme, which was unable to show improvements as high as 50 metres in 6MWT in its development, said Dr Gerald Cox, a paediatrician with the Boston Children Hospital, Massachusetts. However, it may prove difficult for the Phase III AT-GAA trial to show a 25-metre improvement over Lumizyme -a benchmark noted in an analyst report – and it is more likely the trial will show noninferiority, he added. Propel will include ERT-naïve and ERT-experienced patients, with a targeted enrolment of 100.

The Phase I/II data show that AT-GAA will enhance the quality of life, but the data are still just a mild-to-moderate improvement over Lumizyme, leading to the expectation that Phase III superiority will not be shown, said Dr David Rapoport, Professor of Medicine at Mount Sinai Hospital, New York, US. While Lumizyme is an ERT, AT-GAA comprises an ERT coupled with a pharmacological chaperone.

Other endpoint measurements also marginal

Amicus also released results on several other endpoints measuring muscle strength, pulmonary function and fatigue, which experts also considered mild improvements and not large enough to show superiority to Lumizyme in the upcoming Phase III trial.

The improvements in the manual muscle test score seen in Phase I/II will likely continue in the Phase III but are considered marginal to mild, said Rapoport, Cox and Marsden.

This improvement can strongly impact the quality of life, as it means patients are better able to hold and lift objects, they noted. This is a secondary endpoint in the Phase III trial.

For the ERT-switch ambulatory group, the manual muscle test score showed a mean increase of 4.5% in total body score, the ERT-switch non-ambulatory cohort showed a mean increase of 4.3% and ERT-naïve patients showed an increase of 2.0%.

The increase in forced vital capacity (FVC) seen in the Phase I/II show the potential to increase breathing durability when patients exert themselves, said Kishnani and Cox. FVC is defined as the amount of air that can be forcibly exhaled from the lungs after taking the deepest breath possible. A significant amount of Pompe patients have respiratory problems, according to public information.

The Phase I/II data are better than what was seen with Lumizyme, which showed stability or decline in FVC in the Phase III trial, Cox and Rapoport noted. AT-GAA’s Phase I/II FVC data showed a 5% increase from baseline at month 18 for ERT-naïve patients (n=5) and a decrease of 3.7% in ERT-switch ambulatory patients (n=8). The reduction is small, and it is fair to say that breathing is well preserved, noted Rapoport.

The data, though, can be classed as a mild improvement and will unlikely prove significantly superior to Lumizyme, said Dr Cox, Dr Marsden and Dr Rapoport. Increases of 20% or above lead to patient improvements in breathing, added Dr Rapoport.

The maximum inspiratory pressure (MIP) test results show that the breathing is well preserved with small losses and gains throughout the 18-month period, said Rapoport. MIP is a measure of the strength of inspiratory muscles, primarily the diaphragm, and allows for the assessment of ventilatory failure, restrictive lung disease and respiratory muscle strength, according to the National Institutes of Health. The data are encouraging, as the disease is progressive; however, there is little evidence of disease reversal. The MIP data showed an increase of 6.2% in ERT-naïve patients (n=5) and a decrease of 2.8% in ERT-switch ambulatory patients (n=9).

The fatigue severity score data also show a slight reduction in fatigue; however, these changes are modest, said Dr Cox, Dr Marsden and Dr Rapoport. The data showed a decrease of 3.8% in ERT-switch ambulatory patients, a 13.3% reduction in ERT-switch nonambulatory patients and a 2% reduction in ERT-naïve patients.

Lumizyme’s key advantage could be its safety profile, where data so far indicate a lack of immunogenic reactions, and that will likely continue in the Phase III, said Dr Cox and Dr Marsden. Lumizyme is renowned for immunogenic reactions when first administered to patients, said Dr Cox, Dr Marsden and Dr Rapoport. AT-GAA’s most common adverse events reported thus far are nasopharyngitis, abdominal pain and diarrhoea.

by Mina Moawad in London
Mina Moawad is a reporter for Pharmaceutical Technology parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.