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.                

Kalydeco for G551D

Vertex Pharmaceutical's Cystic Fibrosis drug Kalydeco has been FDA approved for people with the G551D mutation since 2012.  Kalydeco has been proven very effective for these patients, as the results from clinical trials reveal.  Below (Vertex 2012 presentation) is sweat chloride, and FEV1 results from the phase 3 G551D clinical trial that led to FDA approval.

 

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The results above at 24 and 48 weeks show extremely sustainable efficacy, versus placebo. Other improvement considerations, would be the dosing of once daily to improve adherence, and bio-availability for oral consumption, with  low or moderate fat containing food.  Kalydeco is currently dosed 150 mg every 12 hours, and prescribed to be taken with fat-containing food. Thank you for reading. 

 

Contact: 586-431-8000                            

VX-661 Corrector for Cystic Fibrosis

Vertex is currently involved with four phase 3 cystic fibrosis clinical trials for people with the F508del mutation, and the combination of potentiator Ivacaftor + corrector VX-661.  Today they gave an update regarding one of the four phase 3 clinical trials that are in progress.  The complete press release is here Vertex Provides Update on Ongoing Phase 3 Program for VX-661 in Combination with Ivacaftor for the Treatment of Cystic Fibrosis. 

                 

GLPG2222 and GLPG2451 for Cystic Fibrosis

Galapagos updated their cystic fibrosis program.  The significant news today, was that the company was expected to test potentiator GLPG2451 with corrector GLPG2222, from a press release on June 15th.  Today, they have not made up their mind in full whether they are going to do a combination with 2451 and 2222, as potential for part of a triple combination.  GLPG2451 phase 1, will have a slight delay with results in early 2017, from expected end of 2016.   Thank you for reading.