dm+d

Unassigned

New Medicines

Moderate to severe major depressive disorder (MDD)

Information

New formulation - repurposed medicine
Axsome Therapeutics
Axsome Therapeutics

Development and Regulatory status

None
None
Pre-registration (Filed)
Apr 22Axsome have renewed filling with FDA and anticipate a decision in Q2 22 [15].
Aug 21The FDA has informed Axsome that it will not have made a decision by PDUFA target action date of 22nd August 2021, no additional information has been requested from the Company and the review of the application is ongoing [14].
Aug 21Less than two weeks out from FDA decision the FDA has identified deficiencies in Axsome´s submission for approval of AXS-05 in MDD. Details of the deficiencies and implications for the filing are awaited [13].
Apr 21FDA has granted Priority Review for bupropion/dextromethorphan for the treatment of MDD. [12]
Nov 20Pre-submission activities for a new drug application (NDA) to the FDA for AXS-05 for treatment of MDD are nearing completion. Due to a COVID-related logistical delay from one vendor, the company now expects to submit the NDA in January instead of by year-end. Axsome completed a pre-NDA meeting with the FDA in July [9].
Sep 20Axsome appears to be focussed solely on US launches for its products at present; no plans described for EU/UK development. Axsome has previously said that if its products are approved for marketing outside the US, it intends to commercialise their product candidates outside the US with a marketing and sales collaborator or collaborators, rather than with their own sales force [10].
Mar 20US filing will be Q4 20 for MDD [8].
Dec 19Axsome plan to file a NDA with US FDA in 2H 20 [7].
Jul 19Axsome announces it is enrolling two open-label studies in order to build safety databases of patients to support the filing of a New Drug Application for AXS-05 in the treatment of MDD and AXS-07 in the acute treatment of migraine [5].
May 19Axsome Therapeutics accelerates development status and plan for bupropion/dextromethorphan in the treatment of MDD and treatment resistant depression (TRD), following a Breakthrough Therapy meeting with the US FDA [4].
Mar 19US FDA granted Breakthrough Therapy designation for bupropion/dextromethorphan for the treatment of MDD. The designation was based on the results of from the phase II ASCEND study.[2]

Category

Fixed-dose combination of bupropion (inhibitor of norepinephrine and dopamine uptake and a nicotinic acetylocholine receptor antagonist) plus dextromethorphan (non-competitive NMDA receptor antagonist, and a sigma-1 receptor agonist).
In the UK, the prevalence of major depressive disorder is estimated to be between 5% and 10% of people seen in primary care and 10% to 14% of medical inpatients, although it may be underdiagnosed. Between 10% and 15% of older people have symptoms of depression. The risk of relapse is 50%, 70%, and 90% after the first, second, and third episodes of major depressive disorder respectively. The rate of major depressive disorder in women is twice as high as in men. [1]
Moderate to severe major depressive disorder (MDD)
Oral

Trial or other data

Jun 22Axsome Therapeutics announce PIII GEMINI trial meets primary endpoint of baseline changes in the MADRS score to week six as well as the majority of secondary outcomes [17].
May 22PII ASCEND trial published in The American Journal of Psychiatry. [16]
Dec 20Clinical response on the MADRS (≥50% reduction from baseline) was achieved by 39.7% of pts at week 2 and 73.2% of pts at Week 6 which was sustained or increased with long-term treatment (84.6% and 82.8% of pts achieved a clinical response at 6 and 12 months, respectively). Remission from depression (MADRS ≤10) after treatment with AXS-05 was achieved by 21.5% of pts at week 2 and 52.5% of pts at week 6 (which was also sustained/increased with long-term treatment to 12 months). AXS-05 was well tolerated with long-term dosing. Commonly reported adverse events were dizziness (12.7%), nausea (11.9%), headache (8.8%), dry mouth (7.1%), and decreased appetite (6.1%).[11]
Nov 20 Axsome completed the COMET (Clinical Outcomes with NMDA-based Depression Treatment) PIII open-label, long-term safety trial (NCT04039022) to support the planned NDA filing of AXS-05 in MDD in August. The three PII open-label efficacy sub-studies of the COMET trial have also been completed. These sub-studies are evaluating the efficacy and safety of AXS-05 in three clinically pertinent MDD patient populations: the COMET-TRD trial in treatment resistant MDD (TRD), the COMET-AU trial in antidepressant unresponsive MDD, and the COMET-SI trial in MDD with suicidal ideation. Efficacy results from these studies are on track to be reported in Q4 20 [9].
Dec 19PIII GEMINI study (n=327 in US) meets primary endpoint of statistically significant reduction in MADRS total score vs placebo at week 6, with mean reductions from baseline of 16.6 and 11.9 points, respectively (p=0.002) [7].
Oct 19PIII GEMINI study (NCT04019704) is no longer recruiting; collection of primary outcome data is expected to complete Dec 19 [6].
Jul 19 Axsome Therapeutics initiates PIII trial to assess safety and efficacy of bupropion/dextromethorphan in patients with MDD including TRD (NCT04039022; AXS-05-303). This open label study intends to enrol approximately 300 patients in the US [4].
Jul 19PIII GEMINI (Glutamatergic and Monoaminergic Modulation in Depression) trial launched of AXS-05 in major depressive disorder. About 300 pts with a confirmed diagnosis of moderate to severe MDD will be randomised 1:1 to AXS-05 or placebo for 6 weeks. The trial will evaluate assessments including the Montgomery-sberg Depression Rating Scale (MADRS), safety parameters, clinician-rated scales, as well as patient-reported outcome measures. Topline results from the GEMINI trial are anticipated in the second half of 2019. [2,3]
Jan 19PII ASCEND (Assessing Clinical Episodes in Depression, NCT03595579, n=80) randomised double blind trial completed. This evaluated the safety and efficacy of bupropion/ dextromethorphan in pts with major depressive disorder (MDD) . The trial met its primary endpoint with reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) total score, at week 6. Patient enrolment was completed in November 2018. The primary end point of the trial was to determine the types and rates of adverse events; discontinuations due to adverse events in a time frame of six weeks. AXS 05 was generally safe and well tolerated with no serious adverse events. Common adverse effects were nausea, dizziness, dry mouth, decreased appetite, and anxiety. The overall, rates of adverse events were similar between AXS 05 and bupropion. Treatment with AXS 05 was not associated with psychotomimetic effects, weight gain, or sexual dysfunction. There was no meaningful difference between the two treatment arms in discontinuations due to adverse events. AXS 05 met its primary end point and demonstrated reduction of 17.2 point in the MADRS total score vs. 13.7 point reduction for bupropion (p=0.013) at week 6. Of pts who received AXS 05, 47% achieved remission vs. 16% of those who received bupropion (p=0.004) at week 6. AXS 05 showed rapid improvement in depressive symptoms on the Clinical Global Impression-Improvement scale (CGI-I) at Week 1 (p=0.045) and 59% vs. 27% in bupropion pts at Week 6. [2]

Alzheimer's disease-associated agitation

Information

Licence extension / variation - repurposed medicine
Axsome Therapeutics
Axsome Therapeutics

Development and Regulatory status

None
None
Phase III Clinical Trials

Category

Fixed-dose combination of bupropion (inhibitor of norepinephrine and dopamine uptake & a nicotinic acetylocholine receptor antagonist) plus dextromethorphan (non-competitive NMDA receptor antagonist, & a sigma-1 receptor agonist).
Alzheimers disease is the most common form of dementia, accounting for around 50% of cases. It is estimated to affect 496,000 people in the UK. In the later stages, symptoms include agitation [1].
Alzheimer's disease-associated agitation
Oral

Treatment-resistant depressive disorder

Information

Licence extension / variation - repurposed medicine
Axsome Therapeutics
Axsome Therapeutics

Development and Regulatory status

Discontinued
Discontinued
Discontinued
Mar 21Axsome no longer appears to be developing AXS-05 specifically for treatment-resistant depression - company latest annual report says it is being developed for MDD, Alzheimer disease agitation and smoking cessation, and it is no longer listed in its pipeline. Presume development discontinued [14,15].

Category

Fixed-dose combination of bupropion (inhibitor of norepinephrine and dopamine uptake and a nicotinic acetylocholine receptor antagonist) plus dextromethorphan (non-competitive NMDA receptor antagonist, and a sigma-1 receptor agonist).
Data from 298 UK general practices showed that the incidence of diagnosed depression fell from 22.5 to 14.0 per 1,000 person-years at risk from 1996 to 2006. The incidence of depressive symptoms, however, rose threefold from 5.1 to 15.5 per 1,000 person-years at risk. The total incidence adding these two incidences together remained unchanged, suggesting that there was a trend for GPs to document symptoms rather than formal diagnoses [1].
Treatment-resistant depressive disorder
Oral