Future Medications

CFTR modulators are one area of Cystic Fibrosis research. These are medications which help the underlying cause of CF, the CFTR channel. Correctors (help the CFTR to get to the surface) and potentiators (help the channel to open, such as Kalydeco) are examples of CFTR modulation.

There are multiple pharmaceutical companies working on CFTR modulation, including Vertex, N30, Pfizer, Genzyme, Galapagos, Proteostasis and Calista Therapeutics. Vertex and N30 have medications in clinical trials.

F508del homozygotes (two copies F508del):
Vertex have two correctors in clinical trials with F508del homozygotes, VX809 and VX661. These help the CFTR channel to reach the surface. These correctors are being trialled in conjunction with Kalydeco, as Kalydeco can increase the function of the channel once it is at the surface. 
VX809: Two 24 week phase 3 trials have commenced, data expected mid 2014. 
VX661: Phase 2 results were released in 2013, a 12 week phase 2 study is planned for 2014. Read more about VX809 & VX661.

N30 have started a phase 1b/2a trial with their compound N6022, which is a CFTR corrector with anti-inflammatory properties. They are trialling their compound with F508del homozygotes: N30 News release and  Trial info

The F508del homozygous group represents about 50% of the CFs in Australia.

F508del heterozygotes (one copy F508del):
VX809 and VX661 are also being trialled with F508del heterozygotes, but the results with VX809 have not been as strong as the homozygote results (VX661 heterozygote results have not been released). F508del homozygotes produce more F508del that VX809 can correct and Kalydeco can potentiate. People with one copy would still have some improvement but there is less F508del that the meds can help. Vertex are working on triple combination therapy, where Kalydeco, a corrector and a new second generation corrector are used together to further increase the improvement. The F508del heterozygous group represents about 40% of the CFs in Australia (but 15% or so of the heterozygotes have a second mutation that Kalydeco alone may help).

Second Generation Correctors:
VX809 & Kalydeco are able to produce 25% of normal CFTR function in the laboratory with F508del homozygotes. To put this in context G551D with Kalydeco reaches 50% function. Vertex are now developing a second generation of medications that are more effective than Kalydeco and VX809. In the lab, when a second generation corrector is added to VX809 & Kalydeco with F508del heterozygotes, approx 33% function is seen, and with homozygotes, 45% function is seen: Latest second generation corrector graphs.

Mutations similar to F508del:
Recent clinical studies found that VX809 increased the CFTR trafficking with E56K, P67L, E92K, L206W, V232D, H1054D, G1061R, L1065P, Q1071P, L1077P, H139R, R258G and S945L. See these two posts for more information: study one & study two

Nonsense Mutations:
Ataluren helps class 1 mutations that have a premature stop codon (end in X), by helping the CFTR protein to be made past the stop codon. These mutations represent about 5% of the population in Australia. Ataluren has completed phase 3 trials, whilst the results were positive (positive results were seen with people who were not on inhaled Tobramycin) more trials are needed in order for this medication to become available. A second phase 3 study is planned to start in 2014 with nonsense mutations. The potential for combination therapy with Kalydeco was also mentioned during the August investor conference.

It is hoped that in the future all CFs will have personalised medications for their specific genes. If you are following this research and you do not know your mutations, I would advise asking your doctor.

These are some images from a recent Vertex investor presentation in Oct 2012. Kalydeco is also called Ivacaftor.

Slide10

Slide12

Source: October 2012 and Feb 2013 Vertex Investor Presentations. These are no longer available online: http://investors.vrtx.com/events.cfm

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Join the conversation! 5 Comments

  1. Hi Gen,
    The small molecule approach is not likely to provide a transformational treatment for all. So it would be interesting to see your views on the work of the UK GTC (I am an enthusiast (albeit with qualifications about the fact that GT is not going to address GI issues, but am interested in all other viewpoints).
    Best wishes,
    David

    Reply
  2. Hi David,

    Sorry about the delay, I’ve been flat out with exams! Currently about 95% of the population in Australia have F508del or a gating/residual function mutation, and will hopefully benefit from the CFTR modulator meds by Vertex, N30 and other companies (I am unsure of the percentages in the UK). Medications like Ataluren may help some of the remaining 5%, however it appears that a reasonable amount of future research is needed in this area. Recently a study investigating VX809 with other class 2 mutations found that several rare class 2 mutations were helped in vitro by VX809, so it is possible some of these people in this 5% may have some benefit (I would like to see more in vitro study data, especially with splicing mutations, however the best way to find out if someone in this 5% can be helped is to trial a combination of the available meds to see if they help). The goal is personalised medications, where a specific combination and dose are given for each person, based on their genes and absorption/metabolism.

    I have been following the work with the gene therapy in the UK and also in Australia. Whilst it appears this will take longer than the CFTR modulator approach in terms of initial access to a treatment, I hope that the gene therapy approach will get all of us closer to the 90-100% of normal CFTR function (G551D with Kalydeco is 50% currently). There have been some people with G551D who have had a smaller response compared to others in terms of FEV1/sweat chloride/symptoms, so gene therapy may help the people who do not have a large improvement with the CFTR modulators. It is also less frequent than twice a day (I think the UK gene therapy trial is a med once a month), and won’t rely on absorption with fat. So it appears there are less variables that influence how well it works, however I wonder if there are other variables that influence the gene transfer in the lungs? Such as immune response and other variables (that we may not be aware of). The main downside to gene therapy is that it currently only helps the lungs, which makes me wonder if gene therapy will be used alone in the future, or in conjunction with CFTR modulators?

    Reply
  3. hOLA SR GEN HANDLEY. ME LLAMO JORGE PRECERUTTI SOY DE ARGENTINA , SIGO EXPECTANTE CADA UNO DE LOS INFORMES Y/O NOVEDADES QUE PERIODICAMENTE EL LABORATORIO BRINDA, TENGO UNA BEBE DE 1 AÑO (Mi nieta9 CON FQ, ELLA ESTA BIEN , QUIERO FELICITARLO , DEBO FELICITAR A TODO EL EQUIPO DE INVESTIGACION , SE INTIMAMENTE QUE LELGARAN A LA CURA EN 2015 , LO SE EN MI INTERIOR . SE QUE CADA DIA QUE ABREN EL LABORATORIO ,ESA LLAVE LA ABREN LOS MILES DE FQ DEL MUNDO ESPERANZADOS EN LA CIENCIA Y CON FE EN DIOS PARA QUE ILUMINE SUS MENTES .. POR OTRO LADO HE VISTO QUE DE LOS 3 CONTINENTES SOLICITAN PACIENTES PAAR ENSAYOS O TRATAMIENTOS LLAMADOS DE FAVOR O BONDADOSOS NO SE BIEN EL NOMBRE TECNICO Y ESTO ES POR LOS COSTOS Y POR LA NECESIDAD DE AVANZAR EN LA INVESTIGACION . BIEN LE DIGO DE LOS 3 CONTINENTES PORQUE NO HE VISTO UNA SOLICITUD DE UN NIÑO MAYOR DE 6 AÑOS O UN JOVEN O UN ADULTO DE LATINOAMERICA ,DONDE HAY IGUAL O MAS PORCENTAJES QUE EN OTROS LADOS DEL MUNDO O PRIMER MUNDO SI UD QUIERE, TAMPOCO VEO ESTADISTICAS DE LATINOAMERICA, ARGENTINA, CHILE, BRASIL, PERU, PANAMA, COLOMBIA, MEXICO,ETC ETC… SE QUE EN VARIOS PAISES NO ESTA LA FQ ATENDIDA O CONCIENTIZADA COMO LO ESTA EN AUSTRALIA O CANADA O USA O ESCOCIA ,ETC PERO GEN , UD DEBE CONTEMPLAR LA SALUD DE UN JOVEN LATINOAMERICANO DIGAMOS EN ESTADO DE TRASPLANTE PARA BENEFICIARLO .. LE PIDO DISCULPAS POR MI ATREVIMIENTO, PERO NO TENGO OTRA FORMA DE DIRIGIRME A UNA PERSONA QUE REALMENTE SIN CONOCER ADMIRO DEMASIADO ¡¡ Un gran abrazo a la distancia ¡¡ A disposicion jorge

    Reply
  4. Dear Gen,
    thank you a lot for this excellent blog. I really love it. Great work!! Gen, when we talk about therapies for CF we just focus on G551D or F508D and so on but why rare mutations not be regarded? I´m happy that there is a cure for people with G551D and will be (hopefully) a cure with F508D, but It makes me sad and I get in fear if rare mutations (in my case especially R560S on both allels) are not mentioned nowhere. Are there any research and developments for people who are suffering on rare muations? Will be there any meds who will help us as well? R560S seems to be a class 2 mutation, will it be possible to extend Lumacaftors indication for it? Do you have information regarding therapy for rare mutation? Do you think there will be drugs for us? I´m disappointed and don´t know where to seek for help and hope. Sorry for the mass of my questionary. Best, Marc

    Reply
  5. Hi Gen, my son has df508 (class II) and G452X (classI), but he has pancreact sufficient. Do u think he will allowed to take the combo VX809 and VX770 been DF508heterozigous?

    Reply

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