TO THE EDITOR:

We are currently experiencing an exciting period of scientific advances in patient care. Precision medicine and personalized medicine have allowed us to dream of the ability to treat numerous diseases based on their root causes. In cystic fibrosis (CF), the recent integration of precision medicine into routine patient care has enabled the management of CFTR protein expression and has brought hope for the treatment of the disease, with improved quality of life and increased life expectancy.

In CF, precision medicine uses three US Food and Drug Administration-approved drugs, namely ORKAMBI® (lumacaftor/ivacaftor), SYMDEKO® (tezacaftor/ivacaftor and ivacaftor), and KALYDECO® (ivacaftor), all of which are manufactured by Vertex Pharmaceuticals, Inc. (Boston, MA, USA). Substantial clinical benefits have been obtained with a novel combination therapy (VX-659-tezacaftor-ivacaftor) in comparison with placebo, with a change of 14 percentage points in percent predicted FEV1 (FEV1%) in individuals with one F508del mutation and one minimal function mutation, as well as a change of 10 percentage points in FEV1% in individuals with two F508del mutations initially treated with tezacaftor-ivacaftor and subsequently treated with tezacaftor-ivacaftor plus VX-659. In addition, treatment with the triple combination therapy of VX-455-tezacaftor-ivacaftor has been tested in phase I and II clinical trials, with significant improvement in FEV1%.(1-5)

The outcomes of CF clinical trials have been remarkable. Although the initial results obtained from precision medicine clinical trials showed only a slight improvement in FEV1% (of < 2-4 percentage points), recent studies have shown a significant improvement in the quality of life and life expectancy of CF patients. However, the economic dimension of precision medicine, including the high cost of developing drugs and running trials, is a barrier to the use and implementation of new therapies. From the discovery of a new molecule to the clinical application of a new drug, high costs are involved. In CF, the final cost of new precision medicine drugs depends on the following: the high cost of clinical trials; lengthy timelines; difficulties in recruiting participants (because the CFTR genotype needs to be identified); limited clinical research capacity; strict regulations; administrative barriers; data collection and interpretation; and difficulties in maintaining and monitoring safety. In addition, health care costs rise exponentially when precision medicine is used.

Although the Brazilian Agência Nacional de Vigilância Sanitária (ANVISA, National Health Surveillance Agency) is charged with the approval and regulation of pharmaceutical drugs, public health care facilities need further authorization to dispense drugs free of charge to the population. In 2018, the Brazilian government approved the first precision medicine drug for use in CF patients in Brazil. However, the costs must be borne by the patient. The next step should be the support from the public health care system to provide the drug free of charge to all CF patients on the basis of their CFTR genotype. However, this raises a controversial question: How much can we afford?

In Brazil, approximately 140 patients at a referral center for CF are eligible for treatment with a precision medicine drug, with total treatment costs estimated at US$ 40,308,420 per year. The classification of CFTR mutations was not taken into account because the US Food and Drug Administration did not approve the use of precision medicine drugs for all CFTR mutations (Table 1),(6) and the costs were calculated on the basis of the US market in order to provide an international overview of the drug price. Neither our institution nor the public health care system can afford to spend that much on (treating) a single disease. A total financial support of US$ 123,710,785.70 should cover all hospital procedures, including all routine medical consultations. In addition, the cost of treating CF patients amounts to approximately one third of the total cost of maintaining hospital activities.

Some insights can help resolve the controversy over the (estimated) cost of treating a disease and pricing the priceless, i.e., the improvement of health. First, a new drug should be prescribed only for patients who will truly benefit from it, primarily on the basis of the individual response to CF drugs in nasal cell cultures (from patients with CFTR and modifier gene variants). (7-10) Second, all CFTR genotypes should be identified in order to determine whether precision medicine is feasible. Third, the government and the pharmaceutical industry should discuss costs, benefits, and a partnership for mutual benefit. Fourth, medical societies, as well as patients and their families, together with nongovernmental organizations and researchers, should discuss the possibilities of precision medicine, implementing medication adherence policies and reducing the costs of long-term therapies. Finally, precision medicine should be used in the treatment of other diseases. For example, ataluren has been discontinued for the treatment of CF, but it is still prescribed for the treatment of Duchenne muscular dystrophy and Becker muscular dystrophy caused by nonsense mutations in the DMD gene.

Precision medicine gives us hope, and genome editing tools are being investigated for the treatment of CF. In the long run, gene therapy will be used as a treatment model for CF.

Is precision medicine cost-effective? Is the heavy upfront investment legitimate? What is the total cost of innovation: developing and releasing a new drug and the moral issue of pricing and profit? This letter is a reflection on the application of new therapies (using CF as model) and their financial impact on health care systems. In addition, this letter invites patients, civil society, governmental officials, and the pharmaceutical industry to discuss the major outcomes of new therapies and markers, including quality-adjusted life years.

The CFTR gene was described as the cause of CF in 1989. Since then, we have dreamed of treating the root cause of the disease. We have made remarkable progress with research on phenotype variability, CFTR variants, and modifier genes, and we should continue to research and translate these findings into new diagnostic methods and therapies. Although high costs can be a barrier, they can be overcome through the collaborative input of all involved parties. We believe in the promise of precision medicine to improve quality of life and life expectancy, and our efforts should be geared toward allowing precision medicine to reach its full expectations.

REFERENCES

1. Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663-1672. https://doi.org/10.1056/NEJMoa1105185
2. Rehman A, Baloch NU, Janahi IA. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015;373(18):1783. https://doi.org/10.1056/NEJMc1510466
3. Taylor-Cousar JL, Munck A, McKone EF, van der Ent CK, Moeller A, Simard C, et al. Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. N Engl J Med. 2017;377(21):2013-2023. https://doi.org/10.1056/NEJMoa1709846
4. Davies JC, Moskowitz SM, Brown C, Horsley A, Mall MA, McKone EF, et al. VX-659-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N Engl J Med. 2018;379(17):1599-1611. https://doi.org/10.1056/NEJMoa1807119
5. Keating D, Marigowda G, Burr L, Daines C, Mall MA, McKone EF, et al. VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N Engl J Med. 2018;379(17):1612-1620. https://doi.org/10.1056/NEJMoa1807120
6. Pereira SV, Ribeiro JD, Ribeiro AF, Bertuzzo CS, Marson FAL. Novel, rare and common pathogenic variants in the CFTR gene screened by high-throughput sequencing technology and predicted by in silico tools. Sci Rep. 2019;9(1):6234. https://doi.org/10.1038/s41598-019-42404-6
7. Kmit A, Marson FAL, Pereira SV, Vinagre AM, Leite GS, Servidoni MF, et al. Extent of rescue of F508del-CFTR function by VX-809 and VX-770 in human nasal epithelial cells correlates with SNP rs7512462 in SLC26A9 gene in F508del/F508del Cystic Fibrosis patients. Biochim Biophys Acta Mol Basis Dis. 2019;1865(6):1323-1331. https://doi.org/10.1016/j.bbadis.2019.01.029
8. Marson FAL, Bertuzzo CS, Ribeiro JD. Personalized or Precision Medicine? The Example of Cystic Fibrosis. Front Pharmacol. 2017;8:390. https://doi.org/10.3389/fphar.2017.00390
9. Marson FAL. Disease-modifying genetic factors in cystic fibrosis. Curr Opin Pulm Med. 2018;24(3):296-308. https://doi.org/10.1097/MCP.0000000000000479
10. de Lima Marson FA, Bertuzzo CS, Ribeiro JD. Personalized Drug Therapy in Cystic Fi-brosis: From Fiction to Reality. Curr Drug Targets. 2015;16(9):1007-1017. https://doi.org/10.2174/1389450115666141128121118