Karuna seeks a novel schizophrenia mechanism

Pivotal data will show whether KarXT can walk the risk-benefit tightrope.

The current generation of antipsychotics all work in a broadly similar way: inhibiting dopamine and serotonin receptors. These therapies leave a lot to be desired, however, with around three quarters of patients having to try multiple treatments and around a quarter eventually deemed non-responders.

Novel mechanisms are needed, but developing these has proven tricky. One project that previously showed promise was Lilly’s muscarinic agonist xanomeline, but high rates of cholinergic side effects such as nausea, vomiting and syncope scuppered development.

Now xanomeline is back in a different guise and its current owner, Karuna Therapeutics, hopes to have ameliorated these adverse events. The Puretech Health affiliate has developed KarXT, a coformulation of xanomeline with trospium chloride, a peripheral muscarinic receptor antagonist. The idea is that trospium cancels out xanomeline’s peripheral side effects but does not hamper its effect in the brain.

A key test of this approach is set for mid-year with the readout of Karuna’s first schizophrenia pivotal trial, Emergent-2.

Project KarXT (xanomeline + trospium)
Company Karuna Therapeutics
Market cap $3.2bn
Product NPV $4.7bn
% of market cap 147%
Indication Schizophrenia
Event type Topline data from ph3 Emergent-2 
Date Mid-2022 

The group hopes to replicate the impressive result from the phase 2 Emergent-1 study, which found an 11.6-point difference between KarXT and placebo on the positive and negative syndrome scale (PANSS) total score at week five.

On Karuna’s side is the fact that Emergent-2 is “very, very similar” to Emergent-1, Karuna’s chief operating officer, Andrew Miller, tells Evaluate Vantage. “The overall study size is modestly larger, but we have the same primary endpoint and same basic criteria.”

Still, there is often a drop-off in efficacy between phase 2 and phase 3, and this is something that Karuna is prepared for. Mr Miller says the company has been “appropriately conservative” in its assumptions, with Emergent-2 90% powered to detect a 6.5-point delta between KarXT and placebo.

He adds that such a difference would still be clinically meaningful. Notably, the most recent antipsychotic to gain approval, Intra-Cellular Therapies’ Caplyta, did so off the back of a 4.2-point placebo-adjusted benefit on PANSS in one phase 3 study; the other pivotal trial failed.

Heart effects

As for adverse events, Karuna investors will be keeping an eye on the aforementioned cholinergic effects, as well as heart rate; an increase in the latter has been seen with xanomeline. Mr Miller notes that so far this rise has been fairly small – about 5-6 beats per minute – and it “tends to trend back towards baseline with time”.

Stifel analysts term this issue “probably benign”, noting that Takeda’s Vyvanse, which has a similar effect on heart rate, is FDA approved for ADHD in children.

Overall, Mr Miller concludes: “I certainly wouldn't position KarXT as an adverse effect-free treatment. I suspect we'll continue to see some patients experiencing some mild or moderate xanomeline side effects.”

But he adds that if KarXT can show a similar adverse event profile as in phase 2, when discontinuations were similar between drug and placebo, “it’s going to be very favourable”.

Second shot

If Emergent-2 falls short, Karuna has another shot with the identical Emergent-3 trial, due to read out in the first quarter of next year.

The group is also testing KarXT in schizophrenia patients with inadequate response to standard of care, in the phase 3 Arise study. If successful, Karuna plans to file a supplemental NDA here.

Stifel describes KarXT as “about as derisked as you can get in neuropsychiatry” and has given the project a 75% probability of success in schizophrenia. However, studies in CNS disorders can and do go wrong, often when the placebo group does better than expected.

If Karuna negotiates these pitfalls, the sellside expects KarXT to bring in nearly $2bn by 2028, according to consensus forecasts compiled by Evaluate Pharma. For now, Stifel believes the project will largely be given to non-responders to current therapies, but if Emergent-2 impresses this could lead to broader use.

Karuna is looking for partners outside the US – it already has Zai Lab on board in Greater China – but plans to go it alone on its home turf. And the company has the resources to do so, with $440m in the bank at the last count.

Competition could be coming in selective muscarinic agonism, but Karuna is in the lead for now. Flawless execution in phase 3 would be a good start if the biotech wants to stay ahead of its rivals.  

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