EU approves PTC’s ataluren, but how the drug works?

PTC Therapeutics (NASDAQ: PTCT) has received EU’s conditional approval for Translarna (ataluren, PTC124), the world’s first approved treatment for Duchenne muscular dystrophy (DMD). PTC is obligated to complete its confirmatory phase 3 trial in DMD and submit additional data. But, how it works?

About 10% of inherited diseases are caused by premature termination codon mutations. Suppressing premature termination codons and restoring functional protein production may have clinical potential for the treatment of these genetic disorders.

PTC124 was identified through two high-throughput screens[1]. This compound can induce ribosomal read-through of premature but not normal termination codons. It was described as effective in animal models of DMD[1], cystic fibrosis[2], and dysferlin deficiency[3].

The originally identification of PTC124 relied on the detection of increased firefly luciferase (FLuc) activity in HEK293 cells harboring LUC-190 nonsense alleles. The up-regulation of FLuc activity was attributed to the increased translation of full-length FLuc protein. In other words, PTC124 increased the frequency of read-through of premature nonsense mutation in FLuc gene.

Later, NIH’s scientists found that PTC124 can up-regulate FLuc activity independently of premature termination codon read-through[4]. A co-crystal structure revealed that the adduct of AMP with PTC124, known as PTC124-AMP, is a high-affinity inhibitor (Kd=120 pM) of FLuc[5]. PTC124-AMP may induce a stable inhibitor-bound FLuc conformation that protects the enzyme from proteolysis, thereby prolonging half-life of FLuc. The PTC124-based FLuc stabilization was mistakenly interpreted as the read-through of premature nonsense mutation.

PTC has replied to these criticisms[6]. They argued that their characterization of PTC124 also had utilized independent assays of nonsense suppression in disease-relevant systems, including assays measuring synthesis of full-length protein in mdx myotubes, mdx mice, and Cftr−/− transgenic mice.

In July 2008, Genzyme signed a payment of $100 million in upfront cash, plus milestone payments and royalties for the right to develop and market PTC124 outside the US and Canada. But the deal was terminated in September 2011.

In March 2010, PTC/Genzyme announced preliminary results from the 48-week, 174-patient Phase 2b clinical trial of PTC124 for the treatment of nonsense mutation DMD. The primary endpoint of change in 6-minute walk distance (6MWT) did not reach statistical significance.

However, PTC insisted that an average 30 meter improvement (about 10%) in 6MWT is clinically meaningful[7]. PTC applied an conditional approval of PTC124, but the request was rejected by CHMP in January 2014, because of insufficient evidence of efficacy based on single Phase IIb clinical trial.

PTC requested a re-examination of the CHMP opinion, surprising, the CHMP adopted a positive opinion in May 2014, reversing the earlier rejection.

The CHMP pointed out[8] that the main study failed to show that patients taking PTC124 could walk a greater distance in six minutes than patients taking placebo. Insufficient data had been provided to determine how the medicine works in the body and how its effects change with the dose. However, there was some evidence of effectiveness when PTC124 is used at a dose of 40 mg/kg/day. Considering the seriousness of DMD and the unmet medical need it presents, the data available are sufficient to recommend a conditional marketing authorization.

A 238-patient Phase III clinical trial in nonsense mutation cystic fibrosis patients also failed to differ significantly in relative change of FEV1 between PTC124 and placebo (-2.5% vs -5.5%, p=0.12)[9]. However, post-hoc analysis of the subgroup of patients not using chronic inhaled tobramycin showed a positive trend (-0.7% vs -6.4%, p=0.0082). PTC has initiated a new confirmatory Phase 3 clinical trial to confirm that positive trend.

Anyway, PTC can market PTC124 at least until its Phase III study completes next year. Then we can see whether PTC124 provides real efficacy. However, more importantly, how PTC124 works? We may need more time to uncover the truth.

[1] Nature. 2007, 447(7140), 87-91.

[2] Proc Natl Acad Sci USA. 2008, 105(6), 2064-2069.

[3] J Appl Physiol. 2010, 109(3), 901-905.

[4] Proc Natl Acad Sci USA. 2009, 106(9), 3585-3590.

[5] Proc Natl Acad Sci USA. 2010, 107(11), 4878-4883.

[6] Proc Natl Acad Sci USA. 2009, 106(25), E64. doi: 10.1073/pnas.0901936106.

[7] Muscle Nerve. 2013, 48(3), 343-356.

[8] EMA. Positive opinion on the marketing authorisation for Translarna (ataluren).

[9] Lancet Respir Med. 2014, 2(7), 539-547.


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