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A gene therapy pipeline takes shape for a cluster of rare diseases

The toxic globules of sugar and fat slowly pile up in the body’s cells, accumulating in blood vessels and in major organs like the kidney and heart.

Typically, special-purpose proteins within the cell would tear apart and break down the toxins. But for people with Fabry, a rare inherited disease, genetic mutations result in garbled, sometimes missing, instructions for constructing the right proteins.

Without the right disposal tools, cells are helpless to the inexorable buildup of the dangerous molecules. The first warning signs are as varied as they are acute: burning sensations of pain in the hands and feet, abnormally low sweat production and dark skin rashes. Over time, for those most severely affected, symptoms can become dire, leading to organ dysfunction and early death.

Medicines that replace the missing proteins with synthetic versions can check the disease by helping the body clear out the toxins. But the treatments, infused every two weeks, aren’t curative and are taken for life.

A handful of drugmakers are developing a different approach, attempting to use one-time treatments to replace broken genes with functional copies. While testing remains in early stages, promising signs are beginning to emerge.

This week, Avrobio, a Cambridge, Massachusetts-based biotech, reported new results from a Fabry patient treated with the company’s gene therapy one year ago. A biopsy of the man’s kidney showed complete clearance of the disease-causing molecules, known in scientific shorthand as Gb3.

The finding reinforced earlier data from another participant in the small clinical trial, who had an 87% reduction in Gb3 one year after receiving Avrobio’s treatment.

The hope is gene therapies like Avrobio’s can halt and reverse the disease, while also reducing the heavy burden of the chronic treatment that’s now standard care.

“It’s a substantial finding,” said Jack Johnson, co-founder and executive director of the Fabry Support and Information Group. “If it’s a one-time, one-and-done treatment, that’s an incredible improvement in convenience, which will definitely be appealing to patients in the community.”

Biotech roots

Fabry is one of a wide array of diseases caused by breakdowns in cellular metabolism. In each, genetic mutations leave the body’s cells lacking one of the many proteins, or enzymes, used to process complex fats or sugars.

Collectively, the diseases are known as lysosomal storage disorders, referring to the unwanted deposits that amass when the cell’s digestive units, or lysosomes, can’t function properly.

About 50 different lysosomal storage disorders have been identified, the most prominent of which affect a few hundred to a few thousand people in the U.S. Effective treatments are available for only eight, including Fabry.

Development of enzyme replacement therapy, as the drugs are called, has its roots in the biotech industry’s beginning. Genzyme — a company the late Henri Termeer built into a pioneering developer of rare disease drugs — won U.S. approval for the first enzyme replacement therapy in 1991.

Genzyme later developed several other drugs for the lysosomal storage disorders Gaucher, Fabry and Pompe before being acquired by Sanofi for more than $20 billion in 2011.

Shire and BioMarin Pharmaceutical also found success with enzyme replacement therapies, or ERTs. Together, the three biotech companies account for nearly all ERTs approved by the Food and Drug Administration. (Shire is now owned by Takeda.)

Research into lysosomal storage disorders is now helping fuel another biotech boom, this time in gene therapy. Nearly two dozen companies are testing, or plan to test, genetic medicines for lysosomal storage disorders, according to a recent report from Cowen, an investment bank.

Collectively, gene therapy programs aimed at inherited metabolic diseases — mostly lysosomal storage disorders — account for 23% of the roughly 280 gene therapies in the pipeline that Cowen identified. Only treatments for neurological illnesses represented a greater share.

Although gene therapies for blood and muscle diseases like hemophilia and Duchenne muscular dystrophy are currently in the spotlight, the broad pipeline suggests lysosomal storage disorders may be next.

“Gene therapy is galloping [along],” said Mark Thomas, a kidney disease specialist at the Royal Perth Hospital in Australia and an investigator in Avrobio’s Fabry study. “There’s this beautiful surge forward.”

Along with Avrobio, biotechs Orchard Therapeutics and Regenxbio this week reported data for their gene therapies for Hurler and Hunter syndromes, two other lysosomal storage disorders.

Sangamo Therapeutics and Freeline Therapeutics are also testing Fabry gene therapies in human trials, while Sarepta Therapeutics and Roche are studying treatments for Sanfilippo syndrome and Pompe.

However, most efforts directed at lysosomal storage disorders remain in early or preclinical stages, meaning there remains significant ground to cover in the field. Initial study data can capture gene therapy’s impact on markers of diseases, but more consequential health benefits can only be measured over years.

Recent setbacks have also renewed questions about gene therapy development, in particular the replicability of promising early results from handfuls of patients.

In the meantime, other developers making more traditional drugs — such as Amicus Therapeutics, Sanofi and Denali Therapeutics — could improve on current treatment, raising the bar for gene therapy. Denali debuted early, but promising, results for a Hunter syndrome drug on Friday.

‘How much is reversible?’

As with other gene therapy developers, Avrobio’s aim is curative treatment, beginning first by replacing frequent infusions with a one-time therapy.

“We aim to untether patients from biweekly infusions of enzyme,” said Geoff Mackay, the company’s CEO.

So far, that goal appears feasible in Fabry. Three of five men treated in a Phase 1 study in Canada remain off ERT two or more years after receiving Avrobio’s therapy, according to the latest data from the company. Levels of toxic Gb3 in patients’ blood were, on average, 25% lower than they were at the beginning of the study.

The data, Thomas said, are “an immediate in-your-face demonstration that enzyme replacement therapy [offers] partial improvement, but not a cure.”

But the initial version of the therapy wasn’t as potent as Avrobio wanted. The company has since refined the treatment and the process for delivering it to patients — improvements it says make for a more consistent product.

The kidney biopsy data disclosed this week are from the first Fabry patient treated in a mid-stage study using Avrobio’s improved treatment. Though the result was a powerful demonstration of the therapy’s action, showing 100% clearance of toxin, it is far from proof of curative benefit.

“The disease has taken 20, 30 years to accumulate,” said Thomas. “How much of that is ever going to be reversible?”

Kidney biopsy data may be enough for the FDA, though. In a presentation, Avrobio referred to the agency’s 2018 approval of Amicus’ Fabry drug Galafold, which was controversially cleared on the basis of Gb3 reduction in the kidneys. (On Thursday, Amicus announced mixed data for an experimental drug for Pompe.)

Two other patients have been treated in Avrobio’s Phase 2 trial, but kidney biopsy data aren’t available for either. Avrobio intends to expand enrollment in the study, and begin preparing this year for a confirmatory trial of people switching from ERT to its therapy. The company hopes to discuss with the FDA whether an accelerated approval would be possible. 

In addition to its treatment for Fabry, Avrobio is working on gene therapies for Gaucher, cystinosis, Hunter syndrome and Pompe. Results from three cystinosis patients and one Gaucher patient, also disclosed this week, appeared positive, but are also very early.

“It took a long time for the first gene therapy to be approved by the FDA,” said Stephanie Cherqui, a gene therapy researcher and an investigator in Avrobio’s cystinosis study. “Now we’re seeing an exponential increase in the number of projects.”

Correction: A previous version of this article mischaracterized the data Avrobio expects it will need for an accelerated approval in Fabry disease. 

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