CRISPR Therapeutics Provides First ANGPTL3 Data

Good morning, biotech.

Yesterday, regulatory uncertainty hit fever pitch with the appointment of Dr. Vinay Prasad to head the CBER division regulating biologics, including gene therapies and genome editing at the FDA.  Instead of assuming the worst for this line of drug development, I remain a firm believer that those that matter most, very sick people, will continue to push for medicines that can be shown to be safe and effective, and that Dr Prasad keeps to his view that the FDA should not make it harder, and therefore more costly, to develop drugs for severe rare diseases which have shown promise.

With that out of the way, let’s dive into the first data snapshot provided by CRISPR Therapeutics on its first-in-human trial with CTX310 (Cas9 knockout of ANGPTL3) for disorders related to high lipds, especially triglycerides and LDL cholesterol.

 

ANGPTL3 as a genetically and pharmacologically validated target

There is strong genetic evidence that reduced ANGPTL3 activity is associated with cardiovascular benefit.  A (life-long) 50% reduction in ANGPTL3 due to heterozygous loss-of-function variants cuts the odds of developing cardiac artery disease by almost half (Dewey et al,2017).  These subjects have modestly lower triglyceride (-27%) and LDL-cholesterol (-9%) levels.

Pharmacologic inhibition is even more impactful.  The ANGPTL3-targeting monoclonal antibody evinacumab from Regeneron for example lowers TG by about -80% in hypertriglyeridemia patients (Ahmad et al, 2019).  RNAi knockdown with ARO-ANGPTL3 from Arrowhead Pharmaceuticals with an ANGPTL3 knockdown efficiency of ~-70% resulted in approximately -60% TG, -60% remnant cholesterol (known ASCVD risk factor), and a modest -10% LDL-cholesterol reduction in mixed hyperlipidemia patients (Rosenson et al, 2024).

It should be noted, however, that besides an approval in very rare homozygous familial hypercholesterolemia, approval and development in other indications has somewhat stalled with ANGPTL3 inhibitors/knockdown agents.  Indeed, a study with evinacumab in multifactorial severe hypertriglyceridemia subjects failed to show statistically significant triglyceride lowering (Rosenson et al 2023)!  This and the fact that outcomes studies using non-genome editing modalities are lacking, makes ANGPTL3 potentially the most difficult cardiovascular disease target to bring to a large patient populations among the PCSK9, Lpa, and ANGPTL3 trifecta.

 

CTX310 shows steep dose response…and a surprise

CTX310 is an LNP formulation comprising an mRNA encoding Cas9 nuclease and a guide RNA aimed at the angiopoietin-like 3 gene.  Although the company wants to develop CTX310 for homozygous familial hypercholesterolemia which is characterized by LDL-receptor deficiency, the same receptor that standard LNPs rely on for uptake in hepatocyte, I assume that CTX310 does not include ASGPR-targeting via the addition of GalNAc ligands.

CTX310 was tested at 4 doses. It should be added here that the company provided doses on the ‘basis of lean body weight’ probably in the hope that it may in fact be a better predictor of drug delivery to the liver compared to dosing based on pure body weight or fixed doses.

Anyway, the 2 lowest doses (0.1 and 0.3mg/kg) showed no desired pharmacodynamic effect.  In fact, mean LDL-cholesterol strangely increased from baseline by 35% just 30 days after drug administration (n=3).  At 0.6mg/kg (n=3) and 0.8mg/kg (n=1; ~0.48mg/kg not adjusted for lean muscle), however, there was knockdown of serum ANGPTL3 of ‘up to -75%’ with concomitant decreases of TGs and LDLc of -56% and - 29%, respectively, at 0.6mg/kg.  At 0.8mg/kg the company reported a remarkable -65% LDL-cholesterol reduction on day 30 reaching a whopping -80% on day 90 in a patient with severe hypertriglyceridemia (TG>500mg/dL).  Triglycerides were also lowered by over -80% in this subject.

Safety findings, particular in terms of changes in liver enzymes and platelets, were characterized as 'not clinically significant', and clearly need further disclosure.  

Also because of its likely non-ASGPR-targeting nature, severe hypertriglyceridemia should be the most promising indication for CTX310, for example to prevent pancreatitis. The LDL cholesterol effects, however, warrant further investigation and may justify development for ASCVD.  Given that this was seen in just one subject, the 0.1 and 0.3mg/kg LDL-cholesterol increases in LDLc indicating there may be something odd with the assay, and that it is in great contrast to the genetic and pharmacodynamic evidence presented above, further subjects dosed at 0.8mg/kg may not show such dramatic effects.  If the values are real, however, and given the near opposite findings with evinacumab in severe hypertriglyceridemia, a closer look at the genetics of this subject may lead to fresh insights into lipid biology and render ANGPTL3 a more predictable target.