Gene Therapy for Radiation-Induced Dry Mouth

(AQUAx2 Trial)

Recruiting at 26 trial locations

Overseen By Thomas Schlieve, DDS, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: MeiraGTx, LLC

Must not be taking: Immunosuppressants

Disqualifiers: Malignancy, Autoimmune disease, Viral infections, others

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: 1

Duration: Single administration

276 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a gene therapy called AAV2-hAQP1 to determine its effectiveness for dry mouth caused by radiation treatment. The research targets adults who completed radiation for head and neck cancer at least three years ago and continue to experience dry mouth. Participants will receive the treatment directly into their salivary glands in varying doses to identify the most effective one. Individuals who have struggled with radiation-induced dry mouth and have tried or considered other treatments without success might be suitable candidates. As a Phase 2 trial, this research aims to measure the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

If you are taking a prescription sialagogue (a medication that increases saliva, like pilocarpine or cevimeline), you must stop it at least 2 weeks before the screening and not take it during the study. If you are on other medications that affect saliva, you need to be on a stable dose for at least a month before the screening.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that AAV2-hAQP1 has been safe in earlier studies. For example, one study found that a single dose of AAV2-hAQP1 was safe for patients. Participants produced more saliva and experienced relief from dry mouth symptoms, without serious side effects. Another report noted significant improvements in dry mouth symptoms without major side effects. These findings suggest that AAV2-hAQP1 is well-tolerated, offering a good safety profile for those considering joining the trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about AAV2-hAQP1 for treating radiation-induced dry mouth because it represents a novel approach involving gene therapy. Unlike standard treatments like saliva substitutes and medications that stimulate saliva production, AAV2-hAQP1 delivers a specific gene via a viral vector directly to the parotid glands. This gene, hAQP1, potentially restores the glands' ability to produce saliva by promoting water transport. Such a targeted mechanism could offer a more effective and lasting solution for patients suffering from dry mouth after radiation therapy.

What evidence suggests that this trial's treatment, AAV2-hAQP1, could be effective for radiation-induced dry mouth?

Research has shown that a new gene therapy, AAV2-hAQP1, which participants in this trial may receive, could help treat radiation-induced dry mouth. In earlier studies, this treatment improved patients' comfort by adding moisture to their dry mouths. The therapy introduces a specific gene, hAQP1, into the cells that produce saliva, helping to restore normal saliva flow. Animal studies, including those with minipigs, demonstrated that this treatment is effective and safe. These findings offer hope for people experiencing dry mouth after radiation therapy. ^{1 2 3 5 6}

Are You a Good Fit for This Trial?

Adults who've had radiation therapy for head and neck cancer at least 3 years ago, have a certain level of dry mouth severity, and can produce some saliva. They shouldn't have recurring or new cancers, be on specific medications affecting saliva, or have conditions like uncontrolled diabetes, recent smoking history, alcohol misuse, autoimmune diseases affecting salivary glands or certain infections.

Inclusion Criteria

Average screening XQ Total Score at or above a specified threshold

I chose to stop or not start prescribed medication for dry mouth.

I don't have head or neck cancer based on recent exams and scans.

Exclusion Criteria

I am currently using or have recently used medication that weakens my immune system.

I have an autoimmune disease like Sjogren's that affects my salivary glands.

Evidence of active Hepatitis C virus (HCV) infection

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive bilateral intra-parotid administration of AAV2-hAQP1 or placebo

Single administration

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Regular visits (frequency not specified)

What Are the Treatments Tested in This Trial?

Interventions

• AAV2-hAQP1

Trial Overview The trial is testing two different doses of AAV2-hAQP1 gene therapy against a placebo to see if they can safely improve dry mouth caused by past radiation treatments. Participants will receive the treatment directly into their parotid gland (a major salivary gland).

How Is the Trial Designed?

Group I: Cohort 2: AAV2-hAQP1 Group 4 Experimental Treatment 1 Intervention

Eligible participants will receive up to 3 mL of concentration 4 of AAV2-hAQP1 via Stensen's duct to each parotid gland

Group II: Cohort 2: AAV2-hAQP1 Group 3 Experimental Treatment 1 Intervention

Eligible participants will receive up to 3 mL of concentration 3 of AAV2-hAQP1 via Stensen's duct to each parotid gland

Group III: Cohort 1: AAV2-hAQP1 Group 2 Experimental Treatment 1 Intervention

Eligible participants will receive up to 3 mL of concentration 2 of AAV2-hAQP1 via Stensen's duct to each parotid gland

Group IV: Cohort 1: AAV2-hAQP1 Group 1 Experimental Treatment 1 Intervention

Eligible participants will receive up to 3 mL of concentration 1 of AAV2-hAQP1 via Stensen's duct to each parotid gland

Group V: Cohort 1: Placebo group Placebo Group 1 Intervention

Eligible participants will receive up to 3 mL of diluent via Stensen's duct to each parotid gland

Group VI: Cohort 2 Placebo group Placebo Group 1 Intervention

Eligible participants will receive up to 3 mL of diluent via Stensen's duct to each parotid gland

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+

Published Research Related to This Trial

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 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]

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]

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]

The study demonstrated that administering a recombinant adenovirus encoding human aquaporin-1 (AdhAQP1) to the parotid glands of adult rhesus monkeys is safe, with no adverse local or systemic effects observed after treatment.

While the gene transfer was successful in both irradiated and nonirradiated glands, the impact on improving salivary flow rates was inconsistent, indicating that while the treatment is well-tolerated, its effectiveness in enhancing salivary secretion after radiation damage varies among individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of adenovirus-mediated transfer of the human aquaporin-1 cDNA to irradiated parotid glands of non-human primates. O'Connell, AC., Baccaglini, L., Fox, PC., et al.[2006]

In a study involving miniature pigs, the administration of an adenoviral vector carrying the human aquaporin-1 (hAQP1) gene significantly restored salivary flow in parotid glands damaged by ionizing radiation, achieving about 80% of normal levels within three days.

The treatment was safe, showing no significant adverse effects on clinical chemistry or hematology, indicating that localized gene therapy could be a promising approach for managing radiation-induced salivary gland damage in larger animals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased fluid secretion after adenoviral-mediated transfer of the human aquaporin-1 cDNA to irradiated miniature pig parotid glands. Shan, Z., Li, J., Zheng, C., et al.[2018]

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]

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]

Adenoviral-mediated transfer of the human aquaporin-1 (hAQP1) gene to irradiated salivary glands in animal models significantly increased salivary flow to over 80% of control levels, demonstrating its efficacy in restoring function after ionizing radiation damage.

The treatment showed no significant adverse effects on clinical chemistry or hematology, indicating a good safety profile, which supports the development of a clinical trial for patients suffering from radiation-induced salivary gland dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transfer of the AQP1 cDNA for the correction of radiation-induced salivary hypofunction. Baum, BJ., Zheng, C., Cotrim, AP., et al.[2016]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02446249

Safety of a Single Administration of AAV2hAQP1, an Adeno ... Minipig studies have shown that the AAV2hAQP1 strategy for restoring salivary flow to IR-damaged salivary glands is effective without untoward effects after ...

2. investors.meiragtx.com investors.meiragtx.com/news-releases/news-release-details/meiragtx-announces-positive-clinical-data-aquax-phase-1-0

MeiraGTx Announces Positive Clinical Data from the AQUAx ... The data demonstrate clinically important improvements in two different patient reported outcome questionnaires for xerostomia, as well as meaningful increases ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2818419/

Development of a gene transfer-based treatment for ... A significant long-term side effect of radiation therapy for head and neck cancers is xerostomia, a dry mouth, due to salivary gland damage.

4. meiragtx.gcs-web.com meiragtx.gcs-web.com/static-files/da32598a-54de-495d-92c4-9c2d9980a03b

Gene Therapy for the Treatment of Radiation-Induced ... • Introduction of human aquaporin 1 gene (hAQP1) to duct cells via ... ❖ Xerostomia: Subjective feeling of dry mouth – assessed using patient ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3511089/

Early responses to adenoviral-mediated transfer of the ... About half of all surviving patients [Radiation Therapy Oncology Group (RTOG) late grade 2–4 toxicity (2–4)] experience irreversible damage to salivary glands ...

6. ctv.veeva.com ctv.veeva.com/study/safety-of-a-single-administration-of-aav2haqp1-an-adeno-associated-viral-vector-encoding-human-aqua

Safety of a Single Administration of AAV2hAQP1, an Adeno ... Radiation can cause the parotid salivary glands to make less saliva (dry mouth). This can cause problems like infections and tooth decay.