Treatment for Lysosomal Storage Disorder Lowers NfL

A Denali treatment for a rare lysosomal storage disorder, Hunter syndrome, has posted encouraging biomarker results in a small, open-label Phase 1/2 trial. The genetic disorder is caused by mutations in the enzyme iduronate-2-sulfatase, which then fails to break down complex polysaccharides. Their accumulation leads to organ failure and early death. The drug, DNL310, was designed to ferry the missing enzyme into the brain. According to a June 20 press release, two years of treatment cut levels of the neurodegeneration marker neurofilament light by half in cerebrospinal fluid, and by two-thirds in blood. Because NfL is released by dying neurons, this hints at improved neuron survival. A Phase 2/3 study has begun enrolling.

  • Current treatments for the lysosomal storage disorder Hunter syndrome do not enter brain.
  • Denali’s brain shuttle ferries a replacement enzyme into the brain.
  • DNL310, lowered CSF NfL by half at two years, hinting at improved neuron survival.

Only about 2,000 people worldwide are estimated to have Hunter syndrome, also called mucopolysaccharidosis Type II. Because the gene for iduronate-2-sulfatase (IDS) lies on the X chromosome, nearly all are male. They accumulate the glycosaminoglycans heparan sulfate and dermatan sulfate in their lysosomes, leading to heart and liver problems, hearing loss, stiff joints, and stunted growth. The most severe form of the disease, referred to as neuronopathic, affects the brain and children begin to lose ground cognitively around age 5. Their lifespan is 10 to 20 years. The milder form of the disease spares cognition, and people can live to adulthood. The standard of care for this disease, the enzyme replacement therapy idursulfase, is given intravenously and does not enter the brain.

Delayed Effect. Over the first six months on DNL310, serum NfL rose slightly, but then began to fall, decreasing two-thirds by two years of treatment. [Courtesy of Denali.]

Denali developed DNL310 to treat neuronopathic disease. DNL310 fuses IDS to an Fc domain that recognizes the transferrin receptor present in brain blood vessels, allowing the treatment to pass through the blood-brain barrier. In animal models, this “enzyme transport vehicle” strategy boosted brain exposure of the drug 10- to 30-fold, and resulted in widespread distribution in the brain (May 2020 news).

The Phase 1/2 trial enrolled 45 children and teens, almost all with neuronopathic disease. Their mean age was 5. Those on idursulfase switched to study drug, which was given by IV every week, using several different doses and titration schemes. The drug rapidly brought down CSF heparan and dermatan sulfates to normal levels, a drop of 90 percent. It also cut the amount of these polysaccharides in urine by 90 percent, even in children who had previously been on idursulfase, suggesting DNL310 has additional peripheral benefits over the standard of care.

After 24 weeks, the trial transitioned to an extension study, with the 27 remaining participants receiving 15 mg/kg DNL310 weekly. In February, Denali reported 49-week clinical outcome data. The 23 children who reached this milestone had numerically better scores on measures of cognition and adaptive behavior than at baseline. In addition, hearing improved at all four frequencies tested, with three of the four statistically significant.

Biomarker data were initially less encouraging. At 24 weeks, NfL bumped up slightly, by around 10 percent in serum and a third in CSF. However, the picture changed with longer-term use, with the 13 participants who reached two years of treatment posting dramatic drops. The serum NfL decrease reached statistical significance at 61 weeks. In Alzheimer’s disease, too, some downstream biomarkers such as tau tangles show a delayed response to treatment.

Denali will present more data from this extension study at the Society for the Study of Inborn Errors of Metabolism symposium in Jerusalem on August 29-September 1. Meanwhile, the company has started enrolling for a Phase 2/3 trial called Compass that will take place in North and South America and Europe. Denali plans to enroll 54 people split into two cohorts. The first will comprise children from 2 to 6 years of age who have neuronopathic disease, the second, children from 6 to 17 years who have the milder form. Participants will be randomized 2:1 to receive DNL310 or the standard of care.

The FDA granted fast-track designation to DNL310 for Hunter syndrome in March 2021. Other drugs, such as Biogen’s ALS treatment tofersen, have been granted accelerated approval based on reductions in NfL. In a June 20 webinar, Denali’s chief medical officer, Carole Ho, said the company is discussing whether to apply for accelerated approval for DNL310.

The Hunter syndrome results are proof of concept for the enzyme transport vehicle strategy, which Denali has developed to treat mucopolysaccharidosis type 1 with an alpha-L-iduronidase ETV, and MPS type IIIA with a sulfamidase ETV. DNL593, a protein transport vehicle, has been designed to treat progranulin-deficient frontotemporal dementia. A Phase 1/2 study began in February 2022, and will run until November 2025.—Madolyn Bowman Rogers

Comments

  1. I was so happy to see these wonderful results!

    The data are also important from a more general standpoint regarding how we use and interpret NfL in clinical trials. Based on what we knew from traumatic brain injury and disease-modifying treatments in multiple sclerosis, I previously thought that one should expect NfL reduction in response to treatment within 6-12 months, if a drug slowed down neurodegeneration in a clinically meaningful manner. Now, we know that this can be much slower, and that the marker may be quite noisy, especially early on in a treatment trial.

    The data from this Hunter syndrome trial shows that the biomarkers for the immediate targets of the drug normalized quickly, which was very encouraging, but the NfL changes took 2 years of observation to become clear. This resembles what we recently saw in a ceroid neuronal lipofuscinosis case series with enzyme replacement therapy (Iwan et al., 2021), where distinct NfL reductions took years to develop. This means that one should not get too worried about an absence of NfL reduction in shorter treatment trials. One could even accept slight increases in the first phase of the trial, which was seen in this Hunter trial.

    Sharp, several-fold increases however, can indicate neurotoxicity. NfL is increasingly used as a safety marker in, e.g., multiple sclerosis trials. For example, the marker increases several-fold and very rapidly in natalizumab-induced progressive multifocal leukoencephalopathy (Costa et al., 2019), and it identifies chemotherapy-induced neurotoxicity of anti-cancer drugs (Huehnchen et al., 2022).

    It would be so interesting to learn if NfL (maybe together with glial fibrillary acidic protein) could be used as a marker to differentiate neurotoxic from benign ARIA in anti-amyloid antibody trials. Taken together, a dual use of NfL in clinical trials is emerging. It can be used to detect long-term effects on neurodegeneration intensity. Here, one should not expect early reductions. Importantly, one should not give up on a drug on the basis of absence of NfL reduction during a trial, even if it was quite long, if other parameters are encouraging. It can also be used as a safety marker; sharp increases may indicate neurotoxic side effects of the drug.

    View all comments by Henrik Zetterberg

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References

News Citations

  1. Molecular Transport Vehicle Shuttles Therapies into Brain

Therapeutics Citations

  1. QALSODY™
  2. DNL593

External Citations

  1. press release
  2. reported

Further Reading

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