Cystic Fibrosis

Cystic fibrosis (CF) is an autosomal recessive genetic disorder that can shorten life expectancy. It is characterized by pulmonary symptoms, including obstructive lung disease that worsens over time, sinusitis, malabsorption due to insufficient pancreatic exocrine function leading to malnutrition, liver disease such as biliary cirrhosis, and CF-related diabetes mellitus (CFRD).

CF was a uniformly fatal disease in childhood when first described in 1938, but today the predicted median survival is 44.4 years.

Over 50% of people with CF are now 18 years and older, evolving the disease from exclusively a childhood illness to one that affects adults.

Newborn screening, improved therapies for lung health and nutrition, and aggressive treatment of respiratory infections and lung transplantation have improved survival rates.

Newer therapies targeting the genetic defect causing the disease, expanding to more age and genetic variants, promise continued improvement in quality of life and overall health.

Epidemiology

CF is a common genetic disorder in Caucasians, with an incidence of 1:3,200. The incidence varies by race/ethnicity, with lower rates in Hispanic, African, and Asian populations.

It is estimated that 1 in 35 Americans are CF carriers, and there are approximately 30,000 affected individuals in the US, with the highest prevalence in North America, Europe, and Australia.

Around 1,000 new cases are diagnosed annually in the US, and the incidence is equal in males and females. Since 2010, all US states screen newborns for CF, resulting in 60% of new diagnoses being made this way

 Pathogenesis

CF is a multisystem disorder caused by genetic variants in the CFTR gene that lead to malfunctioning chloride channels, resulting in the formation of thick and sticky mucus and various health complications. CF also results in abnormal chloride channel function in sweat glands, leading to excessive salt loss.

CF is an autosomal recessive disorder that requires individuals to inherit two deleterious CFTR variants. There are more than 2,000 different CFTR variants reported that are classified into six distinct groups that reflect abnormalities of CFTR protein synthesis, structure and function, with F508del being the most common CF-causing variant.

44.2% of individuals with CF are homozygous for F508del, and the specific CFTR variants an individual carries determine phenotypic severity and organ involvement.

DIAGNOSIS

The CFF published consensus guidelines in 2017 establishing that a diagnosis of CF can be made if an individual has a clinical presentation consistent with the disease i.e. (1) a positive newborn screening; (2) clinical features consistent with CF (the presence of characteristic phenotypes such as of chronic, recurrent sinus and pulmonary disease, nutritional and gastrointestinal abnormalities, urogenital abnormalities in males (e.g., absence of the vas deferens), and/or salt depletion syndromes, or (3) a positive family history of CF and evidence of CFTR dysfunction (e.g., sweat chloride concentration ≥60mmol/L).

 

CF Management

 Therapies to Maintain Optimal Lung Health

CF is marked by the thickening of airway secretions that cause chronic blockage of mucus, inflammation, and recurring infections that lead to persistent harm to the airways and lung tissue damage (bronchiectasis). A chronic cough and production of sputum are symptoms commonly associated with the condition. The management of respiratory symptoms is directed towards preserving lung function and preventing the occurrence of bronchiectasis and destruction of lung parenchyma.

Clearance of Airway Secretions

Airway clearance therapy (ACT) is crucial for maintaining lung health in CF patients, as it helps to remove airway mucus, decreasing bacterial load, and improving gas exchange. Twice daily ACT is recommended for all CF patients, and frequency is increased during pulmonary exacerbations. Common ACT modalities include manual percussion, positive expiratory pressure devices, and high-frequency chest wall oscillation. Exercise is encouraged but not a substitute for ACT. Nebulized agents such as rhDNase and hypertonic saline are often used to thin CF mucus during ACT, but the choice of therapy should be personalized.

Chronic Airway Infections

Aggressive management of chronic airway infections in CF is critical for preserving lung function. It involves frequent respiratory cultures, surveillance for specific pathogens, and eradication therapy when necessary. Nebulized antibiotics can be used as suppressive therapy to prevent colonization and reduce the risk of antibiotic resistance. Other organisms that can impact lung disease are also monitored. CF patients are prone to developing allergic bronchopulmonary aspergillosis, which requires corticosteroid therapy.

Chronic Airway Inflammation

Cystic fibrosis lung disease is caused by infection and inflammation. Corticosteroids are not routinely recommended for CF unless used for another inflammatory comorbidity. Chronic airway inflammation is managed with high-dose ibuprofen or azithromycin. Although ibuprofen has proven benefits, its use is limited by the risk of gastrointestinal bleeding and the need for monitoring serum levels. Azithromycin is typically given orally three times per week and has been shown to improve lung function and reduce PEx. However, screening for mycobacterial infections is recommended before initiating treatment to avoid the development of resistance.

Therapies to Maintain Optimal Nutritional Status

Poor growth is an early manifestation of CF due to decreased intake, malabsorption, and increased metabolic demands. Malnutrition increases morbidity and mortality in CF. The CFF recommends achieving weight-for-length at or above the 50th percentile by 2 years old, and maintaining a body mass index at or above the 50th percentile in children and adolescents aged 2-20 years. Enteral tube feeding should be discussed as an option to optimize nutritional status. Infants should receive breastmilk if possible or standard infant formula, supplemented with table salt. Fecal elastase should be measured to assess pancreatic function, as most individuals with CF have pancreatic insufficiency, leading to malabsorption, bulky stools, malnutrition, and failure to thrive.

 

Pancreatic Enzyme Replacement Therapy

Pancreatic enzyme replacement therapy (PERT) is recommended for those with pancreatic insufficiency or symptoms of malabsorption. The recommended dosage is 2,000-2,500 units/kg of lipase per meal, up to a maximum of 10,000 units/kg/day. Immobilized lipase cartridges may be used for those on continuous enteral tube feeding. Exceeding recommended dosages can result in fibrosing colonopathy. Optimized PERT can help individuals with CF achieve age-appropriate growth.

 

Fat-Soluble Vitamin Replacement Therapy

Pancreatic insufficiency in CF can lead to malabsorption of fat-soluble vitamins A, D, E, and K. Vitamin deficiencies can cause various health problems, including night blindness, ocular xerosis, rickets, osteopenia, osteoporosis, peripheral neuropathy, myopathy, hemolysis, and coagulopathy. To prevent these complications, CF patients should receive supplemental vitamins, and their serum vitamin levels should be monitored annually. The recommended goal for serum 25-hydroxyvitamin D level is at least 30 ng/ml.

 

CFTR Modulator Therapies

CFTR modulators are a major advancement in CF treatment as they directly target the underlying defect in the CFTR protein. Ivacaftor, the first modulator therapy, is a potentiator that helps improve chloride flow through the CFTR protein at the cell surface. Correctors, such as lumacaftor and tezacaftor, help the CFTR protein to form correctly and move to the cell surface. When added to potentiators, correctors improve the amount of protein that reaches the cell surface. Triple-combination therapy, elexacaftor/tezacaftor/ivacaftor (Trikafta), was approved in 2019 and has shown to be highly effective in improving key measures of disease, including lung function and quality of life. Amplifiers are currently under development and are expected to increase the amount of CFTR protein made by a cell.

 

Vertex Announces U.S. FDA Approval for KALYDECO (ivacaftor) to Treat Eligible Infants With CF Ages 1 Month and Older

On 3 May 2023, Vertex Pharmaceuticals have announced the U.S.Food and Drug Administration (FDA) approved KALYDECO (ivacaftor) for use in children with cystic fibrosis (CF) ages 1 month to less than four months old 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. and EU for the treatment of CF in patients ages four months and older.

The approval was supported by a cohort in the Phase 3, 24-week, open-label study to evaluate the safety, pharmacokinetics and pharmacodynamics of ivacaftor in subjects with CF who are less than 24 months of age and have an ivacaftor-responsive CFTR mutation.

This cohort demonstrated a safety profile similar to that observed in older children and adults.

FDA programs to expedite drug development

 The FDA has several programs aimed at streamlining and accelerating the development and review of new drugs for the treatment of serious or life-threatening conditions, particularly where there is an unmet medical need.

These expedited programs ensure that treatments for such conditions are available as soon as possible, provided that the benefits of the therapy outweigh its risks, taking into account the severity of the condition and availability of other treatment options.

The programs include:

breakthrough therapy designation,

fast track designation,

accelerated approval, and

priority review

 

Fast Track Designation

Fast track designation is a program designed to accelerate the development and review of drugs that address serious medical conditions with an unmet need.

The designation may be granted based on preclinical data. Sponsors of drugs that receive fast track designation can expect more frequent interactions with the FDA during the drug development process.

Additionally, drugs that have received fast track designation can benefit from rolling review, allowing for the submission of completed sections of the New Drug Application (NDA) on a rolling basis rather than waiting for the entire application to be completed before submission.

 

Accelerated Approval

Accelerated approval program expedites the development and approval of drugs for serious or life-threatening conditions

Allows approval of drugs that show an effect on surrogate or clinical endpoints that can predict clinical benefit

Useful when disease course is lengthy and takes time to measure clinical benefit

Post-marketing trials may be required to confirm clinical benefit, and approval may be withdrawn if trials fail to verify predicted benefit

 

Priority Review

The Program applies to new molecular entity NDAs and original BLAs submitted from Oct 1, 2012, through Sep 30, 2017, including resubmissions following Refuse-to-File actions

For applications filed under the Program, the PDUFA review clock begins after the 60-day filing review period that starts from FDA receipt of the original submission

Any drug, including those with other designations like fast track or breakthrough therapy, can be granted priority review if relevant criteria are met

 

Differences between the criteria for breakthrough therapy designation and fast track designation?

Breakthrough therapy and fast track designation programs aim to accelerate drug development and review for serious or life-threatening conditions.

A breakthrough therapy designation requires preliminary clinical evidence that the drug can substantially improve a significant clinical endpoint over available therapies, while a fast track designation requires nonclinical or clinical data demonstrating the potential to address unmet medical needs for the serious condition.

FDA Approves First Respiratory Syncytial Virus (RSV) Vaccine - Arexvy from GSK

On 3 May 2023, the U.S. Food and Drug Administration approved Arexvy, the first respiratory syncytial virus (RSV) vaccine approved for use in the United States.

Arexvy is approved for the prevention of lower respiratory tract disease caused by RSV in individuals 60 years of age and older.

RSV is a highly contagious virus that causes infections of the lungs and breathing passages in individuals of all age groups.

RSV circulation is seasonal, typically starting during the fall and peaking in the winter.

In older adults, RSV is a common cause of lower respiratory tract disease (LRTD), which affects the lungs and can cause life-threatening pneumonia and bronchiolitis (swelling of the small airway passages in the lungs).

According to the U.S.Centers for Disease Control and Prevention, each year in the U.S., RSV leads to approximately 60,000-120,000 hospitalizations and 6,000-10,000 deaths among adults 65 years of age and older.

The safety and effectiveness of Arexvy is based on the FDA’s analysis of data from an ongoing, randomized, placebo-controlled clinical study conducted in the U.S. and internationally in individuals 60 years of age and older.

The main clinical study of Arexvy was designed to assess the safety and effectiveness of a single dose administered to individuals 60 years of age and older.

Participants will remain in the study through three RSV seasons to assess the duration of effectiveness and the safety and effectiveness of repeat vaccination.

Data for a single dose of Arexvy from the first RSV season of the study were available for the FDA’s analysis.

In this study, approximately 12,500 participants have received Arexvy and 12,500 participants have received a placebo.

Among the participants who have received Arexvy and the participants who have received a placebo, the vaccine significantly reduced the risk of developing RSV-associated LRTD by 82.6% and reduced the risk of developing severe RSV-associated LRTD by 94.1%.

Among a subset of these clinical trial participants, the most commonly reported side effects by individuals who received Arexvy were injection site pain, fatigue, muscle pain, headache and joint stiffness/pain.

Among all clinical trial participants, atrial fibrillation within 30 days of vaccination was reported in 10 participants who received Arexvy and 4 participants who received placebo.

The FDA is requiring the company to conduct a postmarketing study to assess the signals of serious risks for Guillain-Barré syndrome and ADEM.

In addition, although not an FDA requirement, the company has committed to assess atrial fibrillation in the postmarketing study

 

Bristol Myers Squibb Receives European Commission Approval for Breyanzi (lisocabtagene maraleucel) for Relapsed or Refractory Large B-cell Lymphoma After One Prior Therapy

Bristol Myers Squibb has received approval from the European Commission for Breyanzi (lisocabtagene maraleucel; liso-cel), a chimeric antigen receptor (CAR) T cell therapy directed towards CD19, for the treatment of adult patients suffering from diffuse large B-cell lymphoma (DLBCL), high grade B-cell lymphoma (HGBCL), primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma grade 3B (FL3B). The treatment is intended for patients who have relapsed within 12 months of completion of, or have shown refractory response to, first-line chemoimmunotherapy.

Approval of Breyanzi was granted after the positive results obtained from the Phase 3 TRANSFORM trial, where the therapy exhibited significant and clinically relevant advancements in the primary endpoint of event-free survival (EFS), and in key secondary endpoints such as complete responses (CR) and progression-free survival (PFS) when compared to standard treatment (which involves salvage immunochemotherapy followed by high-dose chemotherapy and hematopoietic stem cell transplant [HSCT]).  The treatment demonstrated a manageable and well-established safety profile.

In the TRANSFORM study, Breyanzi more than quadrupled median EFS compared to standard therapy (10.1 months vs. 2.3 months) at the time of prespecified interim analysis with a median follow-up of 6.2 months. Results of the primary analysis, with a median follow-up of 17.5 months were consistent with the interim analysis, with median EFS not reached for Breyanzi (95% CI: 9.5-NR) vs. 2.4 months for standard therapy (95% CI: 2.2-4.9).

With Breyanzi, the majority (73.9%) of patients achieved a CR compared to less than half (43.5%) of those who were treated with standard therapy. Median PFS was not reached (95% CI: 12.6-NR) with Breyanzi vs. 6.2 months (95% CI: 4.3-8.6) with standard therapy

The safety profile of Breyanzi is well-established, and in the TRANSFORM study, occurrences of cytokine release syndrome (CRS) and neurologic events were generally low-grade, and mostly resolved quickly with standard protocols and without the use of prophylactic steroids.