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As advancements in medical research continue to unfold, hope brightens for individuals living with cystic fibrosis (CF).
As part of my CEO Blog Series, today, I delve into the landscape of CF medication approval in Australia and the meticulous steps involved in bringing new and affordable treatments to those who need it.
In recent years, a new type of medication, known as cystic fibrosis transmembrane conductance regulator (CFTR) modulators, has become available globally and in Australia for people with CF.
CFTR modulators work differently to other medications for CF as they work by correcting the malfunctioning protein that causes CF. In doing so, these medications directly address the cause of CF, rather than just the symptoms. They are not a cure, but they help the body’s cells to function more normally.
There are four CFTR modulators currently approved for use in Australia and available through the Pharmaceutical Benefits Scheme (PBS):
- 1. Ivacaftor (Kalydeco): Kalydeco was the first CFTR modulator to become available in Australia and was listed on the PBS in 2014. The active ingredient in Kalydeco is called ivacaftor. Ivacaftor binds to the defective CFTR protein at the cell surface and helps to open the channel so that chloride can flow in and out of the cells. This helps the balance of chloride and fluids at the surface of the cells and helps to thin mucus in the lungs and other organs.
- 2. Lumacaftor/Ivacaftor (Orkambi): Orkambi is a combination therapy and was added to the PBS in 2018. Lumacaftor, a corrector, helps the CFTR protein form the right shape, traffic to the cell surface, and stay there longer. But, even with lumacaftor, only about a third of the CFTR protein reaches the cell surface, and those proteins do not open enough to allow chloride to pass through the cell membrane. This is why lumacaftor is combined with the potentiator, ivacaftor, which can hold the gate on the CFTR protein open, allowing enough chloride to flow to reduce the symptoms of CF.
- 3. Tezacaftor/Ivacaftor (Symdeko): Symdeko is also a combination therapy and was added to the PBS in late 2019. Tezacaftor, a corrector, helps the CFTR protein form the right shape, traffic to the cell surface, and stay there longer. Ivacaftor is a potentiator that binds to the defective protein at the cell surface and opens the chloride channel (holds the gate open) so that chloride can flow through.
- 4. Elexacaftor/Tezacaftor/Ivacaftor (Trikafta): is a triple combination therapy and was added to the PBS in 2022 for those aged 12 and older who have at least one copy of the F508del CFTR gene. It has since become available for children aged 6 – 11 years old in Australia and is available for those aged 2 - 5 years old and for rare mutations overseas. Trikafta combines the correctors elexacaftor and tezacaftor, which help to fix flaws in the CFTR protein so that it can form the right shape and traffic to the cell surface. Ivacaftor is a potentiator that binds to the defective protein at the cell surface and opens the chloride channel (holds the gate open) so that chloride can flow through. The combination of these three drugs helps the CFTR protein perform better than the other modulators.
Approving Medications in Australia
The Therapeutic Goods Administration (TGA) serves as the gatekeeper for medications entering the Australian market. The process for medication approval is complex and involves several key stages:
- 1. Research & Development: Pharmaceutical companies invest years of research and development into understanding the mechanisms of CF and developing potential treatments. This phase involves laboratory experiments, preclinical studies, and early-stage clinical trials to assess safety and efficacy. Interestingly, when CFTR modulators were first being developed, 228,000 molecules were screened, with one of these being Kalydeco!
- 2. Clinical Trials: If a medication shows promise in pre-clinical studies, it progresses to clinical trials involving human participants. These trials are conducted in multiple phases, each designed to gather data on safety, dosage, and effectiveness. For CF medications, clinical trials often have multiple endpoints, or outcomes, that will determine if the medication was effective. These often focus on lung function, but can also investigate other outcomes such as BMI, changes in sweat chloride levels, and the number of pulmonary exacerbation events.
- 3. Regulatory Submission: After successful completion of clinical trials, the pharmaceutical company submits a comprehensive submission to the TGA. This submission contains data from pre-clinical and clinical studies, along with manufacturing information and proposed labelling for the medication.
- 4. TGA Review: Upon receiving the submission, the TGA conducts a thorough review of the data to ensure the medication meets stringent safety, quality, and efficacy standards. This review involves assessment by scientific experts, regulatory reviewers, and advisory committees specialising in the relevant therapeutic area.
- 5. Approval Decision: Based on the evidence provided, the TGA makes a decision regarding the approval of the medication. If approved, the medication is granted market authorisation, allow it to be prescribed and marketed in the Australia for the specified indications.
The Journey Continues for the CF Patient
Whilst a TGA approved medication means positive news for people with CF, this news is short lived for most. CFTR modulators are highly specialised and can cost up to $300,000 AUD per year, which is out of reach for most members of our community.
As such, the next step begins to ensure that new medication is added to the Pharmaceutical Benefits Scheme and therefore making it affordable for all eligible Australians. As per the TGA approval, the process of evaluating CFTR modulators for inclusion on the PBS involves several steps overseen by the Pharmaceutical Benefits Advisory Committee (PBAC).
Here’s a quick overview of a successful PBS listing:
1. Submission by the pharmaceutical company to the Department of Health.
2. Evaluation by PBAC, an independent expert body appointed by the Federal Government.
3. Clinical Review by the PBAC.
4. Cost-effectiveness Analysis by health economists within the PBAC.
5. Recommendation to list on the PBS by the PBAC to the Department of Health.
6. Negotiations between Department of Health and Pharmaceutical company.
7. Decision to list on the PBS made by Minister of Health.
8. Access to patients at set price – up to $31.60 per script without a concession card.
Challenges and Opportunities
While the approval process aims to uphold the highest standards to safety and efficacy, it can also present challenges and delays, potentially taking 2-3 years for a new medication to be approved by the TGA and added to the PBS.
Pharmaceutical companies must navigate regulatory requirements, address potential safety concerns, and demonstrate the clinical benefits of their medications. Additionally, the rarity of certain CF mutations, may limit the availability of targeted treatments for specific patient populations.
Despite these challenges, the approval of new CF medications brings hope and promise to individuals and families impacted by the condition. Each approval represents a significant milestone in the journey towards better treatments and improved outcomes for all people with CF.
Conclusion & Looking Ahead
The approval of CF medications in Australia is a complex and rigorous process, guided by the principles of safety, quality, and efficacy. However, because of collaboration between pharmaceutical companies, regulatory authorities, healthcare professionals, and patient advocacy groups such as Cystic Fibrosis Community Care, innovative treatments are making their way from the laboratory to the clinic, offering hope to the CF community.
As research continues to uncover new insights into the underlying mechanism of CF, the landscape of treatment options is expected to evolve. Emerging therapies, including gene-editing technologies, and personalised medicine approaches, hold the potential to revolutionise CF care and transform the lives of those living with the condition.
As we look into the future, continued investment in research and development will be needed as it holds the promise of even greater advancement in the fight against CF, particularly as we look towards no one being left behind.
no one being left behind."
If you have any questions about CF medications, please speak to your medical team or if you need any support or guidance with any aspect of CF, please reach out to our Support Team at 1300 023 222 or support@cfcc.org.au.
Andre Carvalho, CEO Cystic Fibrosis Community Care