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Precision Medicine World Conference (PMWC 2020) Ends Last of Three Full-Day Sessions on Friday, January 24, in California's Silicon Valley

Friday, January 24, was the third and last day of the Precision Medicine World Conference 2020 (PMWC 2020) in California’s Silicon Valley, with seven parallel tracks of talks focusing on different aspects of precision medicine. The tracks were Emerging Therapeutics; AI and Data Intelligence; Diagnostics in Clinical Practice; Molecular Profiling—From Research to Clinic; Health Data, Microbiome, and Patient Education; Showcase 1; and Showcase 2. The first five tracks consisted of leaders in the field discussing the latest advances, sometimes in individual presentations and sometimes in panel discussions. The two Showcase tracks gave new companies the opportunity to present their work in crisp 15-minute talks. This year’s PMWC, the 11th annual PMWC conference in Silicon Valley, and the 17th PMWC meeting overall, including smaller, more regional meetings, was the largest annual meeting ever, with over 2,300 attendees from around the world and over 400 presentations given over the full three days. The conference took place in the Santa Clara Convention Center in the heart of California’s Silicon Valley. The theme of this year’s conference was “How Do We Accelerate Precision Medicine and Deliver on Its Proses?” This year’s conference was co-hosted by UCSF, Stanford Health Care/Stanford Medicine, the University of Michigan, the University of Pittsburgh, and Duke Health. Sponsors of the conference included Illumina, Agendia, Bio-Rad, QIAGEN, RubAdaptive, Agilent, Caprion, GO, Google Cloud, Gritstone, Karius, Molecular Health, RubrYc, Oncocyte, Siemens Healthineers, Sophia, Thermo-Fisher Scientific, Quanterix, and Tabula Rasa HealthCare. Neary 100 companies were exhibitors at the meeting. The conference was organized, as always, by Tal Behar, Co-Founder & President, PMWC LLC, and her husband Gadi Behar, Co-Founder & Chairman, PMWC LLC, Silicon Ventures. The PMWC 2020 Program Chairs were Tal Behal and Michael Pellini, MD, MBA, Managing Partner, Section 32 (a venture fund), and Former CEO, Foundation Medicine.

JENNIFER PUCK, MD, AND SEVERE COMBINED IMMUNODEFICIENY DISEASE (SCID)

On Friday, Jennifer Puck, MD, Professor of Pediatrics at UCSF, began the the Emerging Therapeutics track with a discussion of “New Approaches to Diagnosis and Treatment of Severe Combined Immunodeficiency Disease (SCID).” Dr. Puck had originally conceived and developed the newborn screening test for SCID, that has now been adopted in all 50 states and a growing number of countries. With this test, infants with SCID can be diagnosed and treated early, avoiding infectious complications. In a landmark gene therapy clinical trial for X chromosome-linked SCID, Dr. Puck treated four of the eight SCID infants with successful results, and she is also conducting a clinical trial at UCSF of gene therapy for a different SCID gene, Artemis.
In her pre-meeting Q&A interview with the PMWC, Dr. Puck noted that, “overall, with improvements in bone marrow transplant protocols and supportive care, an unrelated bone marrow donor registry with >20 million volunteers signed up (for the large majority of SCID infants who lack an HLA matched sibling donor), and particularly with newborn screening to identify SCID cases early in life, clinical outcomes from allogeneic hematopoietic cell transplantation, the predominant treatment, have improved since 2000 and now exceed 90%.”

“While survival is excellent, not all patients are completely immune reconstituted with some requiring immunoglobulin infusions because of incomplete ability to make protective antibody responses on their own. We have learned that SCID is not a single disease, but instead, there are over 15 different genes that, when mutated, lead to SCID (and additional genes not yet identified). Also, different mutations may produce completely null phenotypes or allow partially functional gene products to be made, so disease manifestations can vary, influencing treatment choices and outcomes. Some of the genes are expressed in tissues outside the immune system, and mutations in these have effects beyond causing immune deficiency. SCID due to some gene defects, such as X-linked IL2RG, have excellent survival while it is much less good in others such as the DNA repair gene Artemis (DCLRE1C).”

“Individualized treatments according to a patient’s specific gene and mutation may improve survival and outcome further. Gene therapy has been developed for 3 genotypes of SCID, and appears to offer superior immune reconstitution, as well as freedom from graft vs. host disease.”

“We recently published results of 7.5 years of screening 3.25 million infants in California for SCID using the T-cell receptor excision circle (TREC) test. 50 infants with SCID were discovered and promptly treated with 94% survival; and 4 additional infants were found to have complete DiGeorge syndrome treated with thymus transplants. SCID newborn screening is now part of routine newborn screening in all 50 states in the USA and is also being adopted in many countries worldwide.”

“Addition of a correct copy of a SCID gene to the hematopoietic (blood-forming) stem cells isolated from a patient can restore immune function. These cells are removed from the body, transduced with a correct cDNA encoding the relevant gene and re-infused into the patient. Over the last 20 years protocols have evolved, overcoming initial challenges of (i) inability to produce sufficient normal protein to improve clinical status, and (ii) safety issues with first generation vectors associated with leukemia.”

“The current lentivirus vector, combined with targeted, low-dose chemotherapy to open niches in the bone marrow for corrected stem cells, appears to be safe and effective at producing reconstitution of both T cell and B cell immunity. The collaborative study with St. Jude Children’s Research Hospital and UCSF has used this treatment successfully in infants with X-linked SCID, including those identified by newborn screening (as published in April 2019 in the New England Journal of Medicine).” (https://www.nejm.org/doi/full/10.1056/NEJMoa1815408).

With regard to the future of newborn SCID screening and treatment in the next 5-10 years, Dr. Puck said the following, “SCID newborn screening will be adopted widely and will enable affected infants to be identified and treated early. Non-SCID immune disorders are also important to detect early, but without a very sensitive and specific biomarker like TRECs to assay, population-wide screening will be challenging. Deep sequencing of infant dried blood spots may eventually be done, but, at this point, variant interpretation is limiting, along with high cost and turnaround time.”

“Inherited disorders of the hematopoietic system are outstanding targets for gene therapy because hematopoietic stem cells can be isolated, corrected ex vivo, and reinfused. Graft vs. host disease and finding matched donors for transplants will no longer be limiting. SCID has led the way in this field and more genotypes of SCID will be treatable by gene therapy, but diseases such as sickle cell disease and thalassemia are also proving treatable by this means.”

“Gene therapy will move from experimental clinical trials to standard of care; this is already happening. Gene editing may become a clinically useful method of gene therapy, offering advantages over gene addition.”

JULIA VITARELLA, MOTHER OF CHILD WITH BATTEN DISEASE

After many clinical and technological discussions throughout the meeting, PMWC 2020 brought the genetic disease story agonizingly home to the audience by calling to the stage a young mother who has struggled valiantly to gain treatment for her young daughter, stricken with an extremely rare and fatal genetic disease, namely Batten disease. The story of this mother’s battles and of her daughter’s dread disease was riveting and tear-provoking for the hundreds in the audience. Julia Vitarello said that her daughter Mila had been beautifully normal at birth and it was only when she reached 3-4 years old that she started exhibiting a variety of symptoms, including walking weirdly, struggling with certain words, and becoming clumsy, where before she had seemed highly coordinated. Julia took her daughter to many, many doctor appointments, but none could diagnose the problem. When Mila turned 6, Julia said everything got progressively worse, including her loss of vision, and Julia took Mila to the Children’s Hospital Colorado, where, after a long week of many tests, the dread diagnosis of Batten disease was given. Julia learned then that Batten disease is an extremely rare neurodegenerative genetic disease (perhaps 20 victims in the entire world), which leaves children blind, cognitively impaired, and bed-ridden before they die at a young age. “We were told there is no cure for Batten... yet,” Julia said. “But we also learned that very recent genetic therapies were showing great promise. So, we started a foundation (Mila’s Miracle Foundation at https://www.milasmiracle.org/) and set out on a race against time to find and fund a path to a cure for Mila, in hopes of also paving a new path for hundreds of other rare diseases.” Soon, Timothy Hu, MD, PhD, of Boston Children’s Hospital learned of Mila’s disease and was able to create an antisense oligonucleotide (ASO) which was targeted at one of Miras two defective Batten disease genes (the one that appeared normal but that had a retrotransposon insert) and when administered to Mila this ASO resulted in an increase in the ratio of normal to mutated protein. The drug is named milasen, after Mila, and it has already had a partial positive effect in modifying her symptoms, reducing her number of seizures from almost 30 per day to as few as 0 to 5. Nevertherless, Mila remains very much disabled, still blind and having lost the ability to use the few words that she was still able to say. Milasin is not a cure for Mila, but it is the first personalized medicine designed to help one single patient. Julia noted, sadly, that the first partially successful treatment for Mila may have come too late, but she emphasized optimistically that Mila’s Miracle Foundation is now working to turn Mila's treatment into an entirely new path for hundreds of rare diseases.

JOHAN SKOG, PHD, CSO, EXOSOME DIAGNOSTICS

In a morning Clinical Diagnostic Showcase, Johan Skog, PhD, CSO, Exosome Diagnostics, outlined the offerings of his company. These included the ExoDx™ Prostate Test, which is the only exosome-based based prostate cancer test which can help patients decide if a prostate biopsy is necessary, independent of PSA testing and other standard-of-care information. The ExoDx™ Prostate Test is a simple, non-digital rectal exam, urine-based, liquid biopsy test indicated for men 50 years of age and older with a prostate-specific antigen (PSA) 2-10ng/mL, or PSA in the “gray zone,” considering an initial biopsy. The ExoDx Prostate test returns a risk score that determines a patient’s risk of clinically significant prostate cancer (Gleason Score ≥7) on prostate biopsy. A score above the validated cut-point of 15.6 is associated with an increased likelihood of GS≥7 PCa on a biopsy and a score below the cut-point of 15.6 is associated with a decreased likelihood of GS≥7 PCa. This test can help reassure a patient to avoid a prostate biopsy or improve patient compliance with a physician recommendation.

Dr. Skog also referred to biomarker discovery platforms that are proprietary technology of Exosome Diagnostics. These include ExoLution RNA, which analyzes and quantitatively measures small and long RNAs, including non-coding RNAs, mRNAs, miRNAs, isoforms, and FUSIONS; ExoLution Plus, which measures cfDNA, in addition to exoRNA, to further enhance mutation detection; and Exosome Diagnostics Depletion or Enrichment (EDDE), which is the company’s unique platform that uses tissue-specific biomarkers to selectively enhance exosome selection. This distinctive capability, combined with the company’s other proprietary exosome isolation platforms, can generate cell-specific assays.

Dr. Skog added an example of how breast cancer plasma exosomes, enriched by EDDE, correlate very well with matched FFPE from the same interval He noted that positive breast cancer plasma samples cluster with their matched FFPE and that the plasm exosomes and their matched FFPE show high agreement in expression of breast cancer marker genes.

In closing, Dr. Skog noted that the company’s exosomal RNA and cfDNA analysis is superior to cfDNA analysis alone and that, with exosome analysis, the company can detect mutations in patients with no/low cfDNA. He further noted additional benefits of exosomal RNA detecton: including detection of rare mutations, fusions, splice variants which cannot be detected on cfDNA, and whole transcriptome sequencing.

He added that the company’s exosome/RNA profiling technology also enables non-oncological applications, including ones for neurological diseases, cardiovascular diseases, transplant monitoring, placental dysfunction, and more.

OFER SHARON, PHD, CEO, ONCOHOST

Another Clinical Diagnostics Showcase was given on Friday by Ofer Sharon, MD, CEO, OncoHost. Dr. Sharon is a physician and entrepreneur with over 17 years of experience in the oncology drug development industry. He is dedicated to overcoming one of the major obstacles in clinical oncology today – resistance to therapy, and his team at OncoHost is seeking to develop personalized strategies to maximize the success of cancer therapy by identifying host-driven pro-tumorigenic biological processes associated with therapy resistance and tumor spread. Dr. Sharon and his team are developing a first-of-its-kind proteomic profiling platform for the early prediction of cancer treatment responsiveness in patients, as well as for the discovery of new targets to overcome treatment resistance. OncoHost utilizes proprietary proteomic analysis, enabling personalized oncological treatment strategies with improved outcomes and reduced side effects. The company believes that host response profiling and proprietary proteomic analysis can improve our understanding of how cancer treatment can influence tumor progression, better identifying which treatments or drug combinations may result in improved outcomes.

Dr. Sharon previously served as a Chief Medical Officer and New Technologies Scout in companies such as Roche, Merck, and AstraZeneca, and co-founded several healthcare companies.

OncoHost’s proprietary PROphet plaform (Predicting Responsiveness in Oncology Patients based on Host response Evaluation during Treatment) is intended as a technology to allow unlocking the host response from the plasma, and to, thereby, enable early identification of non-responsiveness to cancer treatments and the discovery of new targets to overcome treatment resistance. The PROphet platform involves plasma sample collection, antibody array-based proteomics, bioinformatic analysis, and host response, identification, characterization, and analysis.

MICHAEL OLIN, CEO, OX2 THERAPEUTICS

In an afternoon Emerging Therapeutics Showcase, Michael Olin, PhD, CSO, OX2 Therapeutics, and Assistant Professor in the Department of Pediatrics, Division of Hematology/Oncology at the University of Minnesota, described his group’s work to develop a peptide that may have effectiveness against glioblastoma. Dr. Olin and colleagues have co-founded a new company, OX2 Therapeutics, in order to advance this promising peptide molecule into phase 1 human clinical trials for the treatment of glioblastoma, one of the deadliest brain tumors in humans. The peptide (15 amino acids) has been shown to interfere with the dual paired receptor (CD200R1/CD200AR) immune checkpoint system to counter glioblastoma’s overproduction of soluble CD200 (originally named OX2) that acts to suppress the body’s immune response against the cancer. The group has demonstrated that its CD200 peptide ligand induces cytokine production and up-regulates CD80/86 and MHC-II. In addition, the CD200 peptide ligand overpowers CD200 and PD-L1 immunosuppression, downregulates PD-1 on antigen-presenting T-cells and down-regulates PD-L1 on antigen-presenting cells inhibiting CTLA4 upregulation. The group anticipates moving this promising peptide into clinical trials later this year.

SUMMARY

The many presentations described here and in earlier BioQuick News stories on Day 1 and Day 2 of PMC 2020 represent just a select subset of the over 400 talks and panel discussions that were presented during PMWC 2020 in Silicon Valley, California.

NEXT PMWC CONFERENCES

A smaller regional PMWC East conference will be held this spring in Pittsburgh, Pennsylvania, June 4-5 (https://www.pmwcintl.com/east/), with over 90 speakers scheduled to present.

The next annual PMWC conference (PMWC 2021) will be held February 23-26, 2021 in California’s Silicon Valley.