Vertex Cystic Fibrosis Program

Vertex Pharmaceuticals (VRTX) has been, and will continue to be the leader in therapy for people with Cystic Fibrosis. Below is an update of all the different drugs in clinical trials that the company is currently running, including deuterated ivacaftor (VX-561), formerly known as CTP-656 that was purchased for $160 million from Concert Pharmaceuticals in July. Concert is eligible for up to $90 million more, dependent upon how far VX-561 progresses.

Twice Daily  
Ivacaftor 
Ivacaftor + Lumacaftor
Ivacaftor + Tezacaftor

Twice Daily Triple Combo Phase 2
Ivacaftor + Tezacaftor + VX-440 
Ivacaftor + Tezacaftor + VX-152
Ivacaftor + Tezacaftor + VX-659
Ivacaftor + Tezacaftor + VX-445

Once Daily Triple Combo Phase 2
VX-561 + Tezacaftor + VX-659 readout March 2018
VX-561 + Tezacaftor + VX-445 readout April 2018

The Ivacaftor patent runs to 2027, the Deuterated Ivacaftor (VX-561) patent runs into 2031. The goal for the program is to create a triple combo (1 potentiator, 2 correctors) once daily dosing for the majority of CF people with the F508del mutation. The company plans to run phase 3 triple combo trials in 2018.  Thank you for reading.

CTP-656 Multiple Dosing Phase 1 Results

Concert presented at the European Cystic Fibrosis Society today, and presented phase 1, multiple dosing with solid tablet results, for CTP-656 in healthy volunteers.  We initially were given top-line results in April, so there were not many surprises today.  The important information to consider from this completed phase 1 clinical trial with 7 days of dosing, is the following below under fed conditions.

CTP-656 to M1 Ratios
Single dose CTP-656 to M1 ratio = 1.5
7th day dose CTP-656 to M1 ratio = 1.8

With CTP-656, the highest exposure is to the most active species (parent). 
With Ivacaftor, the highest exposure is to the less-active metabolite (M1) (20% active relative to Ivacaftor).

Next step for Concert and CTP-656, is to initiate a phase 2 efficacy clinical trail 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.

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.

Vertex Pharmaceuticals Passes Advisory Committee

Vertex's (VRTX) drug combo named Orkambi faced the advisory committee on Tuesday this week. The FDA document is here Orkambi Advisory Committee .  The advisory committee voted 12-1 to approve the combination for patients with Cystic Fibrosis who have two copies (homozygous) of the F508del mutation, 12 years and older.  So that opens their market to a substantially much larger population of 20,000 patients. The results from the two phase 3 studies 890-103 and 890-104 are as follows.

Study 809-103

Lumacaftor 400 mg + Ivacaftor 250 mg q12 at week 24 = 2.6% mean absolute improvement over placebo on FEV1 test.

 

Study 809-104

Lumacaftor 400 mg + Ivacaftor 250 mg q12 at week 24 = 3.0% mean absolute improvement over placebo on FEV1 test.

Orkambi 

Lumacaftor 200 mg + Ivacaftor 125 mg, proposed dose every 12 hours.

Lumacaftor and Ivacaftor was administered twice daily, with the safety profile seen as well tolerated. What's intriguing is the fact that Orkambi the proposed combo up for FDA approval is administered as Lumacaftor 200 mg, and Ivacaftor as 125 mg twice daily. In prior trials, Lumacaftor dosages at the 600 mg level, achieved better efficacy than the 400 mg Lumacaftor dose on FEV1.  The reason for using 400 mg instead of 600 mg, is because the drug-drug interaction of Lumacaftor tends to lessen the effects of Ivacaftor up to 80% as dosages increase. The final date for FDA approval falls on July 5th, of 2015, and in the fourth quarter for EU approval. With an annual therapy per patient price of around $300,000, the potential to achieve revenue up to six billion is attainable. Thank you for reading.