AXS-05 and SAGE-217

Axsome and SAGE Therapeutics are in phase 3 development for two promising drugs that treat Major Depressive Disorder or MDD. Both companies have completed phase 2 clinical trials with very good results, and each have achieved the Breakthrough Therapy Designation (BTD) from the FDA. What's different from the current Selective Serotonin Reuptake Inhibitors or SSRI's, is that both AXS-05 and SAGE-217 are fast acting oral delivery drugs that show efficacy within days of treatment, compared to many weeks.
Let's see how AXS-05 and SAGE-217 compare in a side by side analysis of important facts to consider. From the file below, and from listening to company conference calls, both AXS-05 and SAGE-217 could get FDA approval and to commercialization around the same time in 2021. What stands out is that while SAGE Therapeutics currently sports an 8.49B market cap, Axsome Therapeutics just a 768M market cap. Thank you for reading.

Drug	AXS-05	SAGE-217
Action	NMDA	GABA
phase 2	ph 2 compare	ph 2 placebo
Remission wk 6	47%	45% *
BTD	√	√
Pivotal	√	√
phase 3 MDD	n= 300	n= 450
Start	6/1/2019	12/1/2018
End Expected	12/31/2019	12/31/2019
Safety Data Ext	n= 300	n= 600
NDA Filing est	6/1/2020	6/1/2020
Approval est	3/1/2021	3/1/2021
Delivery-oral	b.i.d.	qd
Patent	2034	2034
Market Cap	768M	8.49B
*15 day dosing

AXS-05 Path to Approval for MDD

• Axsome Therapeutics met with the FDA and was given an expedited pathway of AXS-05 for Major Depressive Disorder or MDD. Under this new agreement, the company's phase 2 clinical trial known as Ascend for MDD was given pivotal status, and will only need one other pivotal phase 3 with efficacy, to file a New Drug Application (NDA).
• The company plans to enroll for a new phase 3 placebo clinical trial in the 2nd quarter of 2019, with an expected completion date by the end of 2019. The company plans on initiating this phase 3 with an increased number of clinical sites recruiting participants, which will allow for completion faster over the successfully completed phase 2 Ascend clinical trial for MDD.
• The timeline for filing an NDA would then be in the first half of 2020. If this timeline holds up, AXS-05 could potentially get to commercialization around the same time as Sage Therapeutics drug SAGE-217, which is also pursuing the same MDD indication.

AXS-05 was given Breakthrough Therapy Designation (BTD) from the FDA for Major Depressive Disorder, and the patent extends out to 2034. Thank you for reading.

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.
 

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.

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

SAGE-217 Patent Issued

SAGE-217 was issued patent number US 9,512,165 B2, which runs to April 2034.  The link to other patent applications can be found here SAGE Patent Applications.  SAGE-217 is the oral version of SAGE-547, and will be running four proof-of-concept, phase 2 clinical trials in 2017.  Thank you for reading.                

SAGE-217

The future pipeline will be more dependent upon SAGE-217, which is built around the same premise as SAGE-547, but as a once daily oral delivery. 
The company describes SAGE-217 as "a novel neuroactive steroid that acts as a positive allosteric modulator of synaptic and extra-synaptic GABAa receptor subtypes.  Unlike many of the naturally occurring neuroactive steroids, SAGE-217 has a pharmacokinetic profile to potentially support once-daily oral dosing and a selectivity profile that minimizes potential off-target side effects." 

Patents: SAGE-217 to April 2034

Bottom Line:
Sage Therapeutics is an interesting company with plenty of cash and a very successful phase 2 clinical trial completed.  The future will be focused on their oral, once daily SAGE-217.  Thank you for reading. 

Patent Expiration Dates

A drug's patent is of extreme importance to the company that has developed the drug, and competitors looking for acquisition.  This is a running patent list, as new drugs become of interest.  The typical drug patent extends for 20 years from the priority date, once the patent is approved.  After 20 years, and any additional patent extensions, generic companies are able to replicate, and sell the drug at a very high discount to the expired patented drug.

AVP-923 US 2026                                                          

AVP-923 EU 2023

AVP-786 US 2030
AVP-786 EU 2028
AXS-05  US 2040
AXS-07 US 2036
D-Baricitinib US (August 2032)
D-Baricitinib EU xxxx
Baricitinib US 2028
CTP-543 US 2037
CTP-543 EU xxxx
Ruxolitinib US (Dec 2027)
CTP- 656 US (May 2031)
CTP- 656 EU xxxx
Kalydeco US 2027
Kalydeco EU 2025
CTP-692 2038
CTP- 730 US 2030
CTP- 730 EU 2030
Otezla US 2024 (pending through 2028)
Otezla EU 2028
GLPG0634  US (June 2029)
GLPG 1837  US 2034
ITI- 007 US 2028
JZP-386 US, EU, JP (2030-2032)
Xyrem  2019-2024
MIN-101 GR US 2035
D-Momelotinib US (Jan 2033)
D-Momelotinib EU  xxxx
Momelotinib US (March 2027)
Nuplazid US 2028
Nuplazid EU 2025
Rexulti US (February 2027)

Rexulti EU (December 2026)
SAGE-217 US  April 2034
SAGE-217 EU April 2034
SAGE-547 US  to 2033 - 2037
SAGE-718 US  Sep 2032 or Oct 2037