March 22, 2022
Unlike the must-discussed CRISPR-based editing, which removes undesirable genes by cutting them out — almost like a scissor — Beam Therapeutics’ technology can be likened to an eraser. As recent clinical trials have demonstrated, while sweeping DNA deletions may eliminate a faulty gene, such drastic genetic changes can negatively impact other systems and lead to abnormalities or even death. While pharma has invested billions in propelling CRISPR, if adverse incidents continue, the industry will have to pivot — and Beam Therapeutics’ has an alternative already queued up.
Taking a subtler approach to gene modification, the company focuses on base editors to rewrite a single nucleotide at a time within the genome. This precise targeting can theoretically address the ultimate cause of a disease and ultimately fix it, with minimal impact on other aspects of biology. Beam Therapeutics’ leading candidate BEAM-101 is a potential treatment for sickle-cell disease (SCD) and was cleared for in-human trials in November. In addition to SCD, the company is on track to advance programs for a range of therapeutic areas, including hematology, oncology, and liver, ocular, and CNS diseases, using three different clinically validated delivery modalities; electroporation, non-viral (LNP), and viral (AAV) delivery.
Hoping to turn mankind’s dream of a fountain of youth into reality, Fountain Therapeutics is focused on reversing cellular aging. As aging is inextricably linked with disease, the company emphasizes that, by eliminating aging, the risk of disease is greatly reduced, resulting in an elongated and healthy life span.
Fountain Therapeutics relies on AI-powered technology to precisely uncover aging metrics with the hopes of harnessing these insights to identify key intervention opportunities throughout the aging process. By targeting and treating aging as though it is the disease, the company has generated a great deal of buzz. Eli Lilly and Company, Alexandria Venture Investments, R42 Group, Khosla Ventures, and Nan Fung Life Sciences all are invested in the futuristic biotech.
mRNA was undoubtedly the technology of the year in 2020, but tRNA might usurp it over the next decade. Transfer RNA works in tandem with mRNA, translating the genetic transcripts to directly guide protein assembly in ribosomes. However, if a genetic mutation is present, the tRNA will follow bad instructions, so to speak, and incorporate the wrong amino acids. The result is improperly functioning protein due to an error, such as a prematurely placed stop codon (e.g., knocking out a tumor suppressor gene) or, less commonly, a gain of function mutation (e.g., conversion of a proto-oncogene into an oncogene) . Approximately 10% of all genetic diseases have symptomology attributed to premature stop codons, including subtypes of cystic fibrosis, as well as Duchenne muscular dystrophy.
To address this, Shape Therapeutics is working to develop suppressor tRNA therapies for a range of conditions. The company is also working on RNA editing technology using endogenous enzymes called adenosine deaminases acting on RNA (ADARs) and an adeno-associated virus (AAV) platform that produces highly specific, tissue-tropic AAVs. Using its proprietary ShapeTX platform, Shape Therapeutics redirects the body’s own cells to bypass immunogenicity and DNA damage, which it hopes will help address genetic and other diseases without the risks posed by CRISPR. Aside from generating interest throughout the industry, most notably from Roche, Shape Therapeutics has raised $147.5 million to translate its tRNA technology into a working therapeutic.
Though most successful drugs act on a specific protein, finding an appropriate target protein for neurological and psychiatric diseases has historically been exceptionally difficult, given the brain’s unique composition. This inability to identify the right target has resulted in drugs that target a larger families or classes of proteins, resulting in adverse side effects and low efficacy. To bypass this challenge, the proteins made by specific brain cell types have to be uncovered. Cerevance’s NETSseq technology does just that, allowing even neurons and glial cells to be extensively profiled. By using antibodies against nuclear, endoplasmic reticulum, and membrane proteins, as well as RNA probes against any cell type–specific transcripts, the company can extensively tag postmortem brain tissue and sort its nuclei. These insights are then analyzed via machine learning and AI to reveal potential targets that are expressed in disease.
Cerevance is leveraging this technology in a number of ways, and recently entered a strategic alliance with Takeda to identify novel target proteins expressed in the central nervous system to develop therapies for a range of GI disorders. The company has also looked inward to create therapeutic targets and has initiated phase II trials for CVN424, their own oral candidate for Parkinson’s disease. Cerevance additionally achieved endpoints with their drug CVN058 in a phase Ib study of cognitive impairment linked to schizophrenia.
As a pioneer in creating and understanding stabilized G protein–coupled receptors (GPCRs) and using GPCRs as drug targets, Sosei Heptares aims to enable the design of more efficacious therapies with a reduced side effect profile. By engineering these stabilized or StaR® proteins outside the cell membrane, Sosei Heptares creates proteins that are easier to purify and have a greater chance of success than those that are “wild” or not engineered for stability.
This technology aids in drug discovery and will be applied in a phase II study evaluating the selective M4 agonist HTL-0016878 in schizophrenia patients. In addition to developing medicines internally, Sosei Hepares’ technology is licensed by a range of high-profile industry players, including AstraZeneca, Pfizer, Genentech, AbbVie, Takeda, and GSK.
Vaccine maker Valneva targets diseases with significant unmet need. The company’s portfolio includes vaccines against Lyme disease, chikungunya, cholera, Japanese encephalitis, Zika, Clostridium difficile, and, perhaps most notably, COVID-19. Instead of relying on mRNA to diminish COVID-19 symptoms if contracted, Valneva offers a whole virus candidate that is inactivated and produced on the company’s established Vero cell platform. A recent successfully completed phase III clinical trial demonstrated that Valenva’s VLA2001 was better tolerated than AstraZeneca’s comparator vaccine. VLA2001 also achieved a 95% efficacy rate for both transmission and spread of COVID-19, and none of the participants dosed with VLA2001 experienced severe COVID-19 at all.
Thomas Lingelbach, Chief Executive Officer of Valneva, spoke to these results in a recent press release, noting “These results confirm the advantages often associated with inactivated whole virus vaccines. We are committed to bringing our differentiated vaccine candidate to licensure as quickly as possible and continue to believe that we will be able to make an important contribution to the global fight against the COVID-19 pandemic. We are keen to propose an alternative vaccine solution for people who have not yet been vaccinated.” Given the range of variants spreading rapidly around the globe, a vaccine based on a whole virus could be a potential boon in the pandemic.
Using a proprietary Thin Film Freezing platform (hence the name), TFF converts molecules into inhalable formulations. Pulmonary delivery is attractive, as it is more effective than oral solid dose (OSD), for which only 10% of drugs actually reach their targets. Aside from lacking in efficacy across the board, OSDs contain an array of excipients and other additives that contribute to undesired effects, whereas therapeutic inhalation provides both better effectiveness and response time. Inhaled formulations are also user-friendly, especially when compared with parenterals.
TFF Pharmaceuticals has built a robust pipeline and is also partnering to advance this technology. The company recently announced a collaboration with Augmenta Bioworks on an inhalable monoclonal antibody drug for the treatment of COVID-19. The candidate demonstrated a reduced viral load in SARS-CoV-2+ hamsters, and, following this success, TFF Pharmaceuticals plans to begin human clinical trials as soon as early 2022.
The microbiome is proving to have a greater impact on human health than previously imagined. At the forefront of harnessing bacteria to improve the microbiome and treat disease is Vedanta. Armed with proprietary research on the relationship between the immune system and microbes, Vedanta applies GMP standards to engineer gut commensal bacteria gathered from subjects around the world. Different bacterial strains are characterized on the basis of the immune response they elicit, ranging from immunopotentiation (cancer and infection) to immunoregulation (autoimmunity and allergy). Vedanta is actively advancing an entirely new approach to medicine, one in which a patient might be prescribed a drug comprising live bacterial consortia that will recolonize the intestine and entirely shift the gut, leading to an ideal outcome.
So far, Vendanta’s experiment appears to be working. The company recently announced positive phase II results for VE303 in the treatment of high-risk C. difficile infection, with the drug contributing to a 31.7% absolute risk reduction in the rate of recurrence at eight weeks compared with a placebo.
Dubbed the “good science company,” Agathos is on a mission to ethically create breakthroughs that benefit all members of society. While it seems like a lofty goal for a pharmaceutical company, Agathos Bio serves to provide a moral answer to some of the most controversial issues in the industry, such as fetal tissue testing, non-medical vaccine exemptions, and scalability concerns stemming from expensive gene therapies.
Agathos is committed to innovating with integrity by developing biological systems that are conducive to the delivery of therapeutic molecules. The company’s pipeline consists of biomanufacturing cell line development, stem cell line development, AAV-based gene therapy, a probiotic supplement, and genetically engineered bacteria. The company most recently received a grant for $900,000 from the North Dakota Bioscience Innovation program to continue its good work.
Clinical-stage biotechnology company Mirarti Therapeutics relies on innovative technology to target KRAS-mutated and checkpoint inhibitor–resistant tumors. The company’s pipeline includes sitravatinib, a spectrum-selective receptor tyrosine kinase (RTK) inhibitor that harnesses the body’s immunity to eliminate cancer cells; adagrasib, a selective molecule that shrinks tumors harboring a KRASG12C mutation; and MRTX1133, a small molecule KRASG12D mutation inhibitor for patients with high unmet need.
Mirarti Therapeutics has announced plans to collaborate with Verastem Oncology to combine adagrasib with their RAF/MEK inhibitor VS-6766 in KRASG12C-mutant non-small cell lung cancer (NSCLC) in an upcoming clinical trial. The company also has a strategic partnership with Sanofi and will evaluate the effects of adagrasib when taken with a SHP2 inhibitor in KRASG12C-mutated lung cancer during a phase I–II study.
David is Scientific Editor in Chief of the Pharma’s Almanac content enterprise, responsible for directing and generating industry, scientific and research-based content, including client-owned strategic content, in addition to serving as Scientific Research Director for That's Nice. Before joining That’s Nice, David served as a scientific editor for the multidisciplinary scientific journal Annals of the New York Academy of Sciences. He received a B.A. in Biology from New York University in 1999 and a Ph.D. in Genetics and Development from Columbia University in 2008.