PureTech’s Karuna Gets Another $68m For Re-engineered Lilly CNS Candidate
Executive Summary
Karuna Therapeutics plans to expand its development program for lead candidate KarXT beyond its current Phase II trial in schizophrenia. The series B financing follows a $42m series A in 2018.
Karuna Therapeutics Inc. has raised $68m in a series B round led by ARCH Venture Partners. The firm, an affiliate of PureTech Health PLC, was set up to revive development of the muscarinic acetylcholine receptor agonist xanomeline, formerly under development by Eli Lilly & Co. but discontinued because of its side effects.
Karuna’s KarXT is a co-formulation of xanomeline with the peripherally acting muscarinic antagonist trospium chloride. The purpose of the combination is to create a treatment that harnesses xanomeline’s previously demonstrated therapeutic effects but blunts its peripheral side effects. Xanomeline had shown efficacy in treating psychosis and beneficial effects on cognition in schizophrenia and Alzheimer’s disease.
Trospium chloride, which is approved for overactive bladder in the US and Europe and which has been shown not to enter the central nervous system, has been paired with xanomeline to create a drug that should selectively target M1/M4 muscarinic cholinergic receptors in the brain while blocking their activation in peripheral tissues, thereby obtaining an improved tolerability compared with xanomeline alone.
In trials in mild-to-moderate Alzheimer’s disease in the 1990s, xanomeline reduced disturbing behaviors and at the highest dose tested improved cognitive function. However, at the highest dose, more than half of the patients withdrew because of adverse events (predominantly dose-dependent gastro-intestinal events), and syncope occurred in about 13%.
Since xanomeline has not been observed to cause the serious side effects associated with marketed antipsychotics (such as tardive dyskinesia, metabolic dysfunction, weight gain and sedation), and unlike them appears to address negative and cognitive symptoms as well as positive symptoms of schizophrenia, it has the potential to serve unmet patient needs if its tolerability can be addressed.
Negative symptoms of schizophrenia include severely reduced emotional expressiveness, loss of capacity to experience pleasure, lack of motivation and drive, and social withdrawal, while positive symptoms include hallucination, delusion and thought and movement disorder. Cognitive symptoms include an impaired ability to organize thoughts and activities and make decisions, impaired attention and difficulties with learning, reasoning and comprehension. According to Datamonitor Healthcare, negative symptoms may be present in up to 58% of schizophrenia patients, while 47% of patients experience cognitive deficit.
The most commonly prescribed drugs for schizophrenia across the US, Japan and five major EU markets (Italy, France, Germany, Spain and UK) are the branded and generic versions of the oral D2 and 5-HT2A receptor antagonists aripiprazole (Otsuka Pharmaceutical Co. Ltd.’s Abilify), olanzapine (Lilly’s Zyprexa), risperidone (Johnson & Johnson’s Risperdal) and quetiapine (AstraZeneca PLC’s Seroquel), all of which have been available since the 1990s or early 2000s, according to a survey done by Datamonitor Healthcare in 2017.
While other companies have investigated muscarinic antagonists in the clinic, an analysis of Biomedtracker’s database shows that KarXT is the probably the only one still in development in schizophrenia. There are more than 30 drugs in Phase II or III development for schizophrenia, according to Datamonitor Healthcare.
KarXT Schizophrenia Study
Karuna has completed two Phase I trials of KarXT which showed it to be well tolerated in healthy volunteers and which demonstrated a clinically meaningful reduction in side effects compared with xanomeline alone. A co-formulation in a single capsule is now in a Phase II study in 180 patients with schizophrenia experiencing acute psychosis; top-line data are expected by the end of 2019. Patients will be given either KarXT or placebo capsules twice a day. The primary outcome measure is change in positive and negative syndrome scale (PANSS) total score at week five.
The firm additionally plans to expand development to include geriatric psychosis and pain. The latest financing will also fund pipeline expansion, the development of new formulations of KarXT and the building of company infrastructure.
Karuna’s CEO and chair is Steven Paul, former president of Lilly Research Laboratories, who helped oversee the original development of xanomeline at Lilly, as well as that of Zyprexa.
The $68m financing was led by ARCH Venture Partners with participation from Fidelity Management & Research Company, Eventide Asset Management, Pivotal bioVenture Partners, Partner Fund Management, Wellcome Trust, Sands Capital, Alexandria Venture Investments and PureTech Health, which owns 41% of the company following the financing. PureTech Health has established seven affiliate companies with clinical-stage R&D; its internal programs focus on tissue-selective immunomodulation in oncology, autoimmune and CNS-related disorders. Its overarching interest is in the connections between the brain, the immune system and the gut (the BIG axis).