Market access of Spinraza (Nusinersen) for spinal muscular atrophy: intellectual property rights, pricing, value and coverage considerations

S Simoens and I Huys; Gene Therapy , (7 September 2017) | doi:10.1038/gt.2017.79

In December 2016, Spinraza (Nusinersen), Biogen (Durham, NC, USA) was the first treatment to be registered as an orphan drug by the US Food and Drug Administration for SMA. In Europe, a gene therapy in principle classifies as an Advanced Therapy Medicinal Product (ATMP), covered by a regulatory framework with particular incentives for drug developers. For Nusinersen, the European Medicines Agency recently granted the Accelerated Assessment status in 2016. With respect to its price, it has been reported that the annual wholesale costs of treating a patient with Nusinersen will amount to $750 000 for the first year and $375 000 for subsequent years. Biogen argues that this price is in line with that of other orphan drugs for rare diseases.
Despite marketing authorization of Nusinersen in the United States and in Europe, patient access to this new promising therapy remains uncertain. The price of this new drug clearly triggers several questions in terms of justification, transparency and responsibility.
The aim of this Comment is to identify and to discuss issues related to the market access of Nusinersen for SMA by focusing specifically on intellectual property rights, pricing, value and coverage considerations from the perspective of the company, patients and society.
The pricing of Nusinersen is a black box, although Biogen claims that the price of Nusinersen is in line with its clinical benefit and with prices of other orphan drugs. Any data about the value assessment of Nusinersen is not (publicly)available. This asymmetry (or even absence) of information between Biogen and insurers needs to be tackled in an era when insurers (and society at large) need to make and justify difficult choices. A quantifiable and evidence-driven approach to pricing and value assessment is required and such data need to be available to the stakeholders involved.

Detection of long repeat expansions from PCR-free whole-genome sequence data

Egor Dolzhenko, Joke J.F.A. van Vugt, Richard J. Shaw, Mitchell A. Bekritsky, Marka van Blitterswijk, Giuseppe Narzisi, Subramanian S. Ajay, Vani Rajan, Bryan Lajoie, Nathan H. Johnson, Zoya Kingsbury, Sean J. Humphray, Raymond D. Schellevis, William J. Brands, Matt Baker, Rosa Rademakers, Maarten Kooyman, Gijs H.P. Tazelaar, Michael A. van Es, Russell McLaughlin, William Sproviero, Aleksey Shatunov, Ashley Jones, Ahmad Al Khleifat, Alan Pittman, Sarah Morgan, Orla Hardiman, Ammar Al-Chalabi, Chris Shaw, Bradley Smith, Edmund J. Neo, Karren Morrison, Pam Shaw, Catherine Reeves, Lara Winterkorn, Nancy S. Wexler, The US-Venezuela Collaborative Research Group, David E. Housman, Christopher W. Ng, Alina L. Li, Ryan J. Taft, Leonard H. van den Berg, David R. Bentley, Jan H. Veldink, and Michael A. Eberle. Genome Res. gr. 225672.117 Published in Advance September 8, 2017, doi:10.1101/gr.225672.117

We further applied our algorithm to a set of 152 samples where every sample had one of eight different pathogenic repeat expansions including those associated with fragile X syndrome, Friedreich's ataxia and Huntington's disease and correctly flagged all but one of the known repeat expansions. Thus, ExpansionHunter can be used to accurately detect known pathogenic repeat expansions and provides researchers with a tool that can be used to identify new pathogenic repeat expansions. The software is licensed under GPL v3.0 and the source code is freely available on GitHub.

Nitric oxide prevents Aft1 activation and metabolic remodeling in Frataxin-deficient yeast

David Alsina, Joaquim Ros, Jordi Tamarit, Redox Biology, Available online 6 September 2017, ISSN 2213-2317, doi:10.1016/j.redox.2017.09.001.






A major conclusion of this work is that Yfh1 deficiency activates the iron regulon by a different pathway than iron-sulfur loss. Therefore, alternative pathways for Aft1 activation may exist in yeast which, as discussed above, could be related to the presence of anomalous iron species. We have also observed that metabolic status can be efficiently monitored using a targeted proteomics strategy focusing on key metabolic enzymes. Finally, the observation that NO can mitigate the defects caused by Yfh1 deficiency supports the hypothesis that Yfh1 loss leads to the increased presence of anomalous iron forms, and that this anomalous iron plays a central role in the events caused by Yfh1 deficiency. It also suggests that NO donors could have a therapeutic effect in FRDA patients. NO donors such as SNP or nitroglycerin have been used for more than a century for controlling congestive heart failure associated with heart attack or lowering blood pressure during surgery. Beyond its vasodilating action, neuroprotective properties have been demonstrated for NO in an iron-induced model of Parkinson's disease. This observation, together with the results presented in this work, opens the possibility to explore the potential therapeutic effect of NO donors in mammalian models of FRDA.

RNA biology of disease-associated microsatellite repeat expansions

Kushal J. Rohilla and Keith T. Gagnon, Acta Neuropathologica 20175:63, doi:10.1186/s40478-017-0468-y

This review focuses on the potential impact that simple tandem repeat expansions can have on the biology and metabolism of RNA that contain them and underscores important gaps in understanding. Merging the molecular biology of repeat expansion disorders with the current understanding of RNA biology, including splicing, transcription, transport, turnover and translation, will help clarify mechanisms of disease and improve therapeutic development.
Repeat expansion sequences are known to inhibit or impede RNA Polymerase II (Pol II) initiation or elongation either directly or via induction of a repressed chromatin state. Expansions like the GAA repeat in FRDA have been implicated in reduced or silenced transcription.
Examples of microsatellite repeat expansions modulating splicing include the GAA repeat expansion associated with FRDA. When placed near reporter gene exons or in the first intron of a frataxin minigene system, the GAA repeat caused complex splicing defects and accumulation of aberrant splice products. The mechanism proposed involved binding of various splicing factors to the GAA repeat-containing transcripts.
Therapeutic approaches to control xtrRNA transcription and splicing:
Characterizing the effect of microsatellite expansions on transcription and splicing will directly benefit therapeutic approaches for repeat expansion disorders. Proof-of-principle methods to locally disrupt the interactions of xtrRNA at repeat expansion loci, such as R-loops, have been demonstrated for FXS and FRDA using small molecules and nucleic acids.
For splicing-based therapeutics, blocking inclusion of repeat expansion-containing introns, such as with splice-modulating antisense oligonucleotides or small RNAs, could prove to be useful for disorders like FRDA and C9FTD/ALS.
With the emergence of gene editing technologies, the direct removal of repeat expansions from the genome may also be possible. Removal of genomic repeat expansions could eliminate the possibility of xtrRNA expression or reverse repressive epigenetic states.While potential CRISPR-based therapeutics are exciting, precautions must be taken to address potential pitfalls and challenges like off-target effects, delivery, and cell-type specific mechanisms of DNA damage repair

A Defective mRNA Cleavage and Polyadenylation Complex Facilitates Expansions of Transcribed (GAA)n Repeats Associated with Friedreich’s Ataxia

Ryan J. McGinty, Franco Puleo, Anna Y. Aksenova, Julia A. Hisey, Alexander A. Shishkin, Erika L. Pearson, Eric T. Wang, David E. Housman, Claire Moore, Sergei M. Mirkin, Cell Reports, Volume 20, Issue 10, 5 September 2017, Pages 2490-2500, ISSN 2211-1247, doi:10.1016/j.celrep.2017.08.051

Engineered Axonal Tracts as “Living Electrodes” for Synaptic-Based Modulation of Neural Circuitry

M. D. Serruya, J. P. Harris, D. O. Adewole, L. A. Struzyna, J. C. Burrell, A. D. Nemes, D. Petrov, R. H. Kraft, H. I. Chen, J. A. Wolf, D. K. Cullen, Adv. Funct. Mater. 2017, doi:10.1002/adfm.201701183

Brain–computer interface and neuromodulation strategies relying on penetrating non-organic electrodes/optrodes are limited by an inflammatory foreign body response that ultimately diminishes performance. A novel “biohybrid” strategy is advanced, whereby living neurons, biomaterials, and microelectrode/optical technology are used together to provide a biologically-based vehicle to probe and modulate nervous-system activity. Microtissue engineering techniques are employed to create axon-based “living electrodes”, which are columnar microstructures comprised of neuronal population(s) projecting long axonal tracts within the lumen of a hydrogel designed to chaperone delivery into the brain.

Friedrich’s ataxia: Patients develop severe motor impairments in the absence of pro­prioceptive and epicritic signals from the periphery. Living electrodes could provide an articial sensory arc: by tapping into signals from periphery (such as strain gauges, accelero­meters and gyroscopes worn at joints in all four limbs, or from implanted cuff recordings of peripheral nerves), living electrodes implanted into primary sensory cortices could pro­vide sensory feedback and allow improved voluntary move­ ment and functional independence. Grown with glutamatergic neurons, these living electrodes could be implanted to termi­nate in layer IV of the post­central gyrus; because living elec­trodes are themselves quite small, multiple constructs could be implanted corresponding to different joints (e.g., gyros from the left knee driving a living electrode implanted in the right medial sensory cortex, left elbow and shoulder to right lateral sensory cortex, and viceversa for the right extremities and left hemisphere).

Biogenesis and functions of mammalian iron-sulfur proteins in the regulation of iron homeostasis and pivotal metabolic pathways.

Tracey A. Rouault and Nunziata Maio; The Journal of Biological Chemistry 292, 12744-12753. doi: 10.1074/jbc.R117.789537

Fe-S cofactors are composed of iron and inorganic sulfur in various stoichiometries. A complex assembly pathway conducts their initial synthesis and subsequent binding to recipient proteins. In this minireview, we discuss how discovery of the role of the mammalian cytosolic aconitase, known as iron regulatory protein 1 (IRP1), led to the characterization of the function of its Fe-S cluster in sensing and regulating cellular iron homeostasis. Moreover, we present an overview of recent studies that have provided insights into the mechanism of Fe-S cluster transfer to recipient Fe-S proteins.

Peptide SS-31 upregulates frataxin expression and improves the quality of mitochondria: implications in the treatment of Friedreich ataxia

Hongting Zhao, Huihui Li, Shuangying Hao, Jiping Chen, Jing Wu, Chuanhui Song, Meng Zhang, Tong Qiao & Kuanyu Li; Scientific Reports 7, Article number: 9840 (2017) doi:10.1038/s41598-017-10320-2

We demonstrated that treatment with the mitochondrion-targeted peptide SS-31 reduced frataxin deficiency-induced oxidative stress in lymphoblasts and fibroblasts derived from patients. Interestingly, SS-31 treatment translationally upregulated the protein level of frataxin in a dose-dependent manner. Furthermore, SS-31 treatment increased the enzymatic activities of the iron-sulphur enzymes, including aconitase and complex II and III of the respiratory chain. Further evaluation of the quality of mitochondria showed that mitochondrial membrane potential, ATP content, NAD+/NADH, and the morphology of mitochondria all improved. Our results suggest that SS-31 might potentially be a new drug for the early treatment of Friedreich ataxia.
In summary, SS-31 treatment improves the morphology and function of mitochondria in the FRDA patient-derived cells by upregulating the expression of FXN at the translational level and reducing oxidative stress. In addition, SS-31 treatment significantly enhances the ability of patient-derived cells to withstand challenges from exogenous oxidative stress. The mechanism of the translational upregulation in FXN expression by mitochondrion-targeted SS-31 needs to be further addressed. However, improvement in the quality of mitochondria in FRDA patient–derived cells by SS-31 treatment appears promising. It is reasonable to suggest that SS-31 might potentially be a new drug for the early treatment of FRDA.

Overexpression of Drosophila frataxin triggers cell death in an iron-dependent manner

Oliver Edenharter, Janik Clement, Stephan Schneuwly & Juan A. Navarro, Journal of Neurogenetics Vol. 0 , Iss. 0,0; doi:10.1080/01677063.2017.1363200

In this work, we have increased frataxin expression in neurons to elucidate specific roles that frataxin might play in these tissues. Using molecular, biochemical, histological and behavioral methods, we report that frataxin overexpression is sufficient to increase oxidative phosphorylation, modify mitochondrial morphology, alter iron homeostasis and trigger oxidative stress-dependent cell death. Interestingly, genetic manipulation of mitochondrial iron metabolism by silencing mitoferrin successfully improves cell survival under oxidative-attack conditions, although enhancing antioxidant defenses or mitochondrial fusion failed to ameliorate frataxin overexpression phenotypes. This result suggests that cell degeneration is directly related to enhanced incorporation of iron into the mitochondria. Drosophila frataxin overexpression might also provide an alternative approach to identify processes that are important in FRDA such as changes in mitochondrial morphology and oxidative stress induced cell death.

Are Astrocytes the Predominant Cell Type for Activation of Nrf2 in Aging and Neurodegeneration?

Jeffrey R. Liddell, Antioxidants 2017, 6(3), 65; doi:10.3390/antiox6030065

This review describes the evidence for Nrf2 activation in each cell type in prominent neurodegenerative diseases and normal aging in human brain and animal models of neurodegeneration, the response to pharmacological and genetic modulation of Nrf2, and clinical trials involving Nrf2-modifying drugs.