HMB301H1 Lecture 2 2024 PDF

Lecture Outline How large pharma impacts biotechnology start-up success Market Challenges Access to molecular information & personalized medicine Slide 1  How large pharma impacts biotechnology start-up success...

Lecture Outline How large pharma impacts biotechnology start-up success Market Challenges Access to molecular information & personalized medicine Slide 1  How large pharma impacts biotechnology start-up success Slide 2 The Nature of things…… Novel therapeutics and technologies - initially innovated & developed by small biotechnology startup companies. Large pharmaceutical and biotechnology companies (pharma) usually bring the resulting therapeutics to market Pivotal Startups Large pharma Slide 3 When to start the relationship? Nature Biotechnology | VOL 39 | March 2021 | 266–269 Slide 4 Impact of pharma investors and licensors on start-up success Past decade: drug development shifted from large pharmaceutical companies to small and mid-sized companies In-house R&D Licensing or acquisition ? Slide 5 Novel therapeutic modalities Complete rethinking of manufacturing Complete rethinking of clinical development Complete rethinking of regulatory interactions Complete rethinking of pricing strategy Demands extensive development & manufacturing expertise and….. significant funding! Slide 6 When to start the relationship? Nature Biotechnology | VOL 39 | March 2021 | 266–269 Slide 7  Success rate for start-ups with and without Approved drug large pharma investors IPO (Initial Public Offering) Acquired Slide 8  Median current market capitalization and acquisition value for start-ups with and without large pharma investors Market capitalization Acquisition value ? Slide 9 Influencing factors: large pharma ties The business model The presence of large pharma as strategic investors in venture capital funds Personal ties to large pharma Overlapping strategic considerations Slide 10 Market Challenges Slide 11 Slide 12 Antimicrobial Resistance (AMR) - creates one of the biggest threats to global health Slide 13 Research & development → expensive! Antibiotics: low prices and sales volume (comparatively). → An antibiotic valley of death Slide 14 Risky and unprofitable Slide 15 Slide 16 Slide 17 Slide 18  Push Incentives: stimulate the development by supporting the cost of early research Novel approaches to Pull Incentives- New payment models: encourage investment UK -yearly payment. The size of the payment would depend on the government’s assessment of the value of the antibiotic. USA similar value-based pricing system Slide 19 ? Slide 20 Personalized medicine Photo source: Genetics Literacy Project Slide 21 The research community is collecting more data, and more distinct types of data, than ever before! → Medical breakthroughs are fueled by deep biological understanding of the mechanistic basis of disease Slide 22 (NCI), examined the DNA of tumors and immune cells found around or within cancers in 111 exceptional responders! In 26 of the patients, scientists found genomic changes to the tumors or immune clues that may explain why a drug shrank the responders’ tumors for months or years! Slide 23 The genetics of gene regulation Linking the activity levels of the 20,000 protein-coding human genes (as shown by levels of their RNA) to SNPs in stretches of regulatory DNA Slide 24 Genotype-Tissue Expression project Effects of genetic diversity in healthy individuals How genetic variants affect gene regulation and quantitative traits in humans? Slide 25 Personalized medicine Genome Transcriptome Metabolomics Proteomics The microbiome Pharmacogenomic Photo source: Genetics Literacy Project Slide 26  A pill of microbes A small device implanted into the spine A cell, pulled out of the body, modified, and put back in Cell reprogramming In-utero therapy Embryo manipulations Slide 27 Precise, dose-responsive control of gene expression by oral small molecules MeiraGTx Riboswitch Technology Slide 28 Personalized treatment plans based on individual circadian rhythms: high- throughput approach that combines live- imaging and data analysis techniques to identify the best time of day to target breast cancer cells with specific drugs Slide 29 Personalized medicine: Targeted therapy Gene therapy Immunotherapy Slide 30  Cystic fibrosis Protein-modification drugs Gene therapy In-uterus therapy Slide 31  Cystic Fibrosis For decades, therapies were palliative! 1989, Gene target identified: cystic fibrosis transmembrane conductance regulator (CFTR) Basic mechanism well understood Protein-modification therapies Gene therapies (including in-utero) Phage based therapies And more… Slide 32 Treatments that would target the underlying cause of the disease! Goal: rescue the function of F508del CFTR → most common mutation Challenging! F508del is a complicated target F508del→ loss of a single amino acid about one-third of the way along the CFTR protein leads to two defects: Inefficient trafficking to the cell membrane Dysfunctional channel Slide 33 Slide 34 Need a combination of at least two drugs: A corrector to help stabilize the mutant F508del protein and shepherd it to the cell surface A potentiator to help it function once it gets there! Slide 35 Ivacaftor (Kalydeco) approved in 2012 for G551D (~2% of CF alleles) Slide 36 Corrector Phase I/II VX-659 triple-combination therapy led to improvements in all evaluated efficacy outcomes in patients with Phe508del–MF or Phe508del–Phe508del genotypes Slide 37 Corrector Corrector Potentiator Slide 38 VX-445 is advancing Slide 39 Trikafta (elexacaftor/ivacaftor/tezacaftor)- the first triple combination therapy available to treat patients with the most common cystic fibrosis mutation Trikafta is approved for patients 12 years and older with cystic fibrosis who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene Quick advancement: Priority Review, Fast Track, Breakthrough Therapy, and orphan drug designation Slide 40 Slide 41  Trikafta’s long-term benefits? Corrector Ivacaftor (Kalydeco) approved in 2012 for G551D (~2% of CF alleles) Potentiator Corrector Slide 42 Trikafta has a list price of more than $300,000 a year, and presumably must be taken for life! Let’s take a break Slide 43 Slide 44 Cell Testing Slide 45 Intestinal organoids for Cystic Fibrosis research https://doi.org/10.1016/j.jcf.2019.11.002 Slide 46 Slide 47 Approximately 1,800 faulty versions of the CFTR-encoding gene associated with the disease One size fits all: Amphotericin B (antifungal agent-isolated in 1955)- can form an ion channel in the cellular membrane of airway cells → restores ion transport and antibacterial defences Slide 48  Amphotericin B tackles lung problems in cystic fibrosis Licensed for use in the clinic Slide 49 Early clinical trials- unsuccessful! Switch from adenovirus to AAV- still unsuccessful! Several AAV based therapies in preclinical development 4D Molecular Therapeutics- Engineered tropism! CFTR gene is around 4.6 kilobases! Spirovant proprietary innovations- a functional CFTR that’s a little shorter and a strong promoter that fits within the carrying capacity of the AAV! Slide 50 lentiviral-based therapies (Spirovant and other companies): larger insertion capacity Less likely to be neutralized and destroyed by the immune system than AAVs Stable expression- lentiviruses integrate into host cells’ DNA Non- viral alternatives DNA or RNA based therapies (liposome-based) ReCode Therapeutics (tRNA based read-through approach) Slide 51 Gene editing promises a way to cure the disease by addressing the root cause! Slide 52 Gene editing promises a way to cure the disease by addressing the root cause! Splicing correction in intestinal organoids Slide 53 Base editors Slide 54  664 patients and 154 CFTR mutations represented in an organoid biobank Adenine base editors enable efficient repair of nonsense mutations in CFTR xCas9 increases the target scope of CFTR repair Adenine base editors cause no detectable off-target effects during repair Slide 55 Slide 56 Splice Switch Oligonucleaotides (ASO) Cocktails of three ASOs → specifically increase the expression of CFTR-W1282X mRNA & CFTR protein upon delivery into human bronchial epithelial cells! Slide 57 ? Slide 58 Early intervention! Prevent extensive damage to organs such as lungs & pancreas Irreversible tissue damage detected already at birth! Slide 59  In-utero gene therapy Gene editing advances → renewed interest in the long-sought goal of fixing the disease as early as possible! Surfactant deficiency β-thalassaemia Slide 60 Slide 61 Slide 62 Early detection Previously: Invasive prenatal testing (removing cells from the amniotic fluid or placenta) Currently: a simple blood test can reveal single-gene disorders as early as ten weeks into a pregnancy! The UNITY test, from diagnostics company BillionToOne- detect fetal DNA circulating in the mother’s bloodstream → Determines not only whether the fetus has cystic fibrosis, but also the exact nature of the mutations responsible for the disease! Slide 63 Slide 64 Slide 65 CFTR correction strategies for the treatment of cystic fibrosis Allan et al (2021) Treatment of Cystic Fibrosis: From Gene- to Cell-Based Therapies. Front. Pharmacol. 12:639475. doi: 10.3389/fphar.2021.639475 Slide 66 CELL-BASED THERAPIES Challenges: Penetrating the CF patient's mucus barrier (altered in volume, viscosity and composition). Identification of Suitable Regenerative Cells with Differentiation Capacity Successful ex-vivo CFTR correction Expansion Transplantation back into the patient’s lungs Slide 67  Identification of Suitable Regenerative Cells With Differentiation Capacity Goal: Optimal self-renewing cell that can also differentiate into the cells of the airway epithelium Options: Mesenchymal Stem Cells (MSCs) induced Pluripotent Stem Cells (iPSCs) Adult tissue-resident basal stem cells Slide 68 Mesenchymal stem cells (MSCs) Allogenic source of cells Immunomodulatory and anti-inflammatory properties MSCs co-cultured with CF immortalized airway epithelial cells at air-liquid interface have demonstrated acquisition of an epithelial phenotype, and subsequent restoration of functional CFTR protein MSCs function transiently to reduce inflammation via the secretion of extra-cellular vesicles such as exosomes → ????? Slide 69  Basal Lung Epithelial cells: Expansion of CFTR- Corrected Regenerative Cells That Retain Differentiation Capacity Low numbers harvested Require large numbers (estimated 60 million) of viable cells to repopulate the lung→ extensive cell expansion will be required prior to implantation Bronchial basal cells have a limited lifespan with differentiation capacity that decreases over time in vitro…. Slide 70  Transplantation of CFTR-Corrected Regenerative Cells Basement membrane Mucosal Immunol 11, 21–34 (2018). https://doi.org/10.1038/mi.2017.71 → Need to be engrafted onto the basement membrane of the airway epithelium Slide 71 Challenges: The innate barrier properties of the CF airway epithelium–will likely make the delivery of the corrected basal cells to the basement membrane difficult Competition between endogenous and transplanted cells used to repair the lung epithelium? Disruption of the epithelial cell layer via conditioning or transient injury will be necessary to facilitate effective cell transplantation--injure the already inflamed and infected lungs of CF recipients ? Slide 72  Efficient & specific eradication! UCSD Center for Innovative Phage Applications and Therapeutics (IPATH) Finding the right phage! Launch one of the first clinical trials of phage therapy for CF, funded by a US$5-million Phage Directory - compiling an open-access grant from the Cystic Fibrosis Foundation database that indexes collections around the world Slide 73 Gastrointestinal complications are an early manifestation of cystic fibrosis, affecting roughly 85% of CF infants Typically caused by insufficient secretion of pancreatic digestive enzymes Disease-associated microbiotic changes might slow growth → therapies that normalize the microbiome → help CF infants achieve greater growth. Slide 74 Slide 75 ? Slide 76