Enzyme Replacement Trial Ended Early After Failing to Meet Goals

Marisa Wexler MS avatar

by Marisa Wexler MS |

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A clinical trial extension study involving 12 children with Sanfilippo syndrome type A was terminated early, after efficacy analyses found that the investigational enzyme replacement therapy it was testing failed to show evidence that it could slow the patients’ progressive cognitive or neurological impairment.

After a median of 264.4 weeks — just over five years — the researchers concluded that the enzyme replace therapy (ERT) was “unable to slow the neurocognitive decline of patients.”

“This study was subsequently terminated early because pre-specified efficacy criteria were not met, and the study did not yield clinical proof of concept,” the investigators wrote.

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The findings were published in Molecular Genetics and Metabolism, in a study titled “Long-term safety and clinical outcomes of intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A.

Sanfilippo type A is caused by mutations in the gene SGSH, which renders the body unable to make a functional version of the enzyme N-sulphoglucosamine sulphohydrolase. This leads to a toxic buildup of the complex sugar molecule heparan sulfate in cells, particularly in the brain, which causes a form of childhood dementia.

ERT, as its name suggests, is a treatment strategy that involves the therapeutic administration of missing enzymes into patients who need them. While ERTs for other diseases have yielded some success, this strategy is complicated for Sanfilippo type A because the enzyme needs to get into the brain to work. If the enzyme is injected into the bloodstream — as is done for other ERTs — it won’t be able to get into the brain.

To circumvent this issue, researchers created a formulation to replace the defective enzyme — called rhHNS — that was designed for intrathecal delivery, or injection through the spinal cord directly into the fluid that surrounds the brain and spine.

A first-in-human phase 1/2 clinical trial (NCT01155778), launched in 2010, tested the safety and tolerability of rhHNS in the 12 children, all diagnosed with Sanfilippo A. The children were divided into three groups, with each group receiving a different dose — 10, 45, or 90 mg — of rhHNS. The medication was administered monthly via a surgically implanted device, termed an intrathecal drug delivery device or IDDD.

Results after six months indicated that the treatment was generally safe.

The participants were then enrolled in an extension study (NCT01299727) to further evaluate the safety and effectiveness of this therapy. The children given the 10 mg dose in the earlier study had their dose increased to 45 mg, while the remaining participants continued receiving either 45 or 90 mg as they had before.

The patients’ mean age was 9.6 at the start of the extension, which continued for just over five years.

The enzyme replacement trial was halted earlier than originally planned, because efficacy analyses failed to show any evidence that the treatment was benefiting patients. Specifically, the analyses showed that rhHNS treatment did not slow the decline in neurological or cognitive functions among the dozen children. Brain volume decline also was apparently unaffected by rhHNS treatment.

“In this study, rhHNS IT [intrathecal] up to 90 mg was unable to slow the neurocognitive decline of patients with MPS IIIA [also called Sanfilippo type A],” the researchers wrote.

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Safety analyses were generally consistent with prior data, and rhHNS treatment was overall well-tolerated. Most reported adverse events, or side effects, were mild or moderate in severity.

A total of 49 serious adverse events were reported among 11 of the 12 patients. None of these were deemed related to rhHNS itself; however, most of them were considered to have resulted because of a malfunction in the implanted device used to administer the medication.

Also of note, half of the patients tested positive for antibodies against rhHNS over the course of the trial, suggesting that these children’s immune systems were erroneously recognizing the therapy as a potential infectious threat.

“Issues with the IDDD and observed antibody responses in half the number of patients involved in the study likely negatively impacted clinical outcomes,” the researchers wrote.

The researchers stressed that this study is limited by its small size, the lack of a control group against which to make direct comparisons, and the nature of Sanfilippo disease, which varies markedly from person to person.

“These issues make it difficult to draw firm conclusions about the (lack of) effectiveness of the treatment,” the team wrote.

“The potential for higher efficacy responses with larger doses [of rhHNS] remains plausible,” they added.