Since genomic sequencing has become more affordable and widely accessible, people with skills to organize and interpret this surge of data have become invaluable. They can recognize patterns previously invisible or uncover new possibilities for discovery.
GSK will use this agreement to advance Wave’s preclinical programs, including WVE-006, an innovative RNA editing therapeutic designed to treat both liver and lung manifestations of AATD.
PRISM
PRISM is a context-sensitive implementation science framework designed to assist researchers and practitioners in understanding, assessing and addressing structural drivers of health inequities. It allows stakeholders to make informed decisions and take meaningful actions towards improving patients’ lives, communities and nations as a whole.
Prism 10 features an extensive technology upgrade while remaining intuitive and easy to use. It supports new ways of working with data and graphs, helping users work faster and more effectively than before.
PRISM helps organizations identify and prioritize insider risk quickly. Reduce false alerts and complex rule-setting by automatically prioritizing file activity across 250+ risk indicators from data, users, and destinations – automating workflow management workflows so they can respond swiftly when risk occurs.
WVE-006
WVE-006 is a GalNAc-conjugated RNA editing oligonucleotide designed to correct the disease-causing SERPINA1 Z transcript in patients suffering from AATD. It should restore circulation of wild-type alpha-1 antitrypsin protein while decreasing levels of dysfunctional mutant Z-AAT protein, thus treating both lung and liver manifestations of the condition. Preclinical studies demonstrated potent and durable editing of this Z transcript as well as restoration of functional AAT protein up to 30 micromolar concentration and improvement of several markers of liver disease as well as no bystander edits making WVE-006 an attractive candidate for RNA-based therapies.
Wave is currently recruiting healthy volunteers into its RestorAATion-2 study to assess safety, pharmacodynamics (PD), pharmacokinetics (PK) and proof-of-mechanism data measured as restoration of serum AAT protein levels. They plan to submit their CTA for this trial by 2024.
WVE-007
Wave Life Sciences is at the forefront of RNA medicine, an emerging class of drugs which alters genetic code. Their lead candidate WVE-003 aims to selectively reduce mutant huntingtin (mHTT) while simultaneously protecting healthy wild-type huntingtin protein (wtHTT). Positive clinical data in their SELECT-HD trial has demonstrated this aim is met.
WVE-004 was found to effectively reduce V3 transcripts with an IC50 of 201.7nM in neuronal cell models, showing selectivity by inhibiting all other transcriptional variants, including wtHTT. A total dose of 100 mg WVE-004 significantly lowered poly-GP levels in C9orf72BAC mice’s cortex and spinal cord, slowing caudate atrophy progression while lastingly lowering levels over time – providing durable benefits over time.
WVE-008
WVE-008 is an RNA editing drug in development for alpha-1 antitrypsin deficiency (AATD), using Wave’s proprietary editing technology. Under Wave’s partnership agreement with GSK to advance this program, GSK will receive an upfront payment of $170 million and exclusive global rights to develop WVE-008 globally.
Annotation files of SARS-CoV-2 genomes from waves-1 and wave-2 were extracted using GFF3 annotation files as reference sequences, with genomic coordinates extracted using the most frequent amino acid substitution events such as S:D614G mutations occurring more often in wave-2 samples than wave-1 samples. SARS-CoV-2 strains had D614G and Q675H mutations more prevalent among wave-2 samples compared to wave-1 samples.
These mutations make the virus more infectious, helping it bypass host immune defense systems more quickly. Furthermore, mutations may allow it to find new hosts more rapidly and spread further.
WVE-009
WVE-009 is an experimental treatment option being explored for Huntington’s disease, an autosomal dominant neurological condition with debilitating symptoms. It selectively lowers mutant huntingtin protein (mHTT), sparing normal huntingtin protein (wtHTT). Furthermore, WVE-009 represents one of the only allele selective therapies being investigated as potential treatments against Huntington’s.
Both waves of SARS-CoV-2 sequences from Bangladesh displayed amino acid substitution events within both spike and nucleocapsid proteins (S8 File), while deletion events remained more prevalent in wave-2. Of particular note was G25563T mutation which can lead to ORF3a:Q57H variant and indicates presence of GH clade [76].
GSK will gain access to Wave’s extensive genetic target discovery platform through this collaboration, while Wave will receive a share of future sales of bepirovirsen and other products such as WVE-006, which is Wave’s investigational candidate for alpha-1 antitrypsin deficiency (AATD), using its first-in-class RNA editing therapeutic designed to correct mutant SERPINA1 Z allele transcript and treat both liver and lung manifestations of this condition.
WVE-0011
Wave’s PRISM platform enables researchers to design personalized oligonucleotides that target and edit specific sequences in the human genome, thus providing scientists with tools to effectively detect disease-causing mutations and create therapeutics to correct them. Using this technology could result in more effective treatments or cures for many conditions including Hepatitis B infection, NASH and AATD.
At both waves, mutational patterns of SARS-CoV-2 samples from each wave were compared according to frequency and type. Deletions and transversions were among the most frequent events, while an unusual GG28881AAC trinucleotide substitution was more frequently seen among wave-1 samples.
GSK and Wave have agreed to enter into a discovery collaboration agreement that includes an initial research term. Under this arrangement, Wave may receive up to $130-$175 million in development milestone payments and tiered sales royalties over time.
WVE-0012
Wave Life Sciences and GSK plc are entering into a strategic collaboration to advance oligonucleotide therapeutics for genetic diseases that can be passed down from generation to generation. Together they will work on up to eight preclinical programs together, including WVE-006, an innovative RNA editing therapy developed specifically to treat alpha-1 antitrypsin deficiency (AATD). GSK will lead all GSK programs up to and including indentification studies before taking responsibility for clinical development and commercialization of its GSK programs.
Genome coordinates for SARS-CoV-2 were obtained using NCBI GenBank’s NUCMER command line tool and Giorgi’s GFF3 annotation file, then aligned against their reference genome to determine frequency of amino acid altering mutations per sample. Deletions events were found to be the most prevalent mutation type across both waves; however wave-2 samples revealed higher frequency of C to T transition mutations than wave-1 samples which may contribute to increased transmissibility through mechanisms related to its spike protein [74].
WVE-0013
WVE-0013 is an innovative RNA editing therapy developed to address alpha-1 antitrypsin deficiency (AATD), targeting its mutant SERPINA1 Z allele mutation. This oligonucleotide targets both liver and lung manifestations of this condition; GSK has brought its global expertise in oligonucleotide development while Wave has leveraged their proprietary discovery and drug development platform PRISM in this partnership.
Mutational patterns were similar in samples analyzed from both waves; however, wave-2 samples generally experienced more amino acid altering events and deletions were more frequent in wave-2 than wave-1 samples.
The resulting oligonucleotides can be directly administered to patients without needing complex delivery vehicles, and this collaboration includes an initial four-year research term in which Wave will lead preclinical research for eight GSK programs through IND-enabling studies before handing off responsibility for further clinical development and commercialization to GSK.
WVE-0014
Wave is developing an RNA editing program for AATD on its PRISM platform, offering potential treatment of an inherited genetic disorder with limited treatment options that affects liver and lungs. WVE-006, Wave’s antisense oligonucleotide that targets this condition, will enter preclinical development phase by 2023 before entering clinical development later that same year.
Giorgi was used to align SARS-CoV-2 genome sequences against Wuhan reference sequence using GFF3 annotation file. Mutations events were identified and classified according to their frequency and type; mutational events most frequently observed were C to T transition, followed by A to G transition and G to T transversion.
Results indicated that selection pressure increased between waves 1 and 2, due largely to an increase in insertion/deletion events and mutations that promote transmissibility, such as S:D294D mutation, NSP3:F106F mutations from NSP3, and 5’UTR mutations that enhance transmissibility such as 5’UTR:241 mutations.
