Depression: New Insights Shifting the Treatment Paradigm 2 / October 2018 © Informa UK Ltd 2018 (Unauthorized photocopying prohibited.) Philippa Nutkins Drug Analyst, Citeline Breathing Life into a Stagnant Pipeline It is clear that we are in the middle of an epidemic Selective serotonin reuptake inhibitors (SSRIs), such of mood disorders, with depression alone affecting as Prozac (fluoxetine; Eli Lilly) and Celexa (citalopram approximately 1 in 6 adults in the US.1 The complex hydrobromide; Allergan), remain first-line therapies pathology of depression is not understood, and the in the US and EU markets2. However, with an condition often becomes a lifelong chronic disorder, estimated 10–30% of depression patients becoming creating enormous sociological and clinical burdens. treatment-resistant, high unmet need presents a dilemma for healthcare providers. Depression is a complex phenomenon, with several contributing pathways and a multitude of The development of novel classes of antidepressants symptoms which may or may not be present. In – such as those targeting the NMDA and opioid addition to the unclear aetiology, the translatability receptor pathways – provides hope that future of animal models is lacking in depression, and breakthroughs are on the horizon. This analysis, clinical trials, even of proven antidepressants, are using Pharmaprojects and Trialtrove intelligence, prone to missing their primary endpoints. Such explores the current R&D landscape with an eye factors are contributing to the exit of Big Pharma out towards highlighting novel treatment paradigms of depression, with GlaxoSmithKline, AstraZeneca and assessing where the market might be heading. and Pfizer being high-profile examples. 1. US Department of Health and Human Services (2014) Results from the 2013 National Survey on Drug Use and Health: Mental Health Findings. Available from: https://www.samhsa.gov/data/sites/default/files/NSDUHmhfr2013/ NSDUHmhfr2013.pdf [Accessed 1 August 2018]. 2. Brigitta B (2002) Pathophysiology of depression and mechanisms of treatment. Dialogues Clin Neurosci, 4, 7–20. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181668/ [Accessed 1 August 2018]. © Informa UK Ltd 2018 (Unauthorized photocopying prohibited.) October 2018 / 3 Research and Clinical Activity for Depression Drug Pipeline bipolar disorder and schizophrenia, and Allergan Analysis of Pharmaprojects data (see Figure has reported plans to submit a supplemental 1) illustrates that the development pipeline of New Drug Application (sNDA) in the second half of antidepressant therapies is robust, including 127 2018. Sage Therapeutics is developing a GABA-A active drug programs. Many of these drugs are yet agonist which is showing promise in Phase III to hit the clinic (46 preclinical drugs). However, a trials for post-partum depression. Other Phase III reasonable proportion are in early-stage clinical candidates include Sunovion Pharmaceuticals’ trials; 54 drugs are in Phase I and Phase II Latuda (lurasidone), Lee’s Pharmaceutical’s development. Nine drugs have reached Phase III, Oleptro (trazodone hydrochloride) and Axsome which are profiled in Table 1. These notably include Therapeutics’ AXS-05. NeuroRx has completed rapastinel (Allergan) and esketamine (Johnson & the feasibility enrolment phase of its Phase IIb/ Johnson) – two late-stage ketamine-like candidates. III clinical trial evaluating sequential therapy of The atypical antipsychotic Vraylar (cariprazine; NRX-100 (ketamine formulation) followed by orally Gedeon Richter/Allergan/Recordati/Mitsubishi administered NRX-101 for the treatment of suicidal 3 Tanabe) is also in Phase III trials. Here, a success bipolar depression (see Table 1). in depression would expand its approval beyond Figure 1. Status of antidepressant therapies in active development Drug Count 0 5 10 15 20 25 30 35 40 45 50 Preclinical 46 Phase I 25 Phase II 29 Phase III 9 Pre-registration 5 Launched 13 Source: Pharmaprojects®, September 2018 3. NeuroRx (2018) NeuroRx, Inc. Completes Phase 2b/3 Feasibility Enrollment for First Glx-Targeted Oral Drug Targeting Suicidal Bipolar Depression. Available from: http://www.neurorxpharma.com/assets/6.11.2018---final---neurorx%2c-inc.-completes-phase-2b3-feasibility-enrollment-for-first-glx- targeted-oral-drug-targeting-suicidal-bipolar-depression.pdf [Accessed 13 August 2018]. 4 / October 2018 © Informa UK Ltd 2018 (Unauthorized photocopying prohibited.) Table 1. Phase III antidepressant therapies Drug Components Developer Phase III trials Mechanism esketamine S-enantiomer of Johnson & Several ongoing pivotal NMDA antagonist ketamine Johnson Phase III trials (see Table 3) rapastinel amidated Allergan Several ongoing pivotal Glycine NMDA-associated tetrapeptide Phase III trials (see agonist Table 3) AXS-05 bupropion + Axsome Phase III trial NMDA receptor antagonist dextromethorphan Therapeutics (STRIDE-1) in the US Adrenergic transmitter uptake for treatment-resistant inhibitor depression Dopamine reuptake inhibitor NMDA receptor antagonist Norepinephrine/dopamine dual reuptake inhibitor NRX-100/ ketamine HCL/D- NeuroRx Phase IIb/III trial NMDA receptor antagonist NRX-101 cycloserine + (STABIL-B) for suicidal Glycine NMDA-associated lurasidone bipolar depression agonist 5-HT1A receptor antagonist 5-HT2A receptor antagonist 5-HT7 receptor antagonist Dopamine D2 receptor antagonist Latuda lurasidone Sunovion Phase III for major Dopamine D2 receptor hydrochloride Pharmaceuticals depressive disorder antagonist 5-HT7 receptor antagonist 5-HT1A receptor antagonist 5-HT2A receptor antagonist Vraylar cariprazine Allergan Phase III trial (RGH- Dopamine D2 receptor agonist MD-53) for bipolar Dopamine D3 receptor agonist depression Oleptro trazodone Lee’s Phase II/III trial Histamine H1 receptor Pharmaceutical (Trazodone_1) for antagonist depression 5-HT uptake inhibitor Alpha-1 adrenoreceptor antagonist SAGE-217 Undisclosed Sage Phase III for post- GABA receptor agonist Therapeutics partum depression Source: Pharmaprojects®, September 2018 © Informa UK Ltd 2018 (Unauthorized photocopying prohibited.) October 2018 / 5 In addition, five drugs are filed for approval (see Otsuka’s digital medicine Abilify MyCite has recently Figure 1), including Alkermes’s ALKS 5461, an opioid launched as part of a limited rollout5. Abilify system modulator. After producing mixed data MyCite is a drug-device product which combines from three registrational trials, Alkermes submitted Otsuka’s Abilify (aripiprazole) with the Proteus an NDA to the US Food and Drug Administration ingestible sensor in a single tablet. This digitally (FDA) in January 2018, and a Prescription Drug records ingestion and, with patient consent, shares User Fee Act date of 31 January 2019 has been information with their healthcare professionals assigned4. Other filed treatments include Sage and caregivers. This is a first-of-its-kind drug Therapeutics’ brexanolone (a GABA-A positive and a huge step for both digital health, which allosteric modulator), Otsuka’s ASC-01 and Fabre- aims to leverage data to personalize the patient Kramer’s extended-release formulation of gepirone. experience, and antidepressant drug development. In September 2018, Johnson & Johnson announced The strong correlation of depression with medical the submission of an NDA to the FDA for esketamine noncompliance6 underlines the importance of nasal spray in treatment-resistant depression – capturing medication-taking patterns to help inform if granted approval, it could represent the first illness management, an issue which drugs such as antidepressant with a novel mechanism in decades. Abilify MyCite are starting to address. 4. Alkermes (2018) Alkermes Plc Reports First Quarter 2018 Financial Results. Available from: http://investor.alkermes.com/phoenix. zhtml?c=92211&p=RssLanding&cat=news&id=2344849 [Accessed 13 August 2018] 5. Abilify MyCite (2018) Initial Rollout for the ABILIFY MYCITE® System. Available from: https://www.abilifymycite.com/initial-rollout [Accessed 8 August 2018]. 6. DiMatteo MR, Lepper HS, Croghan TW (2000) Depression is a risk factor for noncompliance with medical treatment: meta-analysis of the effects of anxiety and depression on patient adherence. Arch Intern Med, 160(14), 2101–7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/10904452 [Accessed 13 August 2018]. 6 / October 2018 © Informa UK Ltd 2018 (Unauthorized photocopying prohibited.) Clinical Trials trial starts show a downward trend for depression, Since January 2012, Trialtrove has reported a total decreasing from approximately 39% in 2013 to of 290 industry-sponsored Phase I–III depression 17% in 2018. This is a clear demonstration of the studies targeting depression to have initiated. By far complexity inherent in depression, the limitations of the largest numbers of trials were in Phase I (142), effective psychometric tests to quantify depression followed by 77 Phase III trials (including Phase II/III) and a lack of industry commitment. Regarding and 71 Phase II trials (including Phase II/III). Among Phase I trials, Figure 2 profiles a sharp increase the 67 ongoing industry-sponsored trials, unusually from 2013 to 2014, which declined until another the largest number are in Phase II (27), followed by prominent increase in 2017. The increase in Phase Phase III (21) then Phase I (19). I trials in 2014 can be attributed to the advent of ketamine derivatives. In 2016, there was an increase Figure 2 profiles the percentage of trial starts by in Phase II trials compared to both the previous