GLPG1837 for Cystic Fibrosis

Galapagos released phase 2, SAPHIRA(1) results this week with drug GLPG1837, for Cystic Fibrosis patients with the G551D mutation.  The link to the conference call is here http://edge.media-server.com/m/p/aen3zb2d.

Some details from the conference call:

• The company reported similar ppFEV1, in comparison to FDA approved Kalydeco
• Kalydeco patients at baseline had a sweat chloride reading of around 45 mmol/L
• After the seven day washout period, the sweat chloride level increased to a mean value of 98 mmol/L*
• After 28 days, and dosing up to 500 mg GLPG1837 twice daily, sweat chloride fell to 66 mmol/L
• For patients who exceeded the predicted target concentration, sweat chloride changed from a mean 94 mmol/L to 52 mmol/L
• Sweat chloride did not fall to the original baseline Kalydeco level, of around 45 mmol/L
• GLPG1837 was mentioned as being dose limited up to 600 mg twice daily

* The concentration of chloride in sweat is elevated in individuals with CF.

Thank you for reading.               

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.                

CTP-543 Phase 1 Top-Line Results

Concert Pharmaceuticals announced top-line results this week for CTP-543.  The single and multiple ascending dose study was well-tolerated across all dose groups.  The company is planning on testing four doses (4, 8, 12, and 16 mg BID) in the phase 2 clinical trial scheduled to begin early 2017.  The phase 2 clinical trial will enroll around 100 patients with moderate to severe alopecia areata, with six month readout by the end of 2017.  Thank you for reading.

SAGE-547 Expedited Pathway Revealed

We initially wrote about Sage here, SAGE-547.  This week SAGE revealed through this press release Sage Therapeutics, the expedited pathway for drug SAGE-547 for Postpartum Depression.  The important news was that the FDA in agreement with Sage, anticipates that no additional controlled studies will be necessary to file an NDA.  The company believes that they may be able to file for a new drug application for Postpartum Depression in 2018.  If approved by the end of 2019, the company will have patent until around 2034, or approximately 15 years of exclusivity.  Below are the important aspects of the expedited pathway for SAGE-547, agreed upon by the FDA.

• Current SAGE-547 clinical studies confirmed as appropriate to support registration, if successful
• No additional efficacy studies expected to be required beyond those currently underway
• Trial design of studies 202B and 202C are considered appropriate for registration, with increase in size and other minor modifications
• The primary clinical endpoint for these pivotal trials was unchanged and agree upon with FDA
• Additional patient safety data may be acquired through an open-label program

Below is a year-to-date chart of SAGE.  Despite the company having an extraordinary year with SAGE-547 the stock is down -4.49% this year.  The company currently has $431 million in cash, or about $13.00 per share in cash.  

Source: Shaw Investments, StockCharts.com

Thank you for reading.                

CTP-656 Clinical Trial Initiated

CTP-656 for cystic fibrosis patients with CFTR gating mutations is now loaded in the clinicaltrials.gov website here NCT02971839.  The phase 2 trial is expected to start enrollment in January of 2017 to avoid the busy holiday season approaching.  The readout completion date is by the end of 2017.  Sweat chloride will be the primary endpoint of the study with FEV1 secondary.  With only 6-8 patients in each arm, the trial is not specifically powered for efficacy, but more likely to compare the three different dosages, and decide which one will be taken further into a phase 3 clinical trial, where FEV1 will be the primary endpoint.

Estimated Enrollment:	40
Study Start Date:	January 2017
Estimated Primary Completion Date:	December 2017 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: CTP-656, Dose 1, QD Oral tablet dosed once-daily for 28 days	Drug: CTP-656, Dose 1 (QD)
Experimental: CTP-656, Dose 2, QD Oral tablet dosed once-daily for 28 days	Drug: CTP-656, Dose 2 (QD)
Experimental: CTP-656, Dose 3, QD Oral tablet dosed once-daily for 28 days	Drug: CTP-656, Dose 3 (QD)
Active Comparator: Kalydeco, 150 mg Tablet (open label) 150 mg, oral tablet dosed twice-daily for 28 days	Drug: Kalydeco, 150 mg Tablet (BID; open-label)
Placebo Comparator: Placebo, Oral Tablet, QD Oral tablet dosed once-daily for 28 days	Drug: Placebo (QD)

Detailed Description:

This is a randomized, parallel-group, double-blind, placebo controlled multicenter study to evaluate the safety and efficacy of CTP-656 in CF patients with CFTR gating mutations, compared to Kalydeco, for a total of 28 days. Subjects will be randomized to receive either double-blind CTP-656 or placebo, or open-label Kalydeco.

 

Janus Kinase (JAK) Inhibitors

Janus Kinase Inhibitors - JAK's have shown to be successful in a variety of different disease indications.  The science of these inhibitors is still in the early stages of understanding.   They operate by inhibiting one or more of the family of enzymes, (JAK1, JAK2, JAK3, TYK2), and interfering with the signaling pathway.  They have shown to be successful in cancer and inflammatory diseases to date.  Concert Pharmaceuticals currently owns patents for the following three deuterated JAK inhibitors, with indications that each has shown to be effective in, prior to the company adding deuterium to the entity.

D-Ruxolitinib
Selectivity: JAK1,2 
Indication:  Myelofibrosis, Polycythemia Vera, Alopecia Areata  
Patent: 2032 US

D-Baricitinib
Selectivity: JAK1,2, TYK2
Indication: Rheumatoid Arthritis, Psoriasis
Patent: 2032 US

D-Momelotinib
Selectivity:  JAK1,2
Indication:
Patent: 2033 US

The non-deuterated versions of these JAK's have already shown proof-of-concept (POC), essentially reducing the risk for Concert to bring the drugs to market, for other or same, previously tested indications.  It's rare to have a full runway of patent years ahead, with clinically tested drugs, at your disposal. We'll follow the Janus Kinase landscape with any new findings in the future.  Thank you for reading. 

CTP-543 Alopecia Areata Market Opportunity

Concert Pharmaceuticals will be entering a phase 2 clinical trial with CTP-543, for the indication of moderate to severe alopecia areata, in the first quarter of 2017.  Proof-of-concept (POC), has already been indicated in a small phase 2 academic study by Columbia University with results of the auto-immune disease here JCI.  We are estimating total revenue that CTP-543 could achieve if FDA approved for alopecia areata, based on some recent Dermatologic Drug Prices.

Up to 650,000 affected with alopecia areata U.S. any given time (Concert literature)
30% to 50% may have moderate to severe (195,000 to 325,000) US
Mid range population moderate to severe = 260,000 US
Market capture rate of 25% = 65,000 US moderate to severe
Price per tablet once daily = $23.33 or $700 per month

Peak revenue estimate $700 x 12 x 65,000 = $546 million

Risks to Assessment
Revenue split with another equally effective drug
The pool of potential patients is too high
Market capture rate of 25% too high 
$700 monthly, or $23.33 per tablet
Insurance does not cover the indication       

STAT3 Phosphorylation with CTP-543

Concert Pharmaceuticals is currently running a phase 1 pharmacodynamics (PD) clinical trial, before heading into a phase 2 clinical trial for patients with moderate to severe Alopecia Areata.  The goal of the (PD) part of the phase 1 trial, will test CTP-543's ability to affect downstream gene regulation similar to ruxolitinib, with results in Q1 2017.  Ruxolitinib which is already an FDA approved drug for various cancer indications has been tested for it's ability to affect downstream gene regulation STAT3.  The results for ruxolitinib are below, and which can also be found in this link JAKAVI-ruxolitinib. 

Pharmacodynamics 
Ruxolitinib inhibits cytokine induced STAT3 phosphorylation in whole blood from healthy subjects and MF patients.  Jakafi administration resulted in maximal inhibition of STAT3 phosphorylation 2 hours after dosing which returned to near baseline by 8 hours in both healthy subjects and myelofibrosis patients.

Metabolism
In vitro studies indicate that CYP3A4 is the major enzyme responsible for metabolism of ruxolitinib.  Parent compound is the predominate entity in humans representing 60% of the drug-related material in circulation.  The two major and active metabolites were identified in plasma of healthy subjects representing 25% and 11% of parent AUC.  These metabolites have one-half to one-fifth of the parent JAK-related pharmacological activity.  The sum of all active metabolites contribute to 18% of the overall pharmacodynamics of ruxolitinib.  

Bottom Line:  CTP-543 will be compared to the above ruxolitinib data, after completion of the current phase 1 clinical trial.  The drug will be advancing into a phase 2 clinical trial for patients with moderate to severe Alopecia Areata, in the first quarter of 2017.  CTP-543 is the deuterated version of ruxolitinib.  Thank you for reading.
 

Axsome Therapeutics Progress Update

We originally wrote about Axsome Therapeutics (AXSM) and their drug AXS-05 here AXS-05 A Novel Mechanism Of Action.  Some new information for Axsome occurred this week.  

• First the company completed an agreement for a term loan of up to $20 million dollars from Silicon Valley Bank, with minimal dilution.  This bolsters their cash to around $40 to $50 million.  The company plans to move AXS-05 into a phase 2/3 clinical trial for Alzheimer's patients with agitation symptoms with this new capital.
• Other news that could have an impact on Axsome and their NMDA / bupropion drug combination AXS-05 for TRD (treatment resistant depression), is that competitor Otsuka, who was also pursuing the same indication with AVP-786 (NMDA, Sigma-1), has decided not to advance the drug past their recently completed phase 2 clinical trial.  So at present, AXS-05 is one of the most advanced oral NMDA (dextromethorphan) drug in clinical trials for treatment resistant depression. 

Bottom Line:  The increased cash raise was needed to advance AXS-05 into other clinical trials.  The company is extremely lean, as their quarterly burn rate was just $6.8 million in the second quarter, but is expected to increase with more clinical trials planned.  AXS-05, drug combination for treatment resistant depression, should have phase 3 results mid 2017, with patent into 2034.  Thank you for reading.  

Contact:  586-431-8000

GLPG1837 for Cystic Fibrosis

Galapagos presented data at the 2016 NACFC conference in Orlando yesterday, with a focus on SAPHIRA (2) results with drug GLPG1837 for CF people with the S1251N mutation.

Galapagos Abstract 253
Phase 2 results from SAPHIRA (2) S1251N
The bottom line with this small clinical trial that included n=7 patients, was that the company monitored in line FEV1, but below expectations for sweat chloride (readings in naïve patients that have never received Kalydeco, did not show a reduction in sweat chloride when administered GLPG1837 for 7 days) both compared against what Kalydeco had previously achieved at two weeks, in clinical trials for similar CF patients.  Sweat chloride readings is a biomarker that the FDA will want to see in clinical trials, prior to any approval.
  
Phase 2 from SAPHIRA (1) for G551D 
The company will have top line results by the end of 2016.  The company mentioned that Kalydeco for similar patients in (G551D), the FEV1 was around 6% to 10% improvement at the two week timeframe.  So that may be seen as a close comparison for their top-line results.  Below is a new CF timeline schedule for the company.  

Timeline for Potentiators:
GLPG1837 Phase 2 SAPHIRA (1) G551D readout by end of 2016
GLPG2451 Phase 1 readout first half of 2017
GLPG3067 Phase 1 start in 2017  (NEW)

Timeline for Correctors:
GLPG2222 Phase 2 start Q4 2016
GLPG2737 Phase 1 start Q4 2016
GLPG2851 Phase 1 start 2017

Bottom Line:
GLPG1837 was the first potentiator to enter clinical trials as twice daily dosing for Cystic Fibrosis people.  The company should have a readout by the end of 2016 for n=27 phase 2 clinical trial SAPHIRA (1) participants of the G551D mutation.  This will be an important readout regarding the future of that drug.  Concert should be into a phase 2 clinical trial with drug CTP-656 for G551D participants in the next few months, with readout by the end of 2017.  Thank you for reading. 

Contact: 586-431-8000

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. 

NACFC 2016 Conference October 27-29th

This years North American Cystic Fibrosis Conference (NACFC), will be held in Orlando from October 27th through the 29th.  Below are some abstracts to look for during that conference.  
Concert:  Abstract 224:  CTP-656  Multiple Dose Pharmacokinetic Profile Continues to Support a Once-Daily Potentiator for Cystic Fibrosis Patients with Gating Mutations.  The trial showed a superior PK profile compared to ivacaftor.  

Galapagos:  Abstract 252:  Safety, tolerability, and pharmacokinetics of a novel CFTR corrector molecule GLPG2222 in healthy volunteers.  Full safety and PK data will be presented at the conference.  
Galapagos: Abstract 253:  GLPG1837 in subjects with cystic fibrosis (CF) and the S1251N mutation:  Results from a phase IIA study (SAPHIRA2).  Pending results September.

Proteostasis Therapeutics: Abstract 187:  Phase 1 initial results evaluating safety, tolerability, PK and biomarker data using PTI-428, a novel CFTR modulator, in patients with cystic fibrosis.  PTI-428 is an amplifier designed for any mutation.  

 Vertex:  Abstract 188:  Discovery and biological profile of next-generation CFTR Correctors.  VX-152 and VX-440 are highlighted in this abstract.  Vertex has other abstracts listed, that have been previously presented.

The link to the NACFC abstracts can be found here, 2016 NACFC Abstracts.            
Thank you for reading.                       

Ruxolitinib For Alopecia Areata

This academic Alopecia Areata clinical study by Columbia University, has finally been released in full to the public.  I highlighted what I believe are the important points to consider regarding this study.  The complete study can be found here JCI.  

ITI-007 Phase 3 Results

This is the second phase 3 clinical trial for patients with schizophrenia and Intra-Cellular drug ITI-007.  This trial had Risperidone as an active comparator and a placebo arm, the clinical trial is here NCT02469155.  I am including our write up on the first phase 3 clinical trial (Study '301) here ITI-007 Phase 3 Results, for the specific reason of attempting to uncover how ITI-007 has performed on the PANSS Negative Symptoms subscale.  The first phase 3 clinical trial did not show statistically significant improvement in the PANSS Negative Symptoms subscale from the company PR in September of 2015. Below are the results for the ITI-302 phase 3 study.

• 60 mg -14.6
• 20 mg -15.0
• Risperidone 4mg -20.1
• Placebo -15.1

Today (Study '302) the company released phase 3 clinical trial top line results, that did not mention any significance to the Negative Symptoms in the Intra-Cellular press release. Intra-Cellular's ITI-007 results today should create some skepticism regarding the drug as a viable CNS candidate for Schizophrenia as Risperidone outperformed ITI-007.  The PANSS Negative Symptom subscale had zero mention from today's top-line press release. Based on the two phase 3 clinical trials, ITI-007 does not have a strong effect on the PANSS Negative Symptoms subscale.  AVP-786 is currently in clinical trials being tested for negative symptoms associated with schizophrenia.  Thank you for reading.           

Deuterated Drugs

Giving credit where due.  Below are two well written articles on the deuteration of drugs.  I have taken parts of the articles that seem pertinent to us, for investment purposes.  The complete articles can be accessed from the Concert Pharmaceuticals website below. 

http://www.concertpharma.com/news/in-the-news/

From: "A decades-old drug technology finally nears it's big breakthrough"

Should Teva get regulatory approval, it would open a market in the “many tens of billions of dollars,” said Roger Tung, whose company Concert Pharmaceuticals Inc. is also developing treatments with deuterium.  “It would show the breadth of possibilities,” Tung, the chief executive officer of Lexington, Massachusetts-based Concert, said in an interview. “Deuterium provides unique properties that cannot be attained in any other way.”

From: "Deuterium switcheroo breathes life into old drugs"

Even champions of deuterated drugs note there are plenty of pitfalls. Thomas Gant, scientific founder of the deuterated drug maker Auspex (he’s no longer with the company) and inventor of many deuterated drug candidates, including SD-809, says most synthetic chemists don’t have a good grasp of how chemical reactions operate in the presence of deuterated reagents or substrates.

“It is actually pretty surprising how many reactions that most chemists wouldn’t think would have an effect on the positions of hydrogens will actually cause quite a bit of randomization and dancing around of hydrogen radicals,” he says. “So you run these reactions expecting it to have no effect on your deuterated drug, and in fact, you can see a pretty dramatic effect in some instances. It’ll essentially spread the deuterium around the molecule” so you don’t have the original compound anymore.

As far as intellectual property is concerned, Gant says, it’s important to know the law. Deuterated compounds are considered new chemical entities and can be patented. But to get a patent, he explains, “you have to have actually done the chemistry, produced the deuterated compound, shown the spectra, shown deuterium incorporation rates, and shown biology to demonstrate a perceived benefit.”

It’s not unusual for pharmaceutical companies to include deuterated versions of original drugs in their boilerplate wording for patents. “This is something that companies routinely do to scare off people who don’t understand patents,” Gant says. “People think that the deuterated compounds have been covered. But they haven’t been covered because they haven’t been made and they haven’t been tested. So it might be written in the general description, but it doesn’t actually cover the application of deuterated compounds.  
Thank you for reading.
 

Nuplazid Launch Progression

The launch of Acadia Pharmaceuticals Nuplazid for Parkinson's Disease Psychosis (PDP), so far has been successful based on management conference call discussions. We previously wrote about the commercialization opportunity here, Nuplazid Priced at $23,400 / Year. 

 Chief commercial officer Terry Moore had this to say regarding the launch of Nuplazid, "One of the things I find interesting is we do have physicians report back to us that they are very pleased with what they are seeing in terms of efficacy. But what I find interesting is that they are reporting that the caregiver is reporting that they see the difference at home and that they are reporting that to the physician." 
 
Medicare Part D has it covered as 34/mg, taken as two 17/mg pills a day, for around $2,000 for a 30 day supply.  The annual price is similar to company guidance of $24K per year Nuplazid, for Parkinson's Disease Psychosis, which is the only approved drug for this unmet need. 

Bottom Line:  This market pullback may create a decent entry price for ACAD investors that have been waiting to go long the stock.  No positions in Acadia.  Thank you for reading.
 

D-Ibrutinib

A new patent for Concert Pharmaceuticals here, Deuterated Ibrutinib.  Ibrutinib is sold commercially under the name Imbruvica, and has a 50% - 50% sales sharing agreement by AbbVie and JNJ.  Imbruvica is a Bruton's tyrosine kinase (BTK) inhibitor for the treatment of mantle cell lymphoma, chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia, and is dosed once daily.  The patent expiration date is July 2032, for d-ibrutinib, and 2026 at the earliest for the non-deuterated ibrutinib. 

The drug is going head to head against Astra Zeneca's ACP-196, in a clinical trial below for previously treated subjects, with high risk chronic lymphocytic leukemia.

Estimated Enrollment:	500
Study Start Date:	June 2015
Estimated Primary Completion Date:	June 2019 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: ACP-196 ACP-196 will be orally administered until disease progression or unacceptable toxicity.	Drug: ACP-196
Active Comparator: ibrutinib Ibrutinib will be orally administered until disease progression or unacceptable toxicity.	Drug: ibrutinib

Bottom Line:  Analyst have projected up to 6 billion in annual revenue for Imbruvica, for various cancer indications.  The 500 patient head to head clinical trial against ACP-196 above will not readout until 2019, but more importantly when complete, will display a safety and efficacy comparison for these two drugs.  Thank you for reading.                                        

CRISPER-Cas9

CRISPR-Cas9 is a new gene-editing technology that has gained enormous press the last few years for it's accuracy.  The science is being used to address the underlying genetic causes of human disease. The advantages seen thus far, is that it is faster, less expensive, and more accurate than prior gene-editing technology.  CRISPR-cas9 enables geneticists and medical researchers to edit parts of the genome, by cutting out, replacing or adding parts to the DNA sequence.  There are a few publicly traded companies.  The companies include the following. 

Intellia Therapeutics:  NTLA
Editas Medicine:  EDIT
Cellectis:  CLLS
Crispr Therapeutics: CRSP

Bottom Line:  The above names are worth following, and learning more about the science of CRISPR-cas9 gene-editing.  Thank you for reading.