Clinical Trials

Date: 2021-12-21

Type of information: Interim results

phase: I

Announcement: update

Company: Adverum Biotechnologies (USA - CA)

Product: ADVM-022

Action mechanism:

gene therapy. ADVM-022 utilizes a proprietary vector capsid (AAV.7m8) carrying an aflibercept coding sequence under the control of a proprietary expression cassette and is administered as a single intravitreal injection. Vascular endothelial growth factor (VEGF) activity is associated with wAMD progression and vision loss. Anti-VEGF standard-of-care therapies administered every 4-8 weeks have shown the potential to prevent disease progression and preserve or even improve patients’ vision. Treatment with ADVM-022 is designed to minimize the burden of frequent anti-VEGF injections, the current standard-of-care treatment for wAMD.

Disease: wet age-related macular degeneration (wet AMD)

Therapeutic area: Ophtalmological diseases

Country:

Trial details:

Latest news:

On December 21, 2021, Adverum Biotechnologies, a clinical-stage gene therapy company targeting unmet medical needs in ocular and rare diseases, announced the completion of a review of its ADVM-022 program, outlined plans for the next stage of development in wet age-related macular degeneration (wet AMD) and provided anticipated key milestones for 2022. Dr. Laurent Fischer, M.D., president and chief executive officer at Adverum Biotechnologies, stated: “We are pleased to conclude a thorough review of the totality of data generated in all 55 patients treated with ADVM-022, in wet AMD and diabetic macular edema, some of whom have been followed for over 2.5 years. The data analysis confirms our strategy to advance development of ADVM-022 in wet AMD. We intend to conduct a Phase 2 trial of ADVM-022 in wet AMD at 2 X 10^11 vg/eye dose and a new lower 6 X 10^10 vg/eye dose, with three new enhanced steroid prophylaxis regimens including topical, intravitreal and a combination of systemic and local steroids. Based on learnings from the OPTIC and INFINITY trials and extensive preclinical datasets, as well as the input and support of experts and members of our Scientific Advisory Board, we are confident in the plans we are sharing today to safely develop ADVM-022 in wet AMD, realizing the promise and full potential of our innovative gene therapy.”
Future Development of ADVM-022 for Wet AMD: Phase 2 Trial Design. Subject to regulatory review, Adverum is finalizing the design for a Phase 2 trial of ADVM-022 in wet AMD investigating the 2 X 10^11 (2E11) vg/eye dose and a lower 6 X 10^10 vg/eye (6E10) vg/eye dose, with three new enhanced steroid prophylaxis regimens, which the company anticipates will include a topical, intravitreal (IVT) and a combination of systemic and local steroids. The trial is expected to enroll approximately 72 patients and evaluate similar endpoints to the Phase 1 OPTIC trial in wet AMD. This study design is based on extensive analysis conducted by the company’s clinical development team and incorporates feedback from Adverum’s scientific advisory board and key retina, uveitis and gene therapy experts. IND Amendment. Adverum intends to file an investigational new drug (IND) amendment in the first half of 2022 and engage with the FDA with the aim of securing agreement on the Phase 2 trial design. The company anticipates completing this process by mid-2022. Phase 2 Initiation. Adverum is beginning preparations for the Phase 2 trial of ADVM-022 in wet AMD, with the intention of dosing the first patient in Q32022. Early feedback from potential Phase 2 investigators suggests completion of trial enrollment by year end 2022. Fully Resourced. Adverum reiterates its expectation that its cash position is sufficient to fund the company’s operations, including its development plans for ADVM-022, into 2024. Review of ADVM-022 Program: During the second half of 2021, Adverum undertook a comprehensive review of the company’s ADVM-022 program, including analysis of its preclinical and clinical data. The review solidified the following rationale underpinning the development strategy and Phase 2 study design outlined today for ADVM-022 in wet AMD:

Phase 1 Clinical Outcomes of ADVM-022 in Wet AMD: In October 2021, Adverum presented two-year follow-up data from its Phase 1 OPTIC study in wet AMD patients at the Retina Society’s 54^th Annual Scientific Meeting. The data presented demonstrated a greater than 80% reduction in annualized anti-VEGF injections following the 2E11 vg/eye ADVM-022 IVT injection that is expected to be validated in the Phase 2 study. ADVM-022 in wet AMD has been well tolerated and ocular inflammation was minimal and responsive to steroid eye drops. At latest visit, all 2E11 vg/eye patients were inflammation-free and none required any steroid eye drops to treat inflammation.
Underlying Pathology and Patient Characteristics: The INFINITY data in diabetic macular edema (DME) indicate that poorly controlled diabetes with presence of microvascular and macrovascular diabetic complications are important criteria in the identification of an appropriate patient population for ADVM-022, and these criteria have been considered in the proposed design of the Phase 2 trial in wet AMD.
Patient Safety Update: No clinically relevant reduction in intraocular pressure (IOP) was observed in the 2E11 vg/eye dose group in wet AMD or DME in either OPTIC or INFINITY trials, respectively. Additionally, in the OPTIC trial, clinically relevant IOP decreases were not observed at the 6 X 10^11 (6E11) vg/eye doses in wet AMD patients. No OPTIC patients with diabetes at both 6E11 and 2E11 in wet AMD, had clinically meaningful reduction in IOP.Adverum worked with its advisors and investigators to develop a treatment plan to halt progression to hypotony in DME patients who previously received the 6E11 vg/eye dose (a dose-limiting toxicity) in the INFINITY trial. While Adverum is no longer pursuing an indication in DME or continuing development of the 6E11 vg/eye dose in wet AMD, all patients who experienced hypotony in the 6E11 vg/eye dose in INFINITY have stabilized and the majority recovered a significant amount of vision following the treatment plan.
ADVM-022 Dosing: The company will evaluate a new lower dose of 6E10 vg/eye alongside the 2E11 vg/eye dose used in the OPTIC study. Adverum plans to submit data, including relevant non-human primate protein expression supporting the 6E10 vg/eye dose in humans, at an upcoming 2022 medical conference.Adverum also undertook an analysis of the impact of baseline neutralizing antibodies (NAbs) to AAV.7m8, the company’s novel capsid, on ADVM-022’s treatment benefit to potentially inform the planned Phase 2 trial design. Importantly, in OPTIC patients, the >80% reduction in annualized anti-VEGF injections observed at the 2E11 vg/eye dose further increased when patients with high NAbs were excluded. These data are expected to be submitted to a medical conference in 2022.
Enhanced Steroid Prophylaxis: Adverum, in consultation with experts in retina, uveitis and gene therapy, is pursuing three steroid prophylaxis regimens as part of the Phase 2 study with the goal of establishing a predictable and effective prophylaxis to administer with ADVM-022 IVT gene therapy. Subject to regulatory review, the steroid prophylaxis treatments under consideration includes a local topical steroid regimen that is longer in duration than in the OPTIC trial, a local-IVT steroid to facilitate patient adherence, and an oral systemic steroid in combination with a local steroid option.
On October 09, 2021, Adverum Biotechnologies, has presented data from the INFINITY clinical trial of ADVM-022 in patients with diabetic macular edema (DME) during the American Society of Retina Specialists (ASRS) 39^th Annual Scientific Meeting. INFINITY was a masked study in diabetic patients with DME initiated in May 2020, with cohorts evaluating two dose levels of ADVM-022 compared to a cohort with a single dose level of aflibercept. In early May 2021, the study was immediately unmasked to address patient safety and enhanced clinical management following an unexpected serious adverse event in a patient with DME treated at the high dose, presenting with hypotony, a rapid, clinically relevant decrease in intraocular pressure (IOP) with inflammation refractory to steroids and requiring surgical intervention. To date, two other patients required surgery and a total of five of the twelve patients treated with the high dose have experienced clinically relevant IOP events requiring additional immunosuppressive agents. All of these patients had a history of severe vascular and/or renal disease, and all events occurred 16-36 weeks post treatment. All patients in INFINITY have now been followed for a minimum of 36 weeks and no similar events have been seen in patients with DME treated at the low dose or in patients with wet AMD treated at either the high or low dose. INFINITY Trial Data in DME Patients Presented at ASRS In data being presented from the INFINITY trial (June 22, 2021, cutoff date, n=34) at ASRS, patients with DME were randomized to receive either a single, IVT injection of low 2 x 10^11 vg/eye dose of ADVM-022, high 6 x 10^11 vg/eye dose of ADVM-022, or aflibercept. The data presentation is posted on the Publications page of the Pipeline section of the company’s website. OPTIC Data in Wet AMD Patients 1-2 Years Post Treatment with ADVM-022 Last weekend, new long-term data from the OPTIC trial of ADVM-022 for wet AMD were presented at the Retina Society’s 54^th Annual Scientific Meeting on October 1, 2021. An encore presentation of OPTIC data is scheduled for 8:50 am CT (9:50 am ET) on Monday, October 11, 2021, at ASRS and Adverum plans to post the data presentation on the Publications page of the Pipeline section of the company’s website at or prior to the start of the presentation.
- Key Learnings: Data from the OPTIC trial (July 16, 2021 cutoff date, n=30) demonstrated in heavily treatment experienced patients that a single-IVT injection of ADVM-022 provides sustained durability, a greater than 80% reduction in the need for anti-VEGF and a promising safety profile.
  - Robust aflibercept expression and sustained efficacy providing CST stabilization observed
  - Low ADVM-022-related ocular adverse events occurred at the 2 x 10^11 vg/eye dose
  - No clinically relevant low IOP events observed in either dose
  - These results warrant further studies of ADVM-022 in wet AMD, including evaluation of low doses (2 x 10^11 vg/eye and lower) and enhanced prophylaxis
  - Long-term data from OPTIC and future studies may validate the importance of ADVM-022 in minimizing long-term fluctuations in CST
Key Learnings: ADVM-022 dose and disease state appear to have an impact in determining the therapeutic window which balances efficacy and safety:
- Dose-dependent inflammation observed in DME patients with dose-limiting toxicity at 6 x 10^11 vg/eye may be in part related to the study population which included patients with severe vascular and renal disease
- No clinically relevant reduction in IOP was observed in the 2 x 10^11 vg/eye group
- Further ADVM-022 development will focus on wet AMD and low doses (2 x 10^11 vg/eye and lower)

• On May 17, 2018, Adverum Biotechnologies announced the presentation of additional long-term efficacy data from a preclinical study of ADVM-022 in wet age-related macular degeneration (wAMD) in a poster session at the ASGCT 21st Annual Meeting in Chicago.
After 13 months, a single intravitreal injection of ADVM-022 was found to be safe and statistically significant (p<0.0001) in preventing the development of Grade IV lesions compared to the vehicle control group. The efficacy at 13 months was consistent with earlier-reported data, demonstrating that ADVM-022 induced long-term efficacy that was comparable to aflibercept, an anti-Vascular Endothelial Growth Factor (VEGF) standard-of-care therapy. Additionally, mean CNV complex areas were significantly smaller (p<0.0001) in the ADVM-022 and aflibercept groups, compared with vehicle, when analyzed by spectral domain optical coherence tomography (SD-OCT).
ADVM-022 induced sustained intraocular expression of aflibercept for up to 16 months following a single intravitreal injection. Robust levels of aflibercept protein were detected up to 16 months in aqueous and vitreous humor and, more importantly, in retina and choroid tissues, where neovascularization occurs in wAMD.
A separate pharmacokinetics study revealed that levels of vector-derived aflibercept measured in the vitreous and the retina 56 days post ADVM-022 injection match the levels of aflibercept recombinant protein 3-4 weeks post bolus of protein injection, which is well within the therapeutic window of the standard of care. In addition, the levels of vector-derived aflibercept at 56 days were consistent with those observed in the long-term efficacy study at 16 months. Taken together, these data suggest that a single injection of ADVM-022 administered intravitreally can generate stable levels of aflibercept found to be within the therapeutic window of the standard-of-care recombinant protein.
ADVM-022 was well tolerated, with no serious adverse events. ADVM-022 had mild effects on aqueous and vitreous cell infiltrates, keratic precipitates, and intraocular pressure (IOP). Treatment-related side effects were limited to mild inflammatory responses and related transient IOP decrease. Longitudinal OCT studies, fundoscopy, and fluorescein angiography did not identify changes in retinal morphology, optic nerve head and vascular integrity.

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