|Fifth Annual Pipeline Report|
How the list was compiled
This listing was compiled from company press releases and regulatory filings, published reports in the literature, searches on ClinicalTrials.gov, and presentations at the American Academy of Ophthalmology Retina Subspecialty Day, American Society of Retina Specialists, Retina Society, Association for Research in Vision and Ophthalmology, EURETINA and the Ophthalmology Innovation Summit Retina Innovation Showcase. This year’s listing includes investigational stem cell and gene therapies for exudative disease, gene therapies for exudative retinal disease, treatments for inherited retinal disorders and biosimilars.
New investigative programs in retina have exceeded attrition over the past few years either because products were approved or programs discontinued. This year’s version lists 58 programs, not including the eight biosimilar candidates. Last year’s list had 51 entries.
Three exit the list
Notable exits since last year are brolucizumab (Beovu, Novartis), which was removed because it’s already approved, although Novartis continues to pursue an additional indication for diabetic macular edema. The most notable is what was once called the Port Delivery System (PDS) with ranibizumab but, upon Food and Drug Administration approval last year, underwent a name change to Susvimo (Genentech/Roche).
Iconic Therapeutics’ ICON-1 program in choroidal neovascularization has also been dropped. The company discontinued a Phase II trial last year to pursue a next-generation program for the same indication.
One approval remains on the list
One approval that happened earlier this year remains on the list, albeit under a new name: faricimab is now Vabysmo, the name Genentech/Roche adopted for the bispecific antibody upon its approval by the Food and Drug Administration. Because the approval came in January this year, and there are still meaningful Phase III trial readouts pending, it remains on our list.
One new entry on the main list is IBIf302 (Innovent Biologics), which has been reclassified from a gene therapy. The main list includes five other candidates that weren’t listed last year: AR-13503 (Aerie Pharmaceuticals); ISTH0036 (Isarna Therapeutics); OCS-01 (Oculis); RBM-007 (Ribomic); and UBX1325 (Unity Biotechnology).
The list of gene therapy candidates for exudative retinal disease includes one new entry: the dual transgene therapy 4D-150 (4D Molecular Therapeutics).
The listing of programs for inherited retinal disease includes four new entries: 4D-150 (again), but for X-linked retinitis pigmentosa; MCO-010 (Nanoscope Therapeutics) for Stargardt disease and RP; SAR439483 (Atsena Therapeutics) for Leber congenital amaurosis; and Visomitin (Mitotech) for Leber hereditary optic neuropathy.
This listing includes only therapies in human trials or soon to be in the clinic. It doesn’t include preclinical candidates.
Abicipar pegol (Molecular Partners)
Last year, this was a collaborative venture with AbbVie. However, AbbVie pulled out, leaving Molecular Partners to pursue the candidate on its own. In 2020, the FDA issued a negative Complete Response Letter for abicipar pegol after the Phase III SEQUOIA (n=949, NCT02462486) and CEDAR (n=233, NCT02173496) trials reported high rates of intraocular inflammation (IOI)—15.1 and 15.7 percent in abicipar-treated patients compared with 0 to 0.6 percent in the ranibizumab comparator groups, respectively.1
Molecular Partners chief executive Patrick Amstutz expressed confidence in abicipar pegol after the separation from AbbVie, but the company hasn’t reported any updates since. Both the SEQUOIA and CEDAR trials are listed as completed on ClinicalTrials.gov.
Aflibercept high dose (Regeneron Pharmaceuticals)
Ongoing pivotal trials are evaluating the 8-mg dose of aflibercept in DME (n=640, NCT04429503) and age-related eye disease (n=960, NCT04423718), using the standard 2-mg dose of Eylea as the comparator.
A separate Phase II trial (n=106, NCT04126317) in nAMD showed no new safety issues compared with the standard 2-mg dose. Regeneron reports that a higher proportion of patients in the aflibercept 8-mg group had no retinal fluid compared to patients in the 2-mg group, 43.4 vs. 26.4 percent (p=0.067) at week 16, at which point they had received three injections.
KST4290 (formerly ALK4290, Alkahest)
Alkahest completed a Phase IIb clinical trial, PHTHALO-205 (n=100, NCT04331730), last year, but results haven’t yet been reported. The trial is evaluating visual acuity outcomes after three loading doses of aflibercept in treatment-naive nAMD patients.
AKST4290 is an oral inhibitor of the chemokine C-C motif receptor 3 (CCR3) that blocks the action of eotaxin, an immunomodulatory protein that increases as humans age and contributes to specific age-related diseases. Alkahest hasn’t reported any updates in the past year.
ALK-001 (Alkeus Pharmaceuticals)
Recruiting ended last year in a Phase II/III trial (n=300, NCT03845582) of this oral modified form of vitamin A. ALK-001 aims to replace vitamin A and prevent formation of toxic vitamin A dimers in patients with geographic atrophy secondary to dry AMD. Alkeus is also pursuing concurrent trials in Stargardt disease.
NEW: ANX007 (Annexon Biosciences)
Annexon initiated the Phase II ARCHER trial in GA (n=240, NCT04656561) last spring. The trial is evaluating changes in GA area using monthly and bimonthly dosing. Intravitreal ANX007 is a monoclonal antibody antigen-binding fragment designed to bind to complement factor 1q and inhibit activation of all downstream components of the classical complement cascade, including complement factors 3 and 5, without disrupting their normal function in other complement pathways.
ARCHER is scheduled for completion at the end of next year.
APX3330 (Ocuphire Pharma)
APX3330 is dosed at five 120-mg tablets daily. Results of five Phase II trials, presented at the American Academy of Ophthalmology, reported adverse events in fewer than 5 percent of study patients, a rate similar to placebo.1 Ocuphire is pursuing the Phase IIb ZETA-1 trial in DME (n=100, NCT04692688).
AR-1105; NEW: AR-13503 (Aerie Pharmaceuticals)
Aerie is preparing a Phase III trial of AR-1105, the bioerodable intravitreal dexamethasone implant, in DME. Phase II results in patients with macular edema associated with retinal vein occlusion (n=49, NCT03739593) demonstrated improvements in best-corrected visual acuity and macular edema with an adverse event profile similar to other corticosteroids.2
Meanwhile, Aerie initiated a program to develop AR-13503, an
implant of an active metabolite of netarsudil, a Rho-kinase/protein kinase inhibitor that would be an
adjunct to anti-VEGF treatments. A six-month Phase I study in nAMD and DME (n=18, NCT03835884) advanced to Stage 2. The company is also pursuing a preclinical program of AR-14034 SR (axitinib) implant.
Table. Biologics, steroids and light-activated treatments for exudative disease in human trials
|Click here to view the full table in the January/February 2022 digital edition.|
AXT107 (AsclepiX Therapeutics)
AsclepiX hasn’t reported any updates since initiating enrollment in January 2021 in the Phase I/IIa CONGO trial to evaluate the safety and bioactivity of AXT107 in DME (n=18, NCT04697758). AXT107 aims to inhibit vascular endothelial growth factor A and VEGF-C, and activate the Tie2 pathway as well. AsclepiX is also pursuing programs in nAMD and RVO.
CLS-AX (Clearside Biomedical)
CLS-AX is a proprietary suspension of axitinib, a small-molecule tyrosine kinase inhibitor (TKI) used to treat renal cell carcinoma, formulated for suprachoroidal injection. Axitinib inhibits pan-VEGF through receptor blockade. Early results of the OASIS Phase I/IIa trial for nAMD (n=15, NCT04626128) report that the 0.1-mg dose was well-tolerated with no serious side effects. Ten patients in the first two cohorts treated with CLS-AX went at least two months, and four went three months, without needing retreatment. They averaged nine injections in the year before enrollment. Based on those findings, the dose for the next study cohort will go to 0.5 mg. An extension study to evaluate long-term outcomes is recruiting (n=10, NCT05131646).
Conbercept (Chengdu Kanghong Biotechnology)
The FDA last year granted the anti-VEGF fusion protein conbercept new indications for DME and RVO. Available in China since 2013, conbercept targets VEGF-A and -B along with placental growth factor (PLGF). Data are pending from two Phase III trials in nAMD, PANDA-1 and PANDA-2 (NCT03577899, NCT03630952), each enrolling 1,140 patients. However, the program hit a setback last March when the French government halted the clinical trial. Chengdu Kanghong has said it expects FDA approval this year and a global launch in 2023.
EYP-1901 (EyePoint Pharmaceuticals)
EYP-1901 uses the bioerodable Durasert sustained-release insert with vorolanib, a TKI that has shown potential in previous human trials in nAMD as an oral therapy. Interim six-month results of the Phase I DAVIO trial in nAMD (n=17, NCT04747197) showed that 76 percent of patients didn’t need rescue treatment at four months and 53 percent were rescue-free at six months.3 At six months, BCVA was stable (-2.5 letters), as was central subfield thickness (-1.7 µm). EyePoint says it intends to start a Phase II trial this year.
Elamipretide (Stealth BioTherapeutics)
A subgroup with noncentral GA (n=19) in the Phase I ReCLAIM trial in intermediate AMD (n=40, NCT02848313) demonstrated vision improvements, including an average increase of 4.6 ±5.1 letters at week 24.4 A third of patients demonstrated improvement of >10 letters at the same interval, and 6.7 percent showed a >15-letter improvement. On average, treatment reduced GA growth by 18 percent. Elamipretide, a cell-permeable peptide delivered via a 40-mg subcutaneous injection, is the subject of the ongoing Phase II ReCLAIM-2 study in AMD with noncentral GA (n=180; NCT03891875), completion of which is set for March.
Gene therapies targeting GA, nAMD, DR
NEW: 4D-150 (4D Molecular Therapeutics). 4D reports dosing the first patient in the Phase I/II trial evaluating this dual-transgene, intravitreal therapy in patients with neovascular age-related macular degeneration.
The dose-escalation, randomized, controlled, masked expansion trial is expected to enroll about 60 adults. It will involve multiple dose levels in an open-
ADVM-022 (Adverum Biotechnologies). Adverum reports it’s finalizing the design of a Phase II trial in nAMD that will evaluate two doses of ADVM-022: a 2 x 1011 vg/eye dose and a lower 6 x 1011 vg/eye dose. ADVM-022 is a single intravitreal injection treatment that uses a proprietary adeno-associated vector capsid, AAV.7m8, carrying an aflibercept-coding sequence under the control of a proprietary expression cassette.
The nAMD trial will include three new enhanced steroid prophylaxis regimens, possibly a topical, intravitreal and a combination of systemic and local steroids. The trial is expected to enroll approximately 72 patients, with enrollment starting in the third quarter.
Data from the Phase I OPTIC trial in nAMD (n=30, NCT03748784) demonstrated a >80-percent reduction in yearly anti-VEGF injections following the 2E11 dose.17 The Phase II INFINITY trial in DME (n=36, NCT04418427) reported higher-than-expected rates of intraocular inflammation and iris-related events,18 so the company discontinued the diabetic macular edema program.
GT005 (Gyroscope Therapeutics). A one-time therapy delivered subretinally, GT005 aims to induce complement factor I expression. Interim data from the Phase I/II FOCUS trial (n=45, NCT03846193) in GA reported no treatment-related serious adverse events in 28 patients, while biomarker data from 13 patients demonstrated sustained increased levels of vitreous complement factor I (CFI) as well as sustained decreases in downstream proteins associated with complement system activation.19 A new analysis showed no increases in systemic CFI levels circulating in the blood. Completion of the trial is planned in 2025.
Two other trials are ongoing: Phase II EXPLORE trial (n=75, NCT04437368) evaluating two doses administered as a single injection in GA, due for completion in early 2023; and Phase II HORIZON (n=150, NCT04566445), also evaluating two doses in one injection in GA, with completion scheduled for early next year.
HMR59 (Hemera Biosciences). Results are pending from the HMR-1002 Phase I proof-of-concept study (n=25, NCT03585556) in treatment-naïve patients with new onset nAMD. HMR59 is a soluble form of CD59, the protective protein normally found on the cellular plasma membrane. Patients receive a single intravitreal injection of HMR59 a week after getting an anti-VEGF treatment. They’re being followed for 12 months and treated with additional anti-VEGF monthly as needed.
RGX-314 (RegenxBio). RegenxBio has initiated the ASCENT trial, the second Phase III trial evaluating RGX-314 in nAMD. ASCENT is evaluating subretinal delivery across two dose arms—6.4 x 1010 genomic copies per eye (GC/eye) and 1.3 x 1011 GC/eye—vs. aflibercept. The primary endpoint is noninferiority to aflibercept-based BCVA change at one year. The trial will enroll around 465 patients. RGX-314 is an AAV8 vector that contains a transgene for anti-VEGF fab.
Two Phase II trials of suprachoroidal delivery are also ongoing: AAVIATE in nAMD (n=40, NCT04514653) and ALTITUDE in diabetic retinopathy without center-involved DME (n=40, NCT04567550). In AAVIATE, RGX-314-treated patients had an average six-month change in central retinal thickness of -33 µm compared to -12 µm for the ranibizumab group. RGX-314 patients also showed a 71.8-percent reduction in anti-VEGF treatment burden at six months.19 Two-year results of a Phase I/IIa trial of subretinal delivery of RGX-314 in nAMD (n=42, NCT03066258) demonstrated the treatment was generally well tolerated across five dose cohorts with long-term durability out to three years.20
In ALTITUDE, 15 patients dosed with 2.5 x 1011 GC/eye of RGX-314 demonstrated stable BCVA of +2.6 letters, while five patients in the observational control arm demonstrated stable BCVA of -0.4 letters.19 Five patients (33 percent) demonstrated a two-step or greater improvement in VA vs. none in the control group.21
Enrollment started at the beginning of the year in the pivotal Phase IIb/III ATMOSPHERE study (n=300, NCT040704921) comparing RGX-314 and ranibizumab in patients with nAMD. Completion is expected in 2024.
Investigational therapies for inherited retinal disease
There’s also one name change: AGTC-501 (Applied Genetic Technologies Corporation) was listed as rAAV2tYF-GRK1-RPGR last year.
NEW: 4D-125 (4D Molecular Therapeutics). The Food and Drug Administration granted Fast Track designation to this candidate for retinal dystrophies due to defects in the RPGR gene, including XLRP. 4D-125 aims to deliver a functional copy of the RPGR gene (retinitis pigmentosa GTPase regulator) to photoreceptors. 4DMT is currently enrolling patients in a Phase I/II clinical trial (n=43, NCT04517149). The study is using a standard 3+3 dose-escalation design, followed by dose expansion.
AAV-RPGR (MeiraGTx Holdings/Janssen Pharmaceuticals). This recombinant AAV vector aims to deliver functional copies of the RPGR gene to the subretinal space. In the dose-escalation phase of a Phase I/II clinical trial (n=49, NCT03252847) in XLRP, patients treated with AAV5-RPGR gene therapy demonstrated changes in mean retinal sensitivity and volumetric analysis of the central 30 degrees of the retina that were maintained at 24 months.22 A follow-up study (n=36, NCT04312672) is evaluating long-term safety of the AAV2-RPGR vector.
AGTC-402, rAAV2tYF-PR1.7-hCNGB3 and AGTC-501 (formerly rAAV2tYF-GRK1-RPGR) (Applied Genetic Technologies Corporation). AGTC presented 12-month findings of two Phase I/II trials of gene therapies in achromatopsia: AGTC-402 for mutations in the CNGA3 gene (n=24, NCT02935517); and rAAV2tYF-PR1.7-hCNGB3 for mutations in the CNGB3 gene (n=28, NCT02599922).23 The agents demonstrated biologic activity based on improvements in visual sensitivity and light discomfort, along with a favorable safety profile. Three-month data from pediatric patients in both trials are due in the fourth quarter and an end-of-Phase II briefing packet to the FDA in the first half of 2022.
Meanwhile, AGTC reports it enrolled 14 patients in the SKYLINE trial of AGTC-501, a recombinant adeno-associated virus vector-based gene therapy for XLRP, exceeding the planned target enrollment of 12. SKYLINE is a multi-site expansion of the ongoing Phase I/II study (n=42, NCT03316560). The goal is to identify the proportion of treated eyes that show improvement in visual sensitivity and acuity, as well as functional outcomes.
ALK-001 (Alkeus Pharmaceuticals). The FDA granted Breakthrough Therapy designation to ALK-001, an oral modified form of vitamin A, for Stargardt disease. A Phase II placebo-control study (n=140, NCT02402660) is recruiting patients. ALK-001 is designed to replace vitamin A and prevent formation of toxic vitamin A dimers that have been linked to vision loss. The trial is scheduled for completion in March.
Elamipretide (Stealth BioTherapeutics). Phase II results in LHON (n=12, NCT02693119) showed that two of 16 treated eyes had visual impairment and higher rates of mild ocular surface problems than vehicle. Six treated eyes also had mild cataract, as did five vehicle-treated eyes before switching to elamipretide. Elamipretide is a cell-permeable peptide that targets mitochondrial dysfunction and is delivered subcutaneously.
jCell (jCyte, Santen). jCell is an intravitreal injection of human retinal progenitor cells (hRPC) into the vitreous that aims to preserve or potentially restore some vision in RP and related conditions. One-year Phase IIb results (n=30, NCT04604899) showed that patients treated with a 6-million cell dose had a sustained average improvement of +16.27 letters vs. +1.85 letters in the sham group (p=0.003).24 A separate analysis found a correlation between improvements in central foveal thickness and visual function.25 The Phase IIb and Phase II trials (n=84, NCT03073733) in RP are ongoing.
Lumevoq (GS010, GenSight). The Phase III REFLECT trial (n=98, NCT03293524) in LHON caused by a defect in the ND4 gene demonstrated that 73 percent of bilaterally treated eyes had VA improvement of >15 letters two years after treatment. Lumevoq (lenadogene nolparvovec) is a single intravitreal injection of rAAV2/2-ND4. Three-year data from RESTORE (n=61, NCT03406104), a follow-up trial of the Phase III RESCUE (n=39, NCT02652767) and REVERSE (n=37, NCT02652780) trials, showed sustained VA improvement in treated patients.26 Four-year data are pending.
NEW: MCO-010 (Nanoscope Therapeutics). The FDA has approved an Investigational New Drug (IND) application to begin a Phase II trial in Stargardt disease, and a Phase IIb trial in RP is ongoing. MCO-010 is an ambient-light activatable optogenetic monotherapy.
OCU400 (Ocugen). The FDA accepted the company’s application for a human clinical trial of OCU400 (AAV-NR2E3), a modifier gene therapy that targets nuclear hormone receptors (NHR). The FDA has granted four orphan drug designations for OCU400, and the European Medicines Agency granted two in 2021 for RP and LCA. Ocugen says the platform could be indicated for multiple IRDs. One potential indication is RP caused by PDE6B mutation autosomal-dominant congenital stationary nyctalopia and resulting from genetic mutations found in NR2E3 and rhodopsin. OCU400 consists of a functional copy of the NR2E3 gene.
NEW: SAR439483 (Atsena Therapeutics). Atsena received orphan drug designation for its unnamed investigational AAV-based therapy for LCA caused by biallelic mutations in the GUCY2D gene. The safety and efficacy of the therapy are being evaluated in a Phase I/II clinical trial (n=15, NCT03920007). Study completion is scheduled for February. Atsena is also pursuing human trials for its gene therapy program for X-linked retinoschisis.
NEW: Visomitin (Mitotech). The FDA granted orphan drug designation for treatment of LHON. Visomitin is a topical cardiolipin peroxidation inhibitor. Mitotech says it plans this year to start a Phase II trial for the indication, and reports that a three-year open-label Phase IIa study conducted outside the United States showed improvements in a range of underlying mutations.
FHTR2163, also known as RG6147, is an antigen-binding fragment (Fab) that targets the high-temperature requirement protein A1 (HtrA1), a serine protease gene associated with GA that’s a potential risk factor for nAMD. Phase I results in patients with GA secondary to dry AMD found no dose-limiting toxicities or serious ocular adverse events in 15 patients, including 13 who had three 20-mg injections over 12 weeks.5 FHTR2163 is the subject of two ongoing Phase II trials in GA: GALLEGO (n=360, NCT03972709), which is evaluating outcomes over 76 weeks with completion due later in the year; and an open-label Phase II trial (n=360, NCT04607148) comparing q4-week and q8-week dosing, due at the end of next year.
GB-102 (Graybug Vision)
This proprietary microparticle depot formulation of the pan-VEGF inhibitor sunitinib is intended for twice-yearly injection. The Phase IIb ALTISSIMO trial (n=56, NCT03953079) randomized previously treated nAMD patients into three arms: GB-102 1 mg (n=21), GB-102 2 mg (n=22), both dosed every six months; or bimonthly aflibercept (n=13). Fifty patients completed the 12-month treatment phase of the study. GB-102 2 mg was discontinued after an interim safety analysis. These patients were re-dosed with GB-102 1 mg for the second injection at six months. Median time to first rescue therapy with GB-102 was five months, but 48 percent of patients didn’t need rescue for at least six months. However, the average change in BCVA was lower in the GB-102 arm than the aflibercept arm, although CST was comparable in both arms.6
Graybug had been developing GB-103, a once-yearly formulation of GB-102 for DR, but halted further development based on results of an 18-month, Phase IIb trial. Graybug reports in a regulatory filing that without a funding partner, further development of GB-102 for nAMD or DME, or GB-103 for DR is unlikely.7
GEM103 (Gemini Therapeutics)
GEM103 is a recombinant, human complement factor H. Gemini reports that the Phase II ReGAtta trial in dry AMD (N=62, NCT04643886) showed that GEM103 has been generally well-
tolerated at more than nine months, with a signal to reduce complement activation biomarkers while maintaining supraphysiological levels of CFH over multiple intravitreal injections.
Six-month data of a Phase IIa add-on study in nAMD (n=50, NCT04684394) showed bimonthly treatment of GEM103 plus aflibercept vs. sham plus aflibercept resulted in similar safety profiles, with biological CFH levels five times above baseline through six months. The company ended both studies and says it will provide an update on next steps this quarter.
Biosimilars poised to have an impact
With ranibizumab (Lucentis, Genentech/Roche) already off patent in the United States and losing its European patent protection this year, and aflibercept (Eylea, Regeneron Pharmaceuticals) coming off patent in 2023 in the United States and in 2025 in Europe, clinical trials of biosimilar candidates are moving forward—but there’s also a candidate for a biosimilar referencing ophthalmic bevacizumab (Avastin, Genentech/Roche). This listing breaks the candidates down by their respective reference products.
HLX04-O (Shanghai Henlius Biotech). This candidate probably has more appeal outside the United States, where access to quality compounding pharmacies can be dodgy. Neovascular age-related macular degeneration is the indication for this ophthalmic formulation of the bevacizumab biosimilar HLX04. The first patients were dosed in a single-arm Phase I trial (n=20, NCT04993352). Two Phase III trials in nAMD using ranibizumab are also listed: one that started recruiting last year (n=388, NCT04740671) and a second that has yet to begin recruiting (n=388, NCT 05003245). Last year regulators in China approved the biosimilar for cancer indications.
Byooviz (Biogen). Also known as SB11, this product last year became the first ophthalmology biosimilar to get Food and Drug Administration approval. It’s indicated for nAMD, macular edema following retinal vein occlusion and myopic choroidal neovascularization. It will be launched in the United States after June, according to terms of a global license agreement with Genentech. Last year Samsung Biologics and Biogen, then partners in Samsung Bioepis, completed a Phase III comparator trial (n=705, NCT03150589). Biogen sold rights to other biosimilars to Samsung Biologics but retained the rights to Byooviz.
CHS-201 (Coherus BioSciences). The FDA accepted the Biologic License Application (BLA) for review of this agent, also known FYB201, in October, setting a Biosimilar User Fee action date for August. A Phase III trial (n=712, NCT02611778) was completed late last year with results pending. Coherus says it plans to launch the biosimilar in the second half of the year. Coherus obtained the U.S. license from Bioeq.
Xlucane (Xbrane Biopharma). Bausch + Lomb entered into an agreement with STADA Arzneimittel of Germany and its development partner, Xbrane Biopharma of Sweden, to commercialize Xlucane in the United States and Canada. Xbrane reported a Phase III trial demonstrated equivalency with the reference product (n=580, NCT03805100). The European Medicines Agency accepted the Marketing Authorization Application in September. The company said last June that it would file a BLA with the FDA in the fourth quarter of 2021, but that couldn’t be confirmed at press time.
ALT-L9 (Alteogen). South Korea-based Alteogen reported in April that it completed a Phase I comparator trial (n=28, NCT-04058535) that showed equivalent efficacy in nAMD. Alteogen says the findings may provide a path to a shorter Phase III trial. Alteogen is developing ALT-L9 in collaboration with Kissei Pharmaceutical of Japan.
CT-P42 (Celltrion Healthcare). Celltrion initiated a Phase III trial in diabetic macular edema (n=300, NCT04739306).
LY9004 (Boan Biology). Luye Pharma’s biotech subsidiary has licensed this candidate, also known as OT-702, to Ocumension Therapeutics. It’s in Phase III trials in China, but not in the United States.
SOK583A1 (Sandoz). The Novartis division initiated the Phase III MYLIGHT trial (n=460, NCT04864834) comparing this previously unnamed agent with the reference product.
NEW: IBI302 (Innovent Biologics)
IBI302 is a bispecific anti-VEGF and anti-complement recombinant fully human fusion protein. The Phase Ib clinical trial in nAMD (n=18, NCT04370379) involved multiple intravitreal injections of IBI302 or aflibercept. In the 12 subjects in the IBI302 group, BCVA improved 6.4 letters on average from baseline and central zone retinal thickness decreased 129.3 µm from baseline on average. In the 4-mg IBI302 group, visual acuity improved by 8 letters and mean CRT improved by 134.3 µm. There were no reported treatment-related adverse events. A Phase II trial in nAMD (n=231, NCT04820452) started recruiting last spring.
IONIS-FB-LRx (Ionis Pharmaceuticals)
The Phase II GOLDEN study for GA secondary to AMD (n=330, NCT03815825) is recruiting patients. It’s a placebo-controlled trial that will evaluate change in GA area at week 49. Study completion is expected late in the year. IONIS-FB-LRx is an antisense oligonucleotide (ASO) that inhibits complement factor B gene expression by binding with factor B mRNA.
NEW: ISTH0036 (Isarna Therapeutics)
ISTH0036 is an antisense therapy that targets the transforming growth factor-beta (TFG-ß), a protein that’s been found to be elevated in retinal disease. Isarna announced the enrollment of the first patient in BETTER, a parallel, two-segment Phase IIa clinical study to evaluate ISTH0036, in up to 24 patients with nAMD and DME, but the trial hasn’t been listed at ClinicalTrials.gov. The primary endpoint is retinal fluid and central macular thickness reduction, with improvement of VA as a secondary endpoint. The trial aims to explore the prevention of fibrosis and epithelial-mesenchymal transition as a key differentiator to anti-VEGF therapies.
KSI-301 (Kodiak Sciences)
KS-301, an intravitreal anti-VEGF antibody biopolymer conjugate, is in clinical trials for three indications: nAMD, DME and RVO. One-year data from the Phase Ib trial (n=121, NCT03790852) showed that two- thirds of patients in each disease cohort achieved a six-month or longer treatment-free interval after a year. More than half—54 percent of nAMD patients—required one retreatment and 50 percent of DME patients didn’t need any retreatment at one year.
The Phase IIb/III DAZZLE study (n=550, NCT04049266), comparing KSI-301 and aflibercept in treatment-naive nAMD, is ongoing, as are the Phase III GLEAM (n=450, NCT04611152) and GLIMMER (n=450, NCT04603937) studies, also comparing KSI-301 and aflibercept, in treatment-naive DME.
Meanwhile, Kodiak has completed enrollment in the Phase III
BEACON study (n=550, NCT04592419) of KSI-301 in patients with treatment-naive macular edema due to RVO. Completion is expected later in the year.
LBS-008 (Belite Bio)
LBS-008 is an oral, small-molecule retinol binding protein 4 (RBP4) specific antagonist for dry AMD. Belite Bio says it expects to initiate a Phase III trial for the indication this year. A Phase I trial (n=71, NCT03735810) confirmed safety and tolerability of the drug and that oral administration achieved potentially therapeutic-level target engagement. A global Phase III trial in Stargardt disease started last summer.
NGM621 (NGM Biopharmaceuticals)
NGM621 is an intravitreal formulation of a humanized IgG1 monoclonal antibody engineered to potently inhibit C3. Patient enrollment was completed last summer in the Phase II CATALINA trial (n=240, NTC04465955) for GA. Study completion is expected in 2023.
NEW: OCS-01 (Oculis)
OCS-01 is a topical high-concentration formulation of preservative-free dexamethasone now in Phase III study in patients with DME. The first patients were enrolled in the DIAMOND trial (n=482, NCT05066997) in November. Phase IIb results (n=144), first presented in 2020, showed OSC-01 improved VA and reduced CMT compared to vehicle.8
ONS-5010/Lytenava (bevacizumab-vikg, Outlook Therapeutics)
Based on results of the Phase III NORSE TWO (n=227, NCT03834753) trial, Outlook says it plans to submit a BLA with the FDA in the first quarter of the year for this ophthalmic formulation of bevacizumab. Results showed that 68.5 percent of patients gained ≥5 letters of vision (p=0.0116) and 41.7 percent gained ≥15 letters (p=0.0052).9 Indications would cover nAMD, DME and branch RVO. Late last year Outlook started the Phase III NORSE SEVEN trial (n=120, NCT05112861) to evaluate the agent in vials and a prefilled syringe. Completion is expected by the end of the year. Recruitment in the Phase III NORSE 3 safety trial (n=195, NCT04516278) closed last year.
OpRegen (Lineage Cell Therapeutics)
This cell therapy consists of allogeneic retinal pigment epithelium cells administered to the subretinal space. Enrollment has been completed in the Phase I/IIa trial in GA secondary to dry AMD (n=24, NCT02286089), which demonstrated improvement in VA and GA area among some treated patients. Study completion is scheduled for year-end 2024. Lineage Cell Therapeutics signed an agreement with Genentech/Roche in December to collaborate on the development of OpRegen.
Opthea initiated enrollment in Phase III trials of OPT-302 for nAMD. The ShORe (n=990, NCT04757610) and COAST (n=990, NCT04757636) studies are evaluating intravitreal 2-mg OPT 302 in combination with either 0.5 mg ranibizumab or 2.0 mg aflibercept, respectively, for nAMD.
Topline 52-week results are expected next year, after which Opthea says it will submit applications for approval in both the United States and Europe. The FDA last year granted Fast Track status for OPT-302 in combination with anti-VEGF-A therapy for nAMD.
OTX-TKI (Ocular Therapeutix)
The Phase I clinical trial of this intravitreal axitinib implant for nAMD started enrolling patients last summer (n=20, NCT04989699). Axitinib is the same small-molecule TKI used in CLS-AX. The prospective, randomized, controlled, multicenter trial is evaluating a single OTX-TKI implant containing a 600-µg dose of axitinib, compared with a 2-mg dose of aflibercept administered every eight weeks in subjects previously treated with anti-VEGF therapy.
PanOptica describes this as a selective inhibitor of VEGF receptor 2, and reports that more than half of patients in the Phase I/II trial in nAMD (n=51, NCT03479372) who took the topical drop once daily completed the trial without needing intravitreal anti-VEGF rescue therapy Of those, 88 percent either had clinical improvement or disease stability.
Pegcetacoplan (APL-2, Apellis)
Based on feedback it received from the FDA, Apellis says it plans to submit a New Drug Application for pegcetacoplan for GA in the first half of this year. Results of the Phase III DERBY (n=621, NCT03525600) and OAKS studies (n=673, NCT03525613) showed mixed results.10 OAKS met its primary endpoint, reducing lesion growth by 22 percent with monthly (n=202) and by 16 percent with bimonthly (n=205) treatment at 12 months vs. sham in patients with extrafoveal lesions (n=206).
However, DERBY failed to meet its primary endpoint, although it did reduce lesion growth in these patients: 12 and 11 percent for monthly (n=201) and bimonthly treatment (n=200), respectively, vs. sham. Combined results showed a 17-percent reduction with monthly (n=405) and 14-percent reduction with bimonthly (n=403) treatment. Thirteen patients (1.5 percent) had intraocular inflammation.
NEW: RBM-007 (Ribomic)
RBM-007 is an oligonucleotide-based aptamer with potent
anti-fibroblast growth factor 2 (FGF2) activity, which has been linked to fibrosis in nAMD, among other diseases. Ribomic says the candidate has dual anti-angiogenic and anti-scarring actions that make it a potential additive therapy to
anti-VEGF treatments for nAMD.
Three studies are evaluating RBM-007 for nAMD: TOFU (n=86, NCT04200248), a Phase II trial evaluating the candidate in combination with aflibercept in previously treated patients; RAMEN (NCT04640272), a single-arm, open-label extension trial; and TEMPURA (NCT04895293), an investigator-sponsored trial in treatment-naïve nAMD patients.
The trials have yielded mixed early results. Topline TOFU data showed RBM-007 in combination with aflibercept didn’t demonstrate any vision improvement over aflibercept alone. However, preliminary interim results of TEMPURA have shown improvement in vision and retinal anatomy.
This device is worn like an eye patch. It delivers laser therapy directly to the affected eye using photobiomodulation (PBM), which uses light in the 630-to-900-nm range. The pilot study (n=135, NCT03866473) compared PBM with sham in eyes with center-involved DME and good vision. PBM patients had twice-daily treatments for 90 seconds at 670 nm for four months. Average change in CST at four months was 13 µm
(SD 53) for the treatment group and 15 µm (SD 57) in the placebo group. Rescue therapy was administered in 4.4 percent of the PBM patients and 1.5 percent of the placebo group. PhotoOpTx hasn’t made any announcements on the program since results were posted to ClinicalTrials.gov.
Risuteganib (Allegro Ophthalmics)
Risuteganib is a small-peptide oxidative stress stabilizer. Results of the Phase IIa trial in nonexudative AMD (n=40, NCT03626636) were published in August.11 Risuteganib 1 mg in patients with intermediate disease met the study’s primary endpoint—an ≥8-letter improvement in best corrected visual acuity—in 48 percent of patients in the risuteganib group at week 28 and 7 percent of patients in the sham group at week 12 (p=0.013). No drug-related serious adverse events were reported in the risuteganib group.
The Phase I trial (n=50, NCT04567303) in nAMD is recruiting patients. Completion is expected in 2026. This is a bispecific human Fab form of faricimab delivered via the port delivery system.
THR-149, THR-687 (Oxurion)
THR-149 is a plasma kallikrein inhibitor and THR-687 a pan-arginylglycylaspartic acid (RGD) integrin antagonist. DME is the indication for both.
THR-149 is the subject of a Phase II trial, KALAHARI (n=122, NCT04527107), which is recruiting patients with CI-DME refractory to anti-VEGF. The trial is now in Phase IIb comparing the agent with aflibercept. Topline results are expected in 2023. Phase IIa data reported last year that THR-149 had a favorable safety profile. Part B is comparing three monthly injections of THR-149 and three monthly injections of aflibercept (n=~108). The primary endpoint is mean change in BCVA at three months.
For THR-687, Oxurion has completed enrollment for the first part of the Phase II clinical trial (n=303, NCT05063734), known as
INTEGRAL. Part A of the trial will assess two dose levels of multiple THR-687 injections, results of which will be used to determine the appropriate dose for Part B, which will compare THR-687 and aflibercept. Oxurion says it expects topline Part B data in the second half of 2023.
NEW: UBX1325 (Unity Biotechnology)
Unity describes UBX1325 as the first senolytic therapy in retina—a potent, small-molecule inhibitor of B-cell lymphoma-extra-large (Bcl-xL), which is itself a member of the B-cell chronic lymphocytic leukemia/lymphoma (Bcl-2) family of apoptosis-regulating proteins. The company reported positive results from the Phase I safety trial (n=21, NCT04537884) in DME or nAMD refractory to anti-VEGF treatment.12 Unity says it expects to report this year 24-week data from the nAMD cohort of the Phase I trial, along with 12- and 24-week data from the Phase IIa trial in DME (n=62, NCT04857996), and 16-week safety and efficacy data from the Phase II trial in nAMD (n=46) already in the field. That trial includes an aflibercept control arm.
The FDA approved Vabysmo (faricimab) for nAMD and DME. Faricimab is a bispecific antibody that binds to and neutralizes both angiopoietin-2 (Ang-2) and VEGF-A.
In DME, readouts of the parallel Phase III trials, YOSEMITE (n= 940, NCT03622580) and RHINE (n= 951, NCT03622593), found that faricimab showed noninferiority to aflibercept.13
Average one-year BCVA gains with faricimab were 10.7 and 11.8 letters in YOSEMITE and RHINE with q8-week treatment and 11.6 and 10.8 letters with a personalized treatment interval (PTI) regimen, and 10.9 and 10.3 letters with aflibercept q8-weeks. At one year, more than half of the faricimab PTI arm were on q16-week dosing and more than 70 percent were on q12-week or more dosing. The ongoing Phase III Rhone-X study (n=1,800, NCT04432831) is investigating the long-term effect of faricimab in DME, with completion expected in 2023.
TENAYA (n=671, NCT03823287) and LUCERNE (n=658, NCT03823300) are Phase III trials evaluating faricimab in nAMD over 112 weeks, again with aflibercept as the comparator. Average BCVA gains at week 48 with faricimab up to q16-week treatment were 5.8 and 6.6 letters in TENAYA and LUCERNE and, 5.1 and 6.6 letters with q8-week aflibercept. At week 48, around 45 percent of the faricimab patients were on q16-week dosing. Around 80 percent were getting treatments every 12 weeks or longer.14
Valeda Light Delivery System (LumiThera)
Valeda uses PBM to target damaged photoreceptors. Final topline data from the ELECTROLIGHT pilot study in intermediate dry AMD (n=15, 23 eyes, NCT04522999)
reported that treated patients averaged a 1.28 ± 0.98-letter improvement in BCVA after six months.
Researchers also reported results of a trial using the PBM device in patients with DME (n=19; 30 eyes), which showed a 90 to 70 percent reduction of intraretinal fluid (p=0.031) among other outcomes.15 LumiThera also completed enrollment in the LIGHTSITE III trial (n=96, NCT04065490) in dry AMD. Subjects are receiving three PBM treatments a week for three weeks for a total of nine sessions. The device has been approved in Europe.
This is an oral small-molecule therapy that targets the Connexin43 protein and blocks the formation of hemichannels. InflammX reports it’s in Phase IIb trials for DME and GA, but no trials are listed in ClinicalTrials.gov.
Xipere (Clearside Biomedical)
Formerly known as CLS-TA, Xipere is a proprietary triamcinolone acetonide suspension formulated for suprachoroidal delivery. The Phase II TYBEE trial in DME (n=71, NCT03126786), comparing Xipere plus aflibercept with aflibercept plus sham suprachoroidal injection, showed that neither group achieved clinically meaningful improvement of ≥15 letters at 24 weeks: an average of +11.4 letters in the Xipere group and +13.8 in the sham group.
As for secondary outcomes, the treatment had statistically significant improvement in CST—a reduction of -212.1 (13.83) vs. -178.6 (13.61) µm. The treatment group also had a higher rate of serious adverse events (16.67 vs. 11.43 percent) but lower rates of other adverse events (8.33 vs. 11.43 percent). In May Clearside resubmitted its NDA for the indication of uveitis-associated macular edema.
Zimura (avacincaptad pegol, IVERIC bio)
IVERIC Bio reported completing enrollment in the Phase III GATHER2 trial in GA (n=448, NCT04435366), the second pivotal trial of the C5 inhibitor, with topline data to come later in the year. GATHER2 is evaluating the 2-mg dose over 24 months. Results from the Phase III GATHER1 trial in GA (n=400, NCT04435366), reported in 2020, demonstrated that patients in the 2- and 4-mg treatment cohorts had a 27.4- and 27.8-percent reduction in average GA growth over a year, respectively, compared with sham.16 RS
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