Discoveries made in the biomedical field within the last several years are transformative and will probably lead to major industry disruptions in the near future, attracting new investors and defining the R&D focus of the upcoming decade. This review describes notable innovative areas of the industry, highlights new market players, and shows major R&D breakthroughs.
2020 and the beginning of 2021 showed the world the importance of flexibility in the healthcare sector – COVID-19 pandemics has brought everyone together in a common fight against the virus and boosted the development of biotechnologies, innovative therapies, and drug discovery methods.
Messenger RNA (mRNA) vaccines against Coronavirus disease from Pfizer and Moderna illustrated how powerful RNA-based treatments can be. RNAs are a class of molecules that modulate cellular processes without incorporation into DNA. They act by directly producing antigens inside our cells and triggering necessary immune reactions for us to have the cell memory about the virus in the future.
A completely different innovative approach to rule protein expression is developed by Urania Therapeutics. Urania focuses on RNA in ribosomes to treat monogenic orphan diseases. 10-15% of rare genetic diseases are caused by the loss of a full-length protein during translation. Nonsense mutations in genes lead to the formation of stop codons on mRNA that terminates the process of protein expression before it finishes. Urania works on “readthrough” compounds that help ribosomes to overcome early stop codons and produce a protein of target. Urania is a relevantly new company and in 2019-2020 it raised $6.2 million in Seed funding rounds.
A different method of treatment is to regulate and modify our own RNA molecules, changing protein expression patterns or sometimes even turning off the production of the protein in a body (so-called RNA interference). Massachusetts-based company Arrakis Therapeutics has recently signed a deal with big pharma drugmaker Roche to use Arrakis small molecule RNA-targeted drug discovery platform. Arrakis will receive up to $200 million in this partnership. A more recent collaboration with Amgen is focused on targeted RNA degradation.
AstraZeneca entered a collaboration with Gatehouse Bio to use its ‘sRNAlytics platform’. The platform uses a library of 1.4 million RNA features and exploits machine learning algorithms to determine RNA targets and discover next-generation therapeutics. The collaboration aims to identify new targets for respiratory and cardiovascular diseases.
Epigenetics is a well-known branch of modern genetics and almost every Life Sciences specialist is familiar with this term, however, epitranscriptomics is not that popular. The idea behind epitranscriptomics is analogous, it describes various RNA modifications, for example – methylation. From the therapeutic point of view, factors responsible for RNA modifications are interesting therapeutic targets as they modulate protein expression.
Accent Therapeutics found potential in inhibiting RNA-modifying proteins (RMPs) with inhibitory small molecule drugs (SMDs) to treat various cancer types. Improper functioning of RMPs causes a long list of malignancies, starting from leukemia and finishing with brain tumors, and Accent develops therapies based on this finding. In 2018 Accent received $40 million in Round A from three investors and two years later it raised $63 million more in Round B with strong growth prospects.
Scientific discoveries of Professors Tony Kouzarides and Eric Miska from Cambridge are in the heart of operations of another epitranscriptomics company – Storm Therapeutics. Storm is developing a drug discovery platform focused on RNA-modifying enzymes, especially RNA methyltransferases. In April 2021 Storm announced data about its first-in-class inhibitors of METTL3 that are effective against Acute Myeloid Leukaemia (AML) and solid tumors. The company raised a total of around $40 million in 5 rounds.
Targeting RNA with small molecules
Except for modifying the work of RNA regulators, a different approach of targeting it is a direct influence with small molecules. RNA is notoriously famous for its rigidity towards small-molecule inhibition, however, scientists managed to identify opportunities to change the status quo. Analyzing RNA sequence, it is possible to detect binding pockets and predict the nature of interaction there. To date, bioactive molecules can promote small molecule targeted degradation of RNA targets (ribonuclease-targeted chimeras, RIBOTACs) and even direct cleavage of RNA, locally controlling human transcriptome work.
Expansion Therapeutics originates from San Diego and was founded in 2016. The company raised over $135 million and is focused on targets to fight RNA-mediated diseases via small molecule medicines. A big deal in the world of small molecule RNA targeting is the abovementioned Arrakis Therapeutics, a company named a “life science disruptor” by Xconomy and is confidently moving forward. Its pipeline of drug candidates aims to treat neurological disorders, rare diseases, and cancers.
Deep learning and big data in drug discovery
Artificial intelligence (AI), especially its sub-fields related to machine learning, deep learning, and natural language processing (NLP) has become a strategic focus of many pharmaceutical companies. This is largely conditioned by a wave of proof-of-concept studies, including a recent discovery of a brand-new target and a corresponding preclinical drug candidate for the Idiopathic Pulmonary Fibrosis (IPF) by Insilico Medicine using their modular sophisticated AI platforms PandaOmics and Chemistry42. It took under 18 months and a moderate cost to complete the project from the idea to a preclinical candidate, and just 12 months later, the candidate successfully passed Phase 0 study and entered the Phase I clinical trial. The company also rapidly developed preclinical candidates for Kidney Fibrosis, Immunotherapy, and other therapeutic areas. Insilico Medicine raised more than $300 million from a number of prominent investors. Other examples include Deep Genomics, which applied an AI-driven platform to design an oligonucleotide drug candidate for Wilson's disease in 2019 -- in under 18 months. A more narrow, but still significantly important use case was demonstrated by Google’s DeepMind -- they managed to train a neural net AlphaFold to predict protein folding from their primary amino acid sequences with high precision -- having effectively solved a 50-year old problem of biology.
According to an interactive report “A Landscape of Artificial Intelligence (AI) In The Pharmaceutical Research”, there are more than 360 AI companies in the area of pharmaceutical research, with more than 40 of them having raised above $64 million of total venture capital. The area is steadily growing, with the increasing number of R&D collaborations involving the application of advanced analytical systems and drug design platforms with machine learning modules.
Most AI applications fall within several categories: a) data mining and ontology construction from unstructured and structured data (papers, patents, databases, etc); b) target identification and validation using multimodal data (like omics data); c) virtual screening and de-novo drug design to generate hit and lead molecules; d) drug repurposing e) various supporting modeling during preclinical development; f) supporting clinical operations, such as patient matching, outcome predictions, risk assessments, etc; g) real-world data analytics within pharmacovigilance studies.
It is notable that around 50% of all AI-driven drug discovery companies in the report are focused on small molecules, being a dominant drug modality when it comes to the application of machine learning algorithms.
Image credit: iStock www.istockphoto.com
Personalized cancer immunotherapies are becoming more and more widespread in the last few years – tumor-associated antigen (TAA) and neoantigen therapies received a lot of attention. Recently, TAAs have failed in late-stage clinical trials due to the frequency of their dual localization in both neoplasms and healthy tissues. Injection of tumor-associated antigens can trigger the aggressive immune response and cause unwanted side effects if these antigens are also present in normal tissues.
However, this failure gave rise to the new promising technology – neoantigen treatment, which excludes all antigens that could be present in our body in a normal state and focuses on tumor-specific antigens (TSAs). Unlike TAA, neoantigen is a product of cancer cell mutations that accumulate in affected tissues over time. To validate patient-specific neoantigens leading biotech players like myNEO, OncoDNA, Achilles Therapeutics, and eTheRNA exploit bioinformatics platforms, speeding up and improving the efficacy of target discovery. Investments in this sphere have been on the rise over the last several years. For example, Vaccibody in alliance with Genentech raised over $590 million in 2020 and UK firm Achilles Therapeutics received $146 million on IPO in 2021. To see a broad list of recent neoantigen investments check out this article from Labiotech.
The term "theranostic" stands for “treatment” plus “diagnostics” and describes a special type of cancer drug that recently got the hype. Theranostics use radioactive elements as part of their structure, opposite to standard treatments like chemotherapy, radiopharmaceuticals need only a few injections to start showing notable results.
Theranostics carry big potential on the market and investors realize their value – Australian company Telix Pharmaceuticals signed a deal with China Grand Pharma worth $300 million, while AstraZeneca established a collaboration with a US firm Fusion Pharma to develop radiotherapies together. Lantheus Holdings acquired biotech Progenics that already has several FDA-approved radiotherapeutics. Other key players in the field include NanoMab, Precirix, and Vect-Horus.
Exosomes have been mysterious cell structures for a pretty long time, however, research of the last decades proved they can be useful in the treatment of multiple diseases. Scientists are actively researching the role that exosomes may play in cell-to-cell signaling, hypothesizing that exosomes can merge with and release their contents into cells that are distant from their cell of origin, and influence processes in the recipient cell. Especially valuable is their natural ability to target certain types of cells which makes them perfect transporters for gene therapies and RNA drugs.
In 2020 American biotech Codiak Biosciences entered an IPO with $82.5 million, Aegle Therapeutics received $6.5 million of funding for stem-cell derived exosomes clinical trial support, while Australian exosome company Exopharm initiated a Phase I study of wound healing treatment with exosomes. A UK-based Evox Therapeutics raised $96 million in Round C. In February 2022, The Astellas Institute for Regenerative Medicine entered a collaboration with Exopharm, through which the partners plan to carry out initial lab work, with the goal for Astellas of deciding whether exosome products can be added to its pipeline.
Synthetic biology, or just synbio, aims to engineer biologics and organisms to develop new treatments, improve food production and contribute to the alternative energy resources sector.
An example of an unordinary “synbio drug” is CHAIN Biotechnology’s development – a therapeutic based on Clostridium bacteria, a bacteria present in our gut microbiome. These bacteria are loaded with various metabolites and proteins to cure conditions like inflammatory bowel disease. Another CHAIN’s microbiota therapy is designed to treat ulcerative colitis.
Engineered bacteria can be also used like effective vaccine delivery systems, as shown by a number of clinical trials of a biotech company Prokarium. The company has found one more application of genetically modified microbes – special immunotherapy to fight solid tumors. Prokarium raised more than $48 million from two investors to work further on this idea.
One more astounding branch of synthetic biology is the creation of synthetic DNA to upgrade gene therapies. This technology is being developed by Touchlight Genetics, and one of its major goals is to avoid the usage of bacteria for DNA synthesis due to the possible incorporation of additional irrelevant genes. Another example – Zentraxa, which produces synbio products in a form of adhesives that improve wound healing.
Area of human tissues and organs bioprinting is rapidly developing and is, undoubtedly, a major opportunity in medicine. Bioprinting has just started the process of big industry formation, in 2019 it was estimated at $820 million, however, professionals are forecasting it to reach $4.7 billion within 7 years.
Most bioprinting companies do not have a full product cycle but provide pharma corporations and companies with solutions for their products. An example of a growing leader is German Cellink, which produces bioprinting equipment specializing in regenerative medicine and tissue engineering.
Takeda Pharmaceuticals, a global pharma leader, entered an agreement with Engitix, a UK startup that offers models of extracellular matrix to develop therapeutic agents against fibrotic liver diseases. It is worth noting another representative of the bioprinting world – Aspect Biosystems. Aspect works on bioprinted tissue transplants and has currently in the pipeline pancreatic beta cells transplant that is designed to cure type I diabetes.
Overall, bioprinting opinion leaders claim that bioprinted organs for transplantations are only in plans today, yet other real applications like the production of biomaterials for cosmetics, bioplastics, and preparation of animal-free meat are already taking off commercially.
2020 FDA analysis of the antibiotic industry represented the despair that the field is experiencing in the last several decades. Antibiotic discovery and development have gone from predominantly large pharma to almost all biotech. The number of new antibiotic approvals has dramatically decreased in the last two decades (with a modest increase in recent years).
Two major reasons are responsible for this phenomenon – lack of scientific breakthroughs in the sector since the 90s and economical problems. and it is necessary to understand what is the reason for such a big gap in investments between conventional drug discovery and antibiotics discovery. Oppositely to the cancer sector, where big sales are generated frequently right after approval, often it takes time for antibiotics to get prescribed by physicians and this process can drag for years. The success in achieving market approval plummeted by 50%. But how does the antibiotic market trend today?
Many organizations are initiating grant programs to support low cash companies and bankruptcies. The Biomedical Advanced Research and Development Authority (BARDA) Bioshield program offers 5-year contracts to support the development of antibiotics. Paratek Pharmaceuticals received BARDA’s award that can reach up to $284 million to develop its pulmonary anthrax drug NUZYRA® (omadacycline). Novo Holdings sponsored $165 million into the REPAIR Impact Fund for them to invest in anti-infectives discovery projects.
Iterum Therapeutics works on a challenging issue – multi-drug resistant pathogens. Earlier Iterum raised $200 million in 7 funding rounds, with Sarissa Capital Management and RA Capital Management in the list of investors. In 2021 it became partners with EVERSANA to launch a new antibiotic etzadroxil that showed positive clinical trial results and the FDA is providing the results regarding their decision by the end of July 2021. Entasis Therapeutics, which is a spinout of AstraZeneca with the capitalization of $135 million, currently has 4 antibiotic candidates in the pipeline. 2 of them have already reached Phase 3 and aim to treat Acinetobacter infection and gonorrhea, one is in Phase 1 research and another one - in preclinical studies.
One of the rising stars in the antibiotics field is teixobactin developed by Northeastern University scientists. Teixobactin was discovered with the help of iChip technology which allows the collection of antibiotics from soil samples, previously complicated because of obstacles in lab cultivation of soil bacteria. Teixobactin affects resistant skin pathogens like methicillin-resistant Staphylococcus aureus (MRSA) and, what is remarkable, they do not develop resistance after long-term treatment. Now it is in the preclinical stage of development of NovoBiotic Pharmaceuticals – Northeastern University licensed biotech.
According to Chris De Savi, in contrast to the Gram-positive field, where a variety of treatment options are available, the resistance situation in infections caused by Gram-negative bacteria is dramatic. Pan-resistant Gram-negative enterobacteriaceae or non-fermenters have only increased lately.
The number of new antibiotics and their indications are not keeping up with resistance and the needs of the patients.
To sum up, it is hard to predict how the antibiotic sector will behave in the future. Some signals show that after the long-term struggle it might become an increasingly incentivized area for investors.
Nanotechnologies in Drug Delivery
Many patients with a fragile immune system cannot tolerate current methods of cancer gene therapy based on viruses. To avoid undesirable side effects in vulnerable patients, researchers from Johns Hopkins have developed a new mechanism of drug delivery with poly(beta-amino ester) nanoparticles PBAEs. PBAEs can easily assemble with nucleic acids, e.g. apoptosis genes, which are delivered to cancer cells and weaken them, making them more sensitive to other drugs. PBAEs are also adaptive to different cargo sizes, they can deliver a gene or a set of genes and show themself non-immunotoxic. The Johns Hopkins team of researchers is now testing this method in a group of pediatric patients with brain tumors.
Another nanotechnology in cancer treatment is utilizing spherical nucleic acids (SNAs). They carry high specificity to target genes and molecules and a much lower rate of side effects than conventional drugs. In addition, SNAs can travel throughout the body without restrictions and resistance from the immune system, ensuring that the drug reaches the right place.
Scientists from Northeastern University compared them to linear oligonucleotides and were able to show that SNAs get inside cells more effectively than linear DNA. Continuing the series of experiments, they confronted spinal muscular atrophy treatment with Spinraza (one of the most expensive drugs in the world, with a cost of $125 000 per injection) versus novel SNAs treatment. The study showed highly promising positive results, with SNAs being more effective in muscular atrophy therapy than Spinraza.
Gene Editing (CRISPR-Cas9)
Nobel Prize 2020 in Chemistry was awarded to Emmanuelle Charpentier and Jennifer Doudna for the development of probably the most important gene-editing technology to date – the CRISPR/Cas9. CRISPR, or clustered regularly interspaced short palindromic repeats, slices DNA with the help of two main factors – Cas9 and guide RNA. The technology is borrowed from the bacteria immune system that memorizes foreign DNA of plasmids/viruses and cuts it when detecting its own genome. The guide RNA molecule is complementary to the sequence of targeted DNA and Cas9 is an endonuclease that breaks the DNA apart.
Today CRISPR evolved and is not only a molecular scissor tool but also a gene booster. “CRISPR 3.0”, developed by Yiping Qi, precisely activates up to 7 genes four to six times compared to their normal activity. The scientists use novel technology in plant breeding and crop optimization, however, in combination with traditional CRISPR for gene knockout this approach can become a therapeutic treasure.
Talking about medical applications of CRISPR, June 2021 appeared to be crucial for the technology progress – molecular scissors were for the first time systematically delivered to the human body.
One of the notable players in this space is Intellia Therapeutics, founded by Jennifer Doudna. Intellia is a pioneer in the development of CRISPR/Cas9 genome editing and with pre-clinical and early clinical-stage assets. Other leading players are Beam Therapeutics, Scribe Therapeutics, CRISPR Therapeutics, and Editas Medicine.
The anti-aging drug discovery startup ecosystem is in its early days now, with only a little above one hundred emerging companies – largely at the preclinical stage of development. At the moment, there is no one FDA-approved treatment to specifically slow or revert aging, but a few candidates have made it to Phase 3 clinical trials. Venture capital investments into longevity-focused companies have been growing over the last few years and will probably keep that trend up – until the inflection point when the first anti-aging drug is approved for the market. At that moment of going “from zero to one,” the longevity industry will explode with investments and acquisition deals. Already today some longevity-focused companies achieved striking funding levels and multi-billion dollar valuations.
Examples of new players that joined senescence research within the last few years include Cleara Biotech, Oisín Biotechnologies, and AgeX therapeutics. For example, Oisín Biotechnologies focuses on age-related damage to the body and is searching for solutions to mitigate the consequences of aging. They are targeting senescent cells (also called “zombie” cells) with DNA intervention – exogenous apoptotic gene, trying to clear them out of the body. In a Seed Round of funding, Oisín gathered $7 million to support its research.
Another approach developed by US-based AgeX Therapeutics is to apply stem cells and their derivatives for regenerative medicine. AgeX’s proprietary technology PureStem® ensures the purity and quality of stem cell lines. PureStem® has two cell lines – brown adipose tissue cells to fight Type II diabetes and vascular endothelial progenitors to tackle cardiovascular diseases. AgeX also works on iTR™ technology - artificial genetic tissue regeneration mechanism, UniverCyte™ – technology that modifies cells in a way that they can be transplanted to any person without aggressive immune response and, finally, HyStem® Delivery Technology, hydrogel used as a matrix for bioactive molecules. Multiple developments of this company make it undoubtedly an important innovator in the aging market.
Despite all focus being shifted to tackle COVID-19 in 2020-2021, these two years were dynamic in gut bacteria studies and microbiome industry development, and the microbiome research trend will likely continue into 2022.
Seres Therapeutics was the first company to report success in the clinical trial of microbiome drug SER-287 to treat a recurring bacterial infection, a treatment now in Phase III clinical trial (a collaboration with Nestle Health Science). A breakthrough was made in therapy against Clostridium difficile, the main cause of diarrhea and life-threatening colon inflammation. Small biotech Finch Therapeutics presented 75% of cure results with their experimental microbiome drug.
Another microbiome startup, Rebiotix, also claims that it has positive preliminary data on C. difficile-caused conditions, however. An interesting finding was made at Northeastern University, where scientists proved that specific types of ‘good' gut bacteria can alleviate side effects of chemotherapy, caused by harmful changes in the microbiome.
The standard way to deactivate an aberrant protein in almost any therapeutic direction is to attach a small-molecule inhibitor to it. Small-molecule inhibitors do not ruin target proteins but find a specific site on them and bind tightly, turning off adverse functioning. Protein degraders (PDs) offer an alternative solution – they attract components of the Ubiquitin-proteasome system (UPS) to the target, defined with mechanisms of high selectivity, and redirect the complex to the natural intracellular degrading pathway. So far, existing PDs concentrate around cancer targets – transformed cells produce atypical proteins not present in healthy tissues – however, they can be valuable in various other conditions.
C4 Therapeutics is a notable biotech startup in the area of protein degraders, it designs and develops small molecule drugs called PROTACs (PROteolysis TArgeting Chimeras), recruiting factors for E3 ligases that place ubiquitin chains on the target. The company approaches malignancies with two PROTAC modalities – MonoDACs™ and BiDACs™. BiDACs are known as “heterobifunctional degraders” and mediators between disease-specific proteins and E3 enzymes, while MonoDACs are recruited to an E3 ligase and modify it by creating additional surfaces for the interaction with a target protein. C4 Therapeutics has four protein degrader candidates in the pipeline, with one of them in transition between preclinical and clinical trials and others – in the preclinical step or earlier. The company announced its IPO in October 2020 and currently is estimated at $423 million.
Kymera Therapeutics is another biotech with a focus on PDs, specializing in immuno-inflammatory and oncological disorders. It is the first company to develop heterobifunctional small molecule protein degraders outside of cancer studies that reached clinical trials. Its candidate KT-474 targets IL-1R/TLR signaling pathway, dysregulated in autoimmune diseases like atopic dermatitis and rheumatoid arthritis. First results of the Phase I study showed that KT-474 ruins 90% of the target for six days after injection without any adverse effects. Kymera was founded four years ago in 2017 and is located in Cambridge, Massachusetts. In three investment rounds, it raised $197 million for active growth of the startup and in 2021 closed its IPO with $257 million more.
A UK-based Amphista Therapeutics works on tackling the resistance of cancer treatments through the development of new protein degradation mechanisms. Today, a widespread method of ubiquitin-proteasome system engagement is to attract cereblon ligase or VHL ligase. In its turn, Amphista is trying to break these limits and find principally new components. Potential applications include cancer, neurological and neurodegenerative diseases, immunological, and other unmet medical conditions.