Disease Analysis: Depression

Definition

While it is not uncommon to experience feelings of sadness occasionally, in most people these emotions are usually fleeting and pass after a few days. When this manifests in a depressive disorder, a patient’s symptoms interfere with daily life and normal functioning. Depression is the leading cause of disability globally and can cause a multitude of symptoms, many of which are associated with impairment and, ultimately, decreased productivity. Not only is there the presence of depressed mood, but the condition can subsequently lead to changes in endocrine and immune function, which can increase susceptibility to physical diseases. In the worst cases, depression can lead to suicide.

Latest key takeaways

• Datamonitor Healthcare estimates that in 2021, there were 231.9 million prevalent cases of major depressive disorder (MDD) worldwide, and forecasts that number to increase to 248.9 million prevalent cases by 2027.
• The drug market for depression is projected to expand in the next 10 years, propelled by a growing patient caseload and uptake of new products approved for indications beyond MDD, including post-partum depression (PPD), treatment-resistant depression (TRD), and suicidal ideation.
• The primary distinguishing factor in the depression market is a drug’s ability to satisfy unmet needs. Two recent market entrants, Spravato and Zulresso, have appeared highly attractive in their capacity to fulfill needs through their approvals for difficult-to-treat patient populations coupled with their refreshing first-in-class mechanisms. Novelty in mechanism of action is a key differentiator that has finally reached the depression market after decades of stagnated innovation, since long-standing standard-of-care drug classes have been inadequate in treating depression. Traditional therapies may take four to six weeks to produce clinically meaningful effects, and refractory depression persists.
• First launched in the US in 2019, Spravato is expected to become a blockbuster brand. Johnson & Johnson has characterized its product well through extensive global studies that consolidate physicians’ off-label experience with the related drug ketamine. Crucially, the first-in-class drug is the second product approved by the FDA for TRD and has the potential to confer fast-acting benefits. Furthermore, it is also approved to treat MDD patients with suicidal ideation and behavior.
• The most recent large-impact event in the depression market was the FDA approval of Axsome Therapeutics’ multi-modal drug Auvelity (formerly AXS-05), which is an NMDA receptor antagonist, sigma-1 receptor agonist, and an inhibitor of the reuptake of monoamines. While the approval in August 2022 was just for MDD, the drug also has potential to broadly target different lines of therapy, from first-line and antidepressant-unresponsive MDD patients to TRD and patients with suicidal ideation, depending on the outcome of further trial investigations. Thus, Spravato will be a key competitor as it occupies later lines of therapy. Although Spravato holds the benefit of earlier market entry, Auvelity may secure a broader label and would offer the convenience of oral administration compared to Spravato’s intranasal spray administered by a healthcare professional.
• Serotonergic antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are forecast to be dethroned from their market-leading positions by pioneering drug classes: steroidal antidepressants and N-methyl-D-aspartate (NMDA) receptor modulators. Although growth of the SSRI market will be spearheaded by Trintellix, traditional serotonergic antidepressants have largely been insufficient in treating depression, and the market is characterized by critical unmet need. This poses prominent opportunities for new therapeutic classes to diverge from the sluggish growth trends of established drug classes. Combined sales of the novel products Spravato, Zulresso, SAGE-217, Auvelity, REL-1017, seltorexant, Vraylar, and COMP360 will greatly grow the depression market.
• Sage Therapeutics’ steroidal antidepressant franchise will also expand the market. SAGE-217 is anticipated to become a market-leading brand, boasting a broad label to treat PPD, MDD, and co-morbid MDD with insomnia. Its launch for MDD as a monotherapy will be its greatest opportunity as it may be prioritized in the largest patient population. It will be the only launch for this indication that offers convenient, short-course oral dosing, a rapid onset of action, and a new approach to treatment that makes it very competitive compared to currently marketed therapies.
• In the PPD space, SAGE-217 will build on the market share of its sister product and first-to-market drug for PPD, Zulresso. Despite access hurdles resulting in a slow ramp-up in initial sales since launching in the US in June 2019, Zulresso possesses a robust clinical profile with remarkable, potent effects at 60 hours post-dose. Zulresso patients are expected to switch to the more conveniently administered SAGE-217 following initial Zulresso regimens. This synergy will make Sage Therapeutics’ brexanolone franchise a formidable one.
• REL-1017 is a clinically promising pipeline drug that would expand the NMDA class and enter as a more convenient oral competitor to Spravato for TRD. Demonstrating strong efficacy data with fast clinically meaningful responses at Phase III would allow REL-1017 to be a significant competitor, especially if Relmada successfully expands investigations into MDD and enters into a strategic partnership to pool resources.
• Seltorexant is yet to produce convincing, robust clinical trial data as the drug’s efficacy appears to taper over time. Nevertheless, Johnson & Johnson is moving forward with Phase III investigations into seltorexant as an adjunctive treatment of MDD with insomnia symptoms since greater efficacy was evident in this patient population.
• Designated a breakthrough therapy in 2018, COMPASS Pathways’ COMP360 psilocybin therapy has shown very promising Phase II efficacy data for TRD and MDD, albeit with some expected side effects. Criminal prohibitions on psilocybin have prevented any research on this substance for the last few decades, meaning that this is effectively a “new” drug to treat MDD. Its novelty is attractive in a field which has been dominated by variations of similar products.
• AbbVie’s Vraylar, which is already approved for schizophrenia and bipolar I disorder, is being evaluated as an adjunctive treatment for patients with MDD who have inadequate responses to antidepressants alone, and the drug has shown a range of success in trials so far. If approved in MDD as an adjunctive therapy, Vraylar is unlikely to show superiority to marketed antipsychotics or be used at the first or second line of therapy due to the highly genericized market.
• Although there are vast opportunities for new drugs to achieve substantial sales, there are also risks. Potential barriers to uptake include costliness hindering market access, safety issues necessitating strict REMS programs, and niche target populations, which will reduce a product’s commercial potential.
• Most long-established brands will not enjoy blockbuster growth. The only prominent established brand is Trintellix, and its strong clinical profile for MDD will continue to drive robust sales growth until its patent expiry in 2026 in the US. In contrast, sales of most traditional brands will generally continue to contract as ever-intensifying generic competition progresses through the forecast period covered by Datamonitor Healthcare’s analysis. Fetzima and Rexulti, which are yet to be impacted by generic erosion, will struggle to ramp up the same sales momentum in the crowded generic climate, primarily because they are not distinct enough from existing therapies in their mechanisms and indications. Their lack of novelty is in stark contrast to the new approaches presented by pipeline drugs for MDD such as SAGE-217, Auvelity, and COMP360.
• There are numerous high-impact upcoming events for drugs in the MDD space expected during 2022 and 2023, including topline Phase III trial results for REL-1017, a US approval decision for LY03005, and Phase II/III results for COMP360.