While Avrobio’s available AVR-RD-01 data in Fabry disease is overall too limited to forecast success prospects in the 12-patient phase two trial, experts were divided on whether initial phase two data in one patient is clinically relevant.

The reduction reported in the globotriaosylceramide (Gb3) inclusions per kidney peritubular capillary (PTC) primary endpoint is clinically meaningful, some experts said, but others noted this endpoint has little real-world meaning despite having been used as the basis for previous FDA approvals.

This is despite an analyst report drawing phase two success optimism, noting phase two kidney biopsy data in one patient is consistent with phase one improvements in clinical benefit with gene therapy AVR-RD-01. Approved enzyme replacement therapies (ERTs) in Fabry disease have demonstrated Gb3 inclusions reduction, some experts said, but others noted little is known about the relationship between the inclusions and actual complications of the disease.

Meanwhile, unlike other Fabry disease trials that may recruit men and women, the phase two trial is recruiting only male patients. This could actually make it easier for AVR-RD-01 to deliver clear phase two efficacy results, an expert said. This is because males have higher Gb3 inclusions baseline and so a reduction is easily observable, he explained. However, other experts noted it is unclear if phase two data would change if it hypothetically recruited both men and women, considering female patients have a more highly heterogeneous disease phenotype compared with men.

The phase two AVR-RD-01 trial (NCT03454893) in treatment-naive patients with classic Fabry disease has updated data expected in 1H20, as per a second analyst report. AVR-RD-01 is expected to achieve peak sales of $1.6bn in Fabry disease. Avrobio has a market cap of $618.8m.

Data premature; potential for lacking clinical relevance

As the reduction data so far come from just one patient, it is not possible to predict that the phase two trial overall will yield similar results, said Dr Raphael Schiffmann, medical director at the Institute of Metabolic Disease in the Baylor Research Institute, Dallas, US, and Dr James Shayman, professor in the department of pharmacology at the University of Michigan’s medical school. In one phase two patient, an 87% reduction from baseline in Gb3 inclusions per PTC was observed in a kidney biopsy, according to a July 2019 press release.

In phase one (NCT02800070) secondary efficacy endpoint, plasma globotriaosylsphingosine (lyso-Gb3) levels were reduced by between 33% and 41% across four patients, according to a July 2019 company presentation. Lyso-gb3 is the deacylated form of Gb3, Shayman explained. The two are likely related as Gb3 is the precursor for lyso-Gb3, but there is limited data to draw firm conclusions about their relationship, he added. While it is promising that a lyso-Gb3 reduction was attained, said Shayman, this marker lacks real-world clinical meaning, said Schiffmann.

But the Gb3 inclusions reduction reported in the one phase two patient is clinically significant, said Margarita Ivanova, PhD, director of the Translational Medicine Unit in the Lysosomal and Rare Disorders Research Treatment Center, Fairfax, US. Dr Ilkka Kantola, head of the Division of Medicine, Turku University Hospital, Finland, agreed, adding Gb3 inclusions are a symptom observed in almost all Fabry disease patients and so it is a useful biomarker.

Also, Sanofi’s FDA-approved enzyme replacement therapy (ERT) Fabrazyme (agalsidase beta) can reduce Gb3 inclusions and so new treatments should demonstrate the same, Kantola added. Change in Gb3 inclusions is an FDA-recognized Fabry disease primary endpoint, an Avrobio spokesperson noted. Fabrazyme was approved by the FDA in April 2003.

Although Gb3 inclusions have been measured as a primary endpoint for ERT studies, little is known about the mechanistic link between Gb3 inclusions and the clinical phenotype of Fabry and its complications, Shayman said. Gb3 inclusions are a pharmacodynamic marker, so the result does not necessarily translate into clinical significance for the real world, Schiffmann said.

The reported phase two reduction seems clinically meaningful but a caveat is that the endpoint targeting the kidney is easier than targeting other organs, including the heart, which is especially important in Fabry, said Dr Aleš Linhart, head of the Internal Cardiovascular Medicine Department at the University Hospital in Prague, Czech Republic. Fabry disease leads to an accumulation of fat molecules that form Gb3 inclusions, which damage organs, such as the kidneys, heart and brain.

A third analyst report noted the phase two 87% reduction is equivalent to three times the reduction attained achieved by Amicus Therapeutics’ approved chaperone therapy Galafold (migalastat) during its pivotal study in Fabry disease. However, this comparison is not apt because there is a lack of long-term Galafold efficacy data, Kantola explained, adding a comparison to ERT would be more appropriate. The efficacy profile of AVR-RD-01 should be compared to that of different kinds of therapies, not just chaperone therapies, Ivanova added.

That said, measuring clinically significant markers for Fabry disease is challenging, Shayman noted. Fabry disease can have severe but infrequent manifestations, such as cardiac sudden death, which kills between a quarter and a third of patients, but continuously monitoring cardiac endpoints to detect an improvement would take many months, if not years, he explained. Some other clinically useful endpoints could be a reduction in neuropathic pain, improvement in the quality of life, improvement in electrocardiogram (ECG) and decline in the rate of kidney disease, Schiffmann said, while Ivanova preferred enzyme activity as a primary endpoint.

Male-only population restriction logical

With regards to phase two recruiting only male patients, such patients usually have higher baseline Gb3 inclusions than females, Schiffmann and Kantola said. Males have inclusions in the vast majority of cells whereas women have a mosaic pattern and on average only half the number of cells affected, Schiffmann explained. But Gb3 inclusion differences can also depend upon genotype and inactivation of the Barr body, an X chromosome in a female somatic cell, so generalisations according to gender should be avoided, Shayman said.

Still, it would be easier to observe a reduction in Gb3 inclusions in male patients, Schiffmann noted, adding the male restriction ensures a uniform trial population. Female patients are subject to different disease variables, which could modify their response to treatment, such as different enzyme activation patterns in different organs, so it is logical to start testing exclusively on males, Linhart said. However, it is difficult to gauge potential phase two data if, hypothetically, both genders were recruited because of variation within the female Fabry disease population, Linhart added. Some females are almost asymptomatic, some females are as symptomatic as males and some have a mild disease, he explained.

As Fabry disease is an X-linked disorder, males are often more severely affected than females, Ivanova said. In the event the treatment garners approval, it would likely be in males only due to the lack of data in females, Shayman added. But the spokesperson said phase two focuses on the classic male disease in order to achieve consistent data and the company anticipates treating females in other trials. Fabry is estimated to affect one in 40,000 males in the US. Statistics for females are unclear as females can carry the gene for Fabry while displaying few or no symptoms.

In phase two safety coprimary endpoint, reassuringly, there are no major safety issues so far, Kantola and Schiffmann said. The safety profile seems similar to that of ERT, Ivanova noted. There were no severe adverse effects (AEs) related to AVR-RD-01 and the two serious AEs (SAEs) of febrile neutropenia and thrombophlebitis were resolved, according to the aforementioned presentation. While the safety seems impressive, according to Linhart, it is too early to make assertions about the safety profile as it is uncertain whether the AEs were treatment-related, Shayman said.

Ayisha Sharma is a reporter for Clinical Trials Arena 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.