Alogabat for Angelman Syndrome

(Aldebaran Trial)

Recruiting in Palo Alto (17 mi)

+32 other locations

Age: < 18

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Hoffmann-La Roche

Disqualifiers: Cardiovascular disease, Malignancy, Infections, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial tests Alogabat, a medication, to see if it can help children aged 5-17 with deletion Angelman Syndrome. Researchers will give the medication daily and check for improvements in brain activity over a few months.

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.

What data supports the effectiveness of the drug Alogabat (RO7017773) for Angelman Syndrome?

Research on similar treatments, like gaboxadol and ganaxolone, shows potential benefits for Angelman Syndrome by targeting GABA(A) receptors, which are involved in brain signaling. These studies suggest that drugs affecting these receptors may help improve symptoms like seizures and motor deficits. ^{1 2 3 4 5}

How is the drug Alogabat different from other treatments for Angelman Syndrome?

Alogabat is unique because it is a selective modulator of GABAA receptors, specifically targeting certain subunits, which may offer a more tailored approach to managing symptoms compared to other treatments that do not have this specificity. ^{6 7 8 9 10}

Research Team

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Alogabat (GABA Receptor Agonist)

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Gaboxadol in angelman syndrome: A double-blind, parallel-group, randomized placebo-controlled phase 3 study. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Effects of the synthetic neurosteroid ganaxolone on seizure activity and behavioral deficits in an Angelman syndrome mouse model. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

[(11)C]flumazenil positron emission tomography analyses of brain gamma-aminobutyric acid type A receptors in Angelman syndrome. [2016]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Health-related quality of life and medication use among individuals with Angelman syndrome. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

The STARS Phase 2 Study: A Randomized Controlled Trial of Gaboxadol in Angelman Syndrome. [2021]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Felbamate is a subunit selective modulator of recombinant gamma-aminobutyric acid type A receptors expressed in Xenopus oocytes. [2018]

7. England 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. [2021]

8. England 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. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic modelling to assess clinical drug-drug interaction between AZD7325 and midazolam. [2018]

10. England 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. [2022]