Kaftrio also for people without an F508del mutation?

In November, Vertex submitted an application to the European Medicines Agency EMA to extend the use of Kaftrio to people with specific mutations beyond F508del, aged 2 years and older. Until now, Kaftrio had only been approved and reimbursed for people with at least one F508del mutation, but this extension would also make people with specific rare mutations eligible. This is a first in Europe.

Which mutations are involved?

About 200 mutations are involved, which can be roughly classified into four major groups:

1. People with an N1303K mutation. In Europe, this is the third most common mutation.
2. 5 specific non-canonical splicing mutations: 711+3A→G, 2789+5G→A, 3272‑26A→G, 3849+10kbC→T, and E831X. These splicing mutations are abnormalities in the CFTR gene that result in either lower amounts of protein or a slightly altered (and therefore ineffective) CFTR protein. As a result, there is a significant reduction in the amount of CFTR protein that reaches the cell surface.
3. The 18 mutations tested in a clinical trial conducted by Vertex last year: 2789+5G→A, 3272 26A→G, 3849+10kbC→T, P5L, R117C, L206W, V232D, T338I, R347H, A455E, S945L, L997F, R1066H, D1152H, G85E, R347P, L1077P, M1101K. The results of this study have not yet been published. Vertex did reveal that the lung function of the study participants increased by an average of 9.2% thanks to Kaftrio. This is slightly less than average in people with at least one F508del mutation, but certainly significant. More results are expected early next year.
4. 178 mutations that have already been approved in the United States:

An approval could allow Kaftrio to be prescribed to an additional 2,800 people across Europe, according to the manufacturer.

When can we expect a decision?

EMA declared the dossier admissible at the end of November, meaning that they would be able to start their assessment. This procedure at European level normally takes 6 to 9 months. However, in many countries, an approval by EMA does not necessarily mean that there is access for those eligible, as reimbursement discussions take place on a national level.

We should also remain very cautious. This is the first time such a broad dossier has been submitted to EMA. Moreover, not all evidence comes from clinical studies, but also from lab tests, for example. It remains to be seen whether EMA considers this evidence sufficient. It could also be that EMA gives a partially positive opinion.

So will there be Kaftrio for everyone?

No. We know from studies around Europe that there are still a number of mutations that do respond well to Kaftrio, but are most likely not included in this application. And then there are the stop mutations, resulting in a complete absence of CFTR protein. As modulators do not work in this case, there is no point in seeking approval for these mutations.

Philip Watt, President of CFE stated

‘This is a really welcome first step for those people with CF that currently do not get access to Kaftrio because of their rare CFTR mutation is currently not approved by the EMA. It will take some months now for the Vertex dossier to be considered by the EMA and all being well, sanctioned by the European Commission and national governments. In welcoming this crucial first step – it’s also important to emphasise that some people will never benefit (or may not tolerate) a CFTR modulator – so there is still need for new and innovative therapies beyond Kafrio. The potential of mRNA and gene editing are examples of innovative therapies being researched at present- with still no definitive research outcomes from either and more research needed.’

What will CF Europe do now?

Of course we remain in close contact with Vertex concerning the status of this application. We will also carefully monitor EMA’s decision-making process. This is possibly the first time that a decision on granting marketing authorisation would be based partly on data not directly originating from a clinical trial. This could be an important precedent for future innovative therapies, and not only for people with CF, but for the whole rare disease community.

This article is based on a press release from Vertex Pharmaceuticals.