Psychotropic Drugs in the Pipeline. Norman Sussman, M.D. Professor of Psychiatry New York University School of Medicine

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1 Psychotropic Drugs in the Pipeline Norman Sussman, M.D. Professor of Psychiatry New York University School of Medicine

2 Norman Sussman, MD No Conflict of Interest to Declare

3 Antidepressant Pipeline

4 We need antidepressant treatments that are. Rapidly acting Robust Effective for TRD populations Durable Safe Well tolerated

5 Biological Processes Likely Involved In The Etiology Of Depression. Proposed hypotheses of depressions and their associated drug targets Elena Dale, Benny Bang-Andersen, Connie Sánchez Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs Biochemical Pharmacology, Volume 95, Issue 2, 2015, 81 97

6 Several biological processes involved in the etiology of depression. Summary of current hypotheses of depression. Proposed hypotheses of depression and their associated drug targets are shown in the top oval. Elena Dale, Benny Bang-Andersen, Connie Sánchez Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs Biochemical Pharmacology, Volume 95, Issue 2, 2015, 81 97

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9 Rapastinel (GLYX-13) IV Weak partial glycine site agonist on NMDA receptor Fast-tracked by FDA in 2014 as adjunct in treatment-resistant depression In Phase III trials

10 Esketamine (Ketanest) Intranasal ketamine NMDA receptor antagonist It incorporates the S(+) -enantiomer of the drug ketamine (as opposed to the R- enantiomer). Upon administration, it functions as a non-competitive NMDA receptor antagonist, and to a lesser extent, inhibits the reuptake of dopamine. In Phase II clinical trials

11 NRX-1074 Orally-active Selective partial agonist of the glycine site of the NMDA receptor No psychotomimetic effects In Phase I clinical trials IV formulation in a Phase II clinical trial

12 AV101 (4ClKYN) NMDA receptor antagonist AV-101 is biologically inactive until ingested and enzymatically Converted within astrocytes into 7-CL-KYNA (also known as 7-chlorokynurenic acid). it binds to the NMDA receptors specifically at the glycine binding site. Like most NMDA receptor antagonists, AV-101 is expected to be rapidly-acting for nearly instantaneous antidepressant effects following administration. In Phase II clinical trials

13 Basimglurant (RG7090) mglur5 antagonist initially investigated as a treatment for Fragile X Syndrome Roche realized that RG7090 wasn t wellsuited for the treatment of Fragile X Syndrome, the drug is but found the drug had high potency and a long halflife. Preliminary evidence suggests that it may promote wakefulness and increase delta waves during deep sleep. It appears to increase dopamine levels in the nucleus accumbens. In Phase II clinical trials

14 ALKS-5461: An Opioid Modulator Mu receptor partial agonist / kappa receptor antagonist in Phase III clinical trials A combination drug formulation: buprenorphine + samidorphan (ALKS 33) Under development as an adjunct to antidepressant therapy in TRD

15 ALKS 5461 Samidorphan offsets the euphoria (and abuse potential) of buprenorphine by blunting the effects at the mu receptor. The antagonist effect at the kappa receptor is highly important due to the fact that it inhibits release of peptides called dynorphins. Dynorphin inhibition allows for the release of glutamate (to facilitate neuroplasticity) and improve dopaminergic signaling throughout the brain. Slated for a 2017 release.

16 Mu and Kappa Opiate Receptors Functionally opposing endogenous opioid systems that regulate emotional and perceptual experience Receptor Agonist Effects Antagonist Effects Mu (μ) MOPr * Kappa (Κ) KOPr analgesia euphoria antidepressant anxiety analgesia dysphoria depression stress-induced anxiety anxiety hostility * Principal therapeutic opiates are selective for MOPr antidepressant Chavkin C. Neuropsychopharmacology (2012) 38, S1 S78

ALKS-5461 Receptor Agonist Effects Antagonist Effects Mu (μ) MOPr * Kappa (Κ) KOPr analgesia euphoria antidepressant Buprenorphine anxiety analgesia dysphoria depression

17 ALKS-5461 Receptor Agonist Effects Antagonist Effects Mu (μ) MOPr * Kappa (Κ) KOPr analgesia euphoria antidepressant Buprenorphine anxiety analgesia dysphoria depression stress-induced anxiety anxiety hostility * Principal therapeutic opiates are selective for MOPr ALKS-33 antidepressant Buprenorphine Chavkin C. Neuropsychopharmacology (2012) 38, S1 S78

18 Anhedonia and Brain Opioid Systems Kappa opioid agonists induce depression Anhedonia, a core symptom of depression, is ascribed to a disrupted reward circuitry where the brain opioid system plays a key regulatory role. Stress induces the release of dynorphin, which activates kappa opioid receptors and down regulates DA levels.

19 Amitifadine (EB-1010) Amitifadine (formerly EB-1010) A triple reuptake inhibitor: the greatest potency towards 5-HT reuptake, half as much towards NE reuptake and one eighth towards DA reuptake. This 1 to 2 to 8 ratio approximates the pharmacology of the two-product combination of citalopram and bupropion

20 Amitifadine (DOV-21,947 or EB-1010) In a phase IIb/IIIa, amitifadine did not meet its primary end point of a significant difference in MADRS score, compared with placebo. However, the lack of side effects seen with the 100 mg dose and signs of efficacy in post-hoc analyses suggest that MDD patients may benefit from higher doses.

21 Comparative Effect Size: Amitifadine Vs. Other Antidepressants (not head-to-head) Sources: (1) Tran 2012 (2) Turner 2008 (3) Nelson 2010 w/ Euthymics analysis (4) FDA statistical review w/ Euthymics analysis *Cohen s d at the 6 week primary endpoint. At the 7 week visit the Cohen s d was See Tran et al. (

22 Antidepressant-like effects of the cannabinoid receptor ligands in the forced swimming test in mice Results revealed that acute injection of oleamide (CB1 receptor agonist), caused antidepressant-like effect in the FST. Acute administration of both CB2 receptor agonist, JWH 133 and CB2 receptor antagonist, AM 630 also exhibited antidepressant action. Indeed, all of the CB compounds used, intensified the antidepressant-like effects induced by an acute injection of scopolamine (0.3 mg/kg). Results provide clear evidence that the endocannabinoid system participates in the depressionrelated behavior. Kruk-Slomka M et al. Behav Brain Res May 1;284: doi: /j.bbr Epub 2015 Feb 7.

24 Botox (OnabotulinumtoxinA) Facial nerve inhibitor Target the corrugator and procerus muscles within the face. Facial expression is thought to contribute to depressive states via nerve signaling within the face particularly from the corrugator and procerus muscles. Preliminary evidence from trials indicates that Botox is an effective treatment for depression compared to a placebo (saline injection). In addition, just one treatment session with Botox can yield a sustained antidepressant effect eliminating the need for recurrent injections. In Phase II clinical trials

MORE THAN MONOAMINES: A LOOK AT NOVEL ANTIDEPRESSANTS

MORE THAN MONOAMINES: A LOOK AT NOVEL ANTIDEPRESSANTS Learning Objective Describe the molecular targets of novel agents, including adjunctive treatments, currently being investigated 50% of Patients Respond