SPARK has instigated the formation of numerous start-ups working to bring research from bench to bedside
Listed below are the stories of some of these startups
REPURPOSED SMALL MOLECULE TO TREAT NOVEL HEPATITIS C TARGET
Jeffrey Glenn, MD, PhD
Associate Professor Of Medicine (Gastroenterology And Hepatology) And Of Microbiology And Immunology
Chronic hepatitis C is a viral infection that can lead to swelling of the liver, non-alcoholic cirrhosis, and liver cancer. Many years before Gilead turned the national conversation around HCV to drug pricing, Dr. Glenn’s team was searching for new ways to inhibit Hepatitis C Virus in infected individuals. They identified a compound, previously tested in humans to treat allergies, that acted synergistically with other HCV protease-inhibitors to block viral replication and slow emergence of drug-resistant viral strains. SPARK funded preclinical studies into the efficacy of the drug combination.
Eiger BioPharmaceuticals, founded by Jeffrey Glenn, MD, PhD, licensed the technology and ran a Phase IB clinical trial to evaluate safety and tolerability in HCV-infected subjects (CLEAN-1 trial, NCT00945880). Although the original product was eclipsed by the Gilead launch of sofosbuvir, Eiger is developing a number of other SPARK and Stanford discoveries. The company, now public (NASDAQ: EIGR), is performing multiple phase II studies around the world.
REPURPOSED SMALL MOLECULE ANTAGONIST TO IMPROVE COGNITION IN DOWN’S SYNDROME
Craig Garner, PhD
Professor And Group Leader, German Center For Neurodegenerative Diseases (dzne); Charité–universi- Tätsmedizin Berlin
Reduced cognitive function is a hallmark for children with Down syndrome (DS), impairing learning and memory function, as well as the development of language skills. Currently, there are no effective treatments. While Dr. Garner was at Stanford, his SPARK project was evaluated whether previously approved GABA-A receptor antagonists could be safely administered and improve learning and memory consolidation in animal models of Down syndrome. His studies revealed that pentylenetetrazole (PTZ) had an excellent therapeutic window of efficacy, normalizing cognitive function by improving the consolidation of memories during sleep.
The team has formed a start-up company, Balance Therapeutics, and raised 21M in series A and B. Phase 2 clinical trials are ongoing in Australia.
REPURPOSED SMALL MOLECULE TO TREAT BASAL CELL CARCINOMA
Jean Y. Tang, MD, PhD
Associate Professor Of Dermatology
Dr. Jean Tang’s team discovered that an oral drug, itraconazole, already FDA-approved for treating fungal infections, was effective in treating basal cell carcinomas by inhibiting the hedgehog pathway. Dr. Tang led a SPARK project in two Proof of Concept clinical trials that showed benefits of oral itraconazole in patients with sporadic BCC and in patients with the genetic disease, basal cell nevus syndrome, who develop excessive numbers of tumors. The treatment plan for BCC is much longer than for treating a fungal infection, raising concerns about long-term side effects. The investigators, with SPARK funding and utilizing the expertise of SPARK advisors on drug formulation, developed a novel topical cream to be applied to the skin.
With funding from BridgeBio, Dr. Tang and colleagues founded a start-up company, PellePharm Inc., which now holds the license to topical itraconazole and is advancing treatments for basal cell carcinoma into clinical trials.
INHIBITORS OF A NOVEL PATHWAY TO TREAT HUNTINGTON’S DISEASE AND OTHER POLY-Q DISEASES
Stanley Cohen, MD
Kwoh-Ting Li Professor in the School of Medicine and Professor of Medicine; Professor of Genetics
Dr. Cohen’s team identified the protein complex that is essential for the transcription of the trinucleotide repeats in mutant genes that cause Huntington’s disease as well as several other neurologic diseases such as spinocerebellar ataxia. With SPARK support, Dr. Cohen’s team discovered a small molecule compound that can inhibit this protein complex and improve outcomes in animal models of Huntington disease.
Dr. Cohen has formed a startup company, Nuredis, to develop the lead compound for the treatment of Huntington disease and other trinucleotide repeat diseases.
MULTIPLEXED DIAGNOSTIC TO PREDICT AND DETECT PRE-ECLAMPSIA
Atul Butte, MD, PhD
Professor, UCSF School Of Medicine, Pediatrics
Pre-eclampsia is a serious condition of pregnancy and the postpartum period that can lead to hypertensive crisis, seizures and death of the mother. Because preterm delivery is the only way to control severe preeclampsia, OB-GYNs need a better diagnostic tool to predict the course of pre-eclampsia. Stanford professors Atul Butte, MD, PhD, and Bruce Ling, PhD, used data-mining techniques to examine large gene and protein databases to identify a biomarker array that is both sensitive and specific for pre-eclampsia. In a retrospective study published in 2013, their panel of serum protein biomarkers outperformed all competing diagnostic tests.
Drs. Butte and Ling founded Carmenta Bioscience to develop the test, with a SPARK advisor acting as CEO. Carmenta reported that in clinical trials the diagnostic was 99% accurate in differentiating preeclampsia from control. Carmenta was acquired in 2015 by Progenity.
NOVEL BIOLOGIC TARGETING CD47-MACROPHAGE INTERACTION TO TREAT CANCERS
Chris Garcia, PhD
Younger Family Professor And Professor Of Structural Biology
CD47 is an antiphagocytic signal that cancer cells employ to inhibit macrophage-mediated destruction. Dr. Garcia and his team modified the binding domain of human SIRPα, the receptor for CD47, for use as a CD47 antagonist. They engineered high-affinity SIRPα variants with about a 50,000-fold increased affinity for human CD47 relative to wild-type SIRPα. As high-affinity SIRPα monomers, they potently antagonized CD47 on cancer cells but did not induce macrophage phagocytosis on their own. Instead, they exhibited remarkable synergy with all tumor-specific monoclonal antibodies tested, by increasing phagocytosis in vitro and enhancing antitumor responses in vivo. This “one-two punch” directs immune responses against tumor cells while lowering the threshold for macrophage activation, thereby providing a universal method for augmenting the efficacy of therapeutic anticancer antibodies.
The team has formed a start-up company, ALX Oncology, based on the technology and raised a total of $61 million in funding. They have completed Proof of Concept human studies.
DEVELOPMENT OF SMALL MOLECULE TO TREAT AMYLOIDOSIS
Isabella Graef, PhD
Asst. Professor Of Pathology
Transthyretin (TTR) is a protein made in the liver and secreted in the blood. There are over 100 known mutations in TTR that bias the protein to toxic amyloid deposits, resulting in peripheral neuropathy and heart failure. Even the wild-type protein is shown to accumulate in aggregates in old age. Dr. Isabella Graef developed a screen to search for small molecules capable of stabilizing the TTR protein in its native tetramer and preventing aggregation of unstable monomers. Her lab was able to identify a novel small molecule that stabilized both the mutant and wild-type forms of TTR. Testing in patient blood showed the molecule prevented monomer dissociation and reduced toxicity of aggregates. SPARK support helped the team to perform oral dosing studies in animals and show superiority of the small molecule lead to other compounds in development in development for TTR amyloidosis.
With funding from BridgeBio, Dr. Graef founded Eidos Therapeutics, now a public company.
BIOMATERIAL TO TREAT CHRONIC TYMPANIC MEMBRANE PERFORATION
Peter Santa Maria, MD, PhD
Assistant Professor Of Otolaryngology-hns (otology And Neurotology) At The Stanford University Medical Center
Dr. Santa Maria’s SPARK project identified a treatment to allow non-surgical healing of perforated ear drums, a common complication of childhood ear infections. This condition affects up to 200 million children and adults throughout the world, with disproportionate impact in the developing world where surgical repair is not available, and results in hearing loss. Dr. Santa Maria’s treatment replaces surgical repair with a single injection of a therapeutic gel into the ear canal.
The team formed a start-up company Auration Biotech to develop the technology. Astellas has subsequently acquired the rights to develop this therapeutic.
NOVEL SMALL MOLECULE TO TREAT MICROGLIA DYSFUNCTION IN NEURODEGENERATIVE DISEASES
Edgar Engleman, MD
Professor Of Pathology And Of Medicine (immunology And Rheumatology)
Dr. Edgar Engleman’s team developed a novel platform to screen for compounds that regulate microglial metabolism to control neuroinflammation. The team identified a novel small molecule that showed therapeutic efficacy in mouse models of neurodegenerative diseases. SPARK medicinal chemistry advisors worked with the team to optimize the small molecule, and SPARK funding enabled the team to show efficacy in animal models of neurodegenerative diseases. Perhaps most excitingly, treatment with this drug significantly extended survival in an animal model of amyotrophic lateral sclerosis (ALS), an orphan disease with a devastating progressive loss of muscle control and only a two to five year life expectancy after diagnosis.
Dr. Engleman has founded a start-up company, Tranquis Therapeutics, with plans to advance the molecule into clinic trials within three years.
REPURPOSED AND NOVEL SMALL MOLECULES TO IMPROVE MEMORY IN ALZHEIMER’S DISEASE
Mehrdad Shamloo, MS, PhD
Associate Professor (research) Of Neurosurgery And, By Courtesy, Of Comparative Medicine And Of Neurology
Dr. Shamloo found that activation of the beta-adrenergic pathway improved cognitive function in animal models of Alzheimer’s disease. Because chronic administration of existing drugs in this pathway can cause heart failure, SPARK advised that Dr. Shamloo in develop novel small molecule activators that are preferentially concentrated in the brain, thereby improving efficacy and minimizing cardiovascular side effects. With funding and advisor support from SPARK, Dr. Shamloo was successful in identifying a development candidate with the desired characteristics. SPARK also supported research to provide further mechanistic understanding pathway, which expanded use of the drug to additional neurodegenerative conditions such as Parkinson’s disease.
Dr. Shamloo founded a start-up company, CuraSen, to advance the drug into the clinic. The company recently closed a $54.5M Series A financing.
MONOCLONAL ANTIBODY THERAPY TO PREVENT ACUTE GRAFT-VERSUS-HOST DISEASE FOLLOWING HEMATOPOIETIC CELL TRANSPLANTATION
Everett Meyer, MD, PhD
Assistant Professor Of Medicine (blood And Marrow Transplantation) At The Stanford University Medical Center
Everett Meyer, MD, PhD, is a physician scientist and practicing bone marrow transplant physician. His team is developing monoclonal antibodies against a novel immune system target to prevent GVHD. They are evaluating two target proteins. Lead antibodies for both targets significantly increased the survival of mice in a humanized mouse xenograft model of GHVD in which human T cells were used.
The PI has formed a start-up company, Triursus Therapeutics, to advance these drugs and is currently raising funds to initiate clinical trials.
NOVEL SMALL MOLECULE OPIOID ANALGESIC WITH REDUCED SIDE EFFECTS AND ABUSE POTENTIAL
Brian Kobilka, MD
Helene Irwin Fagan Chair In Cardiology; Professor Of Molecular And Cellular Physiology; Professor, By Courtesy, Of Chemical And Systems Biology
The analgesic effects of opioids are believed to be due to their activation of the Mu opioid receptor (µOR), whereas the potentially lethal side effects of opioids are thought to be mediated by their stimulation of the β-arrestin pathway. The Stanford team and their collaborators have developed novel biased agonists of the mu opioid receptor that have the potential to induce analgesia with reduced side effects. Animal studies show the lead compound is highly effective in alleviating pain while having fewer respiratory and GI side effects as well as reduced abuse potential.
The investigators partnered with investors and started a new company Epiodyne.