IVERIC bio Profile
IVERIC bio, Inc. operates as a science-driven biopharmaceutical company.
The company focuses on the discovery and development of novel treatments for retinal diseases with significant unmet medical needs. The company is committed to having a positive impact on patients’ lives by delivering high-quality, safe and effective treatments designed to address debilitating retinal diseases, including earlier stages of age-related macular degeneration, or AMD.
The company’s lead asset is its clinical stage product candidate avacincaptad pegol, which is also referred to as ACP or Zimura, a complement C5 inhibitor. In October 2019, the company announced positive 12-month data for GATHER1, its first Phase 3 clinical trial evaluating ACP for the treatment of GA secondary to AMD.
In June 2020, the company started enrolling patients in GATHER2, its second Phase 3 clinical trial evaluating ACP for the treatment of GA secondary to AMD. In July 2021, the company received a written agreement from the FDA under the SPA for the overall design of GATHER2. The SPA is a procedure by which the FDA provides a clinical trial sponsor with an official evaluation and written guidance on the design of a proposed protocol intended to form the basis for a new drug application, or NDA. In connection with the company’s SPA, the FDA recommended, and it accepted, modifying the primary efficacy endpoint for the GATHER2 trial from the mean rate of change in GA area over 12 months measured by fundus autofluorescence, or FAF, at three timepoints: baseline, month 6 and month 12, to the mean rate of growth (slope) estimated based on GA area measured by FAF in at least three timepoints: baseline, month 6 and month 12.
In February 2023, the FDA accepted the company’s NDA for filing and granted priority review with a Prescription Drug User Fee Act, or PDUFA, target action date of August 19, 2023. In addition to ACP, the company is developing its preclinical product candidate IC-500, a high temperature requirement A serine peptidase 1 protein, or HtrA1, inhibitor, for GA secondary to AMD and potentially other age-related retinal diseases. Based on current timelines and subject to successful preclinical development and current good manufacturing practices, or cGMP, manufacturing, the company expects to submit an investigational new drug application, or IND, to the U.S. Food and Drug Administration (FDA) for IC-500 during the first half of 2024.
The company’s portfolio also includes several ongoing gene therapy research programs, each of which uses adeno-associated virus, or AAV, for gene delivery.
In September 2022, the company announced positive 12-month data from the GATHER2 trial. It achieved a 12-month injection fidelity rate of 92.5% for the GATHER2 trial.
In November 2022, the FDA granted breakthrough therapy designation for ACP for the treatment of GA secondary to AMD.
In December 2022, the company completed the rolling submission of its NDA to the FDA for marketing approval of ACP for the treatment of GA secondary to AMD.
In June 2022, the company entered into an exclusive license agreement with DelSiTech Ltd., or DelSiTech, for worldwide development and commercialization rights to its silica based sustained release delivery technology for use with ACP.
Avacincaptad pegol (ACP)
The company is developing its product candidate ACP, a C5 complement inhibitor, for the treatment of Geographic Atrophy (GA) and autosomal recessive Stargardt disease (STGD1). ACP is a chemically synthesized, pegylated RNA aptamer. Aptamers are short molecules made up of a single stranded nucleic acid sequence or an amino acid sequence. The specific three-dimensional structure of an aptamer, which results from its specific sequence, allows it to bind molecular targets with high selectivity and specificity. ACP is a pegylated aptamer, which means that polyethylene glycol, or PEG, a common biochemical compound attached to drugs to increase their duration of action in the human body and to decrease immune response, is linked to the chemically synthesized strand of RNA.
ACP Clinical Programs
The following is a brief description of the completed GATHER1 trial and the ongoing GATHER2 and STAR trials and the open label extension study, and their current status:
GATHER1 (also known as OPH2003; GA secondary to AMD - completed): an international, randomized, double-masked, sham controlled, multi-center Phase 2/3 clinical trial evaluating the safety and efficacy of ACP for the treatment of GA secondary to AMD. In October 2019, the company announced positive 12-month data from this trial and in June 2020, it completed this trial and announced 18-month data from this trial, which supported the 12-month data.
GATHER2 (also known as ISEE2008; GA secondary to AMD - ongoing): an international, randomized, double-masked, sham controlled, multi-center Phase 3 clinical trial evaluating the safety and efficacy of ACP for the treatment of GA secondary to AMD. As agreed to with the FDA in connection with the special protocol assessment (SPA), the primary efficacy endpoint is the mean rate of growth (slope) estimated based on GA area measured by FAF in at least three timepoints: baseline, month 6 and month 12. In September 2022, the company announced positive 12-month data from this trial.
ISEE2009 (also known as the OLE study; open label extension study - ongoing): an international, open label, multicenter study evaluating the safety of ACP 2 mg for patients who completed their month 24 visits in the GATHER2 trial.
STAR (also known as OPH2005; STGD1 - ongoing): an international, randomized, double-masked, sham controlled, multi-center Phase 2b clinical trial evaluating the safety and efficacy of ACP for the treatment of STGD1.
In addition to the GATHER1 trial, the company has completed multiple clinical trials evaluating various doses of ACP in age-related retinal diseases, including:
OPH2001, a Phase 1/2a clinical trial of various doses of ACP for the treatment of GA, with a total of 47 patients enrolled;
OPH2000: a Phase 1/2a clinical trial of various doses of ACP administered in combination with Lucentis (ranibizumab), an anti-vascular endothelial growth factor, or anti-VEGF, agent, for the treatment of wet AMD, with a total of 60 patients enrolled;
OPH2007, a Phase 2a clinical trial of various doses of ACP administered in combination with Lucentis for the treatment of wet AMD, with a total of 64 patients enrolled and treated; and
OPH2002: a very small Phase 2a clinical trial of ACP in combination with anti-VEGF agents for the treatment of idiopathic polypoidal choroidal vasculopathy, or IPCV, in patients for whom anti-VEGF monotherapy had failed.
In the company’s clinical trials, the intraocular pressure (IOP) is monitored before and after each intravitreal injection. Certain of the dosing regimens the company is evaluating in STAR involve multiple intravitreal injections administered on the same day. Based on the company’s clinical experience, it has not seen any meaningful or sustained increase in IOP in clinical trials involving multiple intravitreal injections on the same day, and multiple intravitreal injections likely could be delivered safely on the same day.
As of December 31, 2022, the company’s ACP clinical experience was described as follows.
ACP - GA Trials
GATHER1: Completed Clinical Trial Assessing the Safety and Efficacy of Various Doses of ACP for GA Secondary to AMD
In October 2019, the company announced 12-month data from the GATHER1 trial and in June 2020, it completed and announced 18-month data from this trial. Following the conclusion of the trial, the company has continued to review and analyze the unmasked, individual patient data from this trial.
GATHER2: Ongoing Phase 3 Clinical Trial Assessing Safety and Efficacy of ACP 2 mg for GA Secondary to AMD
In September 2022, the company announced positive 12-month data from the GATHER2 trial.
Post-Hoc Time-to-Event Analysis from GATHER1 and GATHER2
The company conducted an exploratory time-to-event analysis from the GATHER1 and GATHER2 clinical trials evaluating reduction in vision loss with ACP 2 mg versus sham treatment. The post-hoc analysis for vision loss from these pivotal trials signals up to a 59% reduction in rate of vision loss with ACP 2 mg compared to sham treatment at 12 months. Vision loss in this analysis was defined as a loss of greater than or equal to 15 letters (EDTRS) in BCVA from baseline measured at any two consecutive visits up to month 12.
ISEE2009: Open Label Extension Study for Patients Who Completed the GATHER2 Trial
In September 2022, the company initiated an open-label extension study, or the OLE study, which is an international, multi-center clinical trial assessing the safety of intravitreal administration of ACP in patients who completed their month 24 visits in the GATHER2 trial. The trial will continue until each patient has completed their month 18 study visit or until ACP is commercially available in the relevant jurisdiction.
OPH2001: Completed Phase 1/2a Clinical Trial of ACP for GA Secondary to Dry AMD
In 2011, the company completed a multicenter, uncontrolled, open label Phase 1/2a clinical trial to evaluate the safety and tolerability of ACP administered as a monotherapy in patients with GA.
Regulatory Pathway for Marketing Approval of ACP in GA secondary to AMD
To obtain marketing approval of ACP for the treatment of GA secondary to AMD, the company expects that it will need favorable results from a total of two independent, adequate and well-controlled pivotal clinical trials, demonstrating the safety and efficacy of ACP in this indication.
FDA Requirements and Status
Based on the company’s interactions with the FDA, it would be sufficient to establish efficacy by showing statistically significant results on the primary efficacy endpoint in the GATHER1 and GATHER2 trials, which is based on measuring GA area growth using FAF. The FDA required analysis for the primary efficacy endpoint is the mean rate of growth (slope) estimated based on GA area measured by FAF over at least three timepoints: baseline, month 6, and month 12. Both GATHER1 and GATHER2 demonstrated a statistically significant reduction in the mean rate of GA area growth (slope) compared to sham when analyzed using the FDA's required analysis.
The company plans to provide additional supportive safety data from its other completed and ongoing trials of ACP in patients with GA, wet AMD, IPCV and STGD1.
The company has had a number of interactions with the FDA on its development and regulatory pathway for ACP in GA secondary to AMD, including:
In July 2021, the company obtained a SPA from the FDA for the overall design of GATHER2. Based on the information it submitted, the FDA determined that the design and planned analysis of GATHER2 adequately addressed the objectives necessary to support a future regulatory submission.
Over 2021 and 2022, the company had a number of additional interactions with the FDA on the requirements for and the content of its planned NDA of ACP for the treatment of GA secondary to AMD, which clarified its regulatory pathway in this indication.
In November 2022, the FDA granted breakthrough therapy designation for ACP for GA secondary to AMD based on the 12-month results from GATHER1 and GATHER2.
In December 2022, the company completed rolling submission of the NDA for ACP for the treatment of GA secondary to AMD, with the clinical and non-clinical portions of the NDA submitted in November 2022 and the chemistry, manufacturing and controls portion of the NDA submitted in December 2022.
In February 2023, the FDA accepted the NDA for filing and granted the company priority review with a PDUFA target action date of August 19, 2023. The FDA indicated in their acceptance letter that, as of the time of the FDA acceptance letter, they did not identify any potential review issues and were not planning an Advisory Committee meeting for ACP.
EMA and The Medicines and Healthcare Products Regulatory Agency (MHRA) Requirements and Plans
The company plans to submit MAAs (marketing authorization applications) to the European Medicines Agency (EMA) and the MHRA for marketing approval of ACP for the treatment of GA secondary to AMD during 2023, following its planned interactions with regulatory authorities in Europe.
ACP - Potential Pathway in Intermediate AMD
Post-hoc Analyses of GATHER1 Data in Drusen, iRORA and cRORA
The company conducted additional post-hoc analyses on the GATHER1 data, in which it evaluated the progression of iRORA to cRORA, and the progression of drusen to iRORA or cRORA, in patients treated with ACP 2 mg as compared to patients in the corresponding sham group. Drusen, iRORA and cRORA represent progressive stages of AMD.
Plans in Intermediate AMD
As previously disclosed, the company was encouraged by the results of the above post-hoc analyses of the GATHER1 data and was planning to initiate a clinical trial evaluating ACP for the treatment of intermediate AMD, subject to feedback from the FDA and other regulatory authorities. In September 2022, the company obtained favorable feedback from the FDA on its development plans. The company is continuing further discussions with the FDA on using the GATHER1 and GATHER2 clinical trial data included in the NDA submission to support treatment of GA associated with earlier stage disease, including in patients with intermediate AMD.
ACP - STGD1 Trials
STAR: Ongoing Phase 2b Clinical Trial of ACP for STGD1
The company initially completed patient enrollment for this clinical trial in February 2019 with a total of 95 patients enrolled, none of whom have any remaining study visits. In July 2020, the company reopened enrollment in this trial in the United States. The company continues to enroll patients and plan to enroll approximately 25 additional patients, with the goal of enrolling a total of approximately 120 patients.
As STGD1 is an orphan indication, to its knowledge there is only very limited natural history data available regarding the variability of the planned primary efficacy endpoint in the STGD1 patient population it enrolled in this trial. Similar to GATHER1, STAR is designed to be a Phase 2b screening trial, with the potential to demonstrate statistically significant results depending on the magnitude of the potential benefit observed.
ACP - Wet AMD Trials
OPH2000: Completed Phase 1/2a Clinical Trial of ACP for Wet AMD
In 2009, the company completed a multicenter, uncontrolled, ascending dose and parallel group, open-label, first in human Phase 1/2a clinical trial to evaluate the safety and tolerability of multiple intravitreal injections of ACP.
The company’s Phase 1/2a clinical trial was an uncontrolled study with a small sample size and was not powered to detect a difference between ACP dose groups or the efficacy of ACP combination therapy with statistical significance. The primary purpose of the study was to assess safety and tolerability. In addition to the company’s safety assessment, however, it also performed assessments of visual acuity. There was a general trend towards an improvement in visual acuity seen in all treatment groups. The company focused its assessment of vision outcomes on the subgroup of 43 treatment-naïve patients who had received all six ACP injections at the same dosage. The company observed a mean increase in visual acuity from baseline at all time points for these patients, based on the number of Early Treatment of Diabetic Retinopathy Study (ETDRS) letters the patient could read.
OPH2007: Completed Phase 2a Clinical Trial of ACP for the Treatment of-Naïve Wet AMD Patients
In 2018, the company completed a randomized, dose-ranging, open-label, multi-center Phase 2a clinical trial of ACP to evaluate the safety of different dosing regimens of ACP in combination with an anti-VEGF agent in treating wet AMD. The company’s Phase 2a clinical trial was an uncontrolled trial with a small sample size designed to assess safety at different dosages and to detect a potential efficacy signal.
ACP - IPCV Trials
OPH2002: Completed Phase 2a Clinical Trial of ACP for IPCV
In late 2014, the company initiated a very small, uncontrolled, open-label, Phase 2a clinical trial to evaluate ACP’s potential role when administered in combination with anti-VEGF agents for the treatment of IPCV in treatment-experienced patients for whom anti-VEGF monotherapy failed. IPCV is an age-related disease that is similar to wet AMD and is commonly characterized by leakage under the RPE, subretinal hemorrhage and retinal pigment epithelium (RPE) detachment. The company enrolled four patients in the trial. None of the patients had a greater than 15-ETDRS letter decrease in visual acuity, which is considered a significant loss in visual acuity, following treatment in this study. None of the patients experienced any drug-related adverse events and there were no unexpected safety issues from this trial.
IC-500: HtrA1 Inhibitor Product Candidate
In October 2018, the company acquired from funds controlled by Versant Ventures a number of HtrA1 inhibitors. In previous experiments conducted before the acquisition, these HtrA1 inhibitors showed high affinity and specificity for HtrA1 when tested in vitro. In 2020, the company selected the lead compound from this group of HtrA1 inhibitors, which it calls IC-500, for preclinical development. The company is developing IC-500 for the treatment of GA and evaluating HtrA1 inhibition as a potential treatment for other stages of AMD and potentially other age-related retinal diseases.
The company is continuing the preclinical development of IC-500. It has developed a formulation that will be safe and effective for intravitreal administration into the eye, and is conducting cGMP manufacturing activities for IC-500. The company is conducting additional preclinical studies to optimize the dosage, delivery and formulation of IC-500, and planning for IND-enabling toxicology studies to start later in 2023. Based on current timelines and subject to successful preclinical development and cGMP manufacturing, it expects to submit an IND to the FDA for IC-500 during the first half of 2024.
Gene Therapy Research and Development Programs
The company continues to advance its minigene research programs for LCA10, STGD1 and USH2A, respectively. The company describes below the December 2022 transaction in which Opus acquired all of its rights, title and interests in and to its assets primarily related to its former gene therapy product candidates IC-100 and IC-200, which it previously developed for rhodopsin-mediated autosomal dominant retinitis pigmentosa and BEST1-related orphan inherited retinal diseases (IRDs), respectively.
Gene Therapy Products and AAV Vectors
The company is focused on AAV gene therapies, as AAV vectors have generally been found to transduce RPE, photoreceptors and other retinal cells at a high rate, and their safety profile in humans is relatively well-documented as compared to other delivery vehicles, such as lentiviral vectors. There are several naturally-occurring serotypes of AAV, including AAV2, AAV5, AAV8 and AAV9, as well as countless synthetic AAV serotypes. One of the primary limitations with AAV gene therapy is AAV's packaging capacity: an AAV vector can hold only up to approximately 4,700 base pairs of DNA, whereas the genes associated with a number of monogenic IRDs, such as the CEP290 gene associated with LCA10 and the ABCA4 gene associated with STGD1, exceed that size. The company’s gene therapy programs use AAV vectors for delivery of the genetic cargo to cells within the retina.
Minigene Programs
Starting in 2018, the company funded several sponsored research programs at the University of Massachusetts Medical School, or UMMS, seeking to use a minigene approach to develop new gene therapies for several orphan IRDs. These programs (miniCEP290, miniABCA4 and miniUSH2A) are described as follows.
miniCEP290 Program for LCA10
The company’s miniCEP290 program is targeting LCA10, which is associated with mutations in the CEP290 gene. The naturally occurring CEP290 gene is approximately 8,000 base pairs. In a 2018 publication in Human Gene Therapy, researchers at UMMS presented their findings that injection of a CEP290 minigene into a newborn mouse model for LCA10 resulted in rescue of photoreceptor cells, as evidenced by both anatomical and functional measures.
The company was encouraged by the results of the sponsored research. One of the new minigene constructs shows five times longer duration of functional rescue of the photoreceptors as compared to what was observed in the 2018 publication. In July 2019, the company entered into a license agreement with the University of Massachusetts, or UMass, for exclusive development and commercialization rights to this program. UMMS continued experiments to optimize the constructs, which were delayed during 2020 because of restrictions placed by UMMS on animal research activities as a result of the COVID-19 pandemic. The company has identified a lead construct from this program and is considering preclinical development options.
miniABCA4 Program for STGD1
The company’s miniABCA4 program is targeting STGD1, which is associated with mutations in the ABCA4 gene. The size of the naturally occurring ABCA4 gene is approximately 7,000 base pairs. As part of the sponsored research, UMMS generated and evaluated several ABCA4 minigene constructs in both in vitro and in vivo experiments, which yielded to be encouraging results. The company conducted additional experiments to optimize the constructs and assess their efficacy in the mouse model. The company has identified a lead construct from this program and are considering preclinical development options. UMMS granted the company an option to obtain an exclusive license to certain patent applications for this program.
miniUSH2A Program for USH2A-Related IRDs
The miniUSH2A program seeks to develop a mutation independent, minigene therapy for the vision loss associated with USH2A mutations, including vision loss associated with Usher 2A and USH2A-associated nonsyndromic autosomal recessive retinitis pigmentosa. Some of the activities in this program were delayed during 2020 as a result of the closure of UMMS animal research laboratories due to the COVID-19 pandemic. UMMS generated and evaluated several USH2A minigene constructs in in vitro experiments and the company is planning to evaluate their efficacy in animals. The animal experiments were delayed as a result of transitioning the work from UMMS to the company. The company is considering its next steps for this research program. UMMS granted the company an option to obtain an exclusive license to certain patent applications for this program.
Opus Asset Purchase Agreement
As part of the company’s previously stated strategy to seek a licensee for IC-100 and IC-200, in December 2022, IVERIC bio Gene Therapy LLC, or the Iveric Subsidiary, the company’s wholly owned subsidiary, entered into an asset purchase agreement with Opus, or the Opus APA, pursuant to which Opus acquired all rights, title and interests in and to Iveric Subsidiary's assets primarily related to IC-100 and IC-200, including Iveric Subsidiary's exclusive license agreements with the University of Florida Research Foundation, Incorporated, or UFRF, and the Trustees of the University of Pennsylvania, or Penn, for both product candidates and certain related sponsored research agreements.
The Opus APA also contains customary representations, warranties, covenants and indemnification obligations made by Iveric Subsidiary and Opus.
Opus will be responsible for all further research, development, and commercialization of IC-100 and IC-200 globally and replaced Iveric Subsidiary as the exclusive licensee under the license agreements with UFRF and Penn. However, under certain circumstances, Iveric Subsidiary may have certain rights with respect to the potential future commercialization of IC-100 and/or IC-200.
Manufacturing
The company is working with its historical fill/finish manufacturer, Ajinomoto Bio-Pharma Services, or Ajinomoto, on fill/finish of ACP drug product with a new vial, which will allow it to support a more efficient and robust fill/finish operation at a commercial scale.
Intellectual Property
The company’s patent portfolio includes the following:
Patents and Patent Applications In-Licensed from Archemix Corp. (Archemix)
Patents and patent applications covering ACP's composition-of-matter, which have issued in the United States, the countries covered by the European Patent Organisation, which the company refers to as the EPO Countries, China, Japan and certain other jurisdictions, and which are expected to expire in 2025, subject to any patent term extensions.
Patents and patent applications covering the treatment of certain complement mediated disorders with ACP, ACP for use in a method of treating certain complement mediated disorders or a composition comprising ACP for treating certain complement mediated disorders, which have issued in the United States, the EPO Countries, China, Japan and certain other jurisdictions, and which are expected to expire in 2025, 2026 and 2027, subject to any patent term extensions.
Patents and Patent Applications owned by IVERIC bio, Inc.
Patents and patent applications covering methods of use for treating GA, Stargardt disease, IPCV and other conditions, and other proprietary technology relating to ACP, which include two issued United States patents with claims covering methods for treating GA with ACP that are expected to expire in 2034, subject to any patent term extensions, and patent applications that are pending in the United States, the EPO Countries, China, Japan and certain other jurisdictions, which, if granted, are expected to expire in 2034, 2038 and 2040, subject to any patent term adjustments or extensions.
Patent applications covering methods of using ACP to treat intermediate AMD and other forms of AMD, which are pending under the Patent Cooperation Treaty, or PCT, and which, if granted, are expected to expire in 2041, subject to any patent term adjustments or extensions.
Patents and Patent Applications owned by the company’s Subsidiary, Orion Ophthalmology LLC (Orion)
Three families of patents and patent applications covering compositions and methods of use of IC-500 and other HtrA1 inhibitors owned by Orion, some of which are issued patents in the United States or claims that have been allowed by the U.S. Patent and Trademark Office (USPTO), as well as issued patents or allowed claims in other jurisdictions, all of which are expected to expire in 2037, and others are pending in the United States, the EPO Countries, China, Japan and certain other jurisdictions, which, if granted, are expected to expire in 2037, subject to any patent term adjustments or extensions.
Patents and Patent Applications In-licensed Iveric Subsidiary from UMass
Two families of patent applications relating to certain proprietary minigene technology for the treatment of diseases associated with mutations in the CEP290 gene, which are pending in the United States, the EPO Countries, China and certain other jurisdictions, and which, if granted, are expected to expire in 2038 and 2040, respectively, subject to any patent term adjustments or extensions.
Research and Development
The company’s research and development expenses were $117.0 million for the year ended December 31, 2022.
History
The company, a Tennessee corporation, was founded in 2007. It was incorporated in 2007. The company was formerly known as Ophthotech Corporation and changed its name to IVERIC bio, Inc. in 2019.
