A Breath of Fresh Air for Biotechs Working on Cystic Fibrosis Therapies

Researchers from the University of Zurich have determined the structure of a chloride channel, which could be a target for new drugs to treat cystic fibrosis.

Researchers at the University of Zurich have found a new target for future cystic fibrosis treatments. The study, published in Nature, has uncovered the structure of a protein that could help to correct the mechanism underlying the buildup of sticky mucus in patients’ lungs. This could give rise to a new wave of therapeutics for the condition, which at the moment lacks disease-modifying treatments.

Cystic fibrosis is a severe genetic disease affecting the lungs, for which there is currently no cure. It is caused by a malfunctioning chloride channel, CFTR, which prevents the secretion of chloride by cells, leading to the production of thick, sticky mucus in the lung. The condition affects around 70,000 people worldwide, who suffer from chronic infections and require daily physiotherapy.

However, one potential approach to treat cystic fibrosis is to activate the calcium-activated chloride channel, TMEM16A, as an alternative route for chloride efflux. As TMEM16A is located within the same epithelium as CFTR, its activation could rehydrate the mucus layer. The research group used cryo-electron microscopy to decipher the structure of TMEM16A, which is part of a protein family that facilitates the flow of negatively charged ions or lipids across the cell membrane.

The changes that occur in the lungs of cystic fibrosis patients.

TMEM16A is found in many of our organs, playing a key role in muscle contraction and pain perception, as well as in the lungs. It forms an hourglass-shaped protein-enclosed channel, which when bound by positively charged calcium ions, opens to let chloride ions to pass through the membrane.

Current treatments for cystic fibrosis include bronchodilators, mucus thinners, antibiotics, and physiotherapy, which only control symptoms. However, biotechs around Europe are beginning to make progress, with ProQR completing a Phase Ib trial and Galapagos and Abbvie’s triple combination therapy entering Phase I. Antabio has also received €7.6M from CARB-X to develop a new antibiotic against Pseudomonas infections.

The identification of a new target provides patients and biotechs alike with renewed hope of new and effective cystic fibrosis treatments, or even a cure. It will be interesting to see whether small molecules or gene therapy specialists could take advantage of this information.

Original article: https://labiotech.eu/cystic-fibrosis-treatment-target/

New Promising Results from Phase 3 of Combination Therapy

Findings from a phase 3 trial evaluating the efficacy and safety of tezacaftor in combination with ivacaftor in patients with cystic fibrosis (CF) who were homozygous for the Phe508del mutation were published in the New England Journal of Medicine.

The Phe508del mutation has been known to result in greatly reduced conductance regulator (CFTR) protein activity and a loss of chloride secretion, which can lead to impaction of mucus in the airways, gastrointestinal tract, and exocrine organs, with the potential for severe clinical consequences including gradual loss of lung function, nutritional deficits, pulmonary exacerbations, and respiratory failure. It is the most prevalent CFTR mutation worldwide, and affects approximately 46% of American CF patients.

Previous data has shown Ivacaftor’s association with a rate of progressive decline in lung function that is lower than that in untreated patients. In a phase 2 clinical trial involving patients who were homozygous for the Phe508del mutation or heterozygous for the Phe508del and G551D mutations, when combined with the investigational CFTR corrector tezacaftor, it has exhibited enhanced CFTR function and improved lung function.

In August, just one month removed from Vertex’s announcement of positive datafrom Phase 1 and Phase 2 studies, Rare Disease Report covered the acceptance of applications for the use of the tezacaftor/ivacaftor combination treatment in this patient population by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA).

The phase 3 trial enrolled a total of 510 patients 12 years and older with CF who were homozygous for the Phe508del CFTR mutation at 91 sites in the U.S., Canada, and Europe from January 30, 2015 to January 20, 2017. Patients were randomly assigned to be administered either tezacaftor and ivacaftor (administered as a fixed-dose combination tablet containing 100 mg of tezacaftor and 150 mg of ivacaftor in the morning and a tablet containing 150 mg of ivacaftor in the evening) combination therapy or placebo for 24 weeks.

In total, 475 patients completed the full 24 weeks of the trial, with 93.6% (n=235) in the tezacaftor-ivacaftor group and 93% (n=240) in the placebo group. While no significant difference in the body mass index (BMI) was experienced between the groups at week 24, the use of the combination therapy led to a significantly greater absolute change from baseline in the predicted forced expiratory volume in 1 second (FEV1) than placebo. Despite advances in standard-of-care therapy, patients with CF continue to lose lung function at a rate of an estimated 1% to 3% per year. This trial exhibited a significant effect of the combination therapy compared to the placebo, as the mean absolute change from baseline in FEV1 through week 24 was 3.4 percentage points in the former, compared to 0.6 in the latter.

The most common adverse events (AEs) among the enrolled patients included infective pulmonary exacerbation, cough, headache, nasopharyngitis, increased sputum production, pyrecia, hemoptysis, oropharyngeal pain, and fatigue. The incidence of AEs was similar in both the group for combination therapy and the placebo group, however, those treated with lumacaftor-ivacaftor in the phase 3 did not experience an increased incidence of respiratory events (33 patients [13.1%] vs. 41 patients [15.9%]).

This improved safety profile of the tezacaftor-ivacaftor combination supports its use in a broad range of patients with CF, and, if approved, the therapy will be the third of Vertex’s drugs approved for CF patients, and the second intended specifically to treat patients with F508del mutations (Orkami [lumacaftor/ivacaftor]).

For original article please visit: http://www.raredr.com/news/phase-3-combination-therapy-cystic-fibrosis?t=physicians

For the published study please visit: http://www.nejm.org/doi/full/10.1056/NEJMoa1709846?query=genetics#t=articleDiscussion

A Brief Historical Timeline of CF Research to Date

Cystic fibrosis care has seen such rapid advances that the average CF patient has experienced a dramatic evolution in treatment strategies in their lifetime. Here are some of the biggest milestones that shaped modern-day CF treatments.

Continue reading A Brief Historical Timeline of CF Research to Date

Positive Results for Phase 3 Studies of the Tezacaftor/Ivacaftor Combination Treatment

Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) announced that the New England Journal of Medicine (NEJM) published two articles with results from two Phase 3 studies of the tezacaftor/ivacaftor combination treatment, a medicine in development that is designed to treat the underlying cause of cystic fibrosis (CF) in people ages 12 and older who have certain mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Continue reading Positive Results for Phase 3 Studies of the Tezacaftor/Ivacaftor Combination Treatment

Phase 1a study for drug to treat CF regardless of CF Mutation

http://www.businesswire.com/news/home/20171018005403/en/Synspira-Announces-Patient-Dosed-Phase-1a-Study

Synspira Announces First Patient Dosed in Phase 1a Study of SNSP113 in Cystic Fibrosis
— First-in-class drug candidate for treatment of cystic fibrosis regardless of genetic mutation — Continue reading Phase 1a study for drug to treat CF regardless of CF Mutation

Vertex Drug Gets Priority Review for Cystic Fibrosis

http://www.empr.com/drugs-in-the-pipeline/tezacaftor-ivacaftor-vertex-cystic-fibrosis-priority-review-nda/article/684284/

Tezacaftor/Ivacaftor Gets Priority Review for Cystic Fibrosis

The Food and Drug Administration (FDA) has granted Priority Review to the New Drug Application (NDA) of tezacaftor/ivacaftor (Vertex) for the treatment of patients ≥12yrs old with cystic fibrosis (CF) who have two copies of the F508del mutation or one F508del mutation and one residual function mutation.

The NDA submission was based on positive results from 2 global Phase 3 trials, which showed statistically significant improvements in lung function (percent predicted forced expiratory volume in one second, or ppFEV1) in patients treated with tezacaftor/ivacaftor.

The combination treatment consists of ivacaftor (marketed under the brand name Kalydeco), a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, and tezacaftor, a novel CFTR corrector. Tezacaftor is designed to address the processing defect of F508del-CFTR to enable it to reach the cell surface, where ivacaftor can further enhance the protein’s function.

The FDA has set a Prescription Drug User Fee Act (PDUFA) target date of February 28, 2018 to make a decision on the NDA.

For more information visit Vrtx.com.

New cystic fibrosis biotech aims to take a different approach than Vertex

http://www.bizjournals.com/

California-based Synedgen has spun out its experimental cystic fibrosis treatments into a new biotech to be based in the Boston area, with an eye toward complementing existing drugs for the lung disease. Continue reading New cystic fibrosis biotech aims to take a different approach than Vertex

Clinical and Regulatory Progress Across Pipeline Programs for Drug Company

http://www.nasdaq.com/press-release/proteostasis-therapeutics-announces-clinical-and-regulatory-progress-across-pipeline-programs-20170607-00270

Proteostasis Therapeutics Announces Clinical and Regulatory Progress Across Pipeline Programs

Updates Announced During the 40th European Cystic Fibrosis Society Conference

Proteostasis Therapeutics, Inc. (NASDAQ:PTI), a biopharmaceutical company developing small molecule therapeutics to treat diseases caused by Continue reading Clinical and Regulatory Progress Across Pipeline Programs for Drug Company

Cystic Fibrosis Foundation to Give $3 Million for Novel CFTR Therapeutic

Arcturus Therapeutics, Inc. (“Arcturus” or the “Company”), a leading RNA medicines company, today announced that it has entered into a research agreement with Cystic Fibrosis Foundation Therapeutics Inc. (CFFT), the nonprofit drug discovery and development affiliate of the Cystic Fibrosis Foundation in which CFFT will pay up to $3 million to advance LUNAR-CF, a novel messenger RNA (mRNA) therapeutic formulated with Arcturus’ LUNAR™ delivery technology.

Continue reading Cystic Fibrosis Foundation to Give $3 Million for Novel CFTR Therapeutic

News about Concert Pharmaceuticals’ cystic fibrosis drug

http://cen.acs.org/articles/95/web/2017/03/Vertex-buys-Concerts-cystic-fibrosis-drug.htm

Vertex buys Concert’s cystic fibrosis drug
Vertex Pharmaceuticals will pay up to $250 million for Concert Pharmaceuticals’ cystic fibrosis drug CTP-656. Currently in Phase II clinical trials, the drug is a deuterated version of Vertex’s own Continue reading News about Concert Pharmaceuticals’ cystic fibrosis drug