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A different way of thinking about the complement cascade.
Download the Pipeline PDFsThis content originally ran as a poster in the November/December issue. Check out the print publication to view the full size poster, or use the links below to download the PDFs.
Dry AMD Pipeline PDFWet AMD Pipeline PDFWatch as Peter K. Kaiser, MD, explains the poster and follow along with the graphics below.
We may look back on 2023 as a breakthrough year. After decades of research and a handful of almost-there drug candidates, the US Food and Drug Administration determined that two different treatments for geographic atrophy (GA) were safe and effective. Rather than holding our patients’ hands as they marched toward inevitable vision loss, we retina specialists may be able to avert devastating vision loss in a significant number of patients.
But researchers aren’t satisfied with only two options. Dozens of other pipeline candidates remain under investigation for the treatment of GA, many of them complement inhibitors like the approved treatments, pegcetacoplan (Syfovre, Apellis Pharmaceuticals) and avacincaptad pegol (Izervay, Iveric Bio). We lack the depth of experience to know whether complement inhibition will ultimately prove to be the best long-term approach to GA therapy. But for now, we have a breakthrough—and we’ll take it.
With all the focus on dry AMD and GA, it’s easy to forget that seismic shifts have come (or are coming) in wet AMD therapy. The era of biosimilars has arrived, and we should expect more biosimilar candidates under investigation to clear regulatory hurdles in the coming years. Real-world evidence of the safety and efficacy of dual inhibition therapy with faricimab (Vabysmo, Genentech/Roche) has shown that this approach works. To that end, we dedicated significant space in this year’s pipeline update to educating readers on multitarget therapies that were recently approved or are under investigation. The next age of wet AMD therapy may very well rely on simultaneous inhibition of several targets, and the data researchers publish in the coming years will inform the viability of this approach.
Remember that the drugs listed in this poster are not exhaustive. If there is a drug that you think we should include in next year’s poster, email us at cdeming@bmctoday.com.
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Click the below to see how certain therapies play a role in treating dry AMD.
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We recommend that you access this portion of the Pipeline on a desktop computer.
While a larger screen will make it easier to navigate and visualize the Suppress Inflammation diagram below, the mobile experience contains the same content.
Send yourself an email reminder to access this page from a computer »Hover the numbers in the diagram or in the list below to see where each therapy suppresses inflammation along the pathway.
See the diagram below showing where each therapy suppresses inflammation along the pathway.
1
IBI302 (Innovent Biologics)
sCR1 Inhibition/Anti-VEGF
2
OMS721 (Omeros)
Blocks MASP-2
3
OMS906 (Omeros)
Blocks MASP-3
4
ANX007 (Annexon)
C1q Inhibition
5
Ionis-FB-LRx (Ionis/Roche)
Complement Factor B Inhibition
6
Pegcetacoplan (Apellis) FDA Approved
C3 Inhibition
7
CB-2782-PEG (Catalyst Biosciences)
C3 Protease
8
NGM621 (NGM Biotherapeutics)
C3 Inhibition
9
AMY106 (Amyndas Pharmaceuticals)
C3 Inhibition
10
SLN501 (Silence Therapeutics/Mallinckrodt Pharmaceuticals )
siRNA vs C3
11
PRO657 (Mosaic/Ocular Therapeutix)
C3 Inhibition
12
iPTACOPAM (Novartis)
Bb Inhibition
13
NM5072 (NovelMed)
Properdin Inhibition
14
ALXN2040 (Alexion Pharmaceuticals/AstraZeneca)
Complement Factor D Inhibition
15
BCX9930 (BioCryst Pharmaceuticals)
Complement Factor D Inhibition
16
KNP-301 (Kanaph Therapeutics)
Blocks C3b/Anti-VEGF
17
AGN-151151 (AbbVie)
C5 Inhibition
18
cEMDISIRAN (Alnylam Pharmaceuticals)
siRNA C5 mRNA Inhibition
19
Avacincaptad pegol (Iveric Bio) FDA Approved
C5 Inhibition
20
ALXN1720 (Alexion)
C5 Inhibition
21
PASylated Nomacopan (Akari Therapeutics)
Bispecific Inhibition of C5 & LTB4
22
KNP-302 (Kanaph Therapeutics)
C3b and CD59 Inhibition
23
MAC Inhibition Gene Therapy
24
Complement Factor H Gene Therapy
25
Complement Factor H Gene Therapy
26
GEM103 (Gemini Therapeutics)
Recombinant Complement Factor H Therapy
27
Short-Form Complement Factor H Gene Therapy
28
AVD-104 (Aviceda Therapeutics)
Complement Factor H Activation
29
CB-4332 (Catalyst)
Recombinant Complement Factor I
30
Complement Factor I Gene Therapy
TMi-018 (Translatum Medicus Inc)
Blocks M1 Transcriptome Expression
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Five gene therapy–based investigational interventions seek to inhibit MAC formation, either via upregulation of CFH or CFI (leading to inactive C3b) or via increased production of CD59 (a cell surface protein that inhibits MAC formation).1 The exact routes of administration remain under investigation.
Two other investigation gene therapies use a strategy outside of the complement pathway. OCU410 (Ocugen) aims to deliver ROR𝛼 (or RORA) proteins, which have been implicated in controlling inflammation.2 Oculogenex seeks to reduce oxidative stress via gene therapy, using a mechanism that has not yet been widely articulated.
Gene Therapy Delivers RORA Anti-imflammatory Protein
Selective σ-2 Antagonist
siRNA TTR Sliencer
Gene Therapy to Reduce Oxidative Stress
Continue to scroll to see the each pathway displayed in the diagram.
faricimab (Genentech/Roche) FDA-Approved BI 836880 (Boehringer Ingelheim) RO-101 (RevOpsis) ASKG-712 (AffaMed, AskGene Pharma) ABP-201 (AbPro) ❖ ★ AG-73305 (Allgenesis Biotherapeutics) ★ AXT107 (AsclepiX Therapeutics) RGX-314 (REGENXBIO, AbbVie) ADVM-022 (Adverum Biotechnologies) 4D-150 (4D Molecular Therapeutics) EXG-102-031 (Exogenesis Bio)Caveolin Modulator
Ref-1 Inhibitor
SRPK1 Inhibitor
Inhibition of Insulin Receptor Substrate 1 (IRS-1)
Melanocortin Receptor Agonist
Bcl-xL inhibitor
Squalamine analog
pegaptanib (Bausch + Lomb) FDA-approved ranibizumab (Genentech/Roche) FDA-approved Port Delivery System with ranibizumab (Genentech/Roche) Xlucane (Bausch + Lomb) ranibizumab-nuna (Samsung/Biogen) FDA-approved PF582 (Pfenex) ranibizumab-eqrn (Formycon/Coherus) FDA-approved ranibizumab-razumab (Intas) SJP-0133 (Senju Pharma) LUBTO10 (Lupin) Ongavia (Teva Pharmaceuticals) BCD100 (BIOCND/Qilu) CKD-701 (Chong Jun Dang) bevacizumab (Genentech/Roche) Off-label bevacizumab-vikg (Outlook Therapeutics) HLX04-O (Hengenix Biotech) TAB014 (Zhaoke Ophthalmology) CT-P16 (Celltrion) HLX04-O (Shanghai Henlius Biotech) Alymsys (Amneal Pharmaceuticals/mAbxience) AK-3008 (Anhui Anke Biotechnology) MIL-60 (Beijing Mabworks Biotech) brolucizumab (Novartis) FDA-approved abicipar pegol (Molecular Partners) KNP-301 (Kanaph Therapeutics) tarcocimab tedromer (Kodiak Sciences) ○ ▴ aflibercept (Regeneron) FDA-approved ○ ▴ High-dose aflibercept (Regeneron) FDA-approved ○ ▴ ALT-L9 (Alteogen/Kissei) ○ ▴ M710 (Mylan/Momenta) ○ ▴ SB15 (Samsung) ○ ▴ CHS-2020 (Coherus) ○ ▴ SOK583A1 (Sondoz/Novartis) ○ ▴ ABP 938 (Amgen) ○ ▴ OT-702 (Ocumension Therapeutics/Shandong Boan) ○ ▴ FY203 (Formycon/BioEq) ○ ▴ CT-P42 (Celltrion) ○ ▴ AVT-06 (Alvotech) ○ ▴ conbercept (Kanghong Biotech) CDE-approved ○ ▴ conbercept (Kanghong Biotech)The tyrosine kinase cascade is activated when VEGF binds to its receptor, and may be effective at interacting with VEGF receptors 1, 2, and 3,1 and some of the TKIs in the retina pipeline have been used in the oncologic space.2 So far, trials assessing the safety and efficacy of TKIs have evaluated approaches that include intravitreal, oral, and microparticle-based sustained delivery methods.1
The earliest iterations of approved treatments for wet AMD blocked VEGF-A, soon to be followed by an option that blocked VEGF-A, VEGF-B, and PlGF. Despite efforts to show the safety and efficacy of other approaches, no drug approved for the treatment of wet AMD relied on a method other than VEGF and PlGF inhibition—that is, until the approval of faricimab (Vabysmo, Genentech/Roche) in January 2022.
Here’s some of the latest news on multitargeted therapy for wet AMD.
VEGF/Ang-2 inhibition seeks to counter upregulation of Ang-2, which has been implicated in vascular leakage, inflammation, and neovascularization in wet AMD.1 Faricimab is the only therapeutic agent approved for this approach, but researchers continue to evaluate other drug candidates leveraging dual inhibition of VEGF and Ang-2.
VEGF-C/D inhibition has been evaluated in a phase 2b study.2 Current formulations and approaches use intravitreal injection therapy that occurs alongside conventional anti-VEGF or anti-VEGF/Ang-2 treatment. In phase 2b, patients with wet AMD who received high-dose OPT-302 (Opthea) and ranibizumab (Lucentis, Genentech) gained significantly more letters than those who received monotherapy (14.2 vs 10.8 letters, P = .01).2
Integrin inhibition has the potential to be used as a primary therapy, an adjunctive therapy, or as a treatment for patients whose disease has not responded to other treatments.3 The integrins α5β1, αvβ3, and αvβ5 are among the targets under investigation by researchers evaluating various pipeline candidates.
This content originally ran as a poster in the November/December issue. Check out the print publication to view the full size poster, or download the PDFs.
If you wish to include a candidate for wet AMD, dry AMD, or GA therapy in next year's poster, email Peter K. Kaiser, MD, at pkkaiser@gmail.com and Cara Deming, Executive Director of Special Projects, at Bryn Mawr Communications, at cdeming@bmctoday.com.
View previous pipelines to see how it has evolved over the years.
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