MeiraGTx : Results of a Phase 1, Open-label, Dose-escalation Study of Gene Therapy with AAV2-hAQP1 as Treatment for Grade 2 and 3 Radiation-induced Late Xerostomia and Parotid Gland Hypofunction – The AQUAx Study

Results of a Phase 1, Open-label,Dose-escalation Study of Gene Therapy with AAV2-hAQP1 as Treatment for Grade 2 and 3 Radiation-induced Late Xerostomia and Parotid Gland Hypofunction - The AQUAx Study

Oral Abstract I

Michael T Brennan, DDS, MHS

[e-mail]

Disclosures

• I have received financial support from MeiraGTx, LLC for research studies
• I served as an investigator in the completed MGT016 (AQUAx) study, sponsored by MeiraGTx, LLC
• I currently serve as an investigator in the ongoing MGT-AQP1-201 (AQUAx2) study, sponsored by MeiraGTx, LLC

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Radiation-Induced Xerostomia (RIX)

• RIX is one of the most frequent complications of radiation treatment for head and neck cancer
• IMRT has reduced the incidence of RIX, but it still affects >50% of those completing radiotherapy for head and neck cancer
• Persistent Grade 2/3 (Moderate/Severe) RIX is a common, durable, and severely debilitating condition affecting about 30% of those successfully treated for H&N cancer 2 years post-treatment
• Patients' experience
• • Difficulty eating, chewing, and swallowing; taste alterations
  • Speech difficulties and abnormalities
  • Difficulty sleeping; difficulty exercising
  • Uncontrollable dental caries with severe tooth decay/periodontal disease
  • Inability to wear dentures
  • Oral pain and throat pain
  • Burning mouth sensation in 40% of patients
  • Harmful changes in oral flora

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Significant Unmet Medical Need for an Effective RIX Treatment

• >170,000 patients with long-term (i.e., at least 2 years post radiation treatment) grade 2/3 RIX in the US alone1,2,3
• Annually in the US, 54,000 new cases of head and neck cancer and >15,000 new patients with persistent grade 2/3 RIX1,2,3
• Over-the-counteragents such as lozenges, gums, and artificial saliva provide limited relief
• Pilocarpine, the only FDA-approved drug for RIX, is poorly tolerated and not effective in patients with Grade 2/3 RIX

Patients with Grade 2/3 RIX have no effective therapy

Prevalence (US)

170K

Grade 2/3 RIX patients in

the US

U.S. Diagnosed incidence of H&N cancer

Receiving RT

Persistent RIX

Grade 2/3 persistent RIX

1 SEER, Cancer.net

Incidence (US)

15K

New cases of grade 2/3 RIX annually in the US

54K

40K

22K

15K

available today

1. Marta GN et al (2014). Intensity-modulated radiation therapy for head and neck cancer: systematic review and meta-analysis. Radiother Oncol. 110(1):9-15
2. Jensen S.B., et al. (2010). A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of life. Support Care Cancer. 18(8):1039-1060

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AAV2-hAQP1Mechanism of Action

• Acinar cells are particularly vulnerable to radiation treatment

• Acinar cell death and disorganization of gland epithelium following radiation results in hyposalivation

• Expression of the water channel, Aquaporin-1(hAQP1), via viral vector delivered locally into the salivary gland renders duct cells and surviving acinar cells permeable to water

• hAQP1 allows water to flow through the parotid ductal system and out to the oral cavity to moisten the mouth

Ionizing radiation causes irreversible damage to acinar cells, impairing saliva production

Expression of hAQP1 renders cells permeable to water and restores oral wetness

Damaged/		Duct: water
Dysfunctional		Impermeable
Acinus
	AAV2-hAQP1

hAQP1 Pore

Saliva Flow

Damaged/		Duct: water
Dysfunctional	Permeable
Acinus

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AQUAx: Phase 1 Clinical Study Design

• Open-label,multi-center,dose-escalation study (4 sites, US/Canada)
• One-timeadministration of AAV-hAQP1 to one (unilateral) or both (bilateral) parotid glands
• Four dose-escalating cohorts with 3 participants per cohort (n=12 for unilaterally treated and n=12 for bilaterally treated)
• All participants are followed for 1-yearpost-treatment and then invited to enroll in a long-termfollow-up study for a total of 5 years

Primary Endpoint

• Safety

Secondary Endpoints

• Patient reported measures of xerostomia symptoms
• • Xerostomia Questionnaire (XQ)
  • MD Anderson Symptom Inventory - Head and Neck
  • Global Rate of Change Questionnaire (GRCQ)
• Unstimulated whole saliva flow rate

Cohort	Dose
	Unilateral Treatment
1	1 × 1011 vg/gland
2	3 × 1011 vg/gland
3	1 × 1012 vg/gland
4	3 × 1012 vg/gland
	Bilateral Treatment
1b	3 × 1010 vg/gland
2b	1 × 1011 vg/gland
3b	3 × 1011 vg/gland
4b	1 x 1012 vg/gland

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AQUAx: Demographics and Baseline Characteristics

• 24 Participants
• 20 Male, 4 Female
• 23 White, 1 Black/African American
• Average Age: 63.5 years (range 48-79)
• 5+ years out from final radiotherapy treatment (2+ years for HPV+ tumors)
• Average baseline Total Xerostomia Questionnaire (XQ) Score: 46.7 (scale 0-80)
• Average baseline Dry Mouth (Question #10 of MDASI-HN) Score: 7.2 (scale 0-10)

AQUAx: Safety

• AAV2-hAQP1was safe and well-tolerated at all doses tested
• No treatment-related serious adverse events
• • 2 SAEs: obstructive airways disorder and coronary artery disease
  • Assessed by the investigator as not treatment- related
• No dose-limiting toxicities
• No participant discontinued from the study
• 6 mild, treatment-related,treatment-emergent adverse events (TEAEs)
• • All resolved without sequelae

Treatment-RelatedTreatment-Emergent Adverse Events in the AQUAx study

System Organ Class	All Participant
N=24
Preferred Term
N (%)
Participants with >1 treatment-related TEAE	6 (25.0)
Gastrointestinal disorders	2 (8.3)
Oral disorder	1 (4.2)
Salivary gland pain	1 (4.2)
General disorder and administration site	2 (8.3)
conditions	1 (4.2)
Chills	1 (4.2)
Fatigue
1 (4.2)
Injection site pain
Eye disorders	1 (4.2)
Eye disorder	1 (4.2)
Investigations	1 (4.2)
Amylase increased	1 (4.2)
Nervous system disorders	1 (4.2)
Dysgeusia	1 (4.2)

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AQUAx: Xerostomia Questionnaire1

• 8 symptom-specific questions which the participant answers using a scale from 0 (not present) to 10 (worst possible)
• Responses to individual questions are summed to provide the Total Score (0-80), an overall measure of disease burden
• An improvement (decrease) of 8 points or more in XQ Total Score is considered clinically meaningful2

Average Change in XQ Score

Average XQ score improved by 17 points (39.5%) at Month 12, with bilaterally treated participants reporting greater improvement than those treated unilaterally

16/24 (67%) participants reported an improvement of ≥8 points in the XQ Total Score at Month 12

1 Eisbruch A et al. Xerostomia and its predictors following parotid-sparing irradiation of head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2001 Jul 1;50(3):695-704

2 Jabbari S et al. Matched Case-Control Study of Quality of Life and Xerostomia after Intensity-Modulated Radiotherapy or Standard Radiotherapy for Head-and-Neck Cancer: Initial Report. Int. J. Radiat. Oncol. Biol. Phys. 2005;63:725-731

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AQUAx: MD Anderson Symptom Inventory Dry Mouth Question

• Question #10 from MD Anderson Symptom Inventory - Head and Neck1
• During the last 24 hours, please rate "Your dry mouth at its WORST"
• Scale from 0 (not present) to 10 (as bad as you can imagine)

Average Change in DM Score

Average Dry Mouth score improved by 2.7 points (42.2%) at Month 12, with bilaterally treated participants reporting greater improvement than those treated unilaterally

1Rosenthal DI et al. Measuring head and neck cancer symptom burden: the development and validation of the M. D. Anderson symptom inventory, head and neck module. Head Neck. 2007 Oct;29(10):923-31

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