Agitation in Alzheimer's Disease - An Unmet Need Pt 2

We previously wrote about this unmet medical need back in 2016 here Agitation in Alzheimer's Disease - An Unmet Need. Since then, the field has narrowed with some of those companies no longer pursuing this indication for different reasons, but most likely their drug was not successful for this indication in clinical trials. With a safe and effective therapy for these patients experiencing agitation, the likelihood for them remaining in their homes becomes more favorable, as it would be easier on their caregivers, thus reducing the necessity for nursing home care. The companies still pursuing this important indication are as follows.

Axsome Therapeutics - AXS-05 completed first pivotal phase 2/3 

John Hopkins - Escitalopram first phase 3 ongoing

Otsuka - AVP-786 has not successfully completed a pivotal phase 3

Otsuka / Lundbeck - Brexpiprazole completed two phase 3's, with one showing efficacy

The path to FDA approval is especially important, due to becoming a first mover in that space and establishing your product within the medical community. The projected clinical readouts of the current clinical trials are listed in order, as follows. Brexpiprazole 4/2022, AVP-786 6/2022, , Escitalopram 8/2022, AXS-05 9/2022.

AVP-786 has completed one phase 3 clinical trial using the (SPCD) Sequential Parallel Comparison Design. The SPCD is designed to reduce the placebo effect. Avanir disclosed that one of the two doses showed significant efficacy, but the company did not go into detail whether the higher or lower dose achieved the significant efficacy. In the second clinical trial using a Parallel Group Placebo Controlled design, patients did not experience a significant improvement in agitation compared to patients treated with placebo, per Avanir press release. Thus, putting the entire Agitation in Alzheimer's Disease program in question.

Just a bit of history. The non-deuterated version of AVP-786 is known as AVP-923, which is a combination of dextromethorphan and quinidine. In a phase 2 clinical trial run by Avanir for patients with Alzheimer's disease experiencing agitation in 2014, AVP-923 was highly successful utilizing the (SPCD) clinical trial design. That clinical trial success, led to a $3.5 billion buyout of Avanir from giant Otsuka.

Understanding how AVP-786 ended up in Otsuka's hands, you have to go back several years when Concert Pharmaceuticals obtained a patent for the deuterated version of AVP-923, and licensed that version known as AVP-786 to Avanir, who later was acquired by Otsuka. The successful AVP-923 combo of 20mg dextromethorphan, and 10mg quinidine had a potential safety drawback known as QTc prolongation which may have become worrisome to the FDA for this elderly patient population. One of the goals of the deuterated version was to lower the quinidine inhibitor dose down from 10 mg to 4.9 mg as shown in a comparison of exclusion's between AVP-923, and AVP-786 clinical trial design here AVP-923 and AVP-786. 

There is one other issue to consider regarding AVP-786. When Concert Pharmaceutical's provided deuteration to AVP-923 and achieved patent, did the composition of AVP-786 get modified from the original in any way? We could only find one research article that may answer that question, here Deuterated (d6) - dextromethorphan elicits antidepressant effects in mice. This research suggests that AMPA, and Sigma 1, receptor targets of deuterated DM may differ from DM in their small animal study as quoted The data suggests d6-DM has anti-depressant like effects, though it may be recruiting different molecular targets and/or acting through a different mix or ratio of metabolites from regular DM. Perhaps that could be the performance difference between AVP-923 performing so well in the phase 2 clinical trial, and later AVP-786 not highly successful so far in clinical trials with a similar patient population. With limited research, we take that as speculation.

What's important to keep in mind, is that Axsome's AXS-05 is the only drug which the FDA has granted, Breakthrough Therapy Designation (BTD) for this indication. We'll continue to monitor these clinical trials to see if the companies projected completion dates remain the same or change. Axsome Therapeutics AXS-05 is well positioned to become the first safe and effective therapy for this patient population as we await the phase 3 results with their second pivotal clinical trial. Next we will write about Brexpiprazole's path forward. Thank you for reading. 

AXS-05 Phase 2 Results for Treatment Resistant Depression

Axsome Therapeutics released phase 2 results from the COMET Treatment Resistant Depression clinical trial this morning. TRD is defined as those who had ongoing symptoms of depression despite receiving two or more antidepressants during the current major depressive episode. The results were compelling in this open label clinical trial. Below is a recap of what was discovered in the phase 2 trial.

• Mean MADRS of -20.6 improvement from baseline at week 6
• Remission from depression occurred in 43.8% of patients at week 6
• Remission was 62.3% at 6 months and 72.7% at 12 months

The mean MADRS score was 33.1 at baseline, and the adverse event profile was similar to other AXS-05 clinical trials which included, dizziness, nausea, headache, dry mouth and decreased appetite. The New Drug Application for MDD is projected to be submitted to the FDA in January. Thank you for reading.                          

Axsome Therapeutics Second Quarter Update

Axsome released their second quarter results this morning, and an additional press release updating their depression clinical program here AXS-05 Depression Clinial Program. The company accomplished a significant amount of progress on all fronts. This post will focus on the companies lead drug AXS-05 for Treatment Resistant Depression or TRD. Summary below.

COMET TRD Trial - A phase 2 an open label sub-study evaluating the efficacy and safety in TRD patients. Approximately 70 patients will be enrolled. The trial endpoints will include the change from baseline in the Montgomery Asberg Depression Rating Scale or (MADRS) total score, clinical response and remission. Topline results from the COMET-TRD is expected in the fourth quarter of 2020.

MERIT Trial - A phase 2 double blind placebo controlled trial randomized withdrawal study in patients with TRD. Approximately 50 patients will be enrolled. The primary endpoint of the trial is the time to relapse of depressive symptoms. Topline first half 2021.                                           

AXS-12 Breakthrough Therapy Designation

The FDA has granted Axsome Therapeutics the Breakthrough Therapy Designation (BTD) for drug AXS-12 for the treatment of Narcolepsy. This was based off a phase 2 clinical trial completed in 2019, with results here AXS-12 Phase 2 Results. The designation allows for potentially quicker FDA approval of the drug, and increased communication from the FDA. The company is planning for phase 3 testing to begin in the fourth quarter of 2020.

CTP-543 Phase 3 Design

Concert Pharmaceuticals is planning on running two phase 3 clinical trials for the indication of Alopecia Areata, to begin in the fourth quarter of 2020. Detail's of the phase 3 trial are below.

• Patients with moderate to severe Alopecia Areata
• Approximately 700 patients age 18-65 years with ≥ 50% hair loss
• Primary endpoint will be percentage of patients with SALT score ≤ 20
• 3:3:1 randomization to CTP-543 (8 mg BID or 12 mg BID) or placebo for 24 weeks

I like the simple design of this clinical trial, and believe based on the phase 2 CTP-543 results and comparison Clinical Trial Comparison, they can score high efficacy in the range of SALT score ≤ 20. Below is a three year chart of CNCE. Thank you for reading.

AXS-05 Phase 3 Results for Alzheimer's Agitation

Axsome released phase 3 results today from their ongoing clinical trial evaluating AXS-05 for agitation associated with Alzheimer's disease. Currently there is no drug approved for this unmet need. The results below were good, with a rapid and substantial effect. The complete press release is at Axsome.com.

• Cohen Mansfield (CMAI) total score at 5 weeks, p=0.010 versus placebo
• Week 3 compared to placebo p=0.007
• Well tolerated and not associated with cognitive impairment or sedation

AXS-07 Phase 3 for Acute Migraine (Intercept)

This phase 3 clinical trial was called Intercept, the second phase 3 clinical trial completed after the Momentum phase 3 trial for patients experiencing an acute migraine. Below are the highlights of the successful trial, and the Intercept Phase 3.

• Pain Freedom 2 hours after dosing achieved by 32.6% of patients
• Pain Freedom at 24 hours after dosing in 22.7% of patients
• Freedom from most bothersome symptoms achieved in 43.9% of patients
• Rescue medication was used by 15.3% of patients at 24 hours

Based on these results, I expect the company to prepare and file an NDA (new drug application) prior to year end. Thank you for reading.

Market Correction

The S&P 500, has now sold off -29.84% from the all time high achieved just a month ago. The sell-off categorizes it in bear market territory. By looking at the chart below of the S&P 500, the support line from the 2018 December low is just a few percentage points lower, to the price of around 230. Let's see if that prior correction low of December 2018 provides support for this market.