FDA Approves Kalydeco (ivacaftor) as First and Only CFTR Modulator to Treat Eligible Infants with CF as Early as Six Months of Age

In continuation of my update on Kalydeco (ivacaftor) 

Vertex Pharmaceuticals Incorporated  announced the U.S. Food and Drug Administration (FDA) approved Kalydeco (ivacaftor) for use in children with cystic fibrosis (CF) ages six months to less than 12 months who have at least one mutation in their cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to Kalydeco based on clinical and/or in vitro assay data. Kalydeco is already approved in the U.S., Canada and EU for the treatment of CF in patients ages 12 months and older.

“Today’s approval for Kalydeco allows physicians to begin treating the underlying cause of CF in eligible infants as young as six months of age for the first time, with the potential to modify the course of the disease,” said Margaret Rosenfeld, M.D., MPH, Seattle Children’s Research Institute and Department of Pediatrics, University of Washington School of Medicine.

This FDA approval is based on data from a 24-week Phase 3 open-label safety cohort (ARRIVAL) of 11 children with CF aged six months to less than 12 months who have one of 10 mutations in the CFTR gene (G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, G1349D or R117H). The study demonstrated a safety profile similar to that observed in previous Phase 3 studies of older children and adults; most adverse events were mild or moderate in severity, and no patient discontinued therapy due to adverse events. The most common adverse events (≥30%) were cough (64%), nasal congestion (36%) and rhinorrhea (36%). Three serious adverse events, all considered unrelated to study treatment by the investigators, were observed in three patients.

Mean baseline sweat chloride for the children in this cohort was 101.5 mmol/L (n=11). Following 24 weeks of treatment with Kalydeco, the mean sweat chloride level was 43.1 mmol/L (n=6). In the six subjects with paired sweat chloride samples at baseline and week 24, there was a mean absolute change of -58.6 mmol/L (95% CI; -75.9, -41.3).

Results of this study were presented at the 32nd Annual North American Cystic Fibrosis Conference in October 2018.

“The manifestations of CF are often present at birth, which underscores our relentless commitment to reach the youngest CF patients possible in our clinical trials,” said Reshma Kewalramani, M.D., Executive Vice President and Chief Medical Officer at Vertex. “As an important outcome of these efforts, we are now able to treat infants with cystic fibrosis as early as six months of age with Kalydeco.”

Kalydeco was first approved in 2012 in the U.S. and is now available in more than 40 countries with more than 5,000 patients on therapy. For more information on Kalydeco, prescribing information, or patient assistance programs, visit Kalydeco.com or VertexGPS.com.

https://en.wikipedia.org/wiki/Ivacaftor

FDA Approves Kalydeco (ivacaftor) as First and Only CFTR Modulator to Treat Eligible Infants with CF as Early as Six Months of Age

FDA Approves Kalydeco (ivacaftor) for Cystic Fibrosis in Children Ages 12..

 Vertex Pharmaceuticals Incorporated  announced the U.S. Food and Drug Administration (FDA) approved Kalydeco (ivacaftor) to include use in children with cystic fibrosis (CF) ages 12 to <24 months who have at least one mutation in their cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to Kalydeco based on clinical and/or in vitro assay data.

“Cystic fibrosis is a chronic, progressive disease that is present at birth, with symptoms often occurring in infancy,” said Reshma Kewalramani, M.D., Executive Vice President and Chief Medical Officer at Vertex. “With today’s approval, parents and physicians now have a medicine to treat the underlying cause of CF in patients as young as one year of age. We are excited about the progress of our portfolio and continue to support additional research on the potential benefit of early intervention with all of our medicines, with the goal of bringing a treatment to all people living with CF.”

This FDA approval is based on data from the ongoing Phase 3 open-label safety study (ARRIVAL) of 25 children with CF aged 12 to <24 months who have one of 10 mutations in the CFTR gene (G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, G1349D or R117H). The study demonstrated a safety profile consistent with that observed in previous Phase 3 studies of older children and adults; most adverse events were mild or moderate in severity, and no patient discontinued due to adverse events. Two patients had elevated liver enzymes greater than eight times the upper limit of normal, but continued to receive Kalydeco after a dose interruption. The most common adverse events (≥30%) were cough (74%), pyrexia (37%), elevated aspartate aminotransferase (37%), elevated alanine aminotransferase (32%) and runny nose (32%). Four serious adverse events were observed in two patients.

Mean baseline sweat chloride for the children in this study was 104.1 mmol/L (n=14). Following 24 weeks of treatment with Kalydeco, the mean sweat chloride level was 33.8 mmol/L (n=14). In the 10 subjects with paired sweat chloride samples at baseline and week 24, there was a mean absolute change of -73.5 mmol/L. These data were presented at the 41stEuropean Cystic Fibrosis Society (ECFS) Conference in June 2018 and published in The Lancet Respiratory Medicine (Volume 6, No 7, July 2018).

“I’m very excited about the approval of ivacaftor in children ages 12 to less than 24 months as this is the first regulatory approval of a CFTR modulator in this age group,” said Margaret Rosenfeld, M.D., MPH, Seattle Children’s Research Institute and Department of Pediatrics, University of Washington School of Medicine. “The premise of newborn screening for CF is to intervene very early in the course of disease with the goal of improving long term outcomes, so this is a significant milestone for parents and caregivers of young children with CF.”

Kalydeco was already approved in the U.S. for the treatment of CF in patients ages 2 and older who have one of 38 ivacaftor-responsive mutations in the CFTR gene based on clinical and/or in vitro assay data. Vertex submitted a Marketing Authorization Application for a line extension (ages 12 to <24 months) to the European Medicines Agency with a decision anticipated in the first half of 2019.

https://es.wikipedia.org/wiki/Archivo:Carnosine.png

FDA Approves Symdeko (tezacaftor/ivacaftor and ivacaftor) to Treat Cystic Fibrosis in People Ages 12 and Older with Certain Mutations in the CFTR Gene

Vertex Pharmaceuticals Incorporated announced  the U.S. Food and Drug Administration (FDA) approval of  Symdeko (tezacaftor/ivacaftor and ivacaftor) for treating the underlying cause of cystic fibrosis (CF) in people ages 12 and older who have two copies of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or who have at least one mutation that is responsive to tezacaftor/ivacaftor. Symdeko is Vertex's third medicine approved to treat the underlying cause of CF. Vertex is ready to launch Symdeko and will begin shipping it to pharmacies in the United States this week.

Ivacaftotezacaftor

"Today is an exciting day for the CF community. The approval of Symdeko, our third disease-modifying CF medicine, offers many patients an important new treatment option," said Jeffrey Leiden, M.D., Ph.D., Vertex's Chairman, President and Chief Executive Officer. "This approval is an important milestone in our journey to treat every person with CF, and we remain committed to urgently advancing our efforts to develop new medicines that treat the underlying cause of CF for the many people still waiting."

In November 2017, the New England Journal of Medicine published the results of two Phase 3 studies of Symdeko. These studies, named EVOLVE and EXPAND, enrolled approximately 750 people with CF ages 12 and older with two copies of the F508del mutation or with one F508del mutation and one mutation that results in residual CFTR function. Across both studies, patients treated with Symdeko experienced statistically significant and clinically meaningful improvements in lung function and other measures of disease, with a favorable safety profile. The most common adverse events, regardless of treatment group, included infective pulmonary exacerbation and cough. The first data from the ongoing EXTEND rollover study, also presented in November, show that the lung function improvements and the safety and tolerability profiles seen in EVOLVE and EXPAND were sustained for up to 48 total weeks of Symdeko treatment.

"We've already seen the significant impact that disease-modifying medicines can have on patients and are incredibly pleased that there is now a third treatment option that enables more patients to benefit from CFTR modulation," said Patrick Flume, M.D., Director of the Medical University of South Carolina Cystic Fibrosis Center and Principal Investigator for the EXTEND study. "In particular, Symdeko is an important treatment option for patients who either never started or discontinued Orkambi, and it also provides increased benefit over Kalydeco alone for patients with residual function mutations."

The European Medicines Agency (EMA) has validated the Marketing Authorization Application (MAA) for the tezacaftor/ivacaftor combination. The company expects approval in the EU in the second half of 2018.

FDA Approves Symdeko (tezacaftor/ivacaftor and ivacaftor) to Treat Cystic Fibrosis in People Ages 12 and Older with Certain Mutations in the CFTR Gene

Cystic Fibrosis Drug Seems OK for Preschoolers: Study

The cystic fibrosis drug ivacaftorappears safe and effective for young children, a drug company-funded study suggests.

Ivacaftor (trade name Kalydeco, developed as VX-770) is a drug approved for patients with a certain mutation of cystic fibrosis, which accounts for 4–5% cases of cystic fibrosis. Ivacaftor was developed by Vertex Pharmaceuticals in conjunction with the Cystic Fibrosis Foundation and is the first drug that treats the underlying cause rather than the symptoms of the disease. Called "the most important new drug of 2012", and "a wonder drug"  it is one of the most expensive drugs, costing over US$300,000 per year, which has led to criticism of Vertex for the high cost...

"This was a small trial, but we are thrilled to see these results," said study leader Jane Davies, from the National Heart and Lung Institute at Imperial College London in England. "Ivacaftor is a potential new treatment to offer children aged 2 years and older with cystic fibrosis and a [specific gene mutation linked to the disease]. This novel therapy could substantially impact these children's lives, potentially opening the way to even greater progress in years to come."

Cystic fibrosis is a life-threatening genetic disease that destroys the lungs and digestive system. More than 70,000 people worldwide have cystic fibrosis, the researchers said.

One expert explained that ivacaftor has been considered a big advance in the treatment of the disease.

"Ivacaftor, approved in 2012, was the first groundbreaking drug of its kind in that it works to correct the genetic defect in cystic fibrosis patients," explained Dr. Joan Decelie-Germana, director of the Cystic Fibrosis Center at Cohen Children's Medical Center in New Hyde Park, N.Y.

"For many older patients who have been taking it since 2012, they report feeling 'normal,' have no daily symptoms and lung function has stabilized or improved -- it has been a 'game changer,' " she said.

Prior studies found that ivacaftor was safe and effective in children 6 and older, as well as in teens and adults, the researchers said. However, this is the first study to assess the pill's effects in younger children, they added.

The clinical trial included 34 cystic fibrosis patients between the ages of 2 and 5. All of the youngsters had at least one copy of a mutation in a gene linked to cystic fibrosis called the CFTR gene. For six months, they took two daily doses -- 50 milligrams (mg) for children who weighed less than 14 kilograms (31 pounds) and 75 mg for those who weighed more.

The children showed improvement in several areas, including weight gain, pancreatic function and sweat chloride levels, which suggests an improvement in the body's ability to restore the balance of salt in and out of cells. When this process is defective, it leads to cystic fibrosis complications, the researchers said.

The drug was generally well-tolerated by the children, the study showed. The most common problems were coughing and vomiting. Five children had liver function abnormalities, leading one to stop treatment, the researchers said.

Funding for the study was provided by Vertex Pharmaceuticals Inc., maker of ivacaftor. The findings were published Jan. 20 in the journal Lancet Respiratory Medicine.

The study is "groundbreaking for cystic fibrosis care in children aged 2 to 5 years," wrote the authors of an accompanying editorial who are from University Children's Hospital Bern and University Children's Hospital Zurich, in Switzerland.

Cystic Fibrosis Drug Seems OK for Preschoolers: Study - Drugs.com MedNews

Discovery could increase efficacy of promising cystic fibrosis drug

We know that, Ivacaftor (trade name Kalydeco, developed as VX-770) is a potentiator approved for patients with the G551D mutation of cystic fibrosis. Ivacaftor was developed by Vertex Pharmaceuticals in conjunction with the Cystic Fibrosis Foundation.

Cystic fibrosis is caused by any one of several defects in a protein, cystic fibrosis transmembrane conductance regulator, which regulates fluid flow within cells and affects the components of sweat, digestive fluids, and mucus. The defect, which is caused by a mutation in the individual's DNA, can be in any of several locations along the protein, each of which interferes with a different function of the protein. G551D is a standard amino acid abbreviation for a mutation in which the amino acid glycine (G) in position 551 is replaced with aspartic acid (D). G551D is characterized by a dysfunctional CFTR protein on the cell surface. In the case of G551D, the protein is trafficked to the correct area, the epithelial cell surface, but once there the protein cannot transport chloride through the channel. Ivacaftor, a CFTR potentiator, improves the transport of chloride through the ion channel by binding to the channels directly to induce a non-conventional mode of gating which in turn increases the probability that the channel is open.

Accidental discovery of a mutation in CFTR, the R532 mutation, allowed MU researchers to reveal a new "non-strict coupling" relationship that occurs between the consumption of ATP, a molecule that provides energy in the body, and the opening and closing of the CFTR. They argue that the new information uncovered about this mechanism that controls the opening and closing of the CFTR and the passage of ions through it could explain how and where the new cystic fibrosis treatment Kalydeco (Vx-770) works.

"To his credit, Dr. Hwang exploited the behavior of the CFTR mutants to demonstrate that CFTR's gate is not strictly coupled to the nucleotide binding engine (NBD) that binds and splits ATP [energy] to drive conformational changes that regulate chloride flow through the CFTR protein channel," said colleague David Sheppard, PhD, an associate professor in the School of Physiology and Pharmacology at the University of Bristol in Bristol, U.K. who did not participate in the study.

In their study, MU researchers were able to observe the effects of the cystic fibrosis drug Vx-770 on the recently discovered R352 mutation. They found that Vx-770 enhances the activity of the CFTR channel by exploiting this "non-coupling" mechanism, a conclusion also supported by experimental results with the wild-type CFTR protein.

"Traditionally, researchers have defined how energy is utilized and transferred in the CFTR as a 'strict coupling' mechanism, meaning that one ATP molecule opens CFTR's gate, ions pass through and the ATP molecule is hydrolyzed and then the gate closes," Hwang said. "In this new model, we argue that the CFTR uses energy from ATP hydrolysis to carry out its function of chloride flow, but this coupling mechanism is more plastic than we thought and therefore could be subjective to manipulations by drugs such as Vx-770."

CFTR is part of a family of thousands of active transporter proteins called ABC proteins. Although CFTR may share many structural features with its ABC "cousins," as Hwang calls them, it has been unclear as to whether CFTR and its cousins may work in a similar manner.

The new idea of how the CFTR utilizes ATP to carry out its function may bear a broader implication because of the evolutionary relationship between CFTR and other ABC transporter proteins. It opens up a wide variety of therapeutic possibilities for other common diseases, such as cancer, heart disease and diabetes, Hwang said, since many other ABC proteins play critical roles in those human illnesses.

"It's taken years for scientists to solve this particular puzzle about the CFTR protein," Hwang said. "Our recent study provides evidence that these ABC transporter proteins and CFTR, a chloride channel, are two peas in a pod. Mother nature employs the same structural framework with just a little bit of modification to do two totally different things. From a basic science perspective, it's a big deal.".....

Ref : http://www.pnas.org/content/110/11/4404.abstract?sid=3e58deab-1076-4255-b20b-73ff47495950

Discovery could increase efficacy of promising cystic fibrosis drug

FDA Approves Kalydeco to Treat Rare Form of Cystic Fibrosis

The U.S. FDA approved Kalydeco (ivacaftor) for the treatment of a rare form of cystic fibrosis (CF) in patients ages 6 years and older who have the specific G551D mutation in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene. 

“Kalydeco is an excellent example of the promise of personalized medicine – targeted drugs that treat patients with a specific genetic makeup,” said FDA Commissioner Margaret A. Hamburg, M.D. “

The unique and mutually beneficial partnership that led to the approval of Kalydeco serves as a great model for what companies and patient groups can achieve if they collaborate on drug development. 

“Kalydeco is the first available treatment that targets the defective CFTR protein, which is the underlying cause of cystic fibrosis,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “This is a breakthrough therapy for the cystic fibrosis community because current therapies only treat the symptoms of this genetic disease.”

Two 48-week, placebo-controlled clinical studies involving 213 patients, one in patients ages 12 years and older and another in patients ages 6 years to 11 years, were used to evaluate the safety and efficacy of Kalydeco in CF patients with the G551D mutation. In both studies, treatment with Kalydeco resulted in significant and sustained improvement in lung function.

Kalydeco is effective only in patients with CF who have the G551D mutation. It is not effective in CF patients with two copies of the F508 mutation in the CFTR gene, which is the most common mutation that results in CF. If a patient’s mutation status is not known, an FDA-cleared CF mutation test should be used to determine whether the G551D mutation is present.

Ref : http://investors.vrtx.com/releasedetail.cfm?ReleaseID=644158