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.               

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

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                            

GLPG1837 for Cystic Fibrosis

GLPG1837 has advanced into a phase 2 clinical trial for Cystic Fibrosis people with the G551D, or S1251N class III mutation.  This will be the first of two, phase 2 clinical trials testing the drug in CF. The Galapagos press release is here Galagapos starts SAPHIRA Phase 2 study.  In a previous post we compared the phase 1 clinical trial results of GLPG1837 and Concert's CTP-656 side by side, CTP-656 & GLPG1837 Drug Comparison.  The drug will be dosed twice daily, and the trial should be complete by the end of 2016.  Thank you for reading.
 

CTP-656 Clinical Trial Chronology

The company has advanced CTP-656 nicely since receiving U.S. patent in the fall of 2014. Below is a chronology of the drug's clinical progress.
    
    First Half 2017 - European switching study CTP-656, and Kalydeco.
✔ January 2017 - Start phase 2 for mono-therapy, various gating mutations.
✔ February 2016 - Food effect study in healthy male volunteers, solid oral dose.
✔ November 2015 - Multiple ascending dose (PK) crossover study, with CTP-656 and         Kalydeco in healthy volunteers, solid oral dose.
✔ March 2015 - Single ascending dose (PK) crossover study, with CTP-656, and Kalydeco in healthy volunteers, oral suspension.  Second part of phase 1.
✔ March 2015 - Phase 1, D9 and D18 analog (PK) comparison in healthy volunteers.  The first part of phase 1.
✔ 2012 - Pre-clinical D9, D18 and Kalydeco plasma study comparison in dogs.

Thank you for reading.

CTP-656 Cystic Fibrosis Market Opportunity

CTP-656 is the deutered version of Vertex drug Kalydeco.  Today, Vertex gave an updated sales forecast for Kalydeco at the JP Morgan Healthcare Conference.  The company expects 2016 revenues in the range of $675 million.  Kalydeco is provided to Cystic Fibrosis patients as mono therapy for the G551D and R117H mutation.  The annual cost of the therapy is approximately $300,000 annually.
Concert Pharmaceuticals plans on seeking regulatory approval for CTP-656 as mono therapy for people with the G551D and other gating mutations.  What could peak revenue look like for this set of patients excluding the more common F508del.  Below is the worldwide patient population for Kalydeco as mono-therapy, excluding any combination therapies for the most common form of CF, the F508del mutation, for which Orkambi is prescribed for.

• G551D ages 6+ (US) 
• G551D ages 6+ (EU, AUS & CAN)  
• Gating, R117H & Ages 2-5
• 4,000 eligible patients (Vertex Pharmaceuticals 2015 Year End Presentation)

The unique situation Concert finds itself in, if CTP-656 potentially does get FDA approval as mono-therapy, is that the footprint for those 4,000 patients available, have already been established from being prescribed Kalydeco.  The switch to CTP-656 from Kalydeco, could happen seamlessly if the drug is marketed right.
 

Penetration rate of 70% = 2,800 patients
Annual therapy price of $240,000 (20% discounted)
Potential revenue 2,800 patients * $240,000 annual therapy = $672 million

The advantages that CTP-656 offers is a once daily, with less dietary restrictions, that should lead to higher adherence rates. Thank you for reading.

 

Is Adherence to Ivacaftor Suboptimal

From a recent issue of the Journal of Cystic Fibrosis, the authors make a strong case that twice daily Ivacaftor adherence is suboptimal.  Although used interchangeably, let's attempt to differentiate between compliance and adherence. If a doctor prescribes Ivacaftor 150 mg twice daily, and you accept and fill the prescription, you are in compliance with your doctor. Taking Ivacaftor twice daily is adherence to the prescription requirements.  The link to the article is below.  
Adherence_to_Ivacaftor_is_suboptimal
In the small sample study, the authors found that adherence was 61% among patients prescribed Ivacaftor.  Keep in mind they studied patients taking Ivacftor for the G551D mutation, which showed an improvement of over 10% percentage points in clinical trials, in the percent predicted FEV1.  The latest  FDA approved combo Orkambi (Ivacaftor and Lumacaftor) scored much lower on FEV1 for patients with F508del, than what Ivacaftor alone did for G551D patients. There are a few companies currently working on a once daily for CF patients, which could increase adherence rates to a higher level. Thank you for reading.

Orkambi Gets FDA Approval

Today the FDA approved the combination of Vertex's Lumacaftor and Kalydeco (Orkambi) for cystic fibrosis people, 12 years and older, with two copies (homozygous) of the F508del mutation. We originally wrote about Orkambi here Vertex Pharmaceutical Passes Advisory Committee, when they were front and center with the FDA advisory committee.

Orkambi has been appoved for CF patients despite the relatively small improvement in FEV1 in two F508del clinical studies.  How high is the bar set for other companies to get clinically significant improvement over Kalydeco as mono therapy for the G551D mutation, and Orkambi combination therapy, for patients 12 years and older, with two copies of the F508del mutation?

G551D Through 24 weeks Kalydeco 150 mg q12h

• 10.6% and 12.5% FEV1 improvement vs. placebo

G551D Through 48 weeks Kalydeco 150 mg q12h

• 10.5% and 10.0% FEV1 improvement vs. placebo
• 3,000 Worldwide Patients

F508del Through 24 weeks 2 tablets (ivacaftor 125 mg / lumacaftor 200 mg) q12h

• 2.6% and 3.0% FEV1 improvement vs. placebo
• 26,000 U.S. + EU Orkambi Patient Potential

These are the FEV1 (forced expired volume) numbers that other companies will be considering as significant, to improve current therapy for CF patients.  The side effect profile was mild, as a high percentage of patients completed the Vertex clinical trials.  The annual wholesale acquisition cost (WAC) will be priced at around $259,000 per patient for the Orkambi combination.  Thank you for reading.