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.







AXS-07 Phase 3 Results for Acute Migraine (Momentum)

Axsome Therapeutics released phase 3 clinical data with AXS-07 for the treatment of acute migraine, for patients with an inadequate response to prior treatments.
The clinical trial met the two co-primary endpoints; Pain-Free at 2 hours after dose, and Absent most Bothersome Symptoms 2 hours after dose versus placebo. The clinical trial can be found here Momentum Phase 3. The trial also compared AXS-07 to Rizatriptan (a well known and effective generic drug for acute migraine) for these tough to treat patients, who have not responded to prior treatments. Comparisons below are AXS-07 versus Rizatriptan.

• Sustained pain freedom from 2 to 24 hours after dosing.  16.1% vs 11.2%  p=0.038
• Sustained pain relief from 2 to 24 hours after dosing.  53.3% vs 43.9%  p=0.006
• Sustained pain relief from 2 to 48 hours after dosing.  46.5% vs 36.5%  p=0.003
• Rescue medication was used for 23.0% of AXS-07 patients vs 34.7%  p=0.001
• Patient Global Impression of Change, AXS-07 vs Rizatriptan.                             p=0.022
• Return to normal function at 24 hours.                                                                      p=0.027

The clinical trial was a success, as AXS-07 above, compared well to the generic acute migraine drug Rizatriptan. The safety profile of AXS-o7 was similar to placebo. The company plans to file an NDA (new drug application) in the second half of 2020.

AXS-05 Phase 3 Results for MDD (GEMINI)

Axsome Therapeutics (AXSM) is higher today after releasing phase 3 results with AXS-05 for the indication of Major Depressive Disorder or (MDD). The press release is here, AXS-05 Achieves Primary Endpoint in Gemini Phase 3. Some major points from the outstanding results are as follows.

• AXS-05 at week 6 versus placebo  p=0.002
• Rate of remission of depression week 6 versus placebo  p=0.001
• Week 1 AXS-05 versus placebo p=0.007

All scores are based on the Montgomery-Asberg Depression Rating Scale or MADRS. The phase 3 clinical trial details can be found here NCT04019704. The company will file for FDA approval in the second half of 2020 for the indication of MDD, and potentially get approved for that indication in the first half of 2021. Below is the chart of the stock that appreciated +70% today.

AXS-12 Phase 2 Results for Narcolepsy

Axsome Therapeutics (AXSM) today, announced the results of their phase 2 clinical trial with drug AXS-12 (reboxetine) for Narcolepsy. The clinical trial is here clinicaltrials.gov. The trial results were better than anticipated. All comparisons of AXS-12 versus placebo were statistically significant.

• Reduction in Cataplexy attacks compared to placebo p=0.001
• Reduced daytime sleepiness compared to placebo p=0.003
• Improved cognitive function compared to placebo p=0.001
• Sleep quality and sleep related symptoms compared to placebo p=0.007

AXS-12 was safe and well tolerated.  Chart below.



Alopecia Areata Clinical Trial Comparison

Concert Pharmaceuticals, just released CTP-543 Phase 2 Results for patients with moderate to severe Alopecia Areata. The phase 2 results included the 12 mg cohort of the clinical trial, in addition to the already completed 8 mg results. Below are comparison's made with Pfizer's drug PFE-06651600 Phase 2 Alopecia Areata. As seen by the data below, Concert's CTP-543's 12 mg results are shown to be the most efficacious versus their own 8 mg arm, and against Pfizer's PFE-06651600 at 24 weeks. The SALT % Increase (mean) drop from baseline (CTP-543 SALT dropped- 50%), is on a percentage basis the largest SALT improvement of the three results below. Results below are relative improvement from baseline, not placebo adjusted.

• SALT Score of 100 = zero hair growth
• SALT Score of 0 = full hair growth 

The percentage drop of SALT score (hair growth improvement) is one of the tools used to evaluate the efficacy of different Alopecia clinical trial drugs. Next CTP-543 will be tested in two large phase 3 clinical trials, but that won't occur until around mid 2020. 
                                                                  

PFE-06651600
	Total (n=45) at 24 weeks
		Baseline	End of Treatment
SALT (mean)		88.1	54.5
SALT Increase (mean)		-33.6
SALT % Increase (mean)		0	38.1%
% SALT Reduction		% of 45 Patients Achieving Better SALT Scores
30%			47.9%
50%			37.5%
75%			27.0%
90%			25.0%
100%			12.5%
CTP-543 8mg
	Total (n=38) 24 weeks
		Baseline	End of Treatment
SALT (mean)		89.1	51.7
SALT Increase (mean)		-37.4
SALT % Increase (mean)		0	42.0%
% SALT Reduction		% of 38 Patients Achieving Better SALT Scores
30%			not measured
50%			47.0%
75%			29.0%
90%			16.0%
CTP-543 12mg
	Total (n=36) 24 weeks
		Baseline	End of Treatment
SALT (mean)		87.3	43.6
SALT Increase (mean)		-43.6
SALT % Increase (mean)		0	50.0%
% SALT Reduction		% of 36 Patients Achieving Better SALT Scores
30%			not measured
50%			58.0%
75%			42.0%
90%			36.0%

AXS-07 for Acute Migraine

Axsome’s AXS-07 is designed to treat acute episodes of migraine. The drug is a combination of Meloxicam and Rizatriptan. Rizatriptan belongs in a group called triptans which are oral drugs designed to treat moderate to severe migraine headaches. AXS-07 will also compete against a newer group of oral drugs known as CGPR inhibitors similar to Allergan's Ubrogepant. The recently announced news from Axsome, was that the company met with the FDA in May, and was told that the current phase 3 clinical trial for acute migraine AXS-07 Phase 3, if successful, would be the only clinical trial needed to file a new drug application (NDA).  The clinical trial is currently being run under a Special Protocol Assessment (SPA) which was granted by the FDA prior to the trial beginning. Axsome also announced that a 12-month safety study has commenced. Patients will roll off the current phase 3 clinical trial, and into the 12 month safety study, which is a standard requirement for a new drug application to be filed with the FDA. The company is expected to file for FDA approval in the second half of 2020, which could lead to approval in 2021. The patent for AXS-07 runs into 2036.  Thank you for reading. 

Smoking Cessation and AXS-05

A phase 2 Smoking Cessation trial with AXS-05 was completed in April of 2019 by Axsome Therapeutics and sponsor Duke University here Phase 2 Smoking Cessation. From the Axsome press release following results, a quote by James Davis of Duke University and principal investigator of the phase 2 clinical trial had the following to say.
"The findings in this trial are notable because AXS-05 was compared to bupropion, an approved treatment for smoking cessation," said James Davis, MD, Medical Director of the Duke Center for Smoking Cessation, and principal investigator of the trial. "The improvement of AXS-05 over bupropion observed in this trial is similar in magnitude to the improvement over placebo reported for the approved smoking cessation treatment varenicline in studies with a similar design. Reduction in ad-lib smoking was selected as the primary endpoint in this trial, because it has been shown to correlate with smoking abstinence. I look forward to the continued evaluation of AXS-05 as a smoking cessation treatment."
Varenicline is also known under commercialization as Chantix. The drug was developed by Pfizer, and FDA approved in 2006, with patent extending to 2020. After 2020 generic companies can replicate the drug and sell it at much lower prices. The drug has produced annual revenues of around $1 billion for Pfizer, even though the safety profile has come under scrutiny from the FDA. The side effect profile for Chantix is below. 
The most common side effects of CHANTIX include nausea (30%), sleep problems (trouble sleeping, vivid unusual strange dreams) constipation, gas, and/or vomiting.
The potential opportunity for Axsome Therapeutics with AXS-05, would be exhibiting similar efficacy as Chantix has in clinical trials, but with fewer side effects associated with treatment. Current chart below.

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