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CMECNE

FDA Approves New Breakthrough Medication for Cystic Fibrosis

Learning Objectives and CME/Disclosure Information

This activity is intended for healthcare providers delivering care to women and their families.

After completing this activity, the participant should be better able to:

1. Describe the underlying mechanisms of the newer medications to treat cystic fibrosis
2. Describe the findings from the recent trials using triple combination drug formulation used by the FDA to generate a priority review

Estimated time to complete activity: 0.25 hours

Faculty:

Susan J. Gross, MD, FRCSC, FACOG, FACMG President and CEO, The ObG Project

Disclosure of Conflicts of Interest

Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.

Faculty: Susan J. Gross, MD, receives consulting fees from Cradle Genomics, and has financial interest in The ObG Project, Inc.

Planners and Managers: The PIM planners and managers, Trace Hutchison, PharmD, Samantha Mattiucci, PharmD, CHCP, Judi Smelker-Mitchek, MBA, MSN, RN, and Jan Schultz, MSN, RN, CHCP have nothing to disclose.

Method of Participation and Request for Credit

Fees for participating and receiving CME credit for this activity are as posted on The ObG Project website. During the period from 1/15/2020 through 07/15/2022, participants must read the learning objectives and faculty disclosures and study the educational activity.

If you wish to receive acknowledgment for completing this activity, please complete the post-test and evaluation. Upon registering and successfully completing the post-test with a score of 100% and the activity evaluation, your certificate will be made available immediately.

For Pharmacists: Upon successfully completing the post-test with a score of 100% and the activity evaluation form, transcript information will be sent to the NABP CPE Monitor Service within 4 weeks.

Joint Accreditation Statement

In support of improving patient care, this activity has been planned and implemented by the Postgraduate Institute for Medicine and The ObG Project. Postgraduate Institute for Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

Physician Continuing Medical Education

Postgraduate Institute for Medicine designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Continuing Nursing Education

The maximum number of hours awarded for this Continuing Nursing Education activity is 0.2 contact hours.

Designated for 0.2 contact hours of pharmacotherapy credit for Advance Practice Registered Nurses.

Read Disclaimer & Fine Print

SUMMARY:

The FDA has approved a new triple therapy medication (elexacaftor/ ivacaftor/ tezacaftor) for patients with the most common cystic fibrosis (CF) mutation (approximately 90% of the CF population). The FDA granted this application Priority Review, in addition to Fast Track and Breakthrough Therapy Designation. Due to potential benefit to the CF community, the application was reviewed and approved approximately three months prior to the planned review date.

The medication is approved for the following individuals with CF
- ≥12 years
- At least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene

Drug Mechanism of Action

With significant mutations such as F508del mutation, the CFTR protein undergoes two ‘hits’
- Improper folding leading to entrapment in endoplasmic reticulum
- Protein that does reach cell membrane does not become activated (i.e. fails to function correctly)
The drugs developed to treat CF are protein modulators
- Correctors (elexacaftor and tezacaftor): Drugs that correct CFTR protein folding
- Potentiator (ivacaftor): Activate function of the abnormal protein channel at the cell surface

KEY POINTS:

Literature Review (see ‘Learn More – Primary Sources’ below)

Heijerman et al., Lancet 2019 (n=107)

Methods: Double-blind RCT (4 weeks) | homozygous for F508del
- Elexacaftor plus tezacaftor plus ivacaftor or
- Tezacaftor plus ivacaftor for 4 weeks
Primary outcome: Absolute change from baseline in percent predicted forced expiratory volume in one second (ppFEV 1)
Results
- Primary outcome: Triple drug group had improved ppFEV 1 | Treatment difference 10.0% (95% CI, 7.4 to 12.6, p<0.0001)
- Secondary outcomes: Triple drug group also demonstrated improvement related to the following
  - Quality of life (Cystic Fibrosis Questionnaire)
  - Decreased sweat chloride concentration

Middleton et al., NEJM 2019 (n=403)

Methods: Double-blind RCT (24 weeks) | F508del mutation and a mutation on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor or tezacaftor/ivacaftor alone
Primary outcome: Absolute change from baseline in ppFEV 1
Results
- Primary outcome: Triple drug group had improved ppFEV 1 | Treatment difference 13.8% (95% CI, 12.1, 15.4; P<0.0001)
- Other outcome improvements
  - Reduction in rate of pulmonary exacerbations
  - Decreased sweat chloride concentration
  - Increase in BMI
Safety profile
- Similar between the groups
- Many adverse events related to CF rather than medication effects
- Rash and flu were more frequent in patients on triple therapy
- Most common adverse drug reactions included
  - Headaches | upper respiratory tract infections | Abdominal pains | Diarrhea, rashes, increased liver enzymes (ALT and AST)
- The prescribing information for triple medication includes warnings related to
  - Elevated LFTs (transaminases and bilirubin) | Use at the same time with other products that are inducers or inhibitors of Cytochrome P450 3A4 (CYP3A) | Risk of cataracts

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Learn More – Primary Sources:

FDA approves new breakthrough therapy for cystic fibrosis

Lancet: Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial

NEJM Editorial: Realizing the Dream of Molecularly Targeted Therapies for Cystic Fibrosis

FDA Prescribing Information: TRIKAFTA

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FDA Approves New Breakthrough Medication for Cystic Fibrosis