Another knock back for urea cycle disorders 

The past few months have been disappointing for those waiting for progress in the treatment of urea cycle disorders, a group of inherited metabolic conditions with few treatment options. The latest setback comes in the shape of Curevac’s exit from one of the most advanced potentially disease-modifying projects, in what some have interpreted as an ominous move from one of biopharma’s biggest mRNA researchers. 

Gene therapies or mRNA approaches are considered the best hope to improve or possibly even cure these disorders, which are characterised by a build-up of toxic waste products in the body. Curevac this week handed rights to ARCT-810 back to Arcturus Therapeutics; the partners had been due to seek permission to start clinical trials of the mRNA asset in the next couple of months. 

Curevac told Vantage that the decision was based on the profile of this specific agent, taking into account the preclinical dataset and the asset's progress overall. But the move came only three weeks after the FDA placed a similar Translate Bio project, MRT5201, on clinical hold, details about which are also thin on the ground. 

Both projects seek to treat OTC or ornithine transcarbamylase deficiency, the most common urea cycle disorder. Various genetic mutations can cause the urea cycle enzymes to lose effectiveness, with differing levels of severity, causing the build-up of ammonia. Hyperammonaemia affects the nervous system, eventually causing irreversible brain damage.

A liver transplant is the only cure; otherwise treatment revolves around reducing ammonia with scavenging agents like Horizon Therapeutics’ Ravicti, and by limiting the amount of protein in the diet. 

Go slow

Curevac/Arcturus and Translate alike were hoping to use lipid nanoparticles to deliver mRNA encoding a fully functional OTC enzyme to the livers of patients, enabling the production of normal forms of the enzyme.

Translate looked to be slightly ahead until news of the hold emerged. The FDA allowed a trial of the company’s cystic fibrosis mRNA project MRT5005 to begin in mid-2018; this also uses a lipid nanoparticle (LNP) delivery mechanism, so presumably the agency does not have fundamental concerns about Translate’s platform. 

Notably, the start of the cystic fibrosis trial was also delayed by the FDA, so that Translate could answer questions about manufacturing. The hold on MRT5201 seems to be for different reasons – all the company has said so far is that the regulator has “clinical and nonclinical questions” – making it hard to gauge the significance of this pause.

Perhaps a clue can be found in a safety signal that emerged fairly soon after the cystic fibrosis programme began, in mid-2018: one of the first patients dosed developed flu-like symptoms, though a safety committee allowed the trial to continue. Concerns about the potential for immunogenicity with mRNA encapsulated LNPs do exist, and as Translate is one of the first players to take this delivery into the clinic it is perhaps not surprising that the FDA is forcing the group to proceed cautiously. 

Whether Translate's problems have anything in common with Curevac’s decision is impossible to gauge. Arcturus has said it will push on with an application to take ARCT-810 into the clinic later this year, and it will be interesting to see whether it keeps to this timeline. 

Curevac declined to confirm speculation that a liver toxicity signal had been seen, something mooted by the Leerink analyst Geoffrey Porges. 

“[Curevac’s decision] most likely means that Curevac observed significant preclinical safety issues as we would have expected biomarkers to have already established efficacy earlier in preclinical development given the decision to proceed to IND,” he wrote in a note earlier this week. 

The German company told Vantage that it “continues to believe that mRNA is a perfect candidate on which to encode the protein to resolve OTC deficiency, and that LNP is an excellent delivery vehicle”. A swift move into the clinic by both Arcturus and Translate Bio would help remove growing scepticism.

For now, Ultragenyx’s gene therapy is the sole clinical project to watch in OTC deficiency, but results here have been inconclusive. Two doses of DTX301 have been tested in six patients, and both of the three-patient cohorts produced one responder apiece. Encouragingly, both of these patients’ urea cycles returned to normal, and one subject has been stable for eight months, as per the last update. 

But the lack of response in the other four patients, particularly in those who received the higher dose, has raised concerns. Ultragenyx has started a third, higher-dose group in a further three patients; unless this shows a more uniform response it will be hard to see this approach going anywhere fast. 

Initial results from the third cohort of DTX301 are due around the middle of the year, by which time Arcturus and Translate Bio should also have given an update. An important few months for OTC deficiency research approaches.

The recent developments might have broader implications for the mRNA field, Mr Porges wrote. Diseases that require delivery to the liver, where RNA is degraded, should represent low-hanging fruit for mRNA therapies. In OTC deficiency the affected enzymes are expressed in the liver, so failure to get into the clinic in this disorder would be a big blow for the mRNA field.