Key opinion leaders (KOLs) interviewed by GlobalData emphasised a significant lack of neuronopathic therapies in the Gaucher disease landscape. Despite some of the novel therapies in the pipeline, this unmet need is likely to stay largely unfulfilled in the foreseeable future.
Gaucher disease is a rare inherited metabolic disorder in which a deficiency of the enzyme glucocerebrosidase (GCase), caused by mutations in the GBA1 gene, results in the harmful accumulation of certain lipids throughout the body. These lipids, specifically glucocerebroside, accumulate in the spleen, liver, and bone marrow, presenting a unique set of challenges for physicians. Common manifestations include an abnormally enlarged liver and spleen (hepatosplenomegaly), low levels of platelets (thrombocytopenia) and red blood cells (anaemia), as well as skeletal abnormalities. While significant progress has been made in developing therapies, there are considerable unmet needs in the disease landscape.
The signs and symptoms of Gaucher disease vary among the disease’s types: type 1 (non-neuronopathic), type 2 (acute neuronopathic), and type 3 (chronic neuronopathic). Current treatment options consist of enzyme replacement therapy (ERT), which aims to increase GCase levels, or substrate reduction therapy (SRT) to reduce glucocerebroside levels.
Approved ERTs include Sanofi’s Cerezyme (imiglucerase), Takeda’s VPRIV (velaglucerase alfa), and Pfizer’s Elelyso (taliglucerase alfa), while current SRTs include Sanofi’s Cerdelga (eliglustat tartrate) and Actelion Pharmaceutical’s Zavesca (miglustat). While these offer significant therapeutic benefits to type 1 and some type 3 patients, there are numerous unmet needs that must be resolved.
In October 2023, KOLs from the US, UK, and Israel emphasised a serious lack of safe and effective treatments for the central nervous system (CNS) as a prominent unmet need. Generally, type 2 patients demonstrate rapid infantile neurological symptoms such as brain damage, eye movement disorders, and seizures, which are typically fatal within the first two years of life; type 3 patients display milder, progressive neuronopathic symptoms in childhood or adulthood. Type 1 patients can present peripheral neuropathy; however, type 2 and type 3 patients primarily present neurological disease alongside systemic symptoms.
Critically, existing treatments primarily focus on managing systemic manifestations, leaving the CNS unaddressed. ERTs cannot cross the blood-brain barrier and SRTs have not shown therapeutic effects for neurological manifestations in type 3 patients. Research efforts need to prioritise the creation of drugs designed to cross the blood-brain barrier, targeting the CNS to effectively mitigate neurological symptoms.
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KOLs highlighted the potential of Prevail Therapeutic’s (subsidiary of Eli Lilly) PR001, a pipeline gene therapy that delivers a healthy copy of the GBA1 gene, enabling GCase synthesis to facilitate the breakdown of glucocerebroside. Currently in Phase I/II with fast-track FDA designation, PR001 treatment could significantly ameliorate neuronopathic symptoms of patients if adequate safety and efficacy are demonstrated.
In a similar manner, Freeline Therapeutics’ Phase I/II FLT201 gene therapy aims to provide an alternative to ERT and SRT therapies; however, this does not target neuronopathic patients. Gene therapies also present complex ethical considerations in recognition of various cultural and religious beliefs. Ultimately, this development space is worth close monitoring, with KOLs describing gene therapy as “the future” and having the “greatest potential” to displace the current standard of care.
Beyond novel treatments, KOLs emphasise the importance of premarital and pre-natal screening to combat the lack of effective therapies for neuropathic patients, especially in acute infant type 2 patients. By identifying mutations in carriers, appropriate genetic counselling can be offered to educate couples and support family planning.
Indeed, in-depth analysis of the Gaucher disease landscape and discussions with KOLs have identified serious unmet needs. Looking ahead, collaboration between pharmaceutical innovators, dedicated researchers, and regulatory bodies is paramount. In turn, this may support the development of safe and effective therapies to improve the quality of life for patients suffering from neuronopathic Gaucher disease.