In the News: March 2013 – CFTR Modulators, Antibiotics, Mannitol, TOBI Podhaler and Colobreathe

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Clinical Pipeline

CFTR correctors, potentiators, modulators

At the end of February, Vertex Pharmaceuticals, Inc. announced the next phase of its ambitious clinical trials programme for their CFTR modulators. On the back of the success of ivacaftor (Kalydeco) for CF patients with the G551D mutation, the company announced a Phase 3 trial for its VX-809 (corrector) and ivacaftor (potentiator) combination therapy for those with two copies of the F508del mutation. This will involve two simultaneous studies, each lasting 24 weeks and recruiting 500 patients aged 12 and older, across 200 centres in North America, the EU and Australia. The trials are expected to commence in the first half of 2013. In addition, the same therapy combination will be used in a preliminary study to evaluate safety in 6 to 11 year olds with two F508del mutations and an 8 week Phase 2 trial for those with one F508del and one other mutation.

Data from the on-going Phase 2 study of VX-661, another CFTR corrector, in combination with ivacaftor in those with two F508del mutations is expected in the first half of 2013.

At the same time, Vertex is seeking to examine if ivacaftor taken by itself would be useful for those not only with the G551D mutation, but also patients with non-G551D “gating” mutations. They have completed enrolment for a Phase 3 study of ivacaftor in patients with mutations such as G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P and G1349D. These are Class 3 mutations, where the CFTR makes it to the surface but has a gating defect and does not open. They are also still recruiting patients with R117H for a Phase 3 study and patients with “residual function” mutations (often associated with pancreatic sufficiency) such as E56K, P67L, D110E, D110H, R117C, R347H, R352Q, A455E, D579G, S945L, L206W, R1070W, F1074L for a Phase 2 monotherapy study.

Vertex also stated that they are already testing “second-generation” correctors in the lab which may be taken in addition to the VX-809 and ivacaftor combination to further boost their effect.

At the same time, the CF Foundation have confirmed that they are working with a number of partners in addition to Vertex including Pfizer Inc., Genzyme (part of Sanofi) and Proteostasis Therapeutics Inc. doing pre-clinical screening of some 6 million compounds as part of their on-going efforts to find effective Kalydeco-like treatments for all CF mutations.

On March 13th N30 Pharmaceuticals, Inc. announced the commencement of a Phase 1b/2a clinical trial for its own CFTR modulator (N6022) in those with two F508del mutations. N6022 is the first of a novel class of drugs developed by N30 known as GSNOR inhibitors. These are thought to rescue or “correct” the abnormal chloride channel function characteristic of cystic fibrosis and to act as anti-inflammatory agents. This is potentially important because inflammation, particularly of the lung, is the cause of major morbidity in CF patients.

You can find out more about ivacaftor and CFTR from those that did the research – watch the recordings from our CFTR and Kalydeco special event



Another US company PTC Therapeutics, Inc. announced on March 7th that they planned to continue clinical development of Ataluren (a small molecule formerly known as PTC124) in Duchenne Muscular Dystrophy and Cystic Fibrosis. While PTC’s immediate focus is on initiating a Phase 3 trial of Ataluren in patients with Duchenne Muscular Dystrophy, the company is also developing Ataluren for those with Cystic Fibrosis related to ‘non-sense’ mutations. These are mutations that stop the full genetic code being used. Their clinical trial programme in CF is on-going in North America, the EU and Israel.  You can find out more about Ataluren by watching Dr Jane Davies’ talk on Clinical Trials from the UK Clinical Trials Meeting.


Gene Therapy

Aside from these developments in small molecules, the UK CF Gene Therapy Consortium announced that they are still recruiting patients for their (multi-dose) Phase 2 gene therapy trial which is taking place in London and Edinburgh although patients do not need to be based there to participate.  You can find out more about cystic fibrosis genes and the gene therapy studies by taking part in our LIVE EVENT – June 29th – Cystic Fibrosis Genes and Gene Therapy.



In terms of new antibiotic options, on March 20th Savara Pharmaceuticals, Inc. announced a plan for a Phase 2 clinical trial of Aerovanc, a dry powder reformulation of the antibiotic vancomycin which is effective against MRSA but currently only available in IV form, which typically means poor penetration into the lungs and systemic toxicity.  They plan to initiate the trial in the first half of 2013 in 22 centres in the US.


Regulatory Approvals


On March 19th Pharmaxis Ltd. confirmed that the FDA have recommended an additional clinical trial for dry powder mannitol (Bronchitol) to obtain regulatory approval for patients with CF in the US. Bronchitol is already approved for CF patients aged 6 and over in Australia and for adult patients with CF in the EU.   UK’s NICE had previously recommended mannitol for use in some circumstances.


TOBI Podhaler & Colobreathe

On a more positive note, on March 22nd the FDA finally approved the TOBI Podhaler for patients with Pseudomonas aeruginosa in the US. A week later the UK’s NICE published Final Guidance recommending tobramycin dry powder and colistimethate sodium for inhalation as treatment options for people with CF in England and Wales with P. aeruginosa in certain circumstances. These new treatments are more convenient forms of existing nebulised drugs i.e. tobramycin (TOBI Podhaler) and colistimethate sodium (Colobreathe), taken twice a day and delivered by a breath-activated, hand-held inhaler. Colobreathe is recommended for those who cannot tolerate colomycin in its nebulised form. Where colomycin therapy is not appropriate, not tolerated, or has not produced an adequate clinical response, TOBI Podhaler is recommended as an alternative to nebulised tobramycin.

by Oli Rayner, March 2013