Schizophrenia is a chronic psychiatric condition affecting approximately 2.8M people in the U.S. Historically, antipsychotics have been used to treat this devastating condition, yet these medications have significant side effects which results in poor adherence, and many fail to find an effective and/or tolerable therapy. For decades, patients have been in need of medicines that work differently.

At PureTech, we engaged with a group of leading schizophrenia experts who were most excited about efficacy data generated by Eli Lilly with xanomeline, which was not advanced due to tolerability issues.

To overcome this, we invented Cobenfy (formerly known as KarXT)  by combining xanomeline (a muscarinic receptor agonist) with trospium (a peripherally acting antagonist that doesn’t cross the blood brain barrier), and in doing so we unlocked development of the first new class of medicine for schizophrenia in over 50 years. We housed KarXT in our Founded Entity, Karuna Therapeutics, which conducted late-stage development before submitting a New Drug Application to the FDA and ultimately being acquired by Bristol Myers Squibb for $14 billion.

IPF is a rare, progressive and fatal lung disease with a median survival of 2-5 years. There are over 232,000 people in the US and the EU5 countries (Italy, Spain, France, Germany and the United Kingdom) living with IPF.

Pirfenidone is one of only two drugs approved to treat IPF, and it has been shown to improve survival by approximately 2.5 years compared to supportive care alone. However, tolerability issues with both standard-of-care drugs result in patients discontinuing treatment or reducing their dose. This also contributes to nearly three out of every four people with IPF in the US not receiving treatment with these otherwise efficacious medicines.

Deupirfenidone is a deuterated form of pirfenidone, where three hydrogen atoms in the pirfenidone structure are replaced with three heavy hydrogen atoms, intended to make deupirfenidone break down more slowly in the body than pirfenidone. In PureTech’s Phase2b trial, deupirfenidone demonstrated the beneficial pharmacology and clinically-validated efficacy of pirfenidone with a favorable tolerability profile.

For patients with a range of mental health conditions, such as anxiety and mood disorders, there is a growing need for new treatments. Standard of care treatments like selective serotonin reuptake inhibitors (SSRIs) can have mixed efficacy, delayed onset of action and poor tolerability.

Lower levels of allopregnanolone have been documented in patients with mood disorders, such as depression, and there is evidence that allopregnanolone has therapeutic potential in both anxiety and depression, however it can only be administered via a long, cumbersome intravenous infusion.

We created an oral prodrug of endogenous allopregnanolone that retains the activity and potency of allopregnanolone and may have better target engagement, in a more convenient oral form. We’ve done so by linking it to our Glyph™ technology, which allows it to bypass liver degradation. With this approach, we have demonstrated oral bioavailability that is approximately nine times greater than that of previous efforts to develop oral allopregnanolone. This means SPT-300 may significantly expand the potential of this validated mechanism across multiple patient populations where current treatments are burdensome to administer or take weeks to have an effect.