The recent outbreak of Coronavirus in Wuhan China and subsequent spread across the globe is an example of how a viral infection can  cause a deadly systemic inflammatory response (SIRS).  SIRS is a serious medical condition caused by an overwhelming immune response to infection. Immune chemicals released into the blood to combat the infection trigger widespread inflammation, which leads to blood clots and leaky vessels. This results in impaired blood flow, which damages the body’s organs by depriving them of nutrients and oxygen. In severe cases, one or more organs fail. In the worst cases, blood pressure drops, the heart weakens and the patient spirals toward septic shock. Once this happens, multiple organs—lungs, kidneys, liver—may quickly fail and the patient can die (adapted from NIGMS website).

Human coronaviruses (hCoVs) can be divided into low pathogenic and highly pathogenic coronaviruses. The low pathogenic CoVs infect the upper respiratory tract and cause mild, cold-like respiratory illness. In contrast, highly pathogenic hCoVs such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) predominantly infect lower airways and cause fatal pneumonia and systemic inflammatory syndrome (SIRS). SARS and MERS had death rates of approximately 10%-35%. The mortality rate of the Wuhan Coronavirus may be approaching similar levels. Epidemiologists, researchers, clinicians, and governments are racing to find ways to contain and treat the virus. Severe pneumonia caused by pathogenic hCoVs is often associated with rapid virus replication, massive inflammatory cell infiltration and elevated pro-inflammatory cytokine/chemokine responses resulting in acute lung injury, and acute respiratory distress syndrome.  Anti-viral drugs that may reduce the replication of the virus are being evaluated. Treatments to reduce the out-of-control immune response may also be effective.

BioTether Sciences studies and develops plasmapheresis devices to selectively remove inflammatory cytokines and other targeted proteins from the blood. This affinity capture technique short circuits the damaging immune response, returns to body to homeostasis and therefore increases survival from SIRS/septic shock.

By Erik Foehr

BioTether Sciences

Last year saw the approval and marketing of the most expensive drug ever created. Zolgensma, by Novartis, is a one time gene therapy for the rare condition, spinal muscular atrophy. The therapy costs $2.125 million and may be used to treat children around 2 years of age stricken with the disease. Other new drugs with large price tags also added to the growing class of cell and gene therapies that are ‘The Most Expensivest’ drugs ever developed. Spark Therapeutics gene therapy drug for a rare form of blindness, is called Luxturna, and is priced at $425,000 per eye.  A few CAR-T therapies have been approved for cancer over the last couple years,  including Novartis Kymriah for non-Hodgkin Lymphoma.  CAR-T therapies are complex and cost nearly $500,000 for the treatment. 2020 is likely to see several more cell and gene therapy approvals ignite costs like a pile of cash on fire. Million dollar drugs may become commonplace someday.

Cell and Gene Therapy drugs have enormous potential to treat and even cure disease. For instance, Zolgensma, was shown to keep some of the treated children free of the devastating neuromuscular disease years after the therapy was administered. CAR-T therapies have demonstrated astonishing successes curing people of deadly cancers. The FDA projected that 10-20 gene and cell therapies will be approved per year by 2025. That would indicate 3-5 approvals this year, 5-10 next year and so on until cell and gene therapies become a significant part of the biopharmaceutical ecosystem. Hundreds of genetic diseases are being targeted for gene therapy treatment by small biotech start-ups to large multinational biopharmaceutical companies.

How will cell and gene therapies impact the biopharmaceutical and healthcare ecosystems? On the one hand fortunes will be made on the new discoveries, break-throughs, and mega-mergers. Intractable diseases, many rare genetic diseases, with no other treatment option may be ameliorated or even cured. This new class of therapy could improve and save many lives and may even reduce the long term cost burden on the healthcare system. But no one has a clear answer for how to pay for these new million dollar therapies. Cell and gene therapy drugs are being developed for rare diseases, with thousands, hundreds, or even a few dozen treatable patients in the USA. But some new cell and gene therapies may be used on a larger population of patients. Will insurance companies be able to absorb the costs of these million dollar drugs? Can the system find a solution to a low probability, but high impact claims?

These drugs are also extremely expensive to develop, manufacture, and test. CAR-T therapies require highly specialized manufacturing and quality testing systems. Similarly, gene therapies have shown great potential, but have significant challenges relating to vector delivery, immunogenicity, and other safety concerns. Cell and gene therapies are only a small fraction of the overall drug development spend with small molecule and biotherapeutics accounting for over 95% of development dollars. But this new class of drug is going to grow rapidly and will require significant expenditures on in-house and outsourced activities. The outsourced analytical chemistry services spend alone will reach into the hundreds of millions in 2020 and beyond. But that may just be the price to pay for the best, most effective, and expensivest drugs ever developed.

    Like our determined hippopotamus in “The Hippo-Not-Amus”, biotherapeutics are steadily finding mash-ups with medical devices to find creative medical solutions. Novel combination products are being developed and gaining approval in the USA and Europe. In fact, over 30% of biotherapeutics in development are combination products. Novel biodegradable materials, bioelectronic sensors, improved biocompatibility, miniaturization to the nanometer and micrometer scale and other innovations have driven a wave of products. But are these products devices or drugs, or something in between? Is the development path faster as a device or pharmaceutical? Or does the industry and regulators need to consider a new way to develop, review and approve biotherapeutic devices?

    The FDA has an Office of Combination Products (OCP), but it does not regulate combination products, rather it is responsible for designating an FDA Center (Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, or Center for Devices and Radiological Health) to provide premarket review and postmarket regulation. A product’s primary mode of action is used as the basis for that decision. The agency determines a product’s PMA, but manufacturers have the option of submitting a Request for Designation, providing information to support their products’ designation as a drug (CDER), biologic (CBER), or device (CDRH). Once a company knows the jurisdiction of its product, it can establish a cGMP program for manufacturing. https://bioprocessintl.com/manufacturing/formulation/combination-products-for-biotherapeutics-309329/

    BioTether Sciences is developing novel biopharmaceuticals and medical devices that incorporate proteins to exploit ligand-receptor or antigen-antibody binding. We also provide consultation and testing services to help others develop novel therapies for unmet medical needs. Here are a few examples of drug-device mash ups that are exciting and informative to us.

    A great, recent advance is the artificial pancreas. In an NIDDK sponsored study the artificial pancreas, also known as closed-loop control, is an “all-in-one” diabetes management system that tracks blood glucose levels using a continuous glucose monitor (CGM) and automatically delivers the hormone insulin when needed using an insulin pump. In a recent clinical trial, results showed that the artificial pancreas system was more effective at controlling blood glucose levels associated with type 1 diabetes.https://www.nih.gov/news-events/news-releases/artificial-pancreas-system-better-controls-blood-glucose-levels-current-technology

    What about the artificial lymph node? In a proof-of-concept study in mice, scientists used a specialized hyrdrogel that acts like a lymph node to successfully activate immune cells to fight cancer. This strategy could be used recruit immune effector cells to target tumors or to dampen the immune response to self antigens, or become more effective at warding off infection. https://www.sciencedaily.com/releases/2019/04/190418141559.htm

Hydrogels or other natural or artificial polymers can be used to deliver drugs, cells, or just provide favorable conditions for wound healing or prevention of infection.  These products show great promise. In some regulatory jurisdictions they are treated as medical devices, in others, they may be considered a drug.Ventrix, a University of California San Diego spin-off, successfully conducted a first-in-human trial of an injectable hydrogel, designed to repair damage and restore cardiac function in heart failure patients who previously suffered a heart attack.https://physicsworld.com/a/hydrogel-to-repair-heart-proves-safe-to-inject-in-humans/

    Nanomedicine combines the promise of nanotechnology with pharmaceutical intervention to open up entirely new avenues for treatments. A recent surge in the development and application of nanoparticles for biomedical uses includes engineering magnetic particles for magnetic resonance imaging, magnetic hyperthermia and targeted drug delivery.swarms of nanoparticles that deliver vital drugs to the brain, offering new hope to patients in the early stages of a stroke or with glioblastoma. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773933/

Implantable devices have come a long way from the days of faulty stainless steal hip replacements. Improved materials, better more thorough biocompatibility studies, and miniaturization have improved products greatly. Implantable sensors and electrodes that take advantage of new materials, device designs and fabrication strategies enable new and improved biomedical applications. Electronics are used to treat health conditions and injuries, but often they have to be surgically implanted, so when they malfunction or their batteries die, patients have to go back under the knife. Many materials are safe for use in the body, but some leach chemicals when they break down releasing toxic compounds. New materials are being used to design medical devices, for instance, a biodegradable disc-shaped wireless device about the size of a nickel, stimulates peripheral nerves with weak electric shocks. When the nerve is healed, the body naturally breaks down the device and safely removes the waste.https://www.mccormick.northwestern.edu/news/articles/2018/10/researchers-demonstrate-first-example-of-a-bioresorbable-electronic-medicine.html

    The biopharmaceutical-device mash-up is sure to achieve great things. Just like the hippo-not-amus, we need to focus on making the most out of what we have. The incredible properties of biopharmaceuticals (safe, potent, specific) with the precision of medical devices (targeted, timely delivery and  control) is sure to impress.