Ali Tehrani, President & CEO Zymeworks’ (NYSE, TSX:ZYME) marquee partnerships with Merck, Eli Lilly, Celgene, GlaxoSmithKline and Daiichi-Sankyo provide validation for its next-generation oncology platforms, with the potential for $4.1-billion in milestone payments. “We have multiple platforms that individually or together give us a unique ability to build fit-for-purpose therapies, which will do exactly what they are designed to do,” Ali Tehrani, president and CEO, says in an interview with BioTuesdays. “These platforms are the foundation of the company and facilitate targeting differentiated biological pathways to maximize therapeutic effect in a number of different indications,” he adds. The company’s therapeutic platforms include:
Eli Lilly, for example, has advanced two product candidates using Zymeworks' Azymetric platform into late-stage preclinical development under terms of its licensing and collaboration agreements. The company continues to work closely with Lilly to develop other immune-modulating bispecific antibody therapeutics. In addition to partnered programs, Zymeworks is developing its own pipeline, including lead candidates, ZW25, for the treatment of breast, gastric and ovarian cancers, and ZW33, a drug conjugate for breast and ovarian cancers. The company’s pipeline also includes a number of discovery and preclinical programs, targeting solid tumor cancers with bispecific antibody drug conjugates, T cell-engaging bispecifics and checkpoint-modulating bispecifics. Dr. Tehrani explains that ZW25 is a bispecific antibody for HER2-expressing cancers, with unique mechanisms of action that, among other things, targets two distinct HER2 epitopes leading to unique binding geometrics. “Having the objective of five interdependent outcomes has the potential to make ZW25 a more valuable drug, compared with the standard of care,” he adds. ZW25 has orphan drug designation for gastric and ovarian cancers. Early preclinical studies indicate that ZW25 has superior anti-tumor activity, compared with Herceptin or standard of care, in HER2-low breast cancer, HER2-high gastric cancer and HER2-high ovarian cancer. “We are prioritizing breast cancer but looking beyond this indication,” he adds. At the 2017 ASCO meeting in June, Zymeworks presented encouraging clinical data for ZW25 from an ongoing dose escalation Phase 1 study. ZW25 was well tolerated at three different dose levels, with no dose-limiting toxicities. Durable single-agent anti-tumor activity was seen with patients having received up to eight cycles of treatment. According to Dr. Tehrani, a majority of patients in the study with measurable disease had a decrease in the size of target breast and gastric lesions, along with added life expediency. The company plans to present additional Phase 1 data at the 2017 meeting of the European Society for Medical Oncology in September. Before the end of 2017, Zymeworks plans to begin a cohort expansion of the Phase 1 trial, including a separate cohort of ZW25 in combination with chemotherapy. Phase 2 studies could start in the second half of 2018. Dr. Tehrani says there is a potential opportunity to seek accelerated approval of ZW25 before the end of 2019, either as a single agent or in combination with chemotherapy, and have ZW25 in the market after 2021. The company’s other lead drug candidate, ZW33, has a similar mechanism of action to ZW25, with the exception of being an antibody drug conjugate that has the potential to deliver a potent cytotoxin. Dr. Tehrani says that in preclinical studies, ZW33 has demonstrated superior anti-tumor activity, compared with standard of care, in models of breast and/or ovarian cancer. ZW33 has received orphan drug designation for the treatment of ovarian cancer. The company plans to initiate a Phase 1 study of ZW33 before the end of 2017, with top-line data released in the first quarter of 2018. “Our 2018 plans also include filing an IND for one of our wholly-owned discovery programs,” he adds. Pipeline via Features | BioTuesdays by Kilmer Lucas IR http://ift.tt/2webeIu
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Lloyd Segal, president & CEO As president and CEO of upstart Repare Therapeutics, Lloyd Segal was instrumental is arranging the initial funding to create Repare while he served as an entrepreneur-in-residence at Versant Ventures, a leading healthcare investment firm with a hands-on approach to company building. Repare is developing precision oncology drugs that target specific vulnerabilities of tumor cells. Mr. Segal previously was a managing partner at Persistence Capital Partners, a leading healthcare private equity investor. He has held CEO roles at Caprion Pharmaceuticals, which he co-founded, Advanced Bioconcept and Thallion Pharmaceuticals, and has served as a director of several public and private companies in the U.S. and Canada. In 2013, the Financial Times selected him as Outstanding Corporate Director of the Year. In this interview with BioTuesdays, Mr. Segal discusses Repare’s unique technology and how it is being adapted for the treatment of cancer. Let’s begin with a brief history of Repare. The company was originated in late 2015 by Versant Ventures around a technology platform and a first drug target that didn’t come from that platform but has since helped to validate the platform. The platform is a CRISPR-enabled system for novel “synthetic lethal” target identification, first developed in Toronto at the Lunenfeld-Tanenbaum Research Institute labs of Dr. Daniel Durocher, a scientific pioneer and one of the leading voices in DNA damage repair biology – and also a co-founder of the company. The drug target came from Dr. Agnel Sfeir’s lab at the Skirball Institute of Biomolecular Medicine at NYU Langone Medical Center. Dr. Sfeir is also a Repare co-founder, and her research focuses on how mammalian cells maintain the stability of their genomes – a critical component in cancer. When I got involved in the spring of 2016, we had an opportunity to build a company around the CRISPR platform for discovering new synthetic lethal targets against cancer, with a focus on DNA damage repair, and a lead program, targeting DNA-directed DNA polymerase theta (PolQ), a central component of a genetic pathway that repairs doublestrand breaks in cancer cells and mediates genome stability. Can you elaborate on CRISPR? In its simplest form, our CRISPR screens engineer into highly controlled cellular environments a set of genome-wide, targeted site-specific mutations, using a proprietary library of guide mRNA for precise genomic editing. This model system allows us to search for synthetic lethal interactions important in cancer, representing a platform for the development of new, precision oncology drugs. Thanks to Dr. Durocher’s pioneering work in this area, Repare has now established a world-class CRISPR screening platform that is already generating many new and very interesting targets that are specifically lethal to common genetic alterations essential to the viability and proliferation of cancer cells. According to Segal, In its simplest form, our CRISPR screens engineer into highly controlled cellular environments a set of genome-wide, targeted site-specific mutations, using a proprietary library of guide mRNA for precise genomic editing. What is the core concept of synthetic lethality? Synthetic lethality represents a promising avenue to identify molecular pathways uniquely essential to cancer cells. Basically, it describes a genetic phenomenon where one of two gene products is essential for cancers to survive and proliferate. If either one of the genes is missing or mutated, the cancer can thrive, but if both are disabled through mutation or drug targeting, the cancer cannot survive and will actually self-destruct. When we can identify these synthetic pairs, we explore whether we can target the function of one of these genes in the context of a natural mutation, or lesion, such as BRAC1, commonly found in many cancers. If a patient has a particular lesion, they will then be most likely to respond to the drug for that lesion’s synthetic lethal partner. We are thus now able to develop highly specific precision oncology drugs, where we can identify and treat only the patients who are most likely to respond to our drug. As importantly, the drug targets cancer cells with the lesion, while sparing normal cells that lack the cancer-associated lesion, with the goal of reducing off-target toxicity. This kind of genetically guided therapy ultimately yields safer, more effective drugs for patients. Not a silver bullet, but certainly headed in that direction. Can you describe an example of synthetic lethality? In oncology, PARP (poly ADP ribose polymerase) inhibitors were developed for the treatment of cancers with mutations in BRCA1 or BRCA2, and they are revolutionizing cancer treatment. However, they often only work in a subset of patients and also fall prey to evolving resistance, reflecting the need for new, improved, and complementary approaches to treat many cancers. Is it safe to say that you’re exploiting a genetic weakness in cancer cells? Yes. For example, several forms of cancer are more dependent on PARP than regular cells, making PARP an attractive target for cancer therapy. PARP inhibitors improve progression-free survival in certain women’s cancers. For example, PolQ, which is also a BRCA1 synthetic lethal partner, is over-expressed in many tumor types and associated with poor clinical outcomes in ovarian cancer and breast cancers. However, we are working with many other lesions beyond BRCA1. This is really just the beginning. What are the advantages of synthetic lethality? We think this is among the emerging class of agents that can deliver on the promise of precision – if not personalized - medicine, allowing us to develop drugs that only focus on very specific patients, so, for example, the one woman in ten who is BRCA1 mutated will very likely respond to treatment. Because these drugs are designed to target only the cancer cells with lesions that confer synthetic lethality, they provide an enhanced therapeutic window and understanding of when and how drugs are going to work in solid tumors with a high-unmet medical need, while ideally sparing normal tissues. An additional advantage of synthetic lethality is its potential to work synergistically with chemo and immune checkpoint inhibitors. How many programs to you have underway? Our first lesion to be publicly disclosed is BRCA1, which is most often associated with women’s cancer but is also evident in cancers of the prostate, lung and colon. We have three active drug development programs underway, but the only one we’ve disclosed is PolQ, an exciting new target which our founder, Dr. Agnel Sfeir, helped pioneer. We have not disclosed details of our other programs. How close are you to the clinic? Our goal is to be in the clinic in 2019 with our first small molecule inhibitor of a synthetic lethal target for cancer. And a final word about your financing in June. Founding investor, Versant Ventures, coled a $68-million Series A round with MPM Capital. It is the largest global Series A biotech investment so far this year. They were joined by other syndicate investors, including Fonds de solidarité FTQ, Celgene Switzerland, and BDC Capital’s Healthcare Venture Fund. We are funded to achieve our goal of testing multiple precision oncology therapeutics in a clinical setting. via Features | BioTuesdays by Kilmer Lucas Investor Relations http://ift.tt/2vlxEE8 David Matthews, CFO Closely-held Contextual Genomics is giving oncologists a leg up to enhance cancer care with its new Find-It molecular test to detect genetic mutations in cancer patients. “We deliver solutions through our lab partners that harness the clinical and genomic data of cancer patients to improve patient diagnosis and present expanded treatment options to oncologists and patients,” David Matthews, CFO, says in an interview with BioTuesdays. Launched in 2016, the Find-It cancer panel is a multiplex, next-generation sequencing (NGS) genomic assay that screens for known gene mutations found in solid tumors, most of which can be treated with current targeted cancer therapies or drug candidates in Phase 3 clinical trials. Mr. Matthews says that Find-It is designed for rapid deployment into partner labs around the world. The test evaluates the mutation status of tumor DNA at more than 120 well-characterized cancer genes, identifying optimal treatments for patients. “The Find-It test leads to personalized treatment for patients.” Cancer is a genomic disease that evolves over time through mutations in otherwise normal cells. The detection of mutations across the genomes of cancer cells reveals targeted treatment options for patients for which they would otherwise be ineligible. While some 50 new-targeted cancer drugs can only be administered to patients on the basis of knowing the status of specific gene mutations in the patient’s tumor tissue, he points out that there are some 470 targeted cancer drugs in clinical testing that require mutation testing. “Our test will also tell physicians if there is a clinical trial underway with their patient’s specific mutation and aid drug companies with pre-enrolment of patients to exclude potential non-responders to their drug,” Mr. Matthews contends. Mr. Matthews says Contextual’s approach to cancer care is inherently data intensive. “Data driven medicine is part of a transformative paradigm resulting in ultra-high volume datasets that are driving new biomedical discoveries and informing and enabling precision medical care,” he adds. Mr. Matthews explains While some 50 new-targeted cancer drugs can only be administered to patients on the basis of knowing the status of specific gene mutations in the patient’s tumor tissue, he points out that there are some 470 targeted cancer drugs in clinical testing that require mutation testing. “We develop and deploy next-generation sequencing (NGS) tests to detect mutations in cancer DNA, then combine these results with clinical data,” he says. “This results in high volume datasets, which are analyzed and interpreted in relation to a patient’s clinical care.” In addition, he says NGS has the potential to track the evolution of cancer under treatment and provide the data necessary to predict if patients are relapsing while on a given therapy, which allows oncologists to change treatment regimens early in disease management, leading to improved outcomes. While NGS costs are now affordable, he points out that the analysis of the data requires a heavy investment in software development and bioinformatics, which is only available at top tier cancer centers or privately as a premium price medical test. “Our product is an integrated molecular and computational process used by laboratories to generate, analyze and interpret NGS test data collected from cancer patients,” he adds. “With our software-as-a-service platform, laboratories can, in a highly scalable manner, provide oncologists with quality-assured, comprehensive, clinically useful and individualized genomics-based knowledge for each cancer patient, including specific approved targeted therapies.” Mr. Matthews says the company’s focus now is to push its products out into lab networks. At the beginning of 2017, Australia's Sonic Healthcare (ASX:SHL), the industry’s third largest lab company after Labcorp and Quest Diagnostics, agreed to offer Contextual’s Find-It solid tumor test in Australia and then through its network of labs in eight countries. Last week, Contextual teamed up with CORE Diagnostics of India to introduce Find-It in India under the name, geneCORE Hotspot. In a statement, Dr. Zoya Brar, CORE’s founder, said the test is a major diagnostic advancement that would allow doctors to treat each patient in a unique way by identifying mutations driving his or her disease. “This test has the potential to revolutionize cancer care,” she added. Mr. Matthews says the company also is in talks to expand its distribution of Find-It with a lab group in South America. “In our diagnostics business, we receive a royalty from our partner labs’ revenue, which varies depending on reimbursement country-by-country,” Mr. Matthews says. “We see an even greater revenue opportunity from offering our data collection services.” The company also hopes to receive patient referral fees from pharma companies and contract research organizations related to clinical trials. And companies such as Pfizer, AstraZeneca and Sanofi have used Contextual’s products for cancer specific development programs. “We have ongoing discussions for new opportunities in pharma partnering,” he adds. In 2018, Contextual plans to launch Follow-It, a blood-based “liquid biopsy” test to monitor the evolution of a patient’s cancer and how best to manage those patients with changing therapies. The test is performed two-to-four times a year. Mr. Matthews says the current market size of the company’s existing sales pipeline with Find-It is about 15.6 million patients in North America, Europe, China, India and Australia. “With Follow-It, the revenue opportunity is significantly larger.” Market size of existing sales pipeline via Features | BioTuesdays by Kilmer Lucas Investor Relations http://ift.tt/2wLC1Ks Kathy Harrison, CEO Forty-five per cent of patients in Dimerix’s (ASX:DXB) successful Phase 2a trial in chronic kidney disease (CKD), on advice from their physician, applied for and were granted access to remain on DMX-200 under Australia’s Special Access Scheme, which allows participants continued access to a therapy after they complete a clinical study. “This demonstrates physicians’ confidence that DMX-200 was having a positive effect on their patients,” Kathy Harrison, CEO, says in an interview with BioTuesdays. Ms. Harrison explains that physicians’ recommendations were based on patients classified as responders in the trial; achieving a reduction of proteinuria, or protein leaking into the urine because of damage to the kidneys; or a 50% or greater increase in proteinuria four weeks after dosing ceased, suggesting that DMX-200 may have had a potential benefit in slowing disease progression. Dimerix, which was spun out of the University of Western Australia in 2004, is currently reformulating DMX-200 for twice daily dosing from three times a day in preparation for a Phase 2b study to begin in Australia before the end of 2017, with data expected in early 2019. “We met with the FDA last year and their indication to us was that the Phase 2b trial could be supportive of a registration for focal segmental glomerulosclerosis (FSGS), following a single pivotal Phase 3 trial, which will likely be conducted in North America and Europe,” Ms. Harrison says. “The FDA also suggested that we explore efficacy in a refined patient population in the Phase 2b trial, including a group of patients with FSGS for which we have orphan drug designation and is our target for registration,” she adds. “However, we believe DMX-200’s mechanism of action could also be suitable for a wider range of kidney diseases.” FSGS is a rare disease that attacks the kidney’s filtering units, or glomeruli, causing serious scarring, which leads to permanent kidney damage and even failure. Much as a coffee filter keeps coffee grounds in, glomeruli filter blood, taking out the water-like part, which becomes urine, and leaving the protein in the blood. When glomeruli become damaged, proteins begin leaking into the urine, resulting in proteinuria. According to Ms. Harrison, first line therapy is drugs to reduce blood pressure, which can reduce proteinuria but does not stop progression to kidney failure. “There is a huge unmet medical need for a safe treatment, which can significantly reduce proteinuria and prolong the life of the kidney.” CKD is a growing global health problem, driven by factors like increasing incidence of obesity and diabetes. In the U.S. alone, it affects some 26 million people a year. Medicare spending on end-stage renal disease was nearly $33-billion in 2014. “If we can further demonstrate in our studies that DMX-200 reduces proteinuria levels and prevents progression to the need for blood dialysis, we will have a very viable therapy and a huge leap forward in treatment options for patients over the current highest standard of care,” Ms. Harrison contends. She points to estimates from independent analysts that the market potential of a FSGS drug to be $1-billion a year in the U.S. alone. “We have ongoing partnering discussions with Big Pharma and key opinion leaders as they recognize there is limited competition in FSGS.” Ms. Harrison explains that the combination of these drugs was identified using Dimerix’s Receptor-HIT discovery platform, which facilitates identification of pairs of different receptors, known as heteromers, that interact when small molecule drugs, peptides or antibodies, bind to them DMX-200 is an adjunct therapy, consisting of propagermanium, which is given to patients already on the standard-of-care blood pressure drug, irbesartan. Propagermanium targets inflammation in the kidney. Both drugs have been in use for many years and their safety profile is well understood. Ms. Harrison explains that the combination of these drugs was identified using Dimerix’s Receptor-HIT discovery platform, which facilitates identification of pairs of different receptors, known as heteromers, that interact when small molecule drugs, peptides or antibodies, bind to them. That compares with traditional drug analysis, which is largely based on single target receptors. “The technology is particularly well-suited to G-protein coupled receptors (GPCRs), a large and important family of drug targets that play a central role in many biological processes and are linked to a wide variety of diseases,” she points out. “We believe Receptor-HIT can identify new uses for existing drugs and drive the discovery of new drugs and research programs.” Ms. Harrison says DMX-200 originated from the discovery by Dimerix’s scientists that a GPCR called, AT1R, which is targeted by irbesartan, forms a GPCR heteromer with CCR2, which is the target of propagermanium, and that this GPCR heteromer is highly relevant in kidney disease. Dimerix’s Phase 2a study met its primary endpoint of safety and tolerability. In addition, six of the 24 patients who completed the study achieved a greater than 50% reduction in proteinuria during at least one dose level of propagermanium. “This is a 50% improvement over and above the patients’ stable improvement on standard-of-care medication, irbesartan, which classified them as responders,” Ms. Harrison contends. “This result has been deemed clinically meaningful.” In major studies conducted by Sanofi and published in the New England Journal of Medicine and Nephrology Dialysis Transplantation, irbesartan reduced proteinuria by 24% to 38% in patients with diabetic nephropathy and proteinuria. Three further patients in Dimerix’s Phase 2a study experienced an increase in proteinuria of 50% or greater after dosing ceased, compared with their final measure on treatment. “This increase suggests that DMX-200 may have had a possible benefit in slowing disease progression in these patients,” Ms. Harrison suggests. DMX-200 Development & licensing timeline via Features | BioTuesdays by Kilmer Lucas Investor Relations http://ift.tt/2ullOht Har Grover, executive chairman Closely-held Scientus Pharma expects to launch its first cannabis soft gel capsules for the treatment of neuropathic pain at the end of the year, to be followed in early 2018 with a soft gel for epilepsy and post-traumatic stress disorder, and plans for a delayed-release capsule for pain later in 2018. “We are strictly focused on leading the medical cannabis sector towards pharmaceutical standards and target the existing pharmaceutical market more than the ACMPR market,” Har Grover, executive chairman, says in an interview with BioTuesdays, referring to the Access to Cannabis for Medical Purposes Regulations. “We have a pretty simple business model that involves acquiring high-grade dried cannabis from licensed growers, converting it into pharma-grade products and selling into existing distribution channels, which currently are the licensed producers,” he adds. The company also has applied to be a specialized licensed producer, not to grow cannabis plants on any large scale, Mr. Grover points out, but to gain access to end customers. Scientus’ near-term focus is on pain, specifically chemotherapy-induced neuropathic pain, and CNS disorders, such as epilepsy. According to Mr. Grover, cannabis products have the potential to displace 1% to 5% of current pharmaceutical prescriptions. “In our subset of CNS disorders, pain and seizures/epilepsy, we see an addressable market of $1-billion based on conservative market share numbers,” he adds. Mr. Grover explains that Scientus is unique from other specialized licensed dealers of cannabis because, with its two licenses, “we have all of the individual cannabinoids itemized and we are able to manipulate them to create products with different formulations.” While the therapeutic benefits are well established, cannabis has proven to be a challenging API to harness “Tetrahydrocannabinol (THC) is what gives you the high but when combined with cannabinoids (CBD), the pycho-active component of cannabis is dampened,” he points out. “Our initial clinical programs are intended to gather scientific data to support our marketing initiatives and provide physicians with dosing guidelines, but they are not necessarily required for product registration,” he adds. Scientus also is standardizing the active pharmaceutical ingredient (API) that it extracts from the cannabis plant. Mr. Grover says the company has profiled more than 50 phytochemicals, including more than 20 phytocannabinoids to standardize its proprietary extracted resin as an API-like material. “And from there, we can put the material into alternative dosing forms, either a solid, liquid or spray.” Scientus also has large-scale manufacturing in place, with a 45,000-square-foot sterile facility built to GMP standards, boasting three vaults that can store more than $150-million of narcotics inventory. Mr. Grover explains that unlike traditional supercritical fluid extraction to treat cannabis to obtain a pure extract, the company uses a continuous flow process with microwave energy to do its extraction in a single step. As a result, he says Scientus can achieve 70% to 90% savings in energy costs and 40% savings in labor costs. With its continuous flow process, he claims the company can run six manufacturing cycles per day, compared with two-to-three for traditional extraction. according to grover, Tetrahydrocannabinol (THC) is what gives you the high but when combined with cannabinoids (CBD), the pycho-active component of cannabis is dampened “Our continuous flow process results in an API that is 100% decarboxylated so that it is fully active and standardized, compared with supercritical fluid extraction, which results in a decarboxylated API of 60% to 95%.” “We believe that if we establish a precedent with our first oils and capsules, there is a good rationale for Health Canada, from a policy point of view, to expand the sale of more effective capsules and tablets, such as our delayed-release products,” he suggests. While many of the current oil-based capsules permitted for sale would disintegrate in the stomach, Mr. Grover explains that Scientus' delayed-release capsules are designed to provide more effective absorption and biodistribution. Beyond its delayed-release products next year, the company is developing a rapid dissolving sublingual tablet for patients with chronic pain that it hopes to launch in the first half of 2019 and a buccal spray device, which is not inhaled, for 2020. While Canada is at the forefront of regulating medical cannabis, Mr. Grover suggests that Australia and Germany will be on par with Canada in two-to-three years. “We are in the initial stages of replicating our Canadian business model in Australia and Germany,” he adds. In addition, he says “an investment may be worthwhile” in California and New York because of their favorable regulatory environment. Expansion there would require sourcing local cannabis, manufacturing and using local distribution channels. SCIENTUS VALUE PROPOSITION via BioTuesdays Features - BioTuesdays http://ift.tt/2ug0h4S |
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