On December 19, 2024, the U.S. Food and Drug Administration (FDA) approved TRYNGOLZA™ (olezarsen), an RNA-targeted medicine for treating familial chylomicronemia syndrome (FCS). This "first-in-class" antisense oligonucleotide (ASO) therapy marks a breakthrough for small nucleic acid drugs in treating rare diseases.
Besides Tryngolza, several other small nucleic acid drugs are nearing approval. By the end of 2025, at least three such therapies are expected to be approved, including Arrowhead Pharmaceuticals' Plozasiran, Ionis Pharmaceuticals' Donidalorsen, and Fitusiran, developed by Alnylam in collaboration with Sanofi.
Related articles: Nucleic Acid Therapeutics: Approvals and Potential Blockbusters
Type | Name | Company | NDA Date | Target | Indication |
siRNA | Plozasiran | Arrowhead Pharmaceuticals | Nov 18, 2024 | APOC3 | Familial chylomicronemia syndrome |
ASO | Donidalorsen | Ionis Pharmaceuticals | Nov 4, 2024 | KLKB1 | Hereditary Angioedema |
siRNA | Fitusiran | Sanofi/Alnylam | Jun 21, 2024 | SERPINC1 | Hemophilia A or B |
Table 1. Small nucleic acid drugs expected to be approved by 2025
Olezarsen (Tryngolza )
- ◆ Treatment for: Familial Chylomicronemia Syndrome (FCS)
- ◆ Company: Ionis Pharmaceuticals, Inc.
- ◆ Approved Date: December 19, 2024
- ◆ Sales forecast: $112 million (2034. source: GlobalData)
Olezarsen is an RNA-targeted LIgand Conjugated Antisense (LICA) medicine designed to regulate triglyceride metabolism in the blood by lowering the body's production of apolipoprotein C-III (APOC3), a protein produced in the liver.
Figure 1. Olezarsen mechanism of action, source: Ionis official website
On December 19, 2024, the U.S. Food and Drug Administration (FDA) approved TRYNGOLZA™ (olezarsen) as an adjunct to diet for reducing triglyceride levels in adults with familial chylomicronemia syndrome (FCS). TRYNGOLZA is the first FDA-approved treatment shown to significantly reduce triglyceride levels in adults with FCS, offering a clinically meaningful decrease in acute pancreatitis (AP) events when used in combination with a low-fat diet (≤20 grams of fat per day).
The FDA approval was based on positive results from the Phase 3 Balance clinical trial, which included adult patients with genetically confirmed FCS and fasting triglyceride levels ≥880 mg/dL. In the Balance study, TRYNGOLZA 80 mg showed a statistically significant placebo-adjusted mean reduction in triglyceride levels of 42.5% from baseline to six months (p=0.0084). At 12 months, reductions were even more pronounced, with TRYNGOLZA achieving a placebo-adjusted mean reduction of 57% in triglyceride levels. Additionally, TRYNGOLZA demonstrated a significant, clinically meaningful reduction in AP events over 12 months. Only one patient (5%) in the TRYNGOLZA group experienced a single episode of AP, compared to seven patients (30%) in the placebo group who had a total of 11 AP episodes.
Plozasiran
- ◆ Treatment for: Familial chylomicronemia syndrome (FCS)
- ◆ Company: Arrowhead Pharmaceuticals
- ◆ Sales forecast: $707 million (2032. source: GlobalData)
Plozasiran is a first-in-class GalNac-conjugated siRNA therapy designed to reduce the production of APOC3, which is a component of triglyceride-rich lipoproteins (TRLs) and a key regulator of triglyceride metabolism. APOC3 increases blood triglycerides by blocking lipoprotein lipase activity and hindering the liver's uptake of TRLs. Plozasiran treatment aims to decrease APOC3 levels, thereby lowering triglycerides and restoring normal lipid profiles.
Figure 2. Plozasiran mechanism of action
Plozasiran has shown promising results in multiple clinical trials, particularly in the PALISADE study, where it reduced median triglyceride levels by 80% and acute pancreatitis by 83% compared to placebo, making it a potential game-changer for familial chylomicronemia syndrome (FCS).
On November 18, 2024, Arrowhead Pharmaceuticals announced that it had submitted an NDA to the FDA for plozasiran for the treatment of FCS. As the FDA review progresses, Arrowhead also plans to submit applications to other regulatory authorities in 2025.
Donidalorse
- ◆ Treatment for: Hereditary Angioedema (HAE)
- ◆ Company: Ionis Pharmaceuticals, Inc.
- ◆ Sales forecast: $399 million (2034. source: GlobalData)
Donidalorsen, designed with Ionis' Ligand-Conjugated Antisense (LICA) technology, is an investigational GalNAc3-conjugated antisense oligonucleotide (ASO) that binds to prekallikrein mRNA in the liver and reduces the expression of prekallikrein (PKK), a key enzyme involved in activating inflammatory mediators associated with acute attacks of hereditary angioedema (HAE). By silencing the production of PKK, donidalorsen could be an effective prophylactic approach to treating HAE.
In May 2024, Ionis reported positive results for donidalorsen in the Phase 3 clinical trials OASIS-HAE and OASISplus in patients with HAE demonstrating significant and sustained reduction in mean monthly HAE attack rates and continued attack rate improvement of >90% with one year of treatment for both monthly or every two-month dosing. Patients who switched to donidalorsen from prior prophylactic treatment also showed 62% further reduction in mean monthly HAE attack rates from baseline, and 84% of patients who switched reported a preference for donidalorsen.
On November 4, 2024, Ionis announced that the U.S. FDA had accepted the NDA for donidalorsen for the prevention of HAE attacks in adults and adolescents aged 12 years and older. The Prescription Drug User Fee Act (PDUFA) date is August 21, 2025. If approved, donidalorsen would be the first RNA-based therapy for HAE.
Fitusiran
- ◆ Treatment for: Hemophilia A or B
- ◆ Company: Sanofi/Alnylam
- ◆ Sales forecast: $151 million (2034. source: GlobalData)
Fitusiran is a subcutaneous investigational small interfering RNA therapeutic, designed to lower antithrombin (AT) with the goal of restoring sufficient TG to rebalance hemostasis in hemophilia A or B (PwHA/B), with or without inhibitors. Fitusiran works by lowering antithrombin levels, which in turn promotes thrombin generation, restoring hemostatic balance and preventing bleeding.
In two Phase 3 clinical trials, ATLAS-A/B and ATLAS-INH, patients receiving monthly subcutaneous injections of Fitusiran showed a 90% reduction in annualized bleeding rates compared to the control group. The U.S. FDA accepted the New Drug Application (NDA) for Fitusiran injection in June 2024.
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References:
[1] TRYNGOLZA™ (olezarsen) approved in U.S. as first-ever treatment for adults living with familial chylomicronemia syndrome as an adjunct to diet https://ir.ionis.com/news-releases/news-release-details/tryngolzatm-olezarsen-approved-us-first-ever-treatment-adults
[2] Arrowhead Pharmaceuticals Submits New Drug Application to U.S. FDA for Plozasiran for the Treatment of Familial Chylomicronemia Syndrome https://ir.arrowheadpharma.com/news-releases/news-release-details/arrowhead-pharmaceuticals-submits-new-drug-application-us-fda
[3] https://ir.ionis.com/news-releases/news-release-details/ionis-announces-fda-acceptance-new-drug-application-donidalorsen Ionis announces FDA acceptance of New Drug Application for donidalorsen for prophylactic treatment of HAE
[4] https://www.sanofi.com/en/media-room/press-releases/2024/2024-06-21-05-00-00-2902104 Sanofi advances leadership in hemophilia with new data for ALTUVIIIO and fitusiran
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