BeBetter Med has submitted the IND application for BEBT-507, a siRNA that targets TMPRSS6, in patients with iron metabolism disorders (Polycythemia Vera, Disease of Iron Overload, etc.). This marks BeBetter's first potential RNAi therapy to reach the clinical stage. The second siRNA therapy targets NAFLD/MAFLD.
BEBT-507
TMPRSS6 is a serine protease expressed in the liver that negatively regulates the iron-regulatory hormone hepcidin. Using siRNA to silence TMPRSS6 can increase hepcidin levels, offering a therapeutic approach for iron overload and related conditions.
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| TMPRSS6 |
| Patent |
TMPRSS6 Therapies in the Clinical Stage
Different technology modalities, such as ASO, siRNA, and antibody, are being investigated from the preclinical stage to phase 2. Various technological approaches may bring more possibilities for disease treatment.
SapablursenSapablursen (Formerly ISIS 702843, IONIS-TMPRSS6-LRx), developed by Ionis, is a GalNAc-ASO that targets TMPRSS6 mRNA. While it was initially being tested for Polycythemia Vera and β-thalassemia, Ionis terminated the phase 2 trial (NCT04059406) for non-transfusion-dependent β-Thalassemia Intermedia due to the mid-stage results not meeting the minimum efficacy target. However, the phase 2 trial for Polycythemia Vera is still ongoing.
Divesiran
Divesiran (SLN124) is a siRNA developed by Silence Therapeutics using its proprietary mRNAi GOLD™ platform, designed to "silence" TMPRSS6, which is primarily expressed in the liver. Silence initiated trials in patients with Thalassemia, Polycythemia Vera, and Myelodysplastic Syndromes (MDS), but currently, only the phase 1/2 trial for Polycythemia Vera remains active.
The results of the phase 1 trial in healthy volunteers demonstrated that increases in plasma hepcidin levels coincided with sustained reductions in serum iron and transferrin saturation (TSAT). The most significant reductions in serum iron and TSAT were observed after administering SLN124 at 3 mg/kg, suggesting a potential ceiling effect at this dosage.
| Mean serum iron concentration |
9MW3011
9MW3011 (DISC-3405), discovered by Mabwell, is an anti-TMPRSS6 antibody, licensed to Disc Medicine in 2022. Now 9MW3011 is under investigation in the phase 1b trials in patients with Polycythemia Vera and β-thalassemia.
In 2024, Mabwell presented the results of the phase 1 study in healthy volunteers. Subcutaneous DISC-3405 administration demonstrated a dose-dependent pharmacokinetic profile with a terminal half-life greater than 11 days at 300 mg. The drug led to dose-related increases in hepcidin and reductions in serum iron, achieving over 50% reduction from baseline at both 150 mg and 300 mg doses. For the 300 mg dose, this reduction was maintained for at least 4 weeks.
| Results of the ph1 trial of 9MW3011 |
REGN7999 is an antibody inhibitor of TMPRSS6, discovered by Regeneron. In June, Regeneron commenced the first phase 2 trial of REGN7999 in patients with Non-Transfusion Dependent β-thalassemia.
Single doses of REGN7999 (10–900 mg) produced acute increases in serum hepcidin ranging from two-fold to 12-fold across all dose cohorts. Administration of REGN7999 via IV (10–900 mg) and SC (100–900 mg) routes led to acute reductions in serum iron from baseline by 50–70%. The highest SC and IV doses achieved the longest sustained effects, maintaining reduced serum iron levels for up to 7 weeks.
| Results of the phase 1 trial of REGN7999 |
siRNA TMPRSS6
siRNA TMPRSS6A, targeting TMPRSS6, was discovered by Alnylam and acquired (in 2023) by Agios. It is currently in the preclinical stage.
RLYB331
RLYB331 (KY1066) is an anti-Matriptase-2 (MTP-2, TMPRSS6 ) antibody discovered by Sanofi and acquired (in 2022) by Rallybio. Rallybio is currently investigating the antibody in the preclinical stage, with potential applications in targeting severe Anemia.
STP251G
STP251G is in preclinical development for Hemochromatosis and Hypertriglyceridemia, formulated with Sirnaomics’ proprietary GalAhead™ platform that targets TMPRSS6 and APOC3.
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