Nearly three months after an experimental treatment for classic galactosemia was rejected by the US Food and Drug Administration (FDA), there has been little progress in developing therapies to help patients with the genetic disorder.
On Rare Disease Day, 28 February, a clinical expert in galactosemia explains why commercial therapies are not anticipated anytime soon and reasons behind a frozen trial landscape.
What is galactosemia?
Galactosemia is a rare genetic, metabolic disorder caused by a deficiency in the galactose-1-phosphate uridyltransferase (GALT). This means patients cannot break down galactose, causing a buildup of the sugar alcohol galactitol. It is purported that this build-up is toxic and responsible for the progressive neurological element of the disease. The current standard-of-care is a galactose-free diet – no pharmaceutical intervention is currently available.
“Like lots of the inherited metal diseases, this is an enzyme deficiency. And so actually, at a biochemical level, we know exactly what the problem is,” says Dr Robin Lachmann, consultant in inherited metabolic disease at University College London’s National Hospital for Neurology and Neurosurgery.
The issue, according to Dr Lachmann – who is also chair of the scientific committee of the Recordati Rare Diseases Academy, is related to how current treatment modalities are not a fit for galactosemia.
Enzyme replacement therapy has been successful for some lysosomal storage diseases, for example. But for galactosemia, where there’s a systemic lack of enzyme in cells, this approach cannot work.
Lachmann adds: “The problem, if you’re not a lysosomal enzyme, is that we can inject it into the blood, but there’s no way for it to get into the cells throughout the body, including the brain. So actually, enzyme replacement therapy is only useful if there’s a way for the enzyme to get into the cell. So, beyond the lysosome, we can’t do that.”
Then there’s the promise of cell and gene therapy. This modality has been particularly successful in haematological diseases such as sickle cell and haemophilia treatments approved in 2023.
“To get it to every cell in the body is difficult, and the brain is extremely difficult, because you have to inject it straight in. We can just about deliver it to the whole brain in a mouse, but we can’t do it in a human,” Lachmann explains.
“That’s why the gene therapies that have been and continue to be disappointing [in this area], because we just don’t have the technology to get to the genes.”
Clinical trial hurdles
Higher promise from a scientific point of view, says Dr Lachmann, would be in personalised gene editing. This approach, however, has significant commercial barriers.
Lachmann comments: “This isn’t the way with the pharma industry currently – developing individual treatments for individual treatments is not going to happen. It’s something that is done in a lab, not as part of a company.”
Away from shortcomings in drug delivery technology, there is also the hurdle of patient heterogeneity. Similar to many rare diseases, the target population is small with large variance. Designing clinical trials with robust outcomes, therefore, is inherently tricky. Children and adults with galactosemia present on a wide-ranging spectrum of neurological symptoms, making it hard to assess the validity of clinical outcomes.
US biotech Applied Therapeutics found that out first hand with its candidate govorestat. The experimental treatment failed a Phase III trial after failing to improve symptoms in children more than placebo. The endpoint was a composite of measures that looked at speech and listening skills, behaviour symptoms, and daily living activities.
The FDA rejected approval of the therapy in December 2024, with Applied Therapeutics not issuing a public update about the drug since.
Applied Therapeutics did not respond to multiple requests for comment from Pharmaceutical Technology.
Lachmann says: “Companies overall, don’t want to do clinical trials in children. They want to do it in the adults and older patients who have a slowly progressive, very heterogeneous disease. And if you want clinically relevant outcomes, you’re going to have to invest in many years of treatment.”
GlobalData’s Pharma Intelligence Center currently lists eight clinical trials with galactosemia as an indication. Govorest is the most clinically advanced candidate. Many of the other trials have been terminated, whilst completed studies – such as one evaluating arginine – have yielded unsuccessful results.
The Galactosemia Foundation, a charity that advocates for new treatments, has previously stated: “The galactosemia community has gone more than a century with no approved treatment. The time for change is now.”
