Alogabat for Angelman Syndrome

(Aldebaran Trial)

Not currently recruiting at 37 trial locations

Overseen By Reference Study ID Number: BP41315 https://forpatients.roche.com/

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: Hoffmann-La Roche

Disqualifiers: Cardiovascular disease, Malignancy, Infections, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called Alogabat for Angelman Syndrome, a genetic disorder affecting the nervous system and causing developmental delays. The study will explore different doses of Alogabat for children and teens to evaluate its effectiveness and safety. It targets those with a confirmed genetic deletion related to Angelman Syndrome. Participants will be grouped by age to test age-adjusted doses. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it mentions that you cannot use certain prohibited medications within 6 weeks before starting the study. It's best to discuss your current medications with the study team to see if any adjustments are needed.

Is there any evidence suggesting that Alogabat is likely to be safe for humans?

Research has shown that alogabat has been generally well-tolerated in past studies. In one study, children aged 2 to 12 years did not experience serious side effects from the treatment, indicating its safety for them. Another study examined alogabat's short-term effects in the body and also found it to be safe.

Alogabat has mostly been tested in younger age groups, and these studies help ensure the treatment's safety. While the current trial involves different age groups and doses, previous findings suggest alogabat is safe for participants. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Angelman Syndrome?

Alogabat is unique because it offers a targeted approach for Angelman Syndrome, a condition that currently has limited treatment options primarily focused on managing symptoms. Unlike existing therapies that address symptoms like seizures and sleep disturbances, Alogabat works by modulating GABA receptors, which could address underlying neurological issues more directly. Researchers are excited because this mechanism offers the potential for more comprehensive symptom management and improved quality of life for patients with Angelman Syndrome.

What evidence suggests that Alogabat might be an effective treatment for Angelman Syndrome?

Research has shown that alogabat has potential based on early studies. In animal tests, it helped with repetitive behaviors and reduced seizures, suggesting it might alleviate some symptoms of Angelman Syndrome, which often include these issues. Although gaboxadol, a similar drug, did not significantly help children in a past trial, alogabat targets specific brain receptors that might be more effective. Early results from alogabat studies suggest it could improve certain brain-related symptoms. This trial will further investigate alogabat's effectiveness across various age-adjusted dosing arms. More research is needed to confirm these promising signs in people. ^{1 2 4 5 6}

Who Is on the Research Team?

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Are You a Good Fit for This Trial?

This trial is for children and adolescents aged 5-17 with Angelman Syndrome (AS) who have a specific genetic deletion. They must have a BMI within the normal range for their age and sex, not be pregnant or breastfeeding, and either practice abstinence or use contraception. Participants should not have heart issues like QTc prolongation, recent major infections or surgeries, other conditions that could affect the study's results, or a history of certain diseases.

Inclusion Criteria

I use reliable contraception methods, not periodic abstinence or withdrawal.

My BMI is within the normal range for my age and sex.

I am not pregnant, breastfeeding, and either cannot have children or will use birth control.

Exclusion Criteria

I haven't lost a significant amount of blood in the last 3 months.

I haven't been hospitalized for surgery under general anesthesia in the last 12 weeks.

My condition is genetically confirmed as Angelman Syndrome but not as specified in the inclusion criteria.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Part 1 - Dose Confirmation

Participants receive age-adjusted doses of alogabat to confirm dosing and collect PK, EEG, and safety data

6 weeks

Part 2 - Dose Exploration

Dosing based on Part 1 results, exploring changes in EEG beta-band power and safety data

6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Alogabat

Trial Overview The trial is testing different doses of Alogabat in two parts over 12 weeks to understand how it works in kids with AS. It's an open-label study where everyone knows what treatment they're getting. The goal is to find out how safe Alogabat is and how the body processes it.

How Is the Trial Designed?

Group I: Part 2 Optional Cohort Experimental Treatment 1 Intervention

In Part 2 of the study, the dosing will depend upon the interim results with two different dose levels per cohort. Doses can be age-adjusted.

Group II: Part 2 Cohort 2 Experimental Treatment 1 Intervention

In Part 2 of the study, the dosing will depend upon the interim results with two different dose levels per cohort. Doses can be age-adjusted.

Group III: Part 2 Cohort 1 Experimental Treatment 1 Intervention

In Part 2 of the study, the dosing will depend upon the results of Part 1 with two different dose levels per cohort. Doses can be age-adjusted.

Group IV: Part 1 Optional Cohort Experimental Treatment 1 Intervention

If dose adjustments (e.g., increase or decrease in dose) are required, particularly due to uncertainty of the clearance estimates (e.g., due to high variability) or over-/underprediction of the pediatric clearance versus adult clearance, additional participants may be recruited in any of the of the 3 age-groups in order to confirm the exposure equivalence. A total of two optional cohorts may be utilized in this study, allocated to Part 1 and/or Part 2.

Group V: Part 1 Age-adjusted Dose (Age 5-9) Experimental Treatment 1 Intervention

In Part 1 of the study, participants will receive age-adjusted QD doses of alogabat.

Group VI: Part 1 Age-adjusted Dose (Age 10-14) Experimental Treatment 1 Intervention

In Part 1 of the study, participants will receive age-adjusted QD doses of alogabat.

Group VII: Part 1 Adult Alogabat Dose (Age 15-17) Experimental Treatment 1 Intervention

In Part 1 of the study participants will receive alogabat once a day (QD).

Who Is Running the Clinical Trial?

Hoffmann-La Roche

Lead Sponsor

Trials

2,482

Recruited

1,107,000+

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Avastin, Herceptin, Rituxan, Accu-Chek

Dr. Levi Garraway

Hoffmann-La Roche

Chief Medical Officer since 2019

MD from the University of Basel

Dr. Thomas Schinecker

Hoffmann-La Roche

Chief Executive Officer since 2023

PhD in Molecular Biology from New York University

Published Research Related to This Trial

AZD7325, a selective GABA-A receptor modulator, showed no significant effects on cognitive and psychomotor functions in healthy males, indicating a potentially lower side effect profile compared to lorazepam, which caused notable impairments.

The study suggests that AZD7325 may offer anxiolytic effects with reduced cognitive burden, as it demonstrated different response patterns from lorazepam, particularly in measures of alertness and neurophysiological responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The central nervous system effects of the partial GABA-Aα2,3 -selective receptor modulator AZD7325 in comparison with lorazepam in healthy males. Chen, X., Jacobs, G., de Kam, M., et al.[2021]

AZD7325, a selective GABAA receptor modulator, was shown to induce the CYP3A4 enzyme, affecting the metabolism of midazolam in a study involving 24 healthy subjects, which helps understand drug interactions.

The population pharmacokinetic models developed for AZD7325 and midazolam can guide rational dosing regimens in clinical practice, ensuring effective and safe use of AZD7325 while considering its impact on midazolam metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic modelling to assess clinical drug-drug interaction between AZD7325 and midazolam. Zhou, D., Lu, Z., Sunzel, M., et al.[2018]

In a study involving 7 patients with Angelman syndrome (AS) and 4 healthy controls, GABA(A) receptor expression was found to be significantly higher in the cerebral cortex and cerebellum of patients with certain genotypes, indicating a potential alteration in receptor function.

The findings suggest that there is a developmental dysregulation of GABA(A) receptor subunits in AS, which could have implications for understanding the neurological aspects of the syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[(11)C]flumazenil positron emission tomography analyses of brain gamma-aminobutyric acid type A receptors in Angelman syndrome. Asahina, N., Shiga, T., Egawa, K., et al.[2016]

AZD7325, a GABA(A) receptor modulator for anxiety, was found to be a moderate inducer of CYP1A2 and a potent inducer of CYP3A4 in vitro, indicating potential interactions with other drugs metabolized by these enzymes.

However, in clinical studies with healthy volunteers, the expected effective dose of AZD7325 showed only a weak induction effect on CYP3A4 and no effect on CYP1A2, highlighting the importance of clinical exposure in assessing drug interaction risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A clinical study to assess CYP1A2 and CYP3A4 induction by AZD7325, a selective GABA(A) receptor modulator - an in vitro and in vivo comparison. Zhou, D., Sunzel, M., Ribadeneira, MD., et al.[2021]

Ganaxolone, a synthetic neurosteroid, showed significant therapeutic benefits in a mouse model of Angelman syndrome, improving anxiety, seizures, and motor deficits over a treatment period of 4 weeks.

The treatment also restored spatial working memory and synaptic plasticity in the hippocampus, indicating its potential as a symptomatic treatment for Angelman syndrome without developing tolerance to its effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of the synthetic neurosteroid ganaxolone on seizure activity and behavioral deficits in an Angelman syndrome mouse model. Ciarlone, SL., Wang, X., Rogawski, MA., et al.[2018]

Gaboxadol (OV101) was found to be generally safe and well-tolerated in a 12-week study involving 88 individuals with Angelman syndrome, with 90% of participants completing the trial and no life-threatening adverse events reported.

The exploratory efficacy analysis showed significant improvement in clinical severity for those receiving gaboxadol compared to placebo, indicating potential benefits that warrant further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The STARS Phase 2 Study: A Randomized Controlled Trial of Gaboxadol in Angelman Syndrome. Bird, LM., Ochoa-Lubinoff, C., Tan, WH., et al.[2021]

Felbamate effectively enhances GABA currents in specific GABA(A) receptor combinations (alpha(1)beta(2)gamma(2S), alpha(1)beta(3)gamma(2S), alpha(2)beta(2)gamma(2S), and alpha(2)beta(3)gamma(2S)), indicating its selective action on these receptors.

The study suggests that the differential modulation of GABA(A) receptor subunits by felbamate may play a crucial role in its effectiveness for treating refractory epileptic seizures, as it may target specific inhibitory circuits in the brain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Felbamate is a subunit selective modulator of recombinant gamma-aminobutyric acid type A receptors expressed in Xenopus oocytes. Simeone, TA., Otto, JF., Wilcox, KS., et al.[2018]

Darigabat, a selective positive allosteric modulator of GABAA receptors, significantly reduced the frequency and duration of focal seizures in a mouse model of mesial temporal lobe epilepsy, showing comparable efficacy to the established treatment diazepam at certain doses.

The promising results from this preclinical study have led to an ongoing Phase II clinical trial to further assess the efficacy and safety of darigabat in patients with drug-resistant focal seizures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pronounced antiseizure activity of the subtype-selective GABAA positive allosteric modulator darigabat in a mouse model of drug-resistant focal epilepsy. Gurrell, R., Iredale, P., Evrard, A., et al.[2022]

In a phase 3 trial involving 104 children with Angelman syndrome, gaboxadol did not show a significant improvement in clinical symptoms compared to placebo after 12 weeks, with similar CGI-Improvement-AS scores in both groups.

Gaboxadol was well tolerated among participants aged 2 to 12 years, indicating a good safety profile despite the lack of efficacy in improving symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gaboxadol in angelman syndrome: A double-blind, parallel-group, randomized placebo-controlled phase 3 study. Keary, C., Bird, LM., de Wit, MC., et al.[2023]

The study analyzed 87 individuals with Angelman syndrome (AS) and found that their health-related quality of life (HRQoL) was significantly affected, with a mean utility score of 0.44 indicating substantial challenges in self-care, mobility, and daily activities.

A high level of medication use was noted, with an average of 5 medications per person, suggesting that individuals with AS often require multiple treatments to manage their condition and associated symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality of life and medication use among individuals with Angelman syndrome. Khan, N., Cabo, R., Burdine, RD., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05630066

NCT05630066 | A Study to Investigate the ... This is a two-part, Phase IIa, multicenter, 12-week, open-label study. Up to 56 participants with deletion AS aged 5-17 years (inclusive) will be enrolled in ...

2. genentech-clinicaltrials.com genentech-clinicaltrials.com/en/trials/neurodevelopmental-disorder/angelman-syndrome/study-to-investigate-the-pharmacokinetics-and-safety-an-84203.html

A phase IIa, multicenter, open-label, 12-week study to in... A 12-week study to investigate how the body handles alogabat once it is swallowed, how safe it is, and whether it could be effective in treating the symptoms ...

3. withpower.com withpower.com/trial/phase-2-syndrome-2023-8721b

Alogabat for Angelman Syndrome (Aldebaran Trial) In a phase 3 trial involving 104 children with Angelman syndrome, gaboxadol did not show a significant improvement in clinical symptoms compared to placebo ...

4. ctv.veeva.com ctv.veeva.com/study/a-12-week-placebo-controlled-study-to-investigate-the-efficacy-safety-and-tolerability-of-ro701777

A 12-Week Placebo-Controlled Study to Investigate the ... This study will investigate the efficacy, safety, tolerability, and pharmacokinetics of RO7017773 in participants aged 15-45 years who have been ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12319775/

Preclinical pharmacology of alogabat: a novel GABAA-α5 ... The current data for alogabat showed robust dose-dependent efficacy on repetitive behaviors in two disease-relevant mouse models and anti-seizure activity ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04299464

NCT04299464 | A 12-Week Placebo-Controlled Study to ... This study will investigate the efficacy, safety, tolerability, and pharmacokinetics of RO7017773 in participants aged 15-45 years who have been diagnosed ...