Gene Therapy for Dry Mouth

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: MeiraGTx, LLC

Disqualifiers: Withdrew consent, 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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

120 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will assess the long-term safety and efficacy of bilateral intra-parotid administration of AAV2-hAQP1 in adults with Grade 2 or Grade 3 radiation-induced late xerostomia.

Do I need to stop my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications.

What data supports the effectiveness of the treatment AAV2-hAQP1 for dry mouth?

Research shows that AAV2-hAQP1 can increase saliva production in animals with damaged salivary glands, and similar treatments have helped improve saliva flow in humans with radiation-damaged glands. This suggests that AAV2-hAQP1 might be effective in treating dry mouth by enhancing fluid secretion. ^{1 2 3 4 5}

Is the gene therapy AAV2-hAQP1 safe for humans?

Research shows that AAV2-hAQP1 gene therapy appears to be safe in animal studies, with no significant adverse effects observed. In a clinical trial, some patients showed increased saliva flow without major safety concerns, suggesting it may be safe for humans. ^{1 4 5 6 7}

How is the treatment AAV2-hAQP1 for dry mouth different from other treatments?

AAV2-hAQP1 is unique because it uses gene therapy to increase fluid secretion in salivary glands by delivering the human aquaporin-1 (hAQP1) gene, which helps water move across cell membranes, potentially providing long-term relief for dry mouth caused by radiation damage. ^{1 2 4 5 8}

Eligibility Criteria

This trial is for adults with moderate to severe dry mouth (Grade 2 or Grade 3) caused by radiation therapy. Specific eligibility details are not provided, but typically participants must meet certain health standards and may be excluded based on factors that could impact the study's results.

Inclusion Criteria

Received study drug in Study MGT-AQP1-201

Exclusion Criteria

Withdrew consent to participate in Study MGT-AQP1-201.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

Treatment

Participants receive AAV2-hAQP1 gene therapy or transition from placebo to active treatment

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

48-60 months

Treatment Details

Interventions

• AAV2-hAQP1

Trial Overview The trial is testing a gene therapy called AAV2-hAQP1, which is administered into both parotid salivary glands. The goal is to evaluate the long-term safety and effectiveness of this treatment in reducing symptoms of dry mouth following radiation.

Participant Groups

Group I: Active treatment group Experimental Treatment 1 Intervention

Participants who were randomized to placebo treatment in Study MGT-AQP1-201, will be offered to transition from the long-term follow-up schedule to an active treatment schedule at the time of unblinding. Study drug administration should be completed after unblinding and after confirmation of the participant's continued eligibility for treatment. Upon completion of the 12-month primary treatment period, participants will continue in the study according to a follow-up schedule, to complete a total of 60 months of follow-up after AAV2-hAQP1 administration.

Group II: Follow-up group Active Control 1 Intervention

Participants who were randomized to AAV2-hAQP1 treatment in Study MGT-AQP1-201 will continue in this long-term follow-up schedule to complete an additional 48 months of follow-up after their end-of-study visit in Study MGT-AQP1-201. All study participants are to be followed for a period of 60 months after vector administration.

AAV2-hAQP1 is already approved in United States, Canada, United Kingdom for the following indications:

Approved in United States as AAV2-hAQP1 for:

• Radiation-induced late xerostomia (Grade 2/3)

Approved in Canada as AAV2-hAQP1 for:

• Radiation-induced late xerostomia (Grade 2/3)

Approved in United Kingdom as AAV2-hAQP1 for:

• Radiation-induced late xerostomia (Grade 2/3)

Who Is Running the Clinical Trial?

MeiraGTx, LLC

Lead Sponsor

Trials

6

Recruited

310+

Findings from Research

A single dose of AAV2hAQP1 delivered to irradiated parotid glands in minipigs significantly increased salivary flow to about 35% of pre-irradiation levels, demonstrating its efficacy in treating salivary hypofunction.

The treatment was safe, with minimal changes in clinical chemistry and hematology, and it effectively targeted duct cells, suggesting potential for extended relief in patients with similar radiation-induced salivary issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV2-mediated transfer of the human aquaporin-1 cDNA restores fluid secretion from irradiated miniature pig parotid glands. Gao, R., Yan, X., Zheng, C., et al.[2021]

In a clinical trial involving five subjects, administration of the AdhAQP1 gene therapy for radiation-induced salivary hypofunction resulted in significant long-term increases in parotid salivary flow (71-500% above baseline) lasting 3-4.7 years after treatment.

There were no clinically significant adverse events reported, indicating that AdhAQP1 is a safe intervention, and the benefits of the treatment persisted much longer than typically expected from first-generation adenoviral vectors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Late responses to adenoviral-mediated transfer of the aquaporin-1 gene for radiation-induced salivary hypofunction. Alevizos, I., Zheng, C., Cotrim, AP., et al.[2019]

The recombinant adenovirus AdhAQP1 effectively increased the expression of human aquaporin-1 in epithelial cells, leading to a fourfold increase in fluid movement across cell monolayers compared to controls.

In a rat model, administering AdhAQP1 to submandibular glands after radiation treatment resulted in a two- to threefold increase in salivary secretion, suggesting its potential as a treatment for postradiation salivary hypofunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased fluid secretion after adenoviral-mediated transfer of the aquaporin-1 cDNA to irradiated rat salivary glands. Delporte, C., O'Connell, BC., He, X., et al.[2023]

In a clinical trial involving 11 subjects, the adenoviral vector AdhAQP1 significantly improved saliva flow rates and reduced symptoms in patients with radiation-damaged parotid glands, with effects lasting longer than expected (7-42 days).

The study suggests that the human cytomegalovirus promoter/enhancer (hCMVp) in AdhAQP1 remains unmethylated in human salivary gland cells, allowing for prolonged expression and function of the human aquaporin-1 protein, unlike in rodent models where methylation led to decreased expression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Persistence of hAQP1 expression in human salivary gland cells following AdhAQP1 transduction is associated with a lack of methylation of hCMV promoter. Zheng, C., Baum, BJ., Liu, X., et al.[2019]

A 13-week safety study in Balb/c mice showed that the recombinant adeno-associated vector (rAAV2hAQP1) used to treat radiation-induced salivary gland damage was clinically safe, with no significant adverse effects observed in body weight, food or water consumption, and clinical chemistry evaluations.

The treatment resulted in only mild inflammation at the injection site and localized vector distribution, with no significant changes in liver, kidney, or cardiac function, indicating a favorable safety profile for future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity and biodistribution of the serotype 2 recombinant adeno-associated viral vector, encoding Aquaporin-1, after retroductal delivery to a single mouse parotid gland. Momot, D., Zheng, C., Yin, H., et al.[2021]

In a Phase I clinical trial involving a patient with radiation-induced salivary hypofunction, the administration of an adenoviral vector (AdhAQP1) successfully delivered the human aquaporin-1 gene, with detectable levels in parotid saliva one week post-treatment.

The patient remained asymptomatic throughout the study, and no infectious virus or vector was found in serum or subsequent saliva samples, suggesting that the treatment was safe and did not lead to adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transient detection of E1-containing adenovirus in saliva after the delivery of a first-generation adenoviral vector to human parotid gland. Zheng, C., Nikolov, NP., Alevizos, I., et al.[2021]

References

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

AAV2-mediated transfer of the human aquaporin-1 cDNA restores fluid secretion from irradiated miniature pig parotid glands. [2021]

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

Late responses to adenoviral-mediated transfer of the aquaporin-1 gene for radiation-induced salivary hypofunction. [2019]

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

Effect of serotype 5 adenoviral and serotype 2 adeno- associated viral vector-mediated gene transfer to salivary glands on the composition of saliva. [2018]

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

Increased fluid secretion after adenoviral-mediated transfer of the aquaporin-1 cDNA to irradiated rat salivary glands. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Persistence of hAQP1 expression in human salivary gland cells following AdhAQP1 transduction is associated with a lack of methylation of hCMV promoter. [2019]

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

Toxicity and biodistribution of the serotype 2 recombinant adeno-associated viral vector, encoding Aquaporin-1, after retroductal delivery to a single mouse parotid gland. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Transient detection of E1-containing adenovirus in saliva after the delivery of a first-generation adenoviral vector to human parotid gland. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Construction and function of a recombinant adenovirus encoding a human aquaporin 1-green fluorescent protein fusion product. [2011]