Gene Therapy for Radiation-Induced Dry Mouth

(AQUAX2 Trial)

Recruiting at 22 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

120 Participants Needed

Trial Summary

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.

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

Research shows that a similar treatment, AdhAQP1, increased saliva flow in both humans and animals with radiation-damaged salivary glands, with some patients experiencing benefits for several years. This suggests that AAV2-hAQP1 might also help improve saliva production in similar conditions. ^{1 2 3 4 5}

Is the gene therapy treatment AAV2-hAQP1 safe for humans?

Research on a similar treatment, AdhAQP1, showed no significant adverse effects in humans over several years, and animal studies with AAV2-hAQP1 indicated it was safe, with no major health issues observed. ^{1 4 6 7 8}

How does the treatment AAV2-hAQP1 for radiation-induced dry mouth differ from other treatments?

AAV2-hAQP1 is unique because it uses gene therapy to deliver the human aquaporin-1 (hAQP1) gene directly to the salivary glands, which helps restore fluid secretion by increasing water movement in the cells. This approach is different from traditional treatments as it targets the underlying cause of dry mouth by enhancing the gland's natural ability to produce saliva, rather than just alleviating symptoms. ^{1 3 4 6 9}

What is the purpose of this trial?

This trial will test a gene therapy injection into the salivary glands to help adults with severe dry mouth caused by radiation therapy produce more saliva. Gene therapy for dry mouth disorders has moved from theoretical to clinical proof with an initial trial using a specific method to express a protein in patients with radiation-induced dry mouth.

Eligibility Criteria

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

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

Evidence of active Hepatitis C virus (HCV) infection

Timeline

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)

Treatment Details

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).

Participant Groups

Group I: AAV2-hAQP1 Group 2 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 II: 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 III: 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+

Findings from Research

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]

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]

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]

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]

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]

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 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]

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]

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]

References

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

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

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

Increased fluid secretion after adenoviral-mediated transfer of the human aquaporin-1 cDNA to irradiated miniature pig parotid glands. [2018]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Transfer of the AQP1 cDNA for the correction of radiation-induced salivary hypofunction. [2016]

4. 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]

5. England 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. [2006]

6. 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]

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. 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]

9. 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]