A deep dive into neuropsychiatric therapeutics • Competitive landscape • Emerging treatments • Key concerns & more Exhibit 1: late-stage competitive landscape across key indications The global disease burden for these indications is immense, with >50M total patients & >$900B in lost productivity in the US alone – figures that are expected to rise over the coming decades. Current treatment for most indications centers around SSRIs and similar antipsychotic agents. These work by increasing intrasynaptic levels of monoamine neurotransmitters such as serotonin, norepinephrine and dopamine. However, these drugs have multiple issues: • Not fast acting (can take months to kick in) • Non-responder rates vary from 40-85% depending on the indication • High treatment-discontinuation rates • Array of side effects including loss of motivation, trouble focusing and various bodily dysfunctions These outcomes are driven by a poor understanding of the underlying disease biology, which has inhibited a more personalized treatment approach. There is immense heterogeneity in these diseases, but we lack the biomarkers to properly stratify patients. Running effective clinical trials has thus been a challenge in this space, exacerbated by the subjective nature of endpoint measurement. That all feeds into a huge unmet need: Exhibit 2: Unmet need by indication For the vast majority of patients, we must do a lot better. Luckily, novel MoAs and therapies are emerging that offer a multi-modal treatment approach that better aligns with how the underlying diseases function. Among these are a variety of psychedelic approaches, where investment has accelerated following the 2019 approval of $JNJ Spravato, a more potent form of ketamine. The market map below illustrates the size of this space - notable late-stage assets include Compass Pathway’s COMP360 for TRD and MAPS MDMA for PTSD Exhibit 3: Psychedelic Market Map Beyond psychedelics, there are also non-drug therapies such as electroconvulsive therapy and novel traditional drugs such as muscarinic acetylcholine receptors (i.e. $KRTX KarXT). In general, these therapies target non-monoaminergic mechanisms (notably different than SSRIs). Commercial uptake of these novel therapies will be a key focus point moving forward, particularly in indications such as depression where SSRIs are the dominant frontline therapy. Nearly all of these have gone generic, which means payors usually require patients to fail multiple SSRIs before considering more expensive, novel treatments. Coupled with provider & patient unfamiliarity and the absence of long-term or H2H data, near-term novel launches may see limited early adoption, as we saw with Spravato. With that said, there are still many treatment-refractory patients for whom these therapies would benefit immediately. For psychedelics specifically, a CPT III code will go live on Jan 1, 2024, which will help track reimbursement and build up usage data. That's all - follow me @andrewpannu for more biotech analyses like this in the future!