Adverum Provides Update on ADVM-022 and the INFINITY Trial in Patients with Diabetic Macular Edema

— Based on latest analyses, company is revising ADVM-022 development plan to focus on wet AMD and low doses (2 x 10^11 vg/eye and lower); no longer planning development for DME —

— Company to host conference call and webcast today at 1:30 pm PT / 4:30 pm ET —

REDWOOD CITY, Calif., July 22, 2021 (GLOBE NEWSWIRE) — Adverum Biotechnologies, Inc. (Nasdaq: ADVM), a clinical-stage gene therapy company targeting unmet medical needs in ocular and rare diseases, today provided an update on the ADVM-022 development program following a thorough review of data available from the INFINITY clinical trial in patients with diabetic macular edema (DME) and the OPTIC clinical trial in patients with wet age-related macular degeneration (wet AMD). The data from the studies show marked differences in the safety profile between the two patient populations and between the low (2 x 10^11 vg/eye) versus high (6 x 10^11 vg/eye) doses. Adverum no longer plans future development for DME after a dose-limiting toxicity (DLT) not seen before in ocular gene therapy or anti-VEGF treatment has been observed at the high dose (6 x 10^11 vg/eye) in patients with DME. The company is planning to evaluate ADVM-022, a single intravitreal (IVT) injection gene therapy, at low doses (2 x 10^11 vg/eye and lower) and with alternative prophylactic regimens in a future Phase 2 clinical trial in wet AMD.

Wet AMD and DME have different pathophysiological causes with different risk factors. While the root cause of the DLT is not yet known, diabetic patients with DME typically have multiple underlying comorbidities, such as severe vascular disease, which can contribute to inflammatory factors that may induce an increase in vascular permeability and disrupt the blood-ocular barrier in DME patients.ⁱ

As disclosed in late April 2021, Adverum immediately unmasked INFINITY and began closely monitoring all patients treated to date with ADVM-022 following a Suspected Unexpected Serious Adverse Reaction (SUSAR) of hypotony in the treated eye of a patient with DME who received a single high dose of ADVM-022. Additional patients in INFINITY treated with a single high dose of ADVM-022 have, despite close monitoring and aggressive treatment, experienced adverse events that have included rapid, clinically-relevant decreases in intraocular pressure refractory to steroids and requiring subsequent additional treatment. These events occurred 16-36 weeks after treatment with the high dose. No similar clinically-relevant events have been observed to date in DME patients in INFINITY treated with the low dose or to date in any wet AMD patients in OPTIC treated at either the high or low dose. The company is closely managing patient care working with the data monitoring committee (DMC), its scientific advisory board (SAB), leading retina specialists, and investigators. All clinical trial sites and the U.S. Food and Drug Administration (FDA) have been advised of these cases.

“Our primary focus remains patient safety,” said Laurent Fischer, M.D., president and chief executive officer at Adverum Biotechnologies. “We deeply appreciate the continued expertise shared by the DMC, the SAB, retina specialists, and investigators to guide best patient care decisions. Gene therapy is a new and very promising, yet challenging field, as we work to develop durable treatments for patients. Our team is grateful for all of the patients and investigators participating in our clinical studies for their critical roles as we strive to shift the treatment paradigm through developing a one-time intravitreal gene therapy for patients.”

Dr. Fischer continued, “Based on an ongoing, thorough review of the clinical and non-clinical data for ADVM-022, we are planning future development for wet AMD and we no longer plan to pursue DME. The data show marked differences for ADVM-022 in patients with wet AMD versus DME. Our fully dedicated team and expert advisors are working relentlessly to better understand the root cause of the events experienced by certain high-dose patients in INFINITY and potential risk factors in these patients with DME. Following completion of our analysis and discussions with advisors and regulators, we are planning a Phase 2 clinical trial in wet AMD patients to explore additional low doses with alternative prophylactic regimens to support the best possible path for delivering ADVM-022 safely to patients.”

“Working collectively, the DMC, SAB, investigators, leading specialists, and Adverum have taken swift action to assess and provide the best care to patients,” said Szilárd Kiss, M.D., Associate Professor in Ophthalmology and member of Adverum’s Scientific Advisory Board. “In unmasking INFINITY, the company has taken the right steps immediately to share findings real-time and ensure investigators can closely monitor patients and manage patient safety. Dose finding has been a challenge for the field of gene therapy, and while AAV remains a very safe delivery system, we should expect as with any biologic product that unexpected dose-limiting toxicities may be encountered. It is important to learn from the data generated by this field to bring new treatments with durable efficacy and well-managed safety to patients.”

Long-term data from the OPTIC trial (n=30) of ADVM-022 for wet AMD have demonstrated long-term durability and maintained efficacy following a single, in-office IVT injection. Safety and efficacy data presented at the Association for Research in Vision and Ophthalmology (ARVO) in April 2021 showed 60% of patients were injection-free beyond one year and patients had an 85% reduction in annualized injection frequency following a single low dose (n=15). The company plans to present additional long-term data at a medical conference in the fall of 2021.

The company plans to report financial results for the second quarter 2021 on August 5, 2021 after market close and remains well capitalized to execute on its priorities.

Recent Developments

• Adverum no longer plans future development of ADVM-022 for DME.
• Data from the ADVM-022 program show marked differences in the safety profile between the AMD and DME patient populations and between the low (2 x 10^11 vg/eye) versus high (6 x 10^11 vg/eye) dose. Some patients in INFINITY treated with a single high dose of ADVM-022 have experienced adverse events, despite close monitoring and aggressive treatment, that have included rapid, clinically-relevant decreases in intraocular pressure refractory to steroids and requiring subsequent additional treatment.
  • In OPTIC (n=30) in wet AMD, Adverum has requested that all patients be evaluated in person by investigators to receive additional monitoring. Their clinical data have been reviewed following the INFINITY SUSAR. No similar clinically-relevant events have been observed to date post treatment with either the high or low dose in OPTIC. Patients in OPTIC have reached a follow up period of between 52 weeks and 2.5 years post treatment.
  • In INFINITY (n=34) in DME, all patients are being monitored closely. No similar clinically-relevant events have been observed to date in patients treated with the low dose (n=13). For patients treated with the high dose (n=12), aggressive immunomodulatory regimens are being recommended to mitigate potential risk. To date, five of these twelve patients treated with the high dose have experienced similar clinically-relevant events. All of these patients had a history of severe vascular disease, and all events occurred 16-36 weeks post treatment. Three of these patients to date have required surgery on the treated eye. The remaining high-dose patients are being assessed and monitored closely by leading experts. All patients in INFINITY are out a minimum of 24 weeks post treatment.
  • As previously reported, in April 2021 a SUSAR of hypotony occurred in a patient in the INFINITY trial in DME 30 weeks after treatment with a single IVT injection of high dose ADVM-022. The patient has been evaluated and treated by leading experts and, at present, some ocular pressure and some vision have been restored in the patient’s treated eye.
  • Adverum continues to assess and monitor all patients treated with ADVM-022 and to conduct a thorough review of all patient data from INFINITY and OPTIC (n=64) and preclinical data. Working closely with the DMC, SAB, investigators, and leading retina specialists, Adverum continues to investigate the root cause, using rigorous analyses and state-of-the-art technologies to make data-driven decisions on prophylactic regimens and treatment.

Anticipated Milestones for ADVM-022:

• Plan to present long-term OPTIC data in wet AMD in 2H21, including 52-week data from Cohort 4 (high dose of 6 x 10^11 vg/eye with steroid eye drop prophylaxis, n=9), at a medical conference
• Plan to present INFINITY data in DME in 2H21 at a medical conference
• Plan to complete data analysis by YE21 to develop a protocol and seek investigator and regulatory feedback on a Phase 2 clinical trial in wet AMD to evaluate low doses (2 x 10^11 vg/eye and lower) of ADVM-022 and alternative prophylactic regimens

Conference Call Today
Adverum will host a conference call and webcast today at 1:30 pm PT / 4:30 pm ET to provide an update on the ADVM-022 development program. The live webcast will be accessible under Events and Presentations in the Investors section of the company’s website. To participate in the conference call, dial 1-877-705-6003 (domestic) or 1-201-493-6725 (international) and reference Adverum conference call and webcast. Due to high call volume, it is recommended call participants dial in 15 minutes in advance. The archived audio webcast will be available on the Adverum website following the call and will be available for 30 days.

About the OPTIC Trial of ADVM-022 in Wet AMD
This multi-center, open-label, Phase 1, dose-ranging trial was designed to assess the safety and tolerability of a single intravitreal (IVT) administration of ADVM-022 in patients with wet AMD who are responsive to anti-vascular endothelial growth factor (VEGF) treatment. Wet AMD is a leading cause of vision loss in patients over 60 years of age, with a prevalence of approximately 1.2 million individuals in the U.S. and 3 million worldwide.

In Cohort 1 (n=6) and Cohort 4 (n=9), patients received a high dose (6 x 10^11 vg/eye) and in Cohort 2 (n=6) and Cohort 3 (n=9), patients received a low dose (2 x 10^11 vg/eye) of ADVM-022. Patients in Cohorts 3 and 4 received six weeks of prophylactic steroid eye drops rather than 13 days of prophylactic oral steroids which were used in Cohorts 1 and 2. The primary endpoint of the trial is the safety and tolerability of ADVM-022 after a single IVT administration. Secondary endpoints include changes in best-corrected visual acuity (BCVA), measurement of central retinal thickness (CRT) and the need for supplemental anti-VEGF injections. Each patient enrolled is being followed for a total of two years with the option to enroll in an extension study for an additional 3 years. For additional information about the OPTIC trial, please visit https://clinicaltrials.gov/ct2/show/NCT03748784 and for information about the long-term extension study, please visit https://clinicaltrials.gov/ct2/show/NCT04645212.

About the INFINITY Trial of ADVM-022 in DME
INFINITY is a Phase 2, multi-center, randomized, double-masked, active comparator-controlled trial designed to assess a single intravitreal (IVT) injection of ADVM-022 in patients with diabetic macular edema (DME), the most common cause of vision loss in patients with diabetic retinopathy (DR).

The INFINITY trial enrolled 36 patients and was designed to demonstrate superior control of disease activity following a single IVT injection of ADVM-022 compared to a single aflibercept injection, as measured by time to worsening of DME disease activity. Participants in this double-masked trial were randomized to one of three arms for their study eye treatment: Arm 1 received high dose (6 x 10^11 vg/eye) of ADVM-022, Arm 2 received low dose (2 x 10^11 vg/eye) of ADVM-022, and Arm 3 received aflibercept at a dose of 2 mg. Patients assigned to receive ADVM-022 were further randomized to receive either a preceding aflibercept or sham ocular injection. Additional objectives include assessments of treatment burden, visual acuity, retinal anatomy, and safety outcomes. For additional information about the INFINITY trial, please visit www.clinicaltrials.gov using Identifier NCT#04418427. 

About ADVM-022 Gene Therapy
ADVM-022 utilizes Adverum’s propriety vector capsid, AAV.7m8, carrying an optimized aflibercept coding sequence under the control of a proprietary expression cassette. ADVM-022 is administered as a one-time intravitreal (IVT) injection, designed to deliver long-term efficacy, reduce the burden of frequent anti-VEGF injections, and improve real-world vision outcomes for patients with wet age-related macular degeneration (wet AMD). In recognition of the need for new treatment options for wet AMD, the U.S. Food and Drug Administration granted Fast Track designation to ADVM-022 for the treatment of wet AMD.

About Adverum Biotechnologies
Adverum Biotechnologies (Nasdaq: ADVM) is a clinical-stage gene therapy company targeting unmet medical needs in serious ocular and rare diseases. Adverum is evaluating its novel gene therapy candidate, ADVM-022, as a one-time, intravitreal injection for the treatment of patients with wet age-related macular degeneration. For more information, please visit www.adverum.com.

Forward-looking Statements
Statements contained in this press release regarding the events or results that may occur in the future are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements include but are not limited to statements: in Dr. Fischer’s quote regarding Adverum planning future development for wet AMD and no longer planning to pursue DME; that Adverum is planning a Phase 2 clinical trial in wet AMD patients to explore additional low doses with alternative prophylactic regimens to support the best possible path for delivering ADVM-022 safely to patients; and under the caption “Anticipated Milestones for ADVM-022.” Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include risks inherent to, without limitation: Adverum’s novel technology, which makes it difficult to predict the time and cost of product candidate development and obtaining regulatory approval; the results of early clinical trials not always being predictive of future results; and the potential for additional SUSARs or adverse events, or any future complications or side effects in connection with use of ADVM-022 to delay or prevent regulatory advancement or approval for ADVM-022. Risks and uncertainties facing Adverum are described more fully in Adverum’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2021, and any subsequent filings with the SEC, especially under the heading “Risk Factors.” All forward-looking statements contained in this press release speak only as of the date on which they were made. Adverum undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

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ⁱ Noma H, Mimura T, Yasuda K, Shimura M: Role of Inflammation in Diabetic Macular Edema. Ophthalmologica 2014;232:127-135. doi: 10.1159/000364955