Thomas Dubensky, Ph.D Chief Scientific Office Aduro Biotech
Development of Cyclic Dinucleotides as a Treatment and an Adjuvant for Cancer Therapy
The production of type 1 interferon (IFN) by host cells in response to an invading pathogen is mediated in part through the STING (Stimulator of IFN Genes) receptor. The STING receptor is generally expressed at high levels in immune cells, including dendritic cells. Once activated, it initiates multiple pathways, including interferons and chemokines, leading to the development of an effective tumor antigen-specific T cell adaptive immune response. Bacterial cyclic dinucleotides (CDNs) trigger IFN in a STING-dependent fashion. A compound (ADU-S100) derived from a CDN-based small molecule platform at Aduro was synthesized to test this approach as a therapeutic opportunity. In mouse tumor models, direct injection of ADU-S100 into melanoma, colon and breast tumors profoundly inhibited tumor growth, both locally and systemically, provided protection against tumor regrowth, and significantly inhibited growth of distal tumors. Other studies demonstrate that vaccination with CDN-adjuvanted recombinant protein induced STING-dependent, antigen-specific CD4 and CD8 T cell responses, and correlated with protective immunity in a viral challenge model.
Dr. Dubensky will address the development of CDN-based targeting of the STING receptor (in collaboration with Novartis) and the likely clinical approaches to best leverage this novel mechanism of action. Other programs will also be discussed, including Aduro's LADD platform of attenuated strains of Listeria that have been engineered to express tumor-associated antigens and induce specific and targeted immune responses in both preclinical and clinical studies.
Lance Berman, M.D.
Senior Vice President and Chief Medical Officer Relypsa
Leveraging Polymer Science to Advance the Treatment of Hyperkalemia
Hyperkalemia is a serious condition that can result in life-threatening cardiac arrhythmias. Patients with compromised renal potassium excretion, primarily patients with chronic kidney disease (CKD), are most at risk of hyperkalemia. Hyperkalemia frequently occurs where the underlying disorder is persistent and generally progressive. Thus, treatment may be needed for long periods of time and/or may need to be repeated. Current options for the ongoing management of recurrent or persistent hyperkalemia have limited utility and include dietary potassium restriction, diuretics, sodium bicarbonate and the cation exchange resins sodium and calcium polystyrene sulfonate.
Until recently, sodium polystyrene sulfonate (Kayexalate), approved by the FDA in 1958, was the only medication in the US specifically indicated for the treatment of hyperkalemia. Since effective lowering of serum potassium with sodium polystyrene sulfonate may take hours to days, treatment with this drug alone may not be sufficient to rapidly correct severe hyperkalemia associated with the rapid tissue breakdown or marked hyperkalemia considered to be a medical emergency. Warning and Precautions added to the Kayexelate label in 2009 and 2011 may also limit its use.
Relypsa applied its polymer technology with the intent to design an orally administered, non-absorbed potassium binder with physicochemical characteristics that would provide effective and sustained reductions in serum potassium and with a safety and tolerability profile that would support long term chronic use. VELTASSA (patiromer) for oral suspension was recently approved by FDA for the treatment of hyperkalemia (given its delayed onset of action, it should not be used as an emergency treatment for life-threatening hyperkalemia). The active moiety, patiromer, is a sodium-free, non-absorbed polymer that binds potassium in exchange for calcium in the gastrointestinal tract, increasing fecal potassium excretion and lowering serum potassium levels. A comprehensive nonclinical and clinical testing program was conducted to support the development of the product for its intended use in humans for the treatment of hyperkalemia. The primary objectives of the clinical development program included: the evaluation of safety and efficacy in subjects with underlying conditions that are common causes of hyperkalemia in the clinical setting; a reduction in serum potassium to within the normal range; and an assessment of safety and tolerability, particularly in support of repeated and long term use.
This talk will provide perspectives on the mechanism of action and clinical development program used to develop patiromer from preclinical to use in patients today.
Jane Lebkowski, Ph.D.
President of R&D and Chief Scientific Officer Asterias Biotherapeutics
Leveraging Polymer Science to Advance the Treatment of Hyperkalemia
Human Embryonic Stem Cells (hESCs) can proliferate indefinitely yet, upon appropriate cues, can also differentiate into all somatic cell lineages. These two properties of hESCs enable the potential development of hESC-derived therapeutic cell populations which can be batch manufactured in central manufacturing facilities, cryopreserved, and distributed for (on demand) use at healthcare providers.
Protocols have been developed to differentiate hESCs into neural, cardiomyocyte, hepatocyte, pancreatic islet, osteoblast, chondrocyte, and hematopoietic cell populations which have been shown to be functional in either in vitro or in vivo animal models of human disease. Asterias has established protocols to produce oligodendrocyte progenitors that, upon transplantation into animals with spinal cord injuries, can remyelinate denuded axons, induce axonal sprouting, and improve locomotor activity. Extensive preclinical studies have been completed to examine the activity, biodistribution, dosing, delivery, potential toxicity and tumorigenicity of the oligodendrocyte progenitors. The safety of these cells is now being tested in the clinic in subjects with complete spinal cord injuries.
In addition Asterias has developed methods to produce dendritic cells from hESCs that have the antigen processing and presentation functionality to stimulate immune responses. In collaboration with Cancer Research UK, Asterias is preparing for a clinical trial using these hESC derived dendritic cells as a cancer immunotherapy in non-small cell lung carcinoma in the neoadjuvant setting. Dr. Lebkowski will describe the preclinical and clinical progress Asterias has achieved for this therapeutic approach that presents a unique set of scientific, clinical and regulatory challenges.
Wendy Young, Ph.D.
Vice President of Discovery Chemistry Genentech
Discovery of GDC-0853: A Highly Potent, Selective and Non-Covalent Btk Inhibitor
Brutonis tyrosine kinase (Btk) plays a critical role in B cell maturation and survival in addition to regulating myeloid cell inflammatory cytokine production, making it an attractive target for the treatment of immunological disorders such as rheumatoid arthritis (RA) and lupus, as well as B-cell malignancies. Mice deficient in BTK enzyme activity (X-linked immune defect, xid) have marked depletion of B cell populations and are resistant to developing collagen-induced arthritis and lupus. Male patients with BTK mutations have a condition known as X-linked agammaglobulinemia, characterized by a severe block in B cell development and diminished serum immunoglobulin levels; however, when treated with intravenous immunoglobulins, they are generally able to lead fairly normal lives which speaks to the potential safety of the target when modulating Btk activity as a therapeutic intervention. To date, Imbruvica is the only BTK inhibitor to launch in oncology indications, while none have yet been approved in immunology indications. Thus there have been significant efforts from the pharmaceutical community with the goal of identifying Btk inhibitors for clinical development in immunology.
Dr. Young will describe the work at Genentech to develop a series of highly potent, selective, non-covalent Btk inhibitors that have proven to be efficacious in several rodent models of RA and lupus. Additionally, compounds in this chemical series were found to remain highly active against the C481S Btk mutant that has been identified in patients that have relapsed on Imbruvica. In this presentation, the SAR, preclinical DMPK and toxicology investigations leading up to the discovery and selection of the lead clinical candidate, GDC-0853 will be described. Additionally, the initial results from Phase 1 clinical trials will be shared.
Managing Director Locust Walk Partners
Recent Trends in the Biopharma Financing and Licensing Market
Three years of strong financial performance in healthcare have generated over $50 billion in potential value back to investors. Last year saw the most capital invested in healthcare companies compared to any other year. The key driver in this performance, record investment in biopharma, saw the largest share of crossover investment by non-traditional biotech investors participating in large mezzanine rounds. The past three years have also seen the largest sustained and most prosperous IPO bull market in healthcare, but the IPO markets have dipped in the beginning of the new year.
When public markets taper off, we start to see spikes elsewhere, such as in partnering activities. Total M&A deal values have reached a decade-high, and partnering deals spiked both in number and value toward the end of 2015 into 2016. Licensing deals have also seen an upward trend in value, with up-front payouts increasing for large and small deals alike. The overall outlook for biopharma is positive, as these exits and successes have led to higher returns and greater investor confidence. Timely and successful fundraising cycles mean venture healthcare has enough capital to support existing investments and new financings, which will reinforce biotech companies as the IPO market declines and non-traditional crossover investors pull away.
Chris Ehrlich will analyze these and other key trends and data from 2015 in the financing and licensing markets of biopharma, and provide his outlook on the opportunities and challenges the biotechnology industry is facing in 2016.
Peter Van Vlasselaer, Ph.D.
Founder, President and Chief Executive Officer ARMO BioSciences
Developing Therapeutic Cytokines to Fight Cancer
With the approval of immune checkpoint inhibitors, immunotherapies have entered mainstream oncology. Justifiable excitement has surrounded the entry of anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) and anti-Programmed Cell Death Protein (PD-1) monoclonal antibodies into the market. However, the sobering reality is that the majority of patients will not respond to these therapies, or will progress within the first year. Additional therapies are therefore needed to increase the percentage of responding patients, extend the duration of responses, expand therapeutic activity into tumor types that are immunologically "cold", and treat patients who are refractory to checkpoint inhibitors.
Combining checkpoint inhibitors can improve anti-tumor activity, but also increases the risk of immune related adverse events. Immuno-oncology agents with novel mechanisms of action however may offer potential options for combination with checkpoint inhibitors (and standard of care chemotherapies) in patients unresponsive to checkpoint inhibitors.
Peter Van Vlasselaer, PhD, will discuss the efforts of ARMO BioSciences, Inc. to develop immunotherapies for difficult-to-treat oncology indications. The company's lead immunotherapy, AM0010, is a PEGylated form of recombinant human IL-10 that primes the tumor micro-environment for immune-mediated therapies. It has demonstrated durable clinical responses in several types of cancer, as both a single agent and in combination with anti-PD-1 monoclonal antibodies and standard-of-care chemotherapies. ARMO plans to initiate the first of several registration-enabling studies for AM0010 in solid tumors, and is developing a robust pipeline including therapeutic cytokines and an anti-PD-1 checkpoint inhibitor.
Robert McDowell, Ph.D
Senior Vice President of Drug Discovery MyoKardia
MYK-461: A Direct Modulator of Cardiac Contractility for the Treatment of Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is the most common form of heritable cardiomyopathy, and is caused by mutations in cardiac sarcomere proteins that cause the muscles forming the left ventricle to contract excessively. As a result, the left ventricles of patients with HCM are abnormally stiff and are prone to both fibrosis and muscle cell death. The consequences include reduced blood volumes and cardiac output, reduced ability of the left ventricle to expand, and high filling pressures. These can all contribute to reduced effort tolerance and symptoms that include shortness of breath and chest pain. It is estimated that as many as 630,000 people in the United States have a form of HCM. In approximately two-thirds of HCM patients, the path followed by blood exiting the heart, known as the left ventricular outflow tract, or LVOT, becomes obstructed by the enlarged and diseased muscle, restricting the flow of blood from the heart to the rest of the body. These patients, who we refer to as obstructive HCM patients, are at an increased risk of severe heart failure and death.
There are currently no approved therapeutic products indicated for the treatment of HCM. Patients are typically treated with drugs indicated for the treatment of hypertension, heart failure or other cardiovascular disorders more generally. These drugs do not address the underlying cause of HCM, do not appear to affect disease progression, and are generally used only in symptomatic patients.
MYK-461 is an orally administered small molecule that modulates the excessive contractility associated with HCM by reducing left ventricular contractility. By directly addressing the underlying pathology of disease, MYK-461 has the potential to slow, prevent, or reverse HCM progression and potentially alleviate the functional consequences and symptoms of HCM. The discovery and early preclinical validation of MYK-461 will be discussed, along with early clinical findings.
Ian McCaffery, Ph.D
Vice President, Translational Sciences Corvus Pharmaceuticals
Novel Immune Therapies for Cancer--the Adenosine Pathway
Development of anti-tumor immunity involves the coordinated activity of multiple immune cell types that mediate antigen presentation to effector cell populations which then invade tumors and target tumor cells that harbor the foreign antigen. Over time, suppressive mechanisms are initiated that are normally involved in regulating the extent of effector cell activity during inflammation. These self-regulatory mechanisms are often co-opted by tumors to evade the immune system.
Therapeutic agents are being developed that stimulate activation and inhibit specific suppressive mechanisms and these agents are demonstrating robust clinical activity in subsets of patients in multiple tumors types. Generation and release of extracellular adenosine during inflammation is known to be an important suppressive mechanism that regulates immune responses and inflammation through activation of receptors that are expressed on effector cells. Accumulation of adenosine in the tumor microenvironment is emerging as an important immune checkpoint, leading to suppression of anti-tumor immunity through inhibition of function of multiple immune cell types, including NK and T cells. CPI-444 is a novel, selective inhibitor of adenosine 2A receptor (A2AR), the key mediator of adenosine mediated immune suppression. In preclinical studies, CPI-444 demonstrated strong anti-tumor activity as a single agent and synergy in combination with multiple immune targeted agents, including anti-PD-L1 antibodies. CPI-444 is being evaluated in a multicenter Phase 1/1b clinical trial in patients with various solid tumors both as a single agent and in combination with TECENTRIQ (atezolizumab), Genentech's investigational cancer immunotherapy that targets PD-L1. Insights into the underlying biological mechanisms of adenosine activity in tumors from ongoing preclinical and clinical studies of CPI-444 will be discussed.
Jeff Zablocki, Ph.D.
Senior Director Gilead Sciences
Discovery of a Late Sodium Current Inhibitor, a Phase II Agent with Pre-clinical Anti-Ischemic and Anti-Arrhythmic Properties
Late sodium current (Late INa) plays an important role in the pathophysiology of ischemia. It is increased during ischemia by reactive oxygen species that modify the Nav 1.5 channel C-terminus, resulting in an incomplete inactivation affording a persistent, or "late" current. GS-6615 (eleclazine), a novel, potent and selective inhibitor of Late INa is currently in clinical development for treatment of hypertrophic cardiomyopathy, Long QT-3 syndrome, and ventricular tachycardia – ventricular fibrillation (VT-VF). The first generation Late INa inhibitor ranolazine not only selectively inhibits Late INa compared to peak INa, but also inhibits IKr and beta-receptors. We will describe the structure activity relationship leading to the discovery of a potent Late INa blocker GS-6615 with a 10-fold selectivity over hERG. GS-6615 was 22 times more potent than ranolazine in reducing ATX-II induced prolongation of monophasic action potential duration with IC50 values of 0.72 and 16 µM, respectively. GS-6615 was 42 times more potent than ranolazine in reducing ischemic burden in vivo. In an ischemia induced model of VT-VF, GS-6615 inhibited the incidence of ventricular arrhythmias (VT and VF) from 65% and 75% respectively in control animals to 0%. GS-6615 represents a new class of potent Late INa inhibitors that will be useful in further delineating the role of inhibitors of this current in the treatment of patients with ischemic heart disease.
Michael Kavanaugh, M.D
Chief Scientific Officer and Head of Research and Non-Clinical Development CytomX Therapeutics
Probody Therapeutics Enable Safer and More Effective Oncology Therapies
Probody therapeutics are fully recombinant antibody prodrugs that are converted to active antibodies by tumor-associated proteases. A Probody therapeutic is engineered by ìmaskingî the antigen binding site of an antibody with a short recombinant extension of the light chain at its NH2-terminus, which interacts with the CDRs and physically blocks the ability of the antibody to bind target. Because of this masking, Probody therapeutics remain substantially inactive in normal tissues and in circulation. However, when the Probody therapeutic encounters a tumor, the mask is designed to be cleaved and removed by tumor-associated proteases, and the antibody becomes fully active within the tumor microenvironment. In this way, Probody therapeutics protect normal tissues while concentrating active antibody in tumors, widening the therapeutic index.
CytomX has demonstrated that the Probody technology is applicable to multiple antibody-based therapies, including naked signal-blocking antibodies, antibody drug conjugates, T cell-engaging bispecifics and CAR-T or CAR-NK cells. This approach is particularly useful for potent antibody-based therapies whose clinical utility is limited by toxicity. For example, CytomX is developing Probody therapeutics directed to immune-oncology targets such as PD-L1 to enable the use of potent combination immune therapies that are currently difficult to use because of immune-related toxicities. Further, because Probody therapeutics have limited interaction with target in normal tissues, Probody drug conjugates allow targeting of highly desirable, first-in-class tumor antigens that are expressed at very high levels in tumors but are not suitable for traditional antibody drug conjugates because they are also expressed in normal tissues and would be expected to result in unacceptable toxicity. Similarly, T cell-engaging bispecific antibodies (TCBs) bring together the very potent tumor killing mechanism of T cells with tumor antigens, but are very unforgiving for the presence of even small amounts of target on normal tissue. Probody therapeutics may allow the broader use of TCBs, particularly for solid tumors.
Preclinical data demonstrating the utility of Probody therapeutics in each of these classes will be presented. CytomX is planning an IND for its first Probody therapeutic directed against PD-L1 by the end of the year, and an IND for a Probody drug conjugate directed against CD-166 in the first half of 2017. A full pipeline of additional candidates is being developed.
Chief Executive Officer & President PaxVax
From Cholera to Zika: Development Pathways for Prophylactic Vaccines
Cholera is an acute enteric infection caused by the bacterium Vibrio cholerae O1 or O139. It is transmitted by the ingestion of water or food containing the organism. The illness principally occurs in countries with insufficient access to safe water and proper sanitation, with even more dramatic impact in areas where basic environmental infrastructures are disrupted or have been destroyed. Contaminated water supplies are the main source of cholera infection, although raw shellfish, uncooked fruits and vegetables and other foods also can harbor V. cholerae and therefore present a risk of infection.
The infectious dose of wild type cholera in humans is in the range of 102 - 106 bacteria. Cholera is characterized in its most severe form (cholera gravis) by a sudden onset of acute electrolyte-rich watery diarrhea that can lead to severe dehydration and death. The extremely short incubation period (approximately 12 hours to 5 days) contributes to the sometimes sudden onset of outbreaks and the quick rise in number of cases.
Cholera (primarily O1) remains an important public health concern primarily in developing countries. Until recently, there was no cholera vaccine available in the United States. PaxVax re-developed a live attenuated bacterial vaccine containing the CVD 103-HgR vaccine strain of Vibrio cholerae serogroup O1, biotype classical, serotype Inaba. Vaxchora is a vaccine indicated for active immunization against disease caused by Vibrio cholerae serogroup O1. Vaxchora is approved for use in adults 18 through 64 years of age traveling to cholera-affected areas. The effectiveness of Vaxchora has not been established in: persons living in cholera-affected areas; persons who have pre-existing immunity due to previous exposure to V. cholerae or receipt of a cholera vaccine. Vaxchora has not been shown to protect against disease caused by V. cholerae serogroup O139 or other non-O1 serogroups.The development of CVD 103HgR and subsequent US FDA licensure of Vaxchora will be discussed as well as an overview of typical development & regulatory pathways for prophylactic vaccines including possible opportunities for a Zika vaccine.
Former Chief Financial Officer and Head of Corporate Development Tobira Therapeutics
Improvement of Fibrosis in Non-Alcoholic Steatohepatitis (NASH) Patients; Clinical Development of a Potential Small Molecule Therapeutic
NASH (Non-Alcoholic Steatohepatitis) is a severe type of non-alcoholic fatty liver disease (NAFLD). NAFLD is the most common liver disease and is associated with obesity and type-2 diabetes. It is characterized by the accumulation of fat in the liver with no other apparent causes. NASH occurs when the accumulation of liver fat is accompanied by inflammation and cellular damage. The inflammation can lead to fibrosis (scarring) of the liver and eventually progress to cirrhosis, portal hypertension, liver cancer and liver failure. NASH is now projected to be the primary cause of liver transplantation and liver cancer by 2020.
Recent scientific advances in the understanding NASH have led to the development of investigational drugs with the potential to address the disease. Tobira has targeted the immuno-inflammatory pathways responsible for liver fibrosis in NASH through inhibition of CCR2/CCR5 (C-C chemokine receptors type 2 and 5). Cenicriviroc (CVC), an experimental oral inhibitor of CCR2 and CCR5 receptors, has been shown to have anti-inflammatory and antifibrotic activity in animal models of acute and chronic liver diseases. The one-year primary analysis results from the Phase 2b CENTAUR study were recently presented at AASLD and Phase 3 is planned for 2017. Christopher will address the preclinical and clinical body of evidence for the potential utility of CVC in this indication and its potential extension to other related indications. The regulatory approaches being considered to expedite delivery of this drug to the marketplace will also be addressed, including potential accelerated approval based upon surrogate endpoints. Finally, the corporate strategies being considered by Tobira and Allergan to advance CVC as a cornerstone of therapy for NASH will be explored.