Press Release
CRISPR Therapeutics Announces Positive Phase 1 Clinical Data for CTX310® Demonstrating Deep and Durable ANGPTL3 Editing, Triglyceride and Lipid Lowering
-Data presented in a late-breaking presentation at the
-Phase 1 clinical data for CTX310® demonstrate robust, dose-dependent reductions in circulating ANGPTL3 with a mean reduction from baseline of -73% (maximum -89%), a mean reduction in triglycerides (TG) of -55% (maximum -84%), and a mean reduction of low-density lipoprotein (LDL) of -49% (maximum -87%) at the highest dose-
-Among participants with elevated baseline TG (>150 mg/dL), a mean reduction of 60% in TG were observed at therapeutic doses-
-CTX310 was well tolerated with no treatment-related serious adverse events and no ≥Grade 3 changes in liver transaminases-
-Findings simultaneously published in
These data were presented today during a late-breaking session at the
"The publication and presentation of these Phase 1 results mark an important milestone for
“Seeing a single-course treatment safely lower both LDL cholesterol and triglycerides is truly unprecedented,” said
“Adherence to cholesterol-lowering therapy remains a major challenge in treating patients with heart disease,” said
CTX310
CTX310 is an investigational, lipid nanoparticle (LNP) delivered CRISPR/Cas9 therapy designed to precisely edit the ANGPTL3 gene in hepatocytes following a single-course IV administration. ANGPTL3 encodes a key protein that regulates TG and LDL levels, both well-established risk factors for atherosclerotic cardiovascular disease (ASCVD). Individuals with naturally occurring loss-of-function mutations in ANGPLT3 have lower TG, lower LDL and a reduced lifetime risk of cardiovascular disease compared to those without such mutations. By reducing ANGPTL3 expression, CTX310 has the potential to durably lower TG and LDL cholesterol in patients with severe or refractory dyslipidemia. More than 40 million people in
Phase 1 Clinical Trial Design
The Phase 1, open label, dose-escalation trial evaluated single-course IV doses of CTX310 ranging from 0.1 to 0.8 mg/kg (lean body weight) targeting ANGPTL3 in four patient groups: homozygous familial hypercholesterolemia (HoFH), severe hypertriglyceridemia (sHTG), heterozygous familial hypercholesterolemia (HeFH), or mixed dyslipidemias (elevated TG and LDL). Eligible participants had uncontrolled TG levels >150 mg/dL and/or LDL cholesterol >100 mg/dL (or >70 mg/dL for those with established ASCVD) despite background standard of care per local guidelines.
The majority of participants were receiving statins and/or ezetimibe, while 40% were taking PCSK9 inhibitors. The trial was designed to evaluate safety and tolerability as primary endpoints, with changes in circulating ANGPTL3 protein, TG, and LDL as secondary endpoints.
Safety and Tolerability
Single-course ascending doses of CTX310 were administered to 15 participants across sequential cohorts, and all participants completed at least 28 days of follow-up as of the data cutoff. CTX310 was generally well tolerated, and no dose-limiting toxicities or serious adverse events related to treatment.
Adverse events were generally mild to moderate. One participant experienced an allergic reaction that resolved the following day with supportive care. Infusion-related reactions occurred in three participants (two at 0.6 mg/kg and one at 0.8 mg/kg dose), all Grade 2. All events resolved, and all participants completed their infusions. One participant with elevated transaminases level at baseline had a Grade 2 elevation of transaminases that peaked by Day 4 and resolved completely by Day 14 without any rise in bilirubin.
Overall, CTX310 demonstrated a well-tolerated safety and tolerability profile that supports continued advancement of the program.
Efficacy Highlights
These new results build upon previously disclosed top-line data from 12 participants across the first four sequential cohorts, corresponding to lean body weight-based doses of DL1 [0.1 mg/kg], DL2 [0.3 mg/kg], DL3 [0.6 mg/kg] and DL4 [0.8 mg/kg]. All participants had at least 30 days of follow-up.
- Dose-dependent reductions in circulating ANGPTL3 protein: Mean (range) among participants treated with 0.1, 0.3, 0.6, 0.7, and 0.8 mg/kg doses were 10% (-22 to 71), 9% (-25 to 64), -33% (-51 to -19), -80% (-87 to -73), and -73% (-89 to -67), respectively, at Day 30 following CTX310 infusion.
- Among participants treated at 0.8 mg/kg, TG reductions of up to 84% were observed, with a mean reduction of 55% at Day 60 following CTX310 infusion.
- In participants with elevated TG (>150 mg/dL) at baseline, mean reductions of 60% were observed at the therapeutic dose levels at Day 60 following CTX310 infusion.
- Among participants treated at 0.8 mg/kg, LDL reductions of up to 87% were observed, with a mean reduction of 49% at Day 60 following CTX310 infusion.
- Two participants on background PCSK9 inhibitors achieved >80% reduction in LDL from baseline.
Results from the Phase 1 clinical trial highlight the potential of CTX310 to safely and durably lower both TG and LDL following a single-course IV administration. These findings underscore its promise as a potentially transformative treatment approach for patients with severe or refractory dyslipidemia.
About In Vivo Programs
CRISPR Therapeutics has established a proprietary lipid nanoparticle (LNP) delivery platform to enable gene editing in the liver using both CRISPR/Cas9 and its novel, proprietary SyNTase™ editing technologies. The Company’s in vivo portfolio includes its lead investigational programs, CTX310 (directed towards angiopoietin-related protein 3 (ANGPTL3)) and CTX320™ (directed towards LPA, the gene encoding apolipoprotein(a) (apo(a)), a major component of lipoprotein(a) [Lp(a)]). Both are validated therapeutic targets for cardiovascular disease. CTX310 and CTX320 are in ongoing clinical trials in patients with heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, mixed dyslipidemias, or severe hypertriglyceridemia, and in patients with elevated lipoprotein(a), respectively. In addition, the Company’s research and preclinical development candidates include: CTX460™, targeting SERPINA1 for the treatment of alpha-1 antitrypsin deficiency (AATD); CTX340™, targeting AGT for the treatment of refractory hypertension; and CTX450™, targeting ALAS1 for the treatment of acute hepatic porphyria (AHP).
About
Founded over a decade ago, CRISPR Therapeutics is a leading gene editing company focused on developing transformative medicines for serious diseases. The Company has evolved from a pioneering research-stage organization into an industry leader, marking a historic milestone with the approval of CASGEVY® (exagamglogene autotemcel [exa-cel]), the world’s first CRISPR-based therapy, approved for eligible patients with sickle cell disease and transfusion-dependent beta thalassemia.
CRISPR Therapeutics Forward-Looking Statement
Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, statements made by Drs. Nicholls, Nissen and Patel in this press release as well as statements regarding any or all of the following: (i) CRISPR Therapeutics preclinical studies, clinical trials and pipeline products and programs, including, without limitation, manufacturing capabilities, status of such studies and trials, potential expansion into new indications and expectations regarding data, safety and efficacy generally; (ii) data included in the above-described oral presentation and any associated abstracts or posters, data included in the above-described article in
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Source: CRISPR Therapeutics AG
