China Fast-Follower Competition Reaches Clinical CRISPR

There is panic among Western biotech that Chinese competitors will eat their lunch with their capital-efficient fast-follower strategy which typically involves rapid clinical translation via investigator-initiated trials.  This issue has now reached the CRISPR space in the form of first clinical data announced by YolTech regarding a PCSK9 base editing trial for the treatment of hypercholesterolemia.

Almost identical to pioneer Verve Therapeutics which reported stellar data earlier this month (discussed here), YolTech’s YOLT-101 formulation involved a GalNAc-LNP encapsulating an adenine base editor mRNA and guide RNA targeting a splice site of the PCSK9 pre-mRNA for gene knockout.  The more detailed nature of the LNP formulation was not disclosed in the accompanying medRXiv publication.   

The trial tested 3 dose levels of YOLT-101: 0.2mg/kg (n=1), 0.4mg/kg (n=2), and 0.6mg/kg (n=3) indicating an unusually rapid move up in the dose level by international standards.  Efficacy was only reported for one subject treated with 0.4mg/kg and the three 0.6mg/kg subjects with heterozygous familial hypercholesterolemia.

Similar to Verve Therapeutics, LDL-cholesterol lowering was roughly -50% for 0.6mg/kg.  Unfortunately, the information provided did not allow for an analysis of the relationship of total dose of YOLT-101 and LDLc reduction.  On the PCSK9 front, YolTech seemingly did better than Verve Therapeutics reaching a mean of -76% versus the -60% for VERVE-102 both at 0.6mg/kg.

This, however, is where the similarities ended.  In terms of the critical safety of a potentially very widely applicable therapy, 3 out of the 6 subjects treated with YOLT-101 exhibited ‘transient elevations in ALT and AST’ that ‘almost’ returned to normal within one month.  Furthermore, 5 of 6 subjects experienced infusion-related reactions involving fever, myalgia, and vomiting. And similar to Verve’s ill-fated VERVE-101 formulation, one subject at the 0.4mg/kg dose experienced chest pain shortly after LNP infusion.

Nevertheless, the authors noted that the trial remains ongoing to ‘validate the therapeutic durability and safety profile’.  Considering the ALT/AST elevations for which more detailed values were not disclosed, it seems questionable whether this is an ethical decision.  Add to this the rapid dose escalation and selective data disclosures, it provides fodder to those criticizing China for allowing human experimentation and Big Pharma taking advantage of it by licensing therapeutic candidates built on such strategies on the cheap, not even mentioning the intellectual property issues of ‘Chinese Beam Therapeutics’