Product Candidate**
PureTech Ownership
Initial Indications
Preclinical
Phase 1
Phase 2
Phase 3
KarXT
18.1% (Karuna)
Schizophrenia, Dementia-related psychosis, Pain

Initial Indication(s):

Schizophrenia, Dementia-related psychosis, Pain

Patient Population:

Schizophrenia (~2.7M),
Dementia-related Psychosis (~1.2M),
Pain

Collaborators:

teva NYU memorialSloanKet

Key Differenciation:

Karuna is targeting muscarinic cholinergic receptors for the treatment of psychosis and cognitive impairment across CNS disorders, including schizophrenia and dementia-related psychosis, as well as pain. Pending the outcome of an end of Phase 2 meeting with the FDA, Karuna's lead program is expected to enter a Phase 3 study by the end of 2020.



KarXT
Schizophrenia, Dementia-related psychosis, Pain
18.1% (Karuna)
Phase 2

Initial Indication(s):

Schizophrenia, Dementia-related psychosis, Pain

Patient Population:

Schizophrenia (~2.7M),
Dementia-related Psychosis (~1.2M),
Pain

Collaborators:

teva NYU memorialSloanKet

Key Differenciation:

Karuna is targeting muscarinic cholinergic receptors for the treatment of psychosis and cognitive impairment across CNS disorders, including schizophrenia and dementia-related psychosis, as well as pain. Pending the outcome of an end of Phase 2 meeting with the FDA, Karuna's lead program is expected to enter a Phase 3 study by the end of 2020.

Targeting muscarinic cholinergic receptors for the treatment of psychosis and cognitive impairment across CNS disorders 

Founded by PureTech, Karuna is targeting muscarinic cholinergic receptors for the treatment of psychosis and cognitive impairment across central nervous system (CNS) disorders, including schizophrenia and dementia-related psychosis, as well as pain. 

KarXT consists of xanomeline, a novel muscarinic acetylcholine receptor agonist that has demonstrated decreases in multiple psychotic symptoms and improvements in cognitive symptoms in placebo-controlled human trials in schizophrenia and Alzheimer’s disease, and trospium chloride, an FDA approved and well-established muscarinic receptor antagonist that has been shown not to measurably cross the blood-brain barrier. KarXT is designed to preferentially stimulate M1/M4 muscarinic receptors in the brain without stimulating muscarinic receptors in peripheral tissues to significantly improve tolerability.

This novel product candidate has the potential to be one of the most promising new mechanisms for the treatment of people with psychosis and cognitive impairments in serious CNS disorders that affect tens of millions of people. If successful, KarXT could provide a new mechanism for treating schizophrenia, a field in which treatments have relied on the same fundamental mechanisms for the last half-century.

In December 2016, we reported positive results from our tolerability proof-of-concept study and are currently conducting a Phase 1 study using a proprietary co-formulation of xanomeline and trospium. A Phase 2 trial to evaluate the efficacy and safety of KarXT in people with schizophrenia is expected to begin in the third quarter of 2018.

  • Program Discovery Process by the PureTech Team
    • PureTech was interested in developing a new approach to treat schizophrenia that was effective but did not have the debilitating side effects of the current class of antipsychotics, realizing that any potential new approaches could have wider applicability. PureTech engaged with a group of leading schizophrenia experts who were most excited about muscarinic agonists, pointing to the data generated by Eli Lilly with xanomeline, which was not advanced at that time due to tolerability issues. PureTech invented and broadly filed patents to cover the concept of combining a muscarinic receptor agonist with a peripherally acting antagonist, and it in-licensed xanomeline from Eli Lilly in May 2012. The core team member who was running this program at PureTech became Karuna’s chief operating officer and PureTech built a team of leading drug developers and neuroscientists around him, including Steven Paul, MD, an expert in central nervous system (CNS) drug discovery and development. Karuna completed an initial public offering (IPO) on the Nasdaq Global Market in July 2019. 
    • Dr. Paul was formerly executive vice president for science and technology and president of the Lilly Research Laboratories at Eli Lilly, and was involved in the original xanomeline work at Eli Lilly. Dr. Paul was also a co-founder of Sage Therapeutics and Voyager Therapeutics, where he also served as chief executive officer, and the former scientific director of the National Institute of Mental Health.
  • Patient Need & Market Potential
    • Psychosis and cognitive impairments are debilitating features of schizophrenia, dementia-related psychosis and other mental illnesses that affect tens of millions of people, but there are no existing medicines that sufficiently and safely treat psychosis and cognition impairments. 
      • There are approximately 2.7 million adults living with schizophrenia and approximately 8.4 million people living with dementia in the United States. 
      • Approximately 1.2 million of the estimated 8.4 million patients with dementia in the United States experience psychosis at some point during the course of their disease. 
      • People with schizophrenia have a ten to fifteen-year reduction in life expectancy compared to the general population, struggle to maintain employment or live independently and are often unable to maintain meaningful interpersonal relationships. 
    • Antipsychotics are the mainstay therapy; however, drugs currently in use all rely on the same fundamental mechanism of action and, despite widespread use, the prognosis for patients remains poor. Current antipsychotics have modest efficacy in many patients and significant side effects. 
      • Current antipsychotics only address psychosis, also known as positive symptoms, such as hallucinations and delusions, but despite treatment, patients often experience residual positive symptoms throughout their lives.
      • There are no approved treatments for the negative symptoms, such as apathy and loss of motivation, or cognitive symptoms, such as changes in working memory and attention, of schizophrenia, or the treatment of dementia-related psychosis. 
      • At least half of patients fail to adequately respond to current antipsychotic drugs.
      • Additionally, current treatments are often associated with severe side effects, including sedation, extrapyramidal side effects such as motor rigidity, tremors and slurred speech and significant weight gain resulting in the complications of diabetes, hyperlipidemia, hypertension and cardiovascular disease. 
    • There is an unmet need for new treatments in schizophrenia that could address the positive, negative and cognitive symptoms and are free of the problematic safety issues with existing medicines. There are currently no approved treatments for dementia-related psychosis. 
    • The current standard of care for neuropathic and inflammatory pain include opioids, nonsteroidal anti-inflammatory drugs, topical agents, anticonvulsants and antidepressants.
  • Innovative Approach to Solving the Problem
    • Karuna is targeting muscarinic cholinergic receptors for the treatment of psychosis and cognitive impairment across CNS disorders, including schizophrenia and dementia-related psychosis, as well as pain. 
    • Xanomeline was previously studied by Eli Lilly in randomized, double-blind, placebo-controlled trials in schizophrenia and AD, demonstrating dose-dependent decreases in multiple psychotic symptoms and related behaviors, including hallucinations, delusions and agitation, as compared to patients on placebo in the treatment of psychosis and improvements in symptoms as measured by both the Alzheimer’s disease Assessment Scale-Cognitive Subscale and the Clinician Interview-Based Impression of Change plus caregiver interview standards. 
    • To PureTech’s knowledge, xanomeline is the only muscarinic agonist that has demonstrated potential therapeutic benefit in humans in either schizophrenia or AD. Like all muscarinic receptor agonists studied to date, however, xanomeline’s tolerability has been limited by side effects arising from muscarinic receptor stimulation in peripheral tissues, leading to nausea, vomiting, diarrhea and increased salivation and sweating, which led Eli Lilly to discontinue development of xanomeline. By pairing xanomeline with trospium chloride, Karuna believes KarXT could potentially alleviate the tolerability issues seen with xanomeline while maintaining the improvement of positive, negative and cognitive symptoms of schizophrenia and psychosis in AD observed in previous Phase 2 studies.
  • Milestones Achieved
    • In November 2019, Karuna announced that KarXT achieved the primary endpoint of its Phase 2 clinical trial for the treatment of acute psychosis in patients with schizophrenia, demonstrating a statistically significant and clinically meaningful 11.6 point mean reduction in total Positive and Negative Syndrome Scale (PANSS) score compared to placebo (p<0.0001) and also demonstrated improved tolerability as compared to placebo. A statistically significant reduction in the secondary endpoints of PANSS-Positive and PANSS-Negative scores were also observed (p<0.001). KarXT demonstrated improved tolerability as compared to placebo, with similar discontinuation rates between KarXT (20 percent) and placebo (21 percent). The study enrolled 182 schizophrenia patients with acute psychosis, 90 of whom received KarXT. The number of discontinuations due to treatment emergent adverse events (AEs) were equal in the KarXT and placebo arms (n=2 in each group). One serious adverse event (SAE) was experienced in the drug treatment arm, in which the patient discontinued treatment and subsequently sought hospital care for worsening psychosis, meeting the regulatory definition of an SAE. In Karuna’s Phase 1 tolerability POC study, KarXT was better tolerated than xanomeline plus placebo and no serious or severe adverse events, or SAEs, were reported.
    • The safety and tolerability of KarXT and dose selection for the Phase 2 clinical trial was supported by results from Karuna’s two Phase 1 healthy volunteer studies in over 140 patients with KarXT. As disclosed in its public filings, Karuna observed in its first Phase 1 randomized, double-blind placebo-controlled study that the addition of trospium to xanomeline was associated with clinically meaningful reductions in the rate of the most common treatment-emergent cholinergic adverse events (ChAEs) than reported with xanomeline plus placebo, including nausea, vomiting, diarrhea and excess sweating and salivation.
    • Karuna’s second Phase 1 study was a randomized, double-blind, placebo-controlled multiple ascending dose trial of KarXT. This trial evaluated twice-a-day dosing of the proprietary KarXT co-formulation containing fixed ratios of xanomeline and trospium, rather than the three-times-a-day dosing previously used with xanomeline. The study demonstrated tolerability at xanomeline dose levels exceeding those shown in previous studies of xanomeline alone. The co-formulation also achieved exposure levels equivalent to or higher than the separate dosage forms used previously. 
    • Xanomeline has also shown potent activity preclinically in a number of models of analgesia, demonstrating the potential of KarXT to treat a variety of pain indications, including acute, inflammatory and neuropathic pain, and addressing the need for non-opioid pain medications.
  • Expected Milestones
    • Karuna has scheduled an end-of-Phase 2 meeting with the United States Food and Drug Administration (FDA) and expects to provide feedback from the meeting in the second quarter of 2020, and pending the outcome of that meeting, anticipates advancing KarXT into a Phase 3 clinical trial by the end of 2020. 
    • Karuna anticipates topline results from a Phase 1b clinical trial for the treatment of experimentally induced pain in healthy volunteers in mid-2020, and topline results from a Phase 1b clinical trial in healthy elderly volunteers to assess the safety and tolerability of KarXT for the treatment of dementia-related psychosis by the end of 2020.

Karuna announced that KarXT achieved the primary endpoint of its Phase 2 clinical trial for the treatment of acute psychosis in patients with schizophrenia. Karuna plans to hold an end-of-Phase 2 meeting with the United States Food and Drug Administration (FDA) in the second quarter of 2020, and pending the outcome of that meeting, anticipates advancing KarXT into a Phase 3 clinical trial by the end of 2020.

 


 KarXT selectively activates muscarinic receptors in the brain


Phase 2 clinical trial primary endpoint: PANSS total score at Week 5




Clinically meaningful and statistically significant improvement in total PANSS vs. placebo

  • 11.6 point improvement at week 5 with p<0.0001 (-17.4 KarXT vs. -5.9 placebo)
  • Statistical separation at every assessed time point
  • Cohen’s d effect size of 0.75