Clinical Trials
For more information about current on going trials and to find any information about any upcoming trails please visit https://www.vwmconsortium.org/clinical-trials/
So much hope in two trials:
Calico Drug Trial for VWM
SOUTH SAN FRANCISCO, Calif., April 26, 2023 – Calico Life Sciences LLC (Calico), a biotechnology organization focused on the biology of aging and healthspan, and founded by Alphabet and Arthur D. Levinson Ph.D., today announced that the first participant has been dosed in a Phase 1b clinical trial, (study M23-523; NCT05757141), evaluating the investigational eIF2B activator ABBV-CLS-7262 as a potential treatment for Vanishing White Matter (VWM) disease. ABBV-CLS-7262 is being developed by Calico in collaboration with AbbVie.
VWM disease is an ultra-rare progressive leukoencephalopathy – a disease of the brain’s white matter – caused by variations in any of the five subunits of an essential enzyme in cells called eIF2B. VWM variations in eIF2B cause a reduction in its enzymatic activity that may lead to chronic activation of the integrated stress response (ISR). The ISR plays a critical role in protein homeostasis and organismal resilience, both of which are implicated in the biology of aging.
When chronically activated in the brain, the ISR causes the white matter to degenerate. Individuals with VWM disease commonly have symptoms such as impaired muscle movement, cognitive decline, and seizures. While symptoms often begin to appear between ages 2 and 6, the disease can present at any age. The disease course is chronic and progressive, and stressors such as fever, infection, and mild head trauma may cause episodes of rapid deterioration. There is currently no cure and no treatment approved for VWM disease.
“Since our founding, Calico has been focused on generating new scientific insights on biology relevant to aging and translating those insights to develop drug candidates for potential patient benefit,” said Arthur D. Levinson, Ph.D., founder and CEO. “ABBV-CLS-7262 is an encouraging outcome of this approach and we are pleased to advance this clinical study in vanishing white matter disease. We are grateful to all the participants in this important trial and are hopeful that ABBV-CLS-7262 will demonstrate its potential as a treatment for this devastating condition.”
“We are delighted with the dedication shown by the vanishing white matter community to help start the testing of this potential treatment,” said Josh Bonkowsky, M.D., Ph.D., Professor of Pediatrics at the University of Utah and Primary Children’s Hospital. “It is exciting to be advancing this work, and it reflects major investments of time and commitment from around the world, including scientists and physicians, who have made this moment possible.”
“At the Amsterdam Leukodystrophy Center we have worked long and hard to better understand vanishing white matter and help develop treatments. It is extremely meaningful and gratifying to collaborate with Calico on the clinical development of ABBV-CLS-7262,” said Marjo van der Knaap, M.D., Ph.D., Amsterdam Leukodystrophy Center, Emma Children’s Hospital and Amsterdam University Medical Center, on behalf of the International VWM Consortium of Clinical Experts. “ABBV-CLS-7262 targets the central cause of vanishing white matter and if it proves to benefit patients, would be a milestone in vanishing white matter therapy development for this disease.”
This Phase 1b trial is a 96-week open-label, single arm study designed to evaluate the safety, tolerability, and pharmacokinetics of ABBV-CLS-7262 in participants diagnosed with VWM disease. This will be the first time an eIF2B activator has been administered to people with VWM disease. The study’s primary outcome measures are the assessment of adverse events over the first 7 weeks together with drug concentrations in plasma over the first 4 weeks of dosing. For more information on study NCT05757141, please visit: www.clinicaltrials.gov.
About ABBV-CLS-7262
ABBV-CLS-7262 targets eIF2B, a guanine nucleotide exchange factor that is essential for protein synthesis and a key regulator of the ISR. In preclinical studies in a mouse model of VWM, ABBV-CLS-7262 blunted the persistent ISR in the brain and spinal cord, primarily in cell types that are known to be severely affected by the human form of VWM, and corrected coordination and movement problems in these mice.
Persistent activation of the ISR has been linked to the development of several neurological disorders, and preclinical studies investigating ABBV-CLS-7262 as a modulator of the ISR have demonstrated its potential as a new therapeutic strategy. ABBV-CLS-7262 is also being investigated as a potential treatment for people with amyotrophic lateral sclerosis (ALS) in two ongoing studies; a Phase 1b study (NCT04948645), and as a regimen in the Phase 2/3 Healey ALS Platform Trial (NCT05740813), sponsored by Professor Merit Cudkowicz, M.D., M.Sc., director of the Sean M. Healey & AMG Center for ALS, chief of the Department of Neurology at Massachusetts General Hospital.
ABBV-CLS-7262 is licensed from the University of California, San Francisco, based on novel technology from the lab of Peter Walter, Ph.D., Professor Emeritus of Biochemistry and Biophysics at University of California, San Francisco.
ABBV-CLS-7262 is an investigational drug not yet approved for use in any country.
About Calico
Calico (Calico Life Sciences LLC) is an Alphabet-founded research and development company whose mission is to harness advanced technologies and model systems to increase our understanding of the biology that controls human aging. Calico will use that knowledge to devise interventions that enable people to lead longer and healthier lives. To learn more about Calico, visit www.calicolabs.com.
Guanabenz Trial for VWM
The first trial participant was included on May 31st 2021. In the first year, 17 children have been included who are treated with Guanabenz (8 boys and 9 girls). The inclusion rate is faster than expected and we are ahead of schedule. Therefore we asked permission from the Dutch authorities for the possibility to include more children in the trial, up to 40.
The age of the children on entering the trial ranged between the 2 and 12 years. The disease duration when entering the trial ranged between the 1 and 8 years.
During the first visit to Amsterdam, the participants are titrated to the maximum tolerated dose of Guanabenz, which implies that all participants have temporary side effects. The minimum required dose of Guanabenz of 1 mg/kg/day was reached in all patients without major side effects. The final dose after the titration phase ranges between 1 and 2 mg/kg/day for the whole patient group. No children have been dosed above the 2 mg/kg/day. Initially, some children have to get used to swallowing the Guanabenz capsules, but after 1 or 2 weeks they all ingest the medication without problems, even the very young children.
All patients experienced the side-effects of sleepiness and drowsiness, as expected. Other important temporary side effects are: feeling unsteady/insecure (“wobbliness” as most children describe it themselves), dry mouth, constipation, nausea and vomiting. In some patients we also observed psychological effects like sad feelings, vivid dreams, nightmares and sometimes visual or tactile hallucinations. It sometimes takes time before the side-effects have resolved; this is different for each child. What we see is that after 3 months almost all children are back to normal, i.e. back in the condition before they entered the trial. To resolve side-effects more quickly it helps for some children to split the dose into two smaller gifts with an interval of several hours. In some cases (temporary) reduction of the dose of Guanabenz or extra medication is necessary (e.g. forlax to treat and prevent constipation, anti-emetics for vomiting, and risperdone to treat hallucinations).
Conclusion
Overall, the Guanabenz is tolerated by the children. There are no major side effects and no important safety issues. The monitor boards gave their permission to continue the trial in its present form. Longer follow-up is needed to determine the efficacy of Guanabenz. On 31st May 2022 we entered the second study year of the Guanabenz trial.
For more information about the Guanabenz clinical trial, visit our clinical trial page.