The Evolution of Liquid Biopsy
TWO PIANISTS, GUARDANT HEALTH and C4 THERAPEUTICS
Biotech firms are bringing future technologies and treatments into the present days, while Stock Market’s evaluators are assessing their values with out-of-date inappropriate methods. The unfair evaluations add to the firms’ burdens and devastate investors who pick the best biotech firms and lose their money nonetheless.
The two players we are presenting today are not yet playing in public, but will evidently go public when the public regains its lost wisdom of evaluating the biotech firms with the objectivity they deserve. Many biotech firms, especially, the development-stage small firms are subjected to negative analysts’ fierce attacks, fabrications and inapt evaluation.
Not able to protect themselves and their shareholders while publicly-traded, an increasing number of biotech firms with breakthrough technologies and products decided to remain private until either a take over occurs, or their products reach the market and generate revenues and incomes that make it hard for the powerful professionals to serve their own agendas at the shareholders’ expense.
We have a lot of examples to cite in this respect.
So, what did these two piano player firms play to make us write about them? Let’s see.
Playing the Guardant 360 Genomic Cancer Test Amazing Music
Guardant Health was founded in 2012 by a team of experts in next-generation sequencing, single-cell genomics and cancer diagnostics. The founders are also entrepreneurs who know business as they do science. In brief, the firm is making available a clinical non-invasive genomic sequencing diagnostic test for cancers. With this test, there is no loss of patients’ time, or subjecting them to invasive methods to learn full information about the cancers. Moreover, the test findings enable the selection of treatments tailored to the unique genomic makeup of each patient’s cancer. A beautiful music in the ears of oncologists and desperate patients.
Guardant Health cancer diagnostic test is called Guardant 360. It is the world’s first comprehensive, non-invasive genomic sequencing test for cancer that helps physicians identify genomic alterations in patients with advanced cancers, without the cost, the risk, or the pain of invasive biopsies.
It the first CLIA/CAP-certified comprehensive next generation sequencing-based liquid biopsy test for cancer genomics. It is a 70-gene blood test used in advanced cancer patients with visceral solid cancers or metastases, and cross-examines all types of genomic alterations. Unlike hotspot tests, Guardant360 sequences complete exons so as it does not miss uncommon or rare mutations. Based on the tumor genomic profile, clinicians receive a report of actionable genomic alterations and a list of FDA-approved treatments and investigational products in clinical trials for which the patient could be eligible. The test is used when an initial biopsy is unobtainable, has insufficient tissue, or brings results that are not appropriate for selecting the right treatment for the right patient.
Raising Capital: While privately traded, Guardant Health was able to complete a first closing on the majority of around $100 million Series D capital raise, which includes equity financing and a term loan facility. The major investor is the healthcare-investment firmOrbiMed, which invests globally across the spectrum of healthcare companies, from venture capital start-ups to large multinational companies. OrbiMed expressed its enthusiasm for the test and its enthusiasm to partner with Guardant Health.
Putting the large amount of money coming from OrbiMed to Guardant Health’ coffers added millions of dollars to another similar amount that was previously raised by other private investors and venture capital firms. Participant in the recent round of financing, include the existing investors Khosla Ventures, Sequoia Capital, Lightspeed Venture Partners, Pejman Mar, Formation 8, Heritage Group, and others.
Being A Private Company
So, being a privately-traded firm did not impede raising large amounts of money. It rather put the firm out of reach of market manipulators. Guardant Health was free to do whatever it considers important to attain its objectives. It intends to use the raised money to expand the technical and commercial lead of its Guardant 360 cancer diagnostic test and further expand its Digital Sequencing™ platform into new product lines that would fill the gaps in a complete cancer-care continuum.
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A Treatment Revolution
Playing the Degronimid Symphony
C4 Therapeutics is developing a new class of targeted protein degradation (TPD) therapeutics for the treatment of diseases. The firm’s Degronimid™ platform incorporates highly selective small molecule binders to target the malformed proteins that cause diseases and facilitate their rapid destruction and clearance from the cell through the naturalubiquitin/proteasome system (UPS).
Degronimids are capable of the following:
– Hitting many more targets, including those previously thought to be undruggable
– Reducing the potential for drug resistance.
– Probably reducing the incidence of chronic and deadly disease recurrences
Putting it in a simple way, one can say that degronimids differ from the current targeted drugs in that Degronimids do not only inhibit the proteins causing diseases, but totally destroy them and eliminate them. They use the proteasome that the cells naturally use to get rid of the unneeded and damaged misfolded proteins.
The proteasome role is to degrade unneeded and damaged misfolded proteins into peptides, which can be further degraded into shorter amino acid sequences that are used in synthesizing new proteins. In nature, unwanted proteins are tagged for degradation with a small protein called ubiquitin. Once a protein is tagged with a ubiquitin molecule, a signal is sent to other ligases to attach additional ubiquitin molecules, which ends up in degrading the tagged protein.
Dana-Farber Cancer Institute scientists have devised the chemical technology, the “Degronimid Platform” that destroys malevolent proteins in tumor cells, not just inhibit them as the current targeted treatments do. This approach, if succeeds in human clinical trials as it did in the laboratory on samples of leukemia cells and in animals with human-like leukemia, it would be a great game changer in the treatment of cancer and other diseases.
The Strategy: Dana-Farber designed an approach that converts an inhibitor drug into a degrader drug through manipulating the cell’s natural protein-elimination system: The proteasome. In nature, used-up or unwanted proteins are tagged for disposal by enzymes that attach a protein called ubiquitin to them. The marked proteins are then brought to the proteasome, where these proteins are ground up and recycled. Three enzymes, E1, E2, and E3, collaborate to affix the tags.
The Dana-Farber team designed a chemical adapter that attaches to the targeted drug molecule. The adapter works like a tiny trailer hitch, enabling the drug to tow the cell’s protein-degradation machinery directly to the protein to be eliminated. Once bound to that protein, the combination drug-and-protein-degrader essentially destroy and demolish the disease-causing protein.
The team tested the technology, which they called “Degronimids” in laboratory samples of leukemia cells. They started with the drug JQ1, which inhibits BRD4, a protein that orchestrates the expression of cancer growth genes. They built an adapter called phthalimide and attached it to JQ1. The phthalimide ( a derivative of thalidomide) to bind snugly to a protein-degrading enzyme E3 (called Cereblon), making it ideal as a trailer hitch.
When investigators treated the leukemia cells with a JQ1-and-phthalimide “conjugate” called dBET1, the targeted protein BRD4 was degraded in less than an hour.
It is said that the potency, selectivity, and rapidity of this clinical approach to protein degradation are unprecedented.
To determine how selective the drug is, the researchers measured the levels of all proteins in leukemia cells one and two hours after treatment. They were stunned to find out that only the three unwanted proteins out of more than 7,000 in the entire cell were degraded: BRD 2, 3, and 4, which was considered an exceptional degree of selectivity guided by the intended targets of JQ1.
The investigators then tested the dBET1 drug in mice bearing a widespread and aggressive form of human leukemia. The results demonstrated a rapid degradation of BRD4 in the tumor cells and a powerful anti-leukemia effect, with few noticeable side effects.
To see if compounds other than JQ1 can be used, the researchers used a compound they called SLF, which targets a protein called FKBP12. When they treated cancer cells with SLF, they found it degraded the vast majority of FKBP12 in the cells within a few hours.
Dana-Farber researchers then worked to create a derivative of dBET1 that can be used as a drug in human patients and extend the conjugate strategy for the treatment of other cancers and other genetically-caused diseases.
All this experience and experimentation and and drug development is now licensed for further development and commercialization to C4 Therapeutics.
In The NEWS
On January 7, 2016, C4 Therapeutics announced that it has launched from Dana-Farber Cancer Institute with the closing of a $73 million Series A round of financing. The unique targeted protein degradation (TPD) and the Degronimid platform technology behind it were described in a seminal paper published in the Journal science in June 2015.
C4 Therapeutics acquired a license from Dana-Farber that provides worldwide exclusivity for all applications of the Degronimid technology. The firm intends to develop many Degronimid drugs over time in proprietary and partnered programs.
C4 Therapeutics was co-founded by Ken Anderson, M.D., Kraft Family Professor of Medicine, Harvard Medical School, Director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber, and a world-renowned expert in protein degradation and multiple myeloma; Nathanael Gray, Ph.D., Professor of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Principal Investigator at Dana-Farber and an expert in kinase inhibitors and drug discovery; software and biotech entrepreneur Marc Cohen; and James “Jay” E. Bradner, M.D., former Associate Professor of Medicine, Harvard Medical School and former Investigator at Dana-Farber.
C4 Therapeutics appointed Jason Fisherman, M.D., as Chief Executive Officer of the Company and Member of the Board of Directors. Dr. Fisherman has a track record of building companies as a venture investor at Synthesis Capital and Advent International, a global private equity firm, where his team led or managed over 35 investments in biotechnology, medical technology and healthcare information services. Prior to joining Advent International, Dr. Fisherman had over ten years of drug research and clinical development experience in biopharmaceutical companies, academia, and at the National Cancer Institute. Dr. Fisherman received a B.A. in Molecular Biophysics and Biochemistry from Yale, an M.D. from the University of Pennsylvania and an M.B.A. from the Wharton School of the University of Pennsylvania.
More information about C4 Therapeutics is available at www.C4Therapeutics.com.
Not being able to invest in these firms today does not mean that we will not be able to invest in them tomorrow when they finally decide to play their symphonies in public.
Regarding Guardant Health, Liquid biopsy testing like the Guardant 360 test developed by Guardant Health are on their way to revolutionize the management of cancer by enabling a better information about the cancer genetics, which enables an accurate selection of the drugs that target the culprit disease-causing proteins, regardless of whether the drugs are still being investigated in clinical trials or approved and marketed.
In the News, Illumina (ILMN) has formed a company called Grail, which raised over $100 million from Illumina and the venture capital Arch Venture Partners, Bill Gates, the founder of Microsoft and Jeffrey P. Besos, the founder of Amazon. Grail is now a majority owned by Illumina. Its task is to develop a blood test that can detect any cancer early enough so it will be easier to treat.
The debate about the test will be hot between those who believe the test will be helpful, or not, feasible, or not and expensive or not. Our guess is that it will be a successful great accomplishment that will further help a successful management of cancer.
Regarding C4 Therapeutics’ new Degronimid therapeutic molecules, the successful lab tests and animal trials brings optimism in the approach that makes disappear the disease-causing abnormal proteins.
This makes a big difference, as inhibiting them with the current targeted treatments is like cutting the serpent’s tail, while sparing its head, which gives a chance for the serpent to sooner or later regenerate and bite again and again.
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