A promising rare disease treatment supported by Orfenix. At Orfenix, we are dedicated to turning academic breakthroughs into life-changing therapies through efficient and socially responsible drug development. One of our key projects focuses on guanabenz, a promising candidate drug for Vanishing White Matter (VWM)—a rare and fatal pediatric brain disorder with no approved treatment options.1 Prof. Dr. Marjo S. van der Knaap discovered that guanabenz may be effective in halting VWM disease progression.2 Orfenix is proud to support her in the journey to bring guanabenz to the market, at a fair price, for the treatment of VWM.
Vanishing White Matter (VWM)
VWM is a disorder that primarily affects the brain white matter causing chronic and progressive disabling motor dysfunction and cognitive decline. Patients often initially appear normal or suffer from mild symptoms such as delays in learning to crawl and walk, muscle stiffness, and difficulty in coordinating movements. With time, however, chronic progressive neurological deterioration develops, leading to loss of motor function (e.g. loss of ability to walk, sit, use of hands), vision loss, epileptic seizures, cognitive decline and behavioural issues. Characteristic of VWM is that minor stress conditions, such as infections and head trauma, can accelerate neurological deterioration, triggering further worsening of symptoms. These stress-provoked episodes cause subacute neurological deterioration that can end in coma and death.1,3
Typically, VWM patients present symptoms in early childhood at 2 to 6 years of age. However, cases are reported with neonatal and adult symptom onset. The age of onset appears to be inversely related to clinical severity; the episodes of deterioration are usually milder in adolescents and adults than in children, while disease onset before the age of 9 months is invariably associated with death within the second year of life.1-3
VWM Treatment
Currently, no treatment exists for VWM. The only measures available focus on managing symptoms and avoiding stresses, such as infections and trauma, that provoke rapid deterioration. The measures, however, do not slow down or stop chronic neurological deterioration.2
Paediatric neurologist Marjo S. van der Knaap, internationally renowned in the field of VWM, is working to change this and is driven to find a drug that can better help her patients. Marjo S. van der Knaap has been pivotal to discovering and understanding VWM; together with her team, she identified the genetic mutations that are causative for VWM and is searching for therapies that can prevent, halt, or delay VWM disease progression.4 In their search, guanabenz was discovered as a promising potential treatment.2
Guanabenz for the treatment of VWM
Guanabenz is an antihypertensive drug that has been used for the treatment of high blood pressure since the 1980s. Over the past two decades, research has revealed that guanabenz affects the integrated stress response (ISR). The ISR is an evolutionarily highly conserved pathway that is activated by different stressors such as fever and viral infection; it helps cells cope with various stress conditions by regulating protein synthesis and gene expression. The protein that is mutated in VWM is a central regulator of the ISR. Consequently, the cellular mechanism needed to respond to stress is dysregulated in VWM. Its effect on the ISR makes guanabenz an interesting therapeutic candidate for the treatment of VWM.5
Studies in VWM animal models show promising results of guanabenz therapy. VWM mouse models treated with guanabenz had significantly better motor performance than untreated animals; with guanabenz treatment, motor test results of VWM mice were not significantly different from the results of healthy control mice.6 Furthermore, guanabenz treated VWM mice had better conserved brain white matter than untreated animals.7
The promising pre-clinical results motivated Marjo S. van der Knaap and her team to investigate the potential of guanabenz for treating VWM in a clinical setting further. In 2021, a non-randomized, open-label clinical study was initiated to investigate the safety, tolerability, pharmacokinetic profile, and potential efficacy of guanabenz in the treatment of young children with VWM.
The guanabenz clinical trial for VWM
The ongoing study involves 33 pediatric patients with early-stage VWM. Study participants had to:
- Have disease onset within 6 years and diagnosis within 8 years
- Retain minimal motor function (ability to walk 10 steps with light support)
The trial is scheduled to conclude on December 1, 2025. While the clinical trial results, which prove the safety and efficacy of guanabenz in treating VWM, are pending, the data observed thus far are encouraging.
Why Orfenix supports this project
At Orfenix, we believe repurposed medicines like guanabenz offer a cost-effective and accelerated path to addressing unmet medical needs in rare diseases. We proudly support the clinical development of guanabenz for VWM and aim to ensure:
- Fair pricing
- Broad patient access
- Sustainable market delivery
We see our role as bridging academia and the pharmaceutical market, ensuring that promising treatments reach the patients who need them most.
References
- https://pmc.ncbi.nlm.nih.gov/articles/PMC6175238/
- https://pmc.ncbi.nlm.nih.gov/articles/PMC8811717/
- https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(06)70440-9/abstract
- https://www.nature.com/articles/ng764z
- https://www.science.org/doi/10.1126/science.1201396?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
- https://onlinelibrary.wiley.com/doi/10.1002/acn3.51611
- https://onlinelibrary.wiley.com/doi/10.1111/nan.12411
