Vertex: Orkambi Approved In Europe. What Vertex Is Doing to Further improve CF Treatments

Europe Approves Orkambi®

The European Commission has granted Marketing Authorization for Orkambi® (lumacaftor/ivacaftor), for cystic fibrosis (CF) in people ages 12 and older who have two copies of the F508del mutation.

There are approximately 12,000 people with CF ages 12 and older who have two copies of this mutation. Vertex will now begin the country-by-country reimbursement approval process across the European Union (EU).

They said: The combination of lumacaftor and ivacaftor represents a step-change in the management of cystic fibrosis because it addresses the underlying cause of the disease. By doing so, it has shown meaningful and sustained benefits.

The question is: Does Orkambi have meaningful and sustained benefits?

Lets See.

In the TRAFFIC and TRANSPORT studies that were the basis for the European approval, the following results were observed:

– Those treated with the combination of lumacaftor and ivacaftor experienced significant improvements in lung function.

– Patients also experienced improvements in body mass index (BMI) and reductions in acute lung infections, including those requiring hospitalizations and intravenous antibiotic use.

– Interim data from PROGRESS demonstrated sustained improvement through 48 total weeks of treatment (24 weeks in TRAFFIC/TRANSPORT + 24 weeks in PROGRESS).

What else?

The combination of lumacaftor and ivacaftor was generally well tolerated in all three studies. The most common adverse events included shortness of breath and/or chest tightness, common cold and gastrointestinal symptoms (including nausea, diarrhea, or gas).

In the extension study, the safety and tolerability results were consistent with those observed in TRAFFIC and TRANSPORT, and no new safety concerns were identified.

Over 48 weeks, the most common adverse events were infective pulmonary exacerbation, cough and increased sputum. The incidence of serious adverse events during the PROGRESS trial was generally similar to TRAFFIC and TRANSPORT.

Cystic fibrosis is a rare, life-threatening genetic disease affecting approximately 75,000 people in North America, Europe and Australia. CF is caused by a defective or missing cystic fibrosis transmembrane conductance regulator (CFTR) protein resulting from mutations in the CFTR gene. Children must inherit two defective CFTR genes — one from each parent — to have CF.

There are approximately 2,000 known mutations in the CFTR gene. Some of these mutations, which can be determined by a genetic, or genotyping test, lead to CF by creating non-working or too few CFTR protein at the cell surface.

The defective function or absence of CFTR proteins in people with CF results in poor flow of salt and water into and out of the cell in a number of organs. In the lungs, this leads to the buildup of abnormally thick, sticky mucus that can cause chronic lung infections and progressive lung damage in many patients that eventually leads to death. The median age of death is in the mid-to-late 20s.

In people with two copies of the F508del mutation, the CFTR protein is not processed and trafficked normally within the cell, resulting in little-to-no CFTR protein at the cell surface. Patients with two copies of the F508del mutation are easily identified by a simple genetic test.


Okambi is a combination of the following:

Lumacaftor, which is designed to increase the amount of mature protein at the cell surface by targeting the processing and trafficking defect of the F508del-CFTR protein, and ivacaftor, which is designed to enhance the function of the CFTR protein once it reaches the cell surface.

Okambi is an oral pill taken every 12 hours – once in the morning and once in the evening.

For complete product information, please see the Summary of Product Characteristics that can be found on once posted.

Collaboration with Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT)

Vertex initiated its CF research program in 1998 as part of a collaboration with CFFT, the nonprofit drug discovery and development affiliate of the Cystic Fibrosis Foundation. Both of our approved CF medicines were discovered by Vertex as part of this collaboration.

What must we expect from Vertex about further improving Cystic Fibrosis treatment?

Vertex’s treatment for cystic fibrosis is a work in progress. Vertex’s first drug, Kalydeco, is for a relatively small group of cystic fibrosis patients with the genetic mutation G551D. Next was Okambi, which, as we see above aimed at treating cystic fibrosis patients with two copies (homozygous) of F508del mutation.

Now, there is VX-661. This is an improved version of VX-809/lumacaftor designed to work better in combination with Kalydeco and future Vertex cystic fibrosis compounds.

In March 2015, Vertex announced data from a 12-week Phase 2 study evaluating VX-661 in combination with ivacaftor in 39 people with CF ages 18 and older who have two copies of the F508del mutation.

The study evaluated two doses of VX-661 (100 mg once daily or 50 mg every 12 hours) in combination with ivacaftor (150 mg every 12 hours). The study showed that the combination regimen was generally well tolerated, and all patients completed 12 weeks of treatment. The most common adverse events were pulmonary exacerbation, which occurred in 38 percent of all patients who received VX-661 and 44 percent of those who received placebo, and cough, which occurred in 33 percent of all patients who received VX-661 and 39 percent of those who received placebo.

Consistent with prior Phase 2 studies that evaluated 4 weeks of treatment with VX-661 in combination with ivacaftor, the new study showed a rapid improvement in lung function within four weeks of treatment, and after patients completed treatment, lung function returned to baseline.

These safety and efficacy data supported Vertex’s ongoing Phase 3 program of VX-661 in combination with ivacaftor.

The Phase 3 program is evaluating VX-661 (100 mg once daily) in combination with ivacaftor (150 mg every 12 hours) and consists of four Phase 3 studies, including a study in people with two copies of the F508del mutation, which began enrollment in February 2015. The other three studies will enroll people with CF who have one copy of the F508del mutation and a second mutation that is either a gating mutation, residual function mutation or a mutation that results in minimal CFTR function.

What do we expect to see as satisfactory for physicians and investors?

We should see equivalent or better improvement in FEV1. We should see absolute improvement of at least 4% or more improvement in FEV1.

We are waiting for these trial results:

What else Vertex is doing in the way of improving its CF treatments?

A strategic research collaboration with CRISPR Therapeutics

Focusing on gene editing CRISPR-Cas9 technology 

For the discovery of potential new treatments aimed at the underlying genetic causes of disease.

Vertex and CRISPR will focus their initial gene editing research on discovering treatments to address the mutations and genes known to contribute to cystic fibrosis and sickle cell disease.

– Vertex and CRISPR will also evaluate a specified number of other genetic targets as part of the collaboration.

– Vertex will have exclusive rights to license up to six new CRISPR-Cas9-based treatments that emerge from the collaboration. CRISPR-Cas9 holds significant promise for the future discovery of potentially transformative treatments for many genetic diseases.

Under the terms of the collaboration, Vertex and CRISPR will jointly use the CRISPR-Cas9 technology to discover and develop potential new treatments that correct defects in specific gene targets known to cause or contribute to particular diseases. The initial focus of the collaboration will be on the use of CRISPR-Cas9 to potentially correct the mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene known to result in the defective protein that causes CF and to edit other genes that contribute to the disease.

Additionally, the companies will seek to discover and develop gene-based treatments for hemoglobinopathies, including sickle cell disease. Additional discovery efforts focused on a specified number of other genetic targets will also be conducted under the collaboration.

The upcoming Prohost Letter #388 will tell you more about gene editing with CRISPR-Cas9 and other editing technologies.

We have a lot to tell you about the biotech evolution.

Stay Tuned.

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