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C3； Pegcetacoplan； Research progress
The complement system is a bridge connecting innate and adaptive immunity, and after activation, it participates in the body's defense response and immune regulation, including enhancing antibody response and having immune memory, lysing foreign cells, clearing immune complexes and apoptotic cells, etc. However, once the complement system is imbalanced or overactivated, it can lead to a variety of diseases, such as acute inflammation such as eye diseases, periodontal diseases, autoimmune system diseases, tumors, kidney diseases, chronic hemolytic diseases and neurodegenerative diseases.
Complement C3 is the highest complement component in serum, mainly synthesized by hepatocytes and macrophages, and participates in the classical activation pathway and bypass activation pathway of complement through activation and cleavage, thereby mediating the complement cascade. Currently, only one drug is approved globally for C3 targets, namely Pegcetacoplan.
The future of the first C3-targeted drug is unknown
Pegcetacoplan is a 13-amino acid cyclic peptide that inhibits the formation of C3 invertase, which in turn inhibits the complement pathway at the source. In October 2020, Sobi and Apellis entered into a partnership on Pegcetacoplan. Under the agreement, Sobi acquires commercial interests in markets outside the U.S. of the drug and will pay Apellis an upfront payment of $250 million + $915 million milestone + $80 million in research and development expenses + double-digit royalties on sales.
In May 2021, Pegcetacoplan was approved by the FDA for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) in adults with treatment-naïve paroxysmal nocturnal hemoglobinuria (PNH), as well as patients with PNH previously treated with C5 inhibitors under the trade name Empaveli. In December 2021, the drug was approved by the European Union for the treatment of adult patients with PNH who have been anemia after receiving C5 inhibitors for at least 3 months, under the trade name Aspaveli. In February 2023, the drug was approved by the FDA for the treatment of secondary dry age-related macular degeneration (AMD) and geographic atrophy of the macula (GA).
Pegcetacoplan is the first FDA-approved C3-targeted therapy for the treatment of PNH and the world's first approved drug for the treatment of macular map atrophy. It is worth mentioning that the drug was successfully shortlisted in the list of the top ten blockbuster new drugs predicted by market research agency Evaluate Vantage in early 2023. However, the future of Pegcetacoplan is not clear at the moment, and in July the American Association of Retinal Specialists said Syfovore had a rare but serious side effect. Moreover, affected by this news, Apellis' stock price has fallen for five consecutive days since July 14, almost cutting off.
In addition, the expansion of new indications for Pegcetacoplan is not smooth. In May, Apellis/Sobi announced that it would discontinue Pegcetacoplan's development for the ALS indication because Pegcetacoplan failed to meet its primary and key secondary endpoints in a II clinical study called MERIDIAN.
Research progress of C3-targeted drugs under investigation
In addition to Pegcetacoplan, there are currently a number of C3-targeted drugs under development around the world, as shown in the table below. According to Yaodu database, most of the C3-targeted drugs under development are in the clinical trial stage, and their drug types are very diversified, involving peptides (such as ZP 10068), fusion proteins, siRNAs (such as ARO-C3), bispecific antibodies (such as LP-005) and chemical drugs (such as APL-1030).
Some C3-targeted drugs under development worldwide
Source: Public information
In terms of specific varieties, ARO-C3, Compstatin 40, etc. are in the phase 2 clinical trial stage.
ARO-C3
ARO-C3 is an RNAi therapy that inhibits the expression of the C3 protein by binding to the mRNA encoding the C3 protein. In March, Arrowhead Pharmaceuticals announced positive interim results in a Phase 1/2 clinical trial of ARO-C3: ARO-C3 resulted in a dose-dependent reduction in serum C3 protein levels, averaging 88% reduction at the highest dose tested. Furthermore, ARO-C3 resulted in a dose-dependent reduction in the biomarker AH50, a biomarker that replaces the hemolytic activity of the complement pathway, with an average reduction of 91% at the highest dose tested. ARO-C3 has a long duration of efficacy and supports subcutaneous injections at quarterly or longer intervals. In addition, ARO-C3 was safe and well tolerated, with no dose-limiting toxicity and no serious adverse events identified, or study interruptions due to adverse events.
Compstatin 40
Compstatin 40, a novel synthetic cyclic peptide designed to intensively inhibit the complement cascade at the C3 level, has been shown to reverse pre-existing, naturally occurring periodontitis in monkeys. In March 2021, Amyndas Pharma announced positive top-line results from a Phase 2 clinical trial evaluating AMY-101 for the treatment of periodontitis and gingivitis: AMY-101 has a statistically significant and clinically significant efficacy in eliminating periodontal inflammation compared to placebo, and is safe and well tolerated.
NGM621
NGM621 is a humanized immunoglobulin 1 (IgG1) monoclonal antibody designed to effectively bind complement C3 and inhibit its activity for a long time. In October 2022, GM Bio announced that NGM621 failed in a Phase 2 clinical study that failed to meet the primary endpoint of geographic atrophy lesion area reduction. It is worth mentioning that NGM621 is a drug discovered in the strategic cooperation between NGM Bio and Merck. However, in December 2022, according to NGM's filing with the U.S. Securities and Exchange Commission, Merck had abandoned NGM621.
LP-005
LP-005 and others are in the phase 1 clinical trial stage. LP-005 is the first complement bifunctional antibody developed by Tianchen Biotech based on the self-developed iCibitorTM technology platform, which acts on C3 and C5 and is intended to be used to treat a variety of complement-related rare and common diseases. In June this year, the drug was approved for clinical use in China for the treatment of adult PNH.
However, the development of C3-targeted drugs has not been smooth. Apellis has abandoned two projects, APL-1030 and APL-2006, of which APL-1030, a first-of-its-kind brain-active C3 inhibitor used to treat neurological disorders. APL-2006 is a bispecific C3 and vascular endothelial growth factor (VEGF) inhibitor used to treat GA and wet age-related macular degeneration (AMD).
summary
Since the approval of the first complement drug Soliris in 2007, the development of complement system drugs has become more and more popular, and more and more complement drug targets have been discovered. The overall progress of C3 targets is relatively slow compared to C5, and the first marketed drug, Pegcetacoplan, is also not progressing smoothly, and serious side effects have been found. In addition, there does not appear to be promising progress in other drug candidates, except for ARO-C3. Most of the new drug research and development are dead, and I hope that C3 target layout companies will not experience a bamboo basket.
Article source: [Yaodu Daily] public number/Yi original