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Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial.

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Title: Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial.
Authors: Kerem E (AUTHOR), Hirawat S (AUTHOR), Armoni S (AUTHOR), Yaakov Y (AUTHOR), Shoseyov D (AUTHOR), Cohen M (AUTHOR), Nissim-Rafinia M (AUTHOR), Blau H (AUTHOR), Rivlin J (AUTHOR), Aviram M (AUTHOR), Elfring GL (AUTHOR), Northcutt VJ (AUTHOR), Miller LL (AUTHOR), Kerem B (AUTHOR), Wilschanski M (AUTHOR)
Source: Lancet. 8/30/2008, Vol. 372 Issue 9640, p719-727. 9p.
Abstract: BACKGROUND: In about 10% of patients worldwide and more than 50% of patients in Israel, cystic fibrosis results from nonsense mutations (premature stop codons) in the messenger RNA (mRNA) for the cystic fibrosis transmembrane conductance regulator (CFTR). PTC124 is an orally bioavailable small molecule that is designed to induce ribosomes to selectively read through premature stop codons during mRNA translation, to produce functional CFTR. METHODS: This phase II prospective trial recruited adults with cystic fibrosis who had at least one nonsense mutation in the CFTR gene. Patients were assessed in two 28-day cycles. During the first cycle, patients received PTC124 at 16 mg/kg per day in three doses every day for 14 days, followed by 14 days without treatment; in the second cycle, patients received 40 mg/kg of PTC124 in three doses every day for 14 days, followed by 14 days without treatment. The primary outcome had three components: change in CFTR-mediated total chloride transport; proportion of patients who responded to treatment; and normalisation of chloride transport, as assessed by transepithelial nasal potential difference (PD) at baseline, at the end of each 14-day treatment course, and after 14 days without treatment. The trial was registered with who.int/ictrp, and with clinicaltrials.gov, number NCT00237380. FINDINGS: Transepithelial nasal PD was evaluated in 23 patients in the first cycle and in 21 patients in the second cycle. Mean total chloride transport increased in the first treatment phase, with a change of -7.1 (SD 7.0) mV (p<0.0001), and in the second, with a change of -3.7 (SD 7.3) mV (p=0.032). We recorded a response in total chloride transport (defined as a change in nasal PD of -5 mV or more) in 16 of the 23 patients in the first cycle's treatment phase (p<0.0001) and in eight of the 21 patients in the second cycle (p<0.0001). Total chloride transport entered the normal range for 13 of 23 patients in the first cycle's treatment phase (p=0.0003) and for nine of 21 in the second cycle (p=0.02). Two patients given PTC124 had constipation without intestinal obstruction, and four had mild dysuria. No drug-related serious adverse events were recorded. INTERPRETATION: In patients with cystic fibrosis who have a premature stop codon in the CFTR gene, oral administration of PTC124 to suppress nonsense mutations reduces the epithelial electrophysiological abnormalities caused by CFTR dysfunction. [ABSTRACT FROM AUTHOR]
Copyright of Lancet is the property of Lancet and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial.
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  Data: &lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Kerem+E%22&quot;&gt;Kerem E&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Hirawat+S%22&quot;&gt;Hirawat S&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Armoni+S%22&quot;&gt;Armoni S&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Yaakov+Y%22&quot;&gt;Yaakov Y&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Shoseyov+D%22&quot;&gt;Shoseyov D&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Cohen+M%22&quot;&gt;Cohen M&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Nissim-Rafinia+M%22&quot;&gt;Nissim-Rafinia M&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Blau+H%22&quot;&gt;Blau H&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Rivlin+J%22&quot;&gt;Rivlin J&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Aviram+M%22&quot;&gt;Aviram M&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Elfring+GL%22&quot;&gt;Elfring GL&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Northcutt+VJ%22&quot;&gt;Northcutt VJ&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Miller+LL%22&quot;&gt;Miller LL&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Kerem+B%22&quot;&gt;Kerem B&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Wilschanski+M%22&quot;&gt;Wilschanski M&lt;/searchLink&gt; (AUTHOR)
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  Data: &lt;searchLink fieldCode=&quot;JN&quot; term=&quot;%22Lancet%22&quot;&gt;Lancet&lt;/searchLink&gt;. 8/30/2008, Vol. 372 Issue 9640, p719-727. 9p.
– Name: Abstract
  Label: Abstract
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  Data: BACKGROUND: In about 10% of patients worldwide and more than 50% of patients in Israel, cystic fibrosis results from nonsense mutations (premature stop codons) in the messenger RNA (mRNA) for the cystic fibrosis transmembrane conductance regulator (CFTR). PTC124 is an orally bioavailable small molecule that is designed to induce ribosomes to selectively read through premature stop codons during mRNA translation, to produce functional CFTR. METHODS: This phase II prospective trial recruited adults with cystic fibrosis who had at least one nonsense mutation in the CFTR gene. Patients were assessed in two 28-day cycles. During the first cycle, patients received PTC124 at 16 mg/kg per day in three doses every day for 14 days, followed by 14 days without treatment; in the second cycle, patients received 40 mg/kg of PTC124 in three doses every day for 14 days, followed by 14 days without treatment. The primary outcome had three components: change in CFTR-mediated total chloride transport; proportion of patients who responded to treatment; and normalisation of chloride transport, as assessed by transepithelial nasal potential difference (PD) at baseline, at the end of each 14-day treatment course, and after 14 days without treatment. The trial was registered with who.int/ictrp, and with clinicaltrials.gov, number NCT00237380. FINDINGS: Transepithelial nasal PD was evaluated in 23 patients in the first cycle and in 21 patients in the second cycle. Mean total chloride transport increased in the first treatment phase, with a change of -7.1 (SD 7.0) mV (p&lt;0.0001), and in the second, with a change of -3.7 (SD 7.3) mV (p=0.032). We recorded a response in total chloride transport (defined as a change in nasal PD of -5 mV or more) in 16 of the 23 patients in the first cycle&#39;s treatment phase (p&lt;0.0001) and in eight of the 21 patients in the second cycle (p&lt;0.0001). Total chloride transport entered the normal range for 13 of 23 patients in the first cycle&#39;s treatment phase (p=0.0003) and for nine of 21 in the second cycle (p=0.02). Two patients given PTC124 had constipation without intestinal obstruction, and four had mild dysuria. No drug-related serious adverse events were recorded. INTERPRETATION: In patients with cystic fibrosis who have a premature stop codon in the CFTR gene, oral administration of PTC124 to suppress nonsense mutations reduces the epithelial electrophysiological abnormalities caused by CFTR dysfunction. [ABSTRACT FROM AUTHOR]
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  Data: &lt;i&gt;Copyright of Lancet is the property of Lancet and its content may not be copied or emailed to multiple sites without the copyright holder&#39;s express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.&lt;/i&gt; (Copyright applies to all Abstracts.)
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