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 TodayAdverum 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
AMDThis 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
DMEINFINITY 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 TherapyADVM-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 BiotechnologiesAdverum
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.
______________________
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
Investor Inquiries
Amy Figueroa, CFA
Vice President, Investor Relations and Corporate Communications
Adverum
E: afigueroa@adverum.com
T: 650- 649-1257
Media Inquiries
Chantal Allan
Sam Brown Inc.
E: chantalallan@sambrown.com
T: 805-242-3080
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