CTP-543 and PFE-06651600

Now that Concert Pharmaceuticals has press released their top line results for CTP-543 8mg twice daily, CTP-543 Results from Interim Analysis of Phase 2a Trial in Patients with Alopecia Areata, a comparison can be made with Pfizer's  phase 2 results for drug PFE-06651600 for moderate to severe Alopecia Areata. In the comparison below, I am focusing on SALT % Increase (mean) End of Treatment. In this category CTP-543 had a 42.00% mean increase of SALT score after 24 weeks, versus a 38.13% increase for Pfizer's drug PFE-06651600. Concerts phase 2 study testing up to 8mg, may not be the highest dose available, as the company is currently testing a 12mg arm in the same phase 2 study.

PFE-06651600
	Total (n=45)	24 weeks
	Baseline	End of Treatment
SALT (mean)	88.1	54.5
SALT Increase (mean)	-33.6
SALT % Increase (mean)	0	38.13%
% 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	42.00%
% SALT Reduction		% of 38 Patients Achieving Better SALT Scores
30%		not measured
50%		47.0%
75%		29.0%
90%		16.0%
100%		0.0%

FDA Advisory Committee Votes 17-1 in Support of Zulresso for PPD

Today the Advisory Committee (ADCOM) voted 17-1 in support of Sage Therapeutics drug Zulresso for Postpartum Depression (PPD). The first and only drug if approved for this unmet medical need, will go into commercialization early 2019 under the name of Zulresso. The press release is here FDA Advisory Committee Votes 17-1. 
The future for the company gets even more exciting with once daily oral drug SAGE-217, which is in phase 3 testing for Major Depressive Disorder or MDD, and has a market potential several times larger than PPD.
SAGE has a talented management team, with plenty of cash to run pivotal clinical trials, and bring new drugs for other indications to market. SAGE-217 has patent to April 2034. Thank you for reading.
 

Janus Kinase Inhibitors for AA

The race is on for an effective and safe drug to treat Alopecia Areata. The two companies at the foremost of drug discovery are Pfizer with drug PF-06651600 and Concert Pharmaceuticals with CTP-543.  So how do the two JAK Inhibitor drugs stack up in limited clinical trials to date.
Columbia University 20 mg bid Ruxolitinib
n=12
% SALT Score Improvement (mean)
66.9%

Liu, King Study 10 mg bid Ruxolitinib
n=8
% SALT Score Improvement (mean)
61.2%

Pfizer PF-06651600
n=45
% SALT Score Improvement (mean)
38.1%                                                               
Next we will add the results of Concert's phase 2 clinical trial of CTP-543 with the 4mg and 8mg doses once press released expected fourth quarter. Thank you for reading.

Pfizer's PF-06651600

Pfizer and Concert Pharmaceuticals are the two companies with the most advanced drugs for the indication of Alopecia Areata. Pfizer has press released results for their lead candidate PF-06651600 here Phase 2 Data in Alopecia Areata. The drug achieved a -33.6 reduction in SALT score at 24 weeks from a baseline of 88.1. Below are the percentages of reduction of SALT score points for both Pfizer drugs. PF-06651600 is the drug that the company will be taking forward into phase 3 clinical trials.
  
Table. Percentage of Patients with Better SALT Scores at Week 24 Weeks
Improvement in SALT ScorePF-06651600 Group %, PF-06700841 Group, %

30%                                                 47.9                                  59.6   

50%                                                 37.5                                  48.9

75%                                                 27.0                                  38.3

90%                                                 25.0                                  31.9

100%                                               12.5                                   12.0

In the Columbia University phase 2 clinical trial Ruxolitinib for Alopecia Areata, 20mg bid dosing achieved good results based on the percentage of SALT improvement from baseline. At this time we do not know what the maximum dose that the FDA will allow Concert to run in clinical trials, as it is currently testing 8mg. CTP-543 is the deuterated version of Ruxolitinib currently in phase 2 clinical trials for Alopecia Areata. Thank you for reading.

Minerva Neurosciences Raises Capital - $8.45

Minerva Neurosciences (NERV) filed Form S-3 on August 10. The form S-3 is a three-year prospectus that allows the company to from time to time, at their discretion, sell shares to raise capital up to $200 million. The supplemental part of the prospectus calls for a takedown of up to $50 million worth of stock sales through investment banker Jeffries. The company held approximately $108 million in cash as of 6-30-18. If the company initiates the complete takedown of $50 million, then the cash will increase to around $156 million, and the dilution would be around 6.2 million shares at current prices to increase the total share count to 45 million shares outstanding.  The companies burn rate is around $13 million per quarter at present.
The phase 3 clinical trial readout of MIN-101 for negative symptoms of schizophrenia, is scheduled for the first half of 2019. So beginning the capital raising process now makes sense. The S-3 filing gives the company the discretion of when and how much capital to raise over the next three years. Below is a chart of Minerva. Thank you for reading.

SAGE-718

Sage Therapeutics' focus is on developing compounds that are positive allosteric modulators (PAM) of both synaptic and extrasynaptic sites of either the GABA receptor or the NMDA receptor system.
The companies second area of focus is on the NMDA receptor with SAGE-718. SAGE-217 targets the GABA receptor, SAGE-718 targets the NMDA receptor. The company is currently in phase 1 testing with oral drug SAGE-718.
The unique position the company finds itself in, is unlike SAGE-217 which primarily targets depression, SAGE-718 will target different indications with zero overlap. Within NMDA hypofunction the company is targeting indications such as Huntington’s, ADHD, and Alzheimer’s disease, potentially creating another very large revenue stream in the future. The company has SAGE-904 which also target’s the NMDA receptor and is in pre-clinical studies.

The patent for SAGE-718 from the company’s 10K below.

We also own twenty families of applications directed to modulators of NMDA receptors. Fifteen of these families of patent applications are directed to compounds that modulate NMDA receptors, including SAGE-718, which can be used to treat NMDA receptor-related disorders such as CNS-related conditions. One of these families of patent applications is directed to using a naturally occurring compound as a biomarker for a subject who would benefit from treatment with a modulator of NMDA receptors. One of these families of patent applications is directed to using a modulator of NMDA receptors to treat a rare NMDA loss of function disorder. Any patents that may issue, if any, from these families of applications directed to modulators of NMDA receptors would have statutory expiration dates in September 2032 and October 2037.

SAGE-217 Gets Expedited Development - $175.76

Very good news from SAGE Therapeutics this morning. The FDA has agreed to give SAGE Therapeutics an expedited pathway for oral drug SAGE-217 for the indications of Postpartum Depression (PPD) and Major Depressive Disorder (MDD). Below is copied directly from the press release this morning.

• Expedited SAGE-217 development plan to support potential NDA submission for MDD and PPD together
•  Previously completed placebo-controlled study in MDD considered as pivotal; initiation of one additional Phase 3 pivotal trial anticipated in 2H of 2018  
• Ongoing study in PPD designated as pivotal; results expected in 4Q 2018
• If successfully developed, SAGE-217 has the potential to be the first durable, rapid-acting, oral, short-course treatment for MDD and PPD

The second half of 2018 will be packed with clinical trial data for PPD and MDD. SAGE-217 is an oral once daily delivered drug with patent to April 2034. Thank you for reading.

Neuroactive Steroids (NAS)

Not all neuroactive steroids are created equal from this chart and abstract below. That may be important when comparing Sage Therapeutics SAGE-217 to Marinus Pharmaceuticals drug Ganaxolone for patients with Postpartum Depression. First let's look at a chart that compares oral SAGE-217 to IV SAGE-547 and IV Ganaxolone for synaptic and extrasynaptic activity of each.

 

SAGE-217 shows much more activity in both synaptic and extrasynaptic activity over a given time period.  Below is another illustration that not all is created equal when considering tonic current. https://www.ncbi.nlm.nih.gov/pubmed/27743930. Here is a paragraph from that abstract.

A sustained increase in tonic current was observed following exposure to ALLO, or SGE-516 and was prevented by inhibiting PKC with GF 109203X. No increase in tonic current was observed with exposure to ganaxolone. In agreement with the observations of an increased tonic current, the NASs ALLO and SGE-516 increased the phosphorylation and surface expression of the β3 subunit-containing GABAARs. Our studies demonstrate that neuroactive steroids have differential abilities to induce sustained increases in the efficacy of tonic inhibition by promoting GABAAR phosphorylation and membrane trafficking dependent on PKC activity.

Thank you for reading.

Brexanolone for Postpartum Depression Submital to the FDA - $145.29

Today, SAGE Therapeutics announced the submittal of a New Drug Application to the FDA for approval of Brexanolone for Postpartum Depression. There is not an FDA approved drug to treat this indication, so this could potentially be the first. I am expecting six months to approval or around October 23, 2018. The company achieved their goal of submittal to the FDA during the first half of 2018 comfortably. The patent for Brexanolone runs to 2034. Thank you for reading.

Esketamine for Depression

This post will focus on Johnson & Johnson's NMDA intranasal Esketamine (form of Ketamine) for treatment resistant depression or (TRD), with rapid onset of effect. Esketamine has received breakthrough therapy designation (BTD) from the FDA in 2013 for treatment-resistant depression, and again in 2016 for major depressive disorder with imminent risk of suicide.  JNJ through Janssen has several Esketamine phase 3 clinical trials for TRD patients currently running. Results from a phase 2 clinical study for patients 20-64 years of age with treatment resistant depression, (lack of treatment with at least two different oral anti-depressants) released results.  The results by Janssen showed a statistically significant effect, with ascending dose-response relationship, and response was observed as quickly as two hours post dose.  The side effect profile is better explained here JAMA Psychiatry in etable 4 supplemental 1. A rundown of the side effect profile from that supplemental is below. 
                                                                56mg                     84mg
Dizziness                                                40%                         47%
Headache                                               15%                          18%
Dissociation                                           35%                         24%
Dysgeusia                                               15%                          29%
Nausea                                                    20%                         24%
Dissociative  Disorder                           5%                          24%               
Oral Hypoesthesia                               20%                          12%     

We'll have to see how the FDA addresses the side effect profile of the intranasal drug. Thank you for reading.
 

SAGE Therapeutics Market Capitalization in Charts - $183.47

Sage Therapeutics - (SAGE) has a CNS drug with a unique fast acting mechanism of action, that has led the company to a current $7.41 billion dollar market capitalization. Previous writing's  about the company can be found here SAGE. Below is a market capitalization chart of SAGE, at certain stock prices.

The current market capitalization of the company is around $7.41 billion. We see SAGE reaching a $10 billion market cap ($240.00) in the near future based solely on their current pipeline, potentially reaching a $15 billion market cap ($361.00) on further success for SAGE-217 in other indications, and potential buyout of the company. The patent for SAGE-217 and SAGE-547 run to 2034. Thank you for reading.

Contact: 586-431-8000

MIN-101 Phase 3 Primary Endpoint - $6.80

Minerva Neurosciences (NERV) has officially begun dosing patients for their pivotal phase 3 clinical trial for the negative symptoms or Schizophrenia. Let's examine the primary endpoint in the phase 3 (Marder NSFS) and compare it with their successfully completed phase 2 primary endpoint PANSS Negative Scale (Pentagonal Structure 5-Factor) to see how the items vary. Below is the phase 2.

Phase 2   PANSS Negative Scale (Pentagonal Structure)            p = 32mg  64mg
N1            Blunted Affect                                                                               .25         .17
N2            Emotional Withdrawal                                                               .01         .02           
N3            Poor Rapport                                                                               .00         .00
N4            Passive/apathetic social withdraw                                          .29         .01
N6            Lack of spontaneity and flow of conversation                      .07          .01
G7            Motor retardation                                                                       .68         .04
G8            Uncooperativeness                                                                     .41          .86
G13          Disturbance of volition                                                              .25          .88
G14          Poor impulse control                                                                  .89         .56

Phase 2   5-Factor Negative Score
32mg p=0.021   effect size 0.45     64mg p=0.003  effect size 0.58

Below is the phase 3 Marder NSFS (negative symptom factor score) items that will be tested versus placebo.

Phase 2   Marder Negative Symptoms Factor Score (NSFS)       p = 32mg  64mg
N1             Blunted Affect                                                                             .25         .17
N2            Emotional Withdrawal                                                              .01         .02
N3            Poor Rapport                                                                               .00         00
N4            Passive/apathetic social withdraw                                          .29         .01
N6            Lack of spontaneity                                                                    .07         .01
G7            Motor retardation                                                                       .68         .04
G16          Active social avoidance                                                              .01         .00

Notice that the phase 2 design included G8, G13, and G14, which scored the lowest on effect for the phase 2 primary endpoint, but will not be included in the phase 3 Marder (NSFS) primary endpoint. The currently running phase 3 primary endpoint includes the same items as the phase 2, (minus G8, G13, G14) with the inclusion of G16 (active social avoidance) which scored a .01 and .00 respectively in the phase 2 clinical trial. The Marder items that were included in the phase 2, would have scored better in itself, than the phase 2 primary endpoint PANSS Negative Scale (Pentagonal Structure) 5-Factor Negative Score of p=0.021 and p=0.003, which was achieved with the 32mg and 64mg dose. Thank you for reading.
   

Patent Board Does Not Institute PGR Proceeding

The press release is here Concert Pharmaceuticals Announces Patent Trial and Appeal Board Did Not Institute PGR Proceeding.  What this means to Concert Pharma is that, Incyte Corporation may be able at some point in time, challenge the patent of CTP-543. The second setback was that Concert has announced that they will not at this time initiate further clinical trials for other auto-immune indications that CTP-543 may have been useful for. The company continues to proceed with CTP-543 in their phase 2 clinical trial for patients with Alopecia Areata.  In addition the phase 3 clinical trial for AVP-786, which was scheduled to read out in July of 2018, has been pushed back to April of 2019, eliminating a potential catalyst for the company in 2018. The second half of 2019, which should reveal AVP-786's trial success, and phase 2 CTP-543 12mg arm effectiveness for Alopecia Areata patients, should be an important time for the company. Thank you for reading.