Dear readers,
I am excited to bring you the latest edition of Compbio, Pharma, & Ramblings! This week’s newsletter comes at the heels of a major announcement a few weeks ago, that the FDA has granted approval for Bristol Myers Squibb’s schizophrenia drug, Cobenfy. Today we’ll discuss why Cobenfy is significant, how it came to be, and some of the science behind it.
Schizophrenia is a common neuropsychiatric disorder that affects roughly 2.8 million Americans. It has a strong genetic component, with heritability estimates up to 80% (so to say, that roughly 80% of the variability of whether people have the disorder can be attributed to their variation in their genetics). Despite its prevalence, treatment options are limited and have been for a long time. The primary treatment options for individuals with schizophrenia are anti-psychotics, namely chlorpromazine. Chlorpromazine was the first anti-psychotic drug, first introduced in the 1950’s. It acts by targeting dopamine receptors which can relieve hallucinations associated with schizophrenia, in some cases. Estimates show that only about 20% of patients with schizophrenia are considered to be “well-treated”, while 50% have a partial response to medication, and 30% have minimal response to treatment. Altogether, there is ample room for improvement and novel treatments.
Chlorpromazine acts by interfering with dopamine receptor binding, but its exact mechanism of action remains unclear. Reasons for this include that the brain is complicated and the mechanisms by which schizophrenia manifests remain poorly understood. In general, it has always been very difficult to conduct research on traits related to the brain. Since the introduction of chlorpromazine in the 1950’s, advancements and changes in how schizophrenia is treated have been slow.
Cobenfy marks a significant development in schizophrenia treatment, as it is the first approved treatment to target something other than dopamine receptors. Its roots come from the drug xanomeline, which was originally Eli Lilly’s Alzheimer's drug, first brought to market in the 1990’s. During clinical trials, its antipsychosis benefits were first documented. It is able to do so by binding to what are called muscarinic receptors, which play a key role in the nervous system and have been shown to be linked to schizophrenia.
Xanomeline’s effectiveness as both to treat Alzheimer’s and to act as an antipsychotic were apparent, but it came with severe gastrointestinal side effects when applied in larger doses. So much so, that the phase II trial for an increased dose of xanomeline had a dropout rate of nearly 50%. The issue was that while xanomeline binds to receptors in the brain leading to the antipsychosis benefits, it also binds to receptors outside of the brain leading to the severe side effects. That’s where Boston-based Karuna Therapeutics came into play, when they acquired xanomeline from Eli Lilly in 2012, for just $100,000. Part of Karuna’s bet was that they could find a way to exploit xanomeline’s antipsychosis benefits for schizophrenia treatment in a way that was both efficacious and safe.
Their approach was to find something to counteract xanomeline’s binding to muscarinic receptors outside of the brain, which were driving the gastrointestinal side effects. The final product includes xanomeline coupled with a drug known as trospium chloride, which is used to treat overactive bladder and has little to do with psychiatry. Trospium chloride is a muscarinic receptor antagonist, so it competes with xanomeline for binding to the muscarinic receptors outside the brain that cause the severe side effects. At the same time, trospium chloride is unable to enter the brain. This means that it can target the same receptors as xanomeline that drive the side effects, while xanomeline is able to freely target the muscarinic receptors in the brain that are responsible for regulating schizophrenia symptoms. After nearly a decade of further development, they showed promising results in a phase III clinical trial.
This prompted BMS to acquire Karuna for a cool $16 billion, with the hopes of finishing what Eli Lilly and Karuna started, and bringing this treatment to market for schizophrenia patients. Just ten months after the acquisition, BMS gained FDA approval for Cobenfy. Looking ahead, BMS is continuing to study the long term effects of Cobenfy and plans to study its potential benefits in Alzheimer’s and bipolar disorder.
As always, with brevity in mind, I haven’t covered everything that there is to know in this space. For those interested in learning more, please find the referenced literature below to help guide your journey.
Have an invigorating and purposeful week!
Tommer
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Referenced Literature:
Fierce Pharma: BMS Karuna buyout pays off with FDA approval for novel schizophrenia med Cobenfy
New York Times: FDA approves first schizophrenia drug in decades
NPR: For the first time in decades, we have a new kind of schizophrenia drug
The Lancet: Efficacy and safety of the muscarinic receptor agonist KarXT
Time: FDA Approves the First New Schizophrenia Drug in Decades