The future of Hunter syndrome treatment, a rare genetic disorder

Hunter syndrome, also known as mucopolysaccharidosis type II (MPS II), is a rare genetic disorder affecting children – almost exclusively boys – that causes an abnormal accumulation of complex sugars in cells. This then has a major impact on different organs and tissues and, as the disease progresses, individuals need medical assistance just to keep their airways open. The disease is one of around 50 diseases classed as lysosomal storage disorders (LSD), in which genetic variations disrupt the normal activity of lysosomes in human cells.

There are two distinct forms of Hunter syndrome: the neuropathic form, which is more severe and accounts for the majority of cases, and the non-neuropathic form, which is less severe. While both types affect many different organs and tissues, children with neuropathic Hunter syndrome also experience a decline in intellectual function and a more rapid disease progression, starting to lose basic functional skills between the ages of six and eight. Their life expectancy ranges between 10 to 20 years. 

Hunter Syndrome is caused by a genetic mutation in the IDS gene, which contains the instructions for the production of an enzyme called iduronate 2-sulfatase (I2S). This enzyme is involved in the breakdown of complex sugars called glycosaminoglycans (GAGs). However, genetic variations in the IDS gene result in a deficiency or a complete absence of I2S, in turn causing an abnormal accumulation of GAGs in cells.

Currently, there is no cure for Hunter syndrome. But biotechs are pursuing different methods of tackling the disease, with several candidates in clinical trials that are showing promise. In this article, we explore the three main technology approaches for treating Hunter syndrome. 

Enzyme replacement therapy: The most popular approach to treat Hunter Syndrome

As enzyme replacement therapy is typically used to replace an absent or deficient enzyme in individuals with an inherited enzyme deficiency syndrome, it makes sense that this is currently the most popular approach to treating Hunter syndrome, with therapies aiming to replace the I2S enzyme. 

Takeda’s Elaprase: the only FDA-approved enzyme replacement therapy for Hunter syndrome

There is already one U.S. Food and Drug Administration (FDA)-approved enzyme replacement therapy for the disease on the market. This is Takeda’s Elaprase; the medicine has been approved since 2006, and the Japanese giant acquired it after it bought out Shire Pharmaceuticals in 2019. 

However, although Elaprase has been shown to improve somatic signs and symptoms of Hunter syndrome, the drug does not cross the blood-brain barrier, meaning it has limited action on the central nervous system (CNS) and, consequently, treating neurological aspects of the disease remains a challenge. For this reason, some companies are investigating novel approaches to enzyme replacement therapies that allow them to cross the blood-brain barrier. 

Denali Therapeutics advances DNL310 in clinical trials

Denali Therapeutics is one such company. It is currently advancing a drug candidate called DNL310 (tividenofusp alfa), which is a weekly intravenous enzyme replacement therapy that uses the company’s Enzyme Transport Vehicle (ETV) technology to bring I2S from the bloodstream into the brain.

The ETV platform is essentially designed to deliver large therapeutic molecules such as antibodies, enzymes, proteins, and oligonucleotides across the blood-brain barrier. In DNL310, the technology works by fusing the I2S enzyme to an Fc domain that has been engineered to bind to the transferrin receptor – a natural transport receptor that helps cells absorb iron from transferrin, a protein that carries iron throughout the body – which is expressed at the blood-brain barrier and delivers the Transport Vehicle and its therapeutic cargo to the brain through receptor-mediated transcytosis, a principal pathway for transport of macromolecules essential for brain function across the blood-brain barrier.

Earlier this month, Denali moved one step closer to its goal of gaining accelerated approval for its Hunter syndrome treatment as it announced the primary analysis and long-term follow-up of a phase 1/2 study of the candidate. 

For the trial, patients received weekly intravenous infusions of DNL310 in either fixed or escalating doses. The primary analysis looked at data after 24 weeks of treatment, with the long-term follow-up planned for about five years – so far, some patients have had more than three years of follow-up. The data showed that the drug met its primary safety endpoints and reduced key biomarkers of the disease, plus patients also experienced long-term improvements in their hearing and cognition.

Denali said in its press release that it plans to submit the drug for accelerated approval early this year and expects it to become available to patients in late 2025 or early 2026. Additionally, the company is continuing to investigate the drug in an ongoing phase 2/3 trial to determine its efficacy and safety compared to idursulfase (the active substance in Elaprase). 

JCR Pharmaceuticals’ JR-141: approved in Japan, advancing in global trials

Also working on a similar approach to Denali is JCR Pharmaceuticals. Its enzyme replacement therapy, JR-141, consists of the I2S enzyme fused with an anti-human transferrin receptor antibody and incorporates the company’s blood-brain barrier-penetrating technology J-Brain Cargo. This technology allows the therapy to cross the blood-brain barrier through transferrin receptor-mediated transcytosis, and its uptake into cells is mediated through the mannose-6-phosphate receptor – a transmembrane glycoprotein that directs enzymes to lysosomes.

JCR’s therapy has already been approved in Japan to treat Hunter syndrome under the brand name Izcargo and is marketed in the country by both JCR and Sumitomo after the pair entered into a co-promotion agreement in 2023. JCR also had an agreement with Takeda to commercialize the treatment outside the U.S. (except for Japan and certain other Asia-Pacific countries), but the collaboration was terminated last year following a strategic assessment by Takeda, meaning all licenses and commercialization rights have reverted to JCR.

Currently, JCR is also conducting global phase 3 clinical trials of JR-141 in the U.S., Latin America, and Europe. In prior phase 1/2 trials, the drug was shown to cross from the bloodstream into the brain and demonstrated promising signs of limiting neurodegeneration.

Once approved by the FDA, both Denali’s and JCR’s enzyme replacement therapies are likely to have significantly better efficacy than Elaprase when it comes to treating the neurological symptoms of Hunter syndrome due to the fact they can cross the blood-brain barrier. Although we will have to wait and see for certain, this means that they could replace Elaprase as the standard-of-care treatment.

A permanent fix with a one-time dose: Treating Hunter Syndrome with gene therapy 

Naturally, gene therapy is also a promising approach for the treatment of Hunter syndrome given that individuals with the disease lack a working copy of the IDS gene. On this basis, gene therapies being investigated for Hunter syndrome generally work by delivering a functional copy of the IDS gene to the CNS. One of the main benefits of this approach is that the disease would be treated through a one-time administration, taking away the burden of regular infusions. 

Although no gene therapies for Hunter syndrome have been approved yet, there are a couple of promising clinical trials taking place testing this method.

Regenxbio’s RGX-121 likely to become the first gene therapy ever approved for Hunter syndrome

The frontrunner in the space right now is Regenxbio. Last year, the gene therapy company began its rolling submission to the FDA for accelerated approval of its candidate RGX-121, an AAV9 vector gene therapy intended to deliver the IDS gene into the CNS using intracisternal or intracerebroventricular delivery.

The submission was based on data from a phase I/II/III trial of RGX-121, for which Regenxbio announced positive results in September 2024. The results showed an 85% median reduction of cerebrospinal fluid (CSF) levels of heparan sulfate (HS) D2S6, a key biomarker of brain disease in Hunter syndrome. Additionally, in the trial, 80% of patients who received the pivotal dose of RGX-121 discontinued intravenous enzyme replacement therapy or remained treatment-naïve.

Regenxbio expects that its submission for the approval of RGX-121 will be completed at some point this year. In preparation for the potential approval, the company recently signed a strategic partnership with Nippon Shinyaku for the development and commercialization of the gene therapy candidate. 

With a regulatory decision expected so soon, RGX-121 is very likely to become the first gene therapy ever approved for Hunter syndrome.

University of Manchester launches gene therapy trial for Hunter syndrome

Another clinical trial for a gene therapy candidate for Hunter syndrome was initiated by researchers at the University of Manchester at the end of 2023 in the U.K. after receiving the go-ahead from the U.K. regulatory authorities. In this combined phase 1 and 2 clinical trial, five children under one year of age with Hunter syndrome were treated with an autologous hematopoietic stem cell (HSC) gene therapy developed by the team at the University of Manchester. 

The process for administering the therapy entails removing some blood-making stem cells from the children’s bone marrow, inserting a working copy of the IDS gene, and then returning them. These treated cells then settle back into the bone marrow, where they go on to produce blood cells that can create the IDS enzyme and distribute it throughout the body, effectively curing the disease. 

The study is still ongoing, as it will take two years to complete. It is evaluating the HSC gene therapy’s safety and tolerability, as well as its pharmacodynamic and clinical efficacy. We can potentially expect to hear more about the results of the study toward the end of this year. 

Hematopoietic stem cell transplantation: An approved method for Hunter syndrome, but not without complications 

Hematopoietic stem cell transplantation (HSCT) is another currently approved option for the treatment of Hunter syndrome. This is when blood stem cells from the bone marrow are taken from one person and given to the patient with Hunter syndrome through an IV. Before starting HSCT, patients may also need chemotherapy to prepare their immune system for the transplant and prevent rejection. 

Through HSCT, donor stem cells circulate into the bloodstream and are able to cross the blood-brain barrier, where the microglial cells secrete the deficient enzyme to the different parts of the brain. Because of this, HSCT has been shown to improve CNS impairment in Hunter syndrome – making it a more effective treatment for neurological aspects of the disease than Elaprase.

However, the downside of the HSCT procedure is that it is invasive and requires a bone marrow donor. This makes it a far less attractive proposition than enzyme replacement therapy or gene therapy. 

Hunter syndrome treatment market shows upward trajectory

Despite the small number of people the disease affects globally – less than 2,000 patients worldwide – there is clearly interest from the biotech community in coming up with better treatment options for it. In fact, the Hunter syndrome treatment market size, which was valued at $702.4 million in 2018,  is expected to grow to around $1.5 billion by 2032, exhibiting a compound annual growth rate (CAGR) of 6.1%. 

According to the report by Fortune Business Insights, one of the key market trends accelerating this growth is the increasing research and development (R&D) investments by important players for the creation of novel therapies for Hunter syndrome due to its recognition as a key orphan disease. Additionally, there is an increasing interest in rare disease therapeutics in general, as major pharmaceutical breakthroughs leading to the development of blockbuster drugs are more probable in these diseases compared to traditional pharmaceutical portfolios.

So, as this year could see the approval of both Denali’s DNL310 and Regenxbio’s RGX-121,  having the promise of a new enzyme replacement therapy that can cross the blood-brain barrier and the first-ever gene therapy for Hunter syndrome on the horizon is likely to bring an enormous sense of hope to those affected by the disease.

New technologies related to Hunter syndrome