Schizophrenia Key Themes

July 2020 Earlier use of long-acting injectables (LAIs) is encouraging Pharma to develop increasingly longer dosing intervals The landscape for LAIs is shifting towards earlier, more aggressive use in a broader patient population ▪ Non-adherence is undisputedly the single biggest contributor to relapse and re-hospitalization. ▪ LAIs are increasingly being positioned as suitable for patients in the early stages of illness, before disease progression associated with poor adherence even occurs. The LAI pipeline is dominated by longer dosing intervals of existing products as companies compete to provide the greatest dosing flexibility

▪ LAIs were typically dosed at 2- to 4-week intervals, but longer dosing intervals have recently been approved and dosing regimens of up to 6 months are in development. ▪ Alkermes has a 2-month formulation of Aristada ( lauroxil) on the market and a 2-month formulation of Abilify Maintena (aripiprazole) is in clinical development with Lundbeck. ▪ Janssen’s Invega Trinza () is the only product on the market with a longer dosing interval, administered once every 3 months, and the company also has a 6-month formulation in phase 3 development. Results of the study are anticipated in the second half of 2020. ▪ LAIs are typically administered by IM injection but Indivior’s Perseris (RBP-7000), a once-monthly injection, became the first approved LAI administered by SC injection in February 2020. LAI formulations of novel oral fail to get off the ground ▪ Lundbeck/Otsuka evaluated a LAI formulation of Rexulti () but decided against further development, and a LAI version of (Intra-Cellular Therapies) failed to even make it into the clinic, suggesting that developers believe the LAI market is well served by existing players. 2 Novel agents with improved tolerability or that address concomitant substance abuse could carve out niche market Novel therapies with an improved tolerability profile will be a welcome addition to the treatment armamentarium ▪ Intra-Cellular’s Caplyta (lumateperone) is a first-in-class compound with a clean side-effect profile that was approved in December 2019; it became available in the U.S. in March 2020. – The product has a unique pharmacologic profile with , dopaminergic and glutamatergic effects that exhibits less off-target engagement than other antipsychotics. – The product will most likely be adopted as a second-line treatment for patients who experience weight gain or movement disorders with earlier atypical antipsychotics. ▪ Alkermes’ fixed-dose combination of and samidorphan (ALKS-3831) is currently under regulatory review for the treatment and is expected to mitigate olanzapine-induced weight gain. The PDUFA target action date is November 2020. Treatments that address concomitant substance use disorders (SUDs) represent a high unmeet need due to the large patient population affected ▪ Twice as many patients with schizophrenia are likely to have a SUD, compared with the general population. Despite the remarkably high proportion of affected patients, there are currently no approved antipsychotics specifically for the treatment of schizophrenia with concomitant SUD. ▪ ALKS-3831 is anticipated to have utility in the treatment of co-occurring use disorder.

Targeting a dual diagnosis is starting to attract more attention, and additional agents addressing concomitant substance use disorders are likely to follow

3 Negative symptoms and cognitive impairment are becoming increasingly popular treatment targets Improving the cognitive deficits associated with schizophrenia remains challenging ▪ Biogen, Boehringer Ingelheim, Takeda, Lundbeck and Astellas Pharma all have compounds in development for the treatment of cognitive impairment associated with schizophrenia. ▪ No currently active compounds have progressed to phase 3, and prior assets failed to show a clinical benefit in pivotal trials, highlighting the challenges associated with this significant unmet need. Treating negative symptoms associated with schizophrenia remains even more elusive ▪ Despite many high-profile setbacks for once-promising prospects, companies continue to evaluate potential candidates for treating predominant negative symptoms of schizophrenia. ▪ (Minerva Neuroscience) was widely expected to become the first agent approved for negative symptoms of schizophrenia but failed to achieve the primary endpoint in the phase 3 study. – In June 2020, the company requested a meeting with the FDA to present these data and plan a path forward. ▪ ACADIA reported positive results from a phase 2 trial of Nuplazid () in November 2019, and a phase 3 study is planned to start in the second half of 2020. – Nuplazid is already marketed in the U.S. for the treatment of Parkinson's disease-associated psychosis and is under regulatory review for dementia-related psychosis, including Alzheimer’s disease. ▪ Numerous assets have now shown promising results at the phase 2 stage, only to go on to fail in phase 3, highlighting just how elusive an effective treatment is for this extremely difficult patient population. An approved therapy for patients with predominantly negative symptoms would be the holy grail for drug development in schizophrenia

4 Why Choose inThought as a Partner? ▪ We are a life science consulting firm made up of MDs, PhDs, and MBAs with deep therapeutic area expertise. Our analysts leverage scientific and medical knowledge as well as business acumen to address strategic problems in healthcare. ▪ Our senior principals have Wall Street analyst experience. We answer questions quickly, always considering the impact to various stakeholders by putting the clinical data, medical opinion, and company business maneuvers into an actionable business context. ▪ Our proprietary inVision platform allows clients to have all of their critical intelligence in one place, customized for their particular key questions and topics, and accessible on demand. ▪ Our Schizophrenia engagements have included: – Competitive Intelligence Monitoring Reports – State of the Art Landscape Reports – Trial Design Analyses – Licensing opportunity identification and due diligence – Deep Dive assessments of companies, drugs, and MOAs – Conference Coverage – KOL interviews – Revenue Forecast Modeling – Probability of Approval Modeling

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Samantha Crofskey, BSc [email protected] 1.732.455.9121

Ms. Crofskey has over 12 years of experience in medical writing, account management and pharmaceutical industry consulting. She provides coverage for the immunology and neurology sectors, including everything from emerging targets and drug development to market analysis and customized business intelligence. Prior to joining inThought, Ms. Crofskey worked as a medical writer for Wolters Kluwer in Auckland, New Zealand before moving to London to work as an Editorial Project Manager at Current Medicine Group, a Springer Healthcare company, and later, as an Editorial Project Manager at BioScience Communications. Ms. Crofskey returned to Wolters Kluwer in 2010 and subsequently joined the inThought team as a consultant in 2011. Ms. Crofskey earned her Bachelor of Science in Neuroscience and Pharmacology from the University of Otago in New Zealand.

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