Miracle drug: Brazil approves never-tested cancer medicine.

Background Brazil recently approved synthetic phosphoetanolamine, a popularly dubbed 'cancer pill', a substance that has been shown to kill cancer cells in lab animal models but was not yet formally accessed in humans, and thus despite the existence of any evidence of its efficacy and safety. Methods The authors describe the recent decision of Brazil to aprove phosphoetanolamine in the context of growing 'judicialization' to promote access to medicines and thus reinforcing a growing sense of legal uncertainty. Results The approval of phosphoetanolamine despite the existence of any evidence of its efficacy and safety represents to the authors one of the saddest and surrealistic episodes in Brazil's recent public health history. Brazil's current economic crisis is fueling the 'judicialization' to promote access to medicines and thus reinforcing a growing sense of legal uncertainty in the context of rising economic constrains and a progressive failing state. The authors state that the Phosphoetanolamine's approval bill violates current legal prohibition of commercialisation of drugs without the Brazilian national drug regulatory agency's approval and thus may represent a potential menace to Brazil's pharmacogovernance and the country's governance to health technology assessment at the Brazilian national health systems. Conclusion Phosphoetanolamine's approval illustrates that the combination of flawed decision making, economic crisis and political interference may threaten weak governance mechanisms for drug regulation and health technology assessment and thus representing an extra burden in the sustainability of universal access-based national health systems.

Identification and Optimization of RNA-Splicing Modulators as Huntingtin Protein-Lowering Agents for the Treatment of Huntington's Disease.

Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. We report the design of a series of HTT pre-mRNA splicing modulators that lower huntingtin (HTT) protein, including the toxic mutant huntingtin (mHTT), by promoting insertion of a pseudoexon containing a premature termination codon at the exon 49-50 junction. The resulting transcript undergoes nonsense-mediated decay, leading to a reduction of HTT mRNA transcripts and protein levels. The starting benzamide core was modified to pyrazine amide and further optimized to give a potent, CNS-penetrant, and orally bioavailable HTT-splicing modulator 27. This compound reduced canonical splicing of the HTT RNA exon 49-50 and demonstrated significant HTT-lowering in both human HD stem cells and mouse BACHD models. Compound 27 is a structurally diverse HTT-splicing modulator that may help understand the mechanism of adverse effects such as peripheral neuropathy associated with branaplam.