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Combatting the Hep B Virus: An Interview with George Hartman, Novira Therapeutics

Dr. George Hartman is the Vice-President of Chemistry and Preclinical Development and cofounder of Novira Therapeutics, a clinical stage, privately-held company that discovers and develops small molecule antiviral drugs for the treatment of chronic hepatitis B (CHB) infection.  Novira’s lead core inhibitor candidate, NVR 3-778, disrupts the HBV lifecycle by inducing the assembly of defective capsids and is a potent inhibitor of HBV replication both in cell culture models and a humanized liver mouse model of CHB. An excellent preclinical safety profile has been established for NVR 3-778 and a Phase 1 clinical trial is underway in New Zealand.  This novel mechanism of action promises to change the paradigm for CHB treatment.  Recently, Novira Therapeutics and Johnson & Johnson have signed a definitive agreement under which Johnson & Johnson will acquire 100% of the capital stock of Novira. Prior to his work at Novira, Dr. Hartman was Executive Director of Medicinal Chemistry at Merck where he was the lead inventor of the antiplatelet agent Aggrastat® (tirofiban hydrochloride) used in the treatment of ischemic coronary syndrome and was associated with several additional drug candidates that progressed into advanced clinical studies.   Dr. Hartman is author of over 200 publications in leading journals and over 140 US patents covering a range of therapeutic areas.  Innovation That Matters (ITM) had the honor of talking with Dr. Hartman on Novira, NVR 3-778, and Novira’s collaboration with WuXi. Novira Therapeutics offers an interesting approach to Hepatitis B therapies. Can you provide us with your perspectives on this indication? Hartman: Hepatitis B infection presents a significant unmet medical need with an estimated 350 million people worldwide living with chronic HBV infection. A significant number of patients with chronic infection incur a higher risk of developing cirrhosis and cancer. It is estimated that 60% of hepatocellular carcinoma (liver cancer) is a direct consequence of HBV infection. Current drugs approved for the management of CHB include PEG-Interferon and nucleot(s)ides which can effectively suppress virus replication, but rarely lead to a cure.  Novira’s novel antiviral drug candidates have the potential to address the limitations of current CHB therapies when used either as mono-therapy or in combination with existing standards of care. NVR 3-778 has made it to Phase 1A Clinical Trials – what distinguishes this therapy from others in the market? Hartman: NVR 3-778 is a small molecule, direct acting antiviral drug candidate that inhibits the HBV core or capsid protein and being investigated for oral administration in patients with Chronic Hepatitis B (CHB). HBV core protein is a novel and promising drug target with multiple activities that enable viral replication and persistence. NVR 3-778 inhibition of the HBV core protein function offers the potential for a more efficient suppression of virus production and replication which could lead to improved durable viral suppression and functional cure rates. Novira is a relatively young company and has already completed its first clinical trials. Can you elaborate on your discovery strategy?   Hartman: Novira is employing innovative chemistry and biology technologies to discover small molecule inhibitors of the HBV core or capsid protein as well as other drug candidates with novel modes of action.  Our employees are experienced preclinical and clinical researchers with broad understanding of the individual disciplines necessary to advance projects with high quality and efficiency.  Key to our advances has been the identification of and collaboration with CROs that provide high quality discovery services.  WuXi has been a very important partner as Novira progressed from the early discovery phase to a clinical-level development company by providing excellent chemistry, biology, ADME and CMC collaboration opportunities.  The competitive advantage provided by WuXi’s integrated access to services across disciplines was an important feature of achieving speed and results.  How would you characterize the Novira-WuXi collaboration? Hartman: Efficient drug discovery requires medicinal chemistry to be matched with excellent synthetic chemistry and it was therefore important that our interactions with WuXi chemistry turned out to be highly flexible and productive.  WuXi chemists have been very interactive and skillful as synthetic schemes are developed and targets are pursued.  Our discovery paradigm has also benefited from the opportunistic use of library synthesis matched with chiral separation and SFC purification methods in place at WuXi.  You have such diverse experiences from working at Merck for over 35 years on various disease areas to co-founding Novira, a smaller company focused on a specific disease area. What have you learned in the transition and what insights can you share from these experiences? Hartman:  The transition from big pharma to the biotech realm has provided very stimulating opportunities and changes.  However, the feature that remains the same is that it is always the quality of the individual scientist and the level of dedication that determines the level of success in the discovery process.  At Novira, we have been able to attract truly world-class colleagues in biology, chemistry and clinical research and that has meant the difference.  Also, we decided early on that innovation and efficient and focused use of resources would empower the company to exceed expectations.  The goal has always been to make quality drugs and to engage and work with whomever could assist in that goal.  We are at an inflection point both in our corporate and scientific endeavors and we are looking forward to that next stage. Thank you, Dr. Hartman, for taking the time to talk with us about the important work you and Novira have been doing over the years.  We wish you much success in this next stage for you and Novira.   Related Articles: Novira’s Novel Approach to Anti-HBV Drug Discovery Congratulations to Novira Therapeutics for its Acquisition Agreement with Johnson & Johnson  

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WuXi NextCODE in Bloomberg on Ending a 30-year Diagnostic Odyssey in Three Weeks

WuXi NextCODE is featured in a Bloomberg Businessweek article on a story of how big-data approach to genomics has helped a patient affected with rare disease end her thirty-year diagnostic odyssey in three weeks.  When Jackie Smith was 3-years-old, doctors had told her parents to take her home and to enjoy her while they could.  Smith, now 35, has lived in the shadow of the diagnosis of rare muscle disease her whole life, because her doctors were unable to diagnose what accounts for her weak limbs and turned-in ankles.  That changed this past February, when Claritas Genomics, which uses WuXi NextCODE’s genome analysis and interpretation system, gave her the answer in less than three weeks. Claritas has developed novel panel of genes that affect children’s nervous systems, which runs nearly instantly on NextCODE’s system, that enabled the identification of her condition as centronuclear myopathy. Although sequencing a person’s DNA is now simple and quickly falling in cost, the challenge today is making sense of that data in the context of all of the available databases, and using more sophisticated systems, like WuXi NextCODE’s, to systematically search for variants that may never have been seen before. “The analysis and interpretation have become the bottleneck in diagnosis now that sequencing is the easy part,” says Jeff Gulcher, CSO at WuXi NextCODE.  Claritas is working to fill in the gaps by isolating specific genes and comparing them against databases of hundreds of thousands of people’s DNA compiled by WuXi NextCODE. While there isn’t yet a cure for Smith’s illness, she is participating in research that may one day lead to treatments or more supportive care.  “Just being connected feels good. I felt alone for a long time,” she says.  For the patients, it is some relief to know the cause of their condition. Getting an accurate diagnosis quickly can be critical and life-changing for families with young children. WuXi NextCODE and Claritas Genomics are working together to mine the world’s DNA databases for the right diagnosis for patients. Read full article “Sifting DNA Databases for the Right Diagnosis” by Michelle Cortez on Bloomberg Business.   Related Links: WuXi NextCODE Featured in Nature as the Innovative Engine of Population-scale Precision Medicine at Genomics England and Beyond WuXi NextCODE Wins Genomics England Clinical Interpretation Tender in both Rare Disease and Cancer Big Data and Genomics Meet the Cloud: the First Unified Global Platform for Precision Medicine deCODE Studies Demonstrate the Power of Truly Big Genomics for Improving Medicine Worldwide WuXi Acquires NextCODE Health to Create Global Leader in Genomic Medicine

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WuXi NextCODE Featured in Nature as the Innovative Engine of Population-scale Precision Medicine at Genomics England and Beyond

WuXi NextCODE is featured in the August issue of Nature in an article on the United Kingdom’s venture in genomic medicine with the 100,000 Genomes Project.  Genomics England aims to sequence 100,000 human genomes by 2017 with the hope that the enrolled participants with rare disease and cancers will benefit from clinical insights into their conditions, and that their genomes will also contribute knowledge of value to the entire patient community.  Researchers will study how to use genomics in healthcare and how best to interpret the data to help patients. Screening the data from the genome is a challenge and this mountain of data needs to be sifted, analyzed and presented in a way that is easily interpreted by doctors and so helpfoul to patients.  Genomics England has chosen a few best-performing companies with innovative systems to help it tackle the thorny interpretation task and WuXi NextCODE is first among them.  Each company has its own, disparate expertise but WuXi NextCODE is, in the words of the Nature article,  “the only finalist with population-wide genomics know-how.” WuXi NextCODE is also the only company chosen – from among 28 of the world’s most ambitious genomics organizations – to provide genome interpretation in both rare disease and cancer. With genome sequencing becoming increasingly affordable and routine, the key challenge now is to make sense of the scale of the data being generated and to make it possible to query in an efficient manner.  Most platforms and companies are limited to analyzing pre-defined panels of genes and variants – those that have already been discovered and are known to play a role in disease.  By contrast, “WuXi NextCODE has created a way to provide information beyond a distilled list of possible variants.  It has built a way to handle large data sets, such that scientists can zoom in and out of a person’s entire genome, and the software continuously pulls out the most up-to-date information about a variant,” writes Nature’s technology editor, Vivien Marx. The key to this capability is WuXi NextCODE’s unique data model and infrastructure.  The “Genomically Ordered Relational Database” enables a physician to find people with cancer who have similar mutations and disease course and who were treated with comparable drugs in the past ten years.  Rather than compare the genomes in their entirety, WuXi NextCODE’s database architecture arranges variants according to genomic position, pulling in a slice of information at a time, making the process computationally efficient.  The platform has also been trained on large data sets, such as the genomic information of 300,000 Icelanders,” Marx notes. The 100,000 Genomes Project uses the generosity of patients and the outstanding skills and talent found in the medical and the life sciences’ sectors to help deliver the project.  Its industry partnership with the world’s leading genomics companies is a powerful boost for the whole field of genomics and WuXi NextCODE is honored to play a part in this. WuXi NextCODE will be demonstrating the power of its interpretation system next week – live and in real-time – at the UK National Health Service’s Health and Care Innovation Expo in Manchester, England, September 2 and 3.  If you are interested in learning more, please drop by the 100,000 Genomes Project pavilion, booth 114! Read the full article “The DNA of a nation” by Vivien Marx on Nature.   Related Links: WuXi NextCODE Wins Genomics England Clinical Interpretation Tender in both Rare Disease and Cancer Big Data and Genomics Meet the Cloud: the First Unified Global Platform for Precision Medicine deCODE Studies Demonstrate the Power of Truly Big Genomics for Improving Medicine Worldwide WuXi Acquires NextCODE Health to Create Global Leader in Genomic Medicine

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Partner in News: TruTag Uses ‘Edible Barcodes’ in Fight against Counterfeit Drug Trade

By Brian Mastroianni Published July 09, 2015 Who knew that the answer to fighting the trillion-dollar global counterfeit drug problem rested in a particle the size of a speck of dust? At least that’s what entrepreneur Dr. Hank Wuh is counting on with TruTag Technologies, one of the companies that falls under the larger umbrella of Skai Ventures, the tech-focused venture capital accelerator that he founded. The central idea behind the tech company are “TruTags” – invisible, edible barcodes that can be planted right onto medicine to verify that the pills and tablets you might consume are the real deal.  Back in 2014, the company was named a Technology Pioneer by the World Economic Forum. According to Wuh, a medical doctor, this kind of wider recognition is an indication that these bite-size barcodes could play a role in a tech revolution sweeping through medicine. “It’s (TruTag) is really a game-changer,” Wuh told “This has huge implications for healthcare. Think about healthcare economics, think about public health — it impacts all of those areas. We think of this technology as a tremendous way to sort of improve the system.” The company’s “tags,” which have a melting temperature of 1,600 degrees, contain “millions of combinations of spectral data,” Wuh said. Within each of the tiny particles is an elaborate nanopore structure – think of it as a series of microscopic holes within a thin membrane, small enough for a single molecule to pass through at a given time. The tags are manufactured “in a secret location in the middle of the Pacific,” Wuh said, half-jokingly, and added that “there’s a very heavy security feature to our business. Manufacturing these structures is part of an elaborate process that involves breaking down the nanopore structures into “uniform-sized particles” that are “completely fabricated and sterilized in one, continuous process.” Wuh asserted that it is best to liken these tiny structures as specific “fingerprints” or “signatures” of data. “There are hundreds of millions of signatures and each signature is tied to a database that provides you with a tremendous amount of information,” he said. Essentially, a drug that has one of these microscopic “signatures” could easily be identified as genuine and not a fake. Wuh said that once the idea for TruTag Technologies was conceived, it took about five years of development to perfect the technology. The tags are FDA-approved to be edible and ingestible. To illustrate how effective this kind of product could be, Wuh pointed to the over-the-counter and prescription drug and supplement market for senior citizens. While seniors make up just over 13 percent of the U.S. population, they consume 40 percent of all prescription drugs and 35 percent of all over-the-counter drugs. People between the ages of 65 and 69 take about 14 prescriptions per year, while individuals between 80 and 84 years-old take 18 prescriptions annually, according to statistics from the American Society of Consultant Pharmacists. “Say mom is in the hospital and the nurse comes in with a cup that has seven pills in it. They are out of the package in the cup and there all of these morning pills together,” Wuh said. “Imagine a hospital setting in the future where every one of these pills will be identified, where you could do a few-seconds scan that can tell you which pill is what, if they’re genuine or authentic, when they expired, what the drug interaction would be. With that information you are back in control – think how powerful that is.” For Wuh, who also has a Masters of Public Health degree from Harvard University, a big component of this company is to empower consumers to understand what they are putting into their bodies, and as a result, make better health decisions. “We want to be able to watch these billions of items that are present in daily life and identify what they are, who made them — whether they are genuine,” Wuh asserted. “The counterfeiting business is not a victimless crime. Not only are jobs lost, but people’s health is put at risk. Imagine someone being treated for diabetes. You want to make sure they have the right medication.” In an interconnected world where smartphones and Apple Watches are becoming ubiquitous, Wuh said that a consumer could think of these edible barcodes as an extension of the wearable craze. While the idea for his company sounds like it belongs in science fiction, Wuh said the idea of tiny microscopic particles containing data about a drug is no more far-fetched than someone 20 years ago saying that a person would have a “supercomputer the size of his palm.” But, with the interconnected age and concerns over personal data, are there any concerns from potential consumers over the idea of ingesting technology that contains so much information? Wuh suggested that those queasy about the idea of literally consuming this kind of data can rest assured. “There’s no privacy issues at all. We are not tracking anyone. We are only protecting people from products that they are consuming,” he said. “Identification is only at the product level, and once they ingest it — once it’s in your body – it’s not retrievable, not traceable. There is really an impenetrable firewall between your body and the information that you are getting from the product.” Wuh said that there has been avid interest in the technology, that the tags are “starting to get adopted” and that a lot of the company’s “customers are very security oriented.” Interest has spanned the globe, with companies approaching TruTag from the U.S., Europe, and Asia. Another sector that has expressed interest is law enforcement. Wuh said that the current process of determining whether or not a drug is a counterfeit is “really quite tedious.” For example, say law enforcement seizes what is perceived to be a counterfeit of a drug like Sovaldi, which is used to treat hepatitis. The law enforcement has to ship it by express mail to a lab that then has to process the drug and run a series of tests. A report is generated and the “final results could come back a week or 10 days later,” he explained. It’s an inefficient process that could be substantially improved upon, Wuh claimed. “I think ‘democratization’ is the perfect way to describe what we are trying to achieve,” Wuh said. “Knowledge is power and people want to know about the products they are consuming.”   Original News Source: Fox News: Related Articles: Fighting Counterfeit Medicines with TruTag Technologies WuXi PharmaTech Corporate Venture Fund Invests in TruTag Security Platform for Drug Safety  

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SAGE Therapeutics on Fast Track towards CNS Cures

This month’s Innovation that Matters (ITM) features Albert J. Robichaud, Ph.D., chief scientific officer of Cambridge, Mass.-based SAGE Therapeutics, which is developing next-generation medicines for the treatment of rare and life-threatening central nervous system (CNS) disorders.  CNS disorders represent 35 percent of the worldwide disease burden and one of the largest global health care markets, but many available drugs do not address areas of the most urgent need and are often accompanied by side effects.  SAGE Therapeutics’ initial focus is on acute and orphan CNS indications with strong preclinical to clinical translation and accelerated development timelines. SAGE Therapeutics’ rich chemistry platform fuels a highly differentiated neuroscience pipeline and has attracted considerable attention including a highly successful IPO, fast track designation of the company’s allosteric modulator of GABAA receptors – SAGE-547 – and positive results in a phase 1/2 and exploratory trial of SAGE-547 in super refractory status epilepticus and postpartum depression, respectively. ITM was able to catch up with the fast-paced CSO: SAGE Therapeutics has decided to focus on neuroscience, an area that was abandoned by many in recent years. What is differentiating about SAGE Therapeutics’ platform? Albert: SAGE Therapeutics’ has taken a unique approach to CNS disorders by targeting therapeutic indications which are genetically, molecularly or translationally focused on two key receptor families in the brain – GABA and NMDA. These are well-known systems with potent pharmacological mechanisms, which when imbalanced are implicated in a plethora of CNS disorders. Because these are mechanisms that we understand well, we are able to target new investigational therapeutics to those and bring them rapidly into human clinical testing.   Will the platform address the obstacles faced by prior unsuccessful CNS drug development? Albert: SAGE Therapeutics has set about doing CNS drug discovery and development somewhat differently from others’ past efforts. We have targeted programs that address well-known mechanisms in the brain and are tractable and translatable from a concise collection of preclinical data. Our initial focus is on acute disorders for which there are few to no targeted treatment options, are defined by molecular or genetic patient populations and possess an objective proof-of-concept pathway. This affords us the ability to rapidly obtain data, with hard and unambiguous endpoints, and clear, rapid and efficient regulatory pathways.   How was SAGE-547 discovered and why is it unique?  Albert: SAGE-547 is a novel and proprietary formulation of the natural endogenous neuroactive steroid allopregnanolone. Although allopregnanolone has been known for decades, this potent GABAA modulator suffers from druggability issues. At SAGE Therapeutics, our focus has been on optimizing the drug properties of not just allopregnanolone, but on fit-for-purpose, novel, synthetic neuroactive steroids. To that end, we have designed and advanced a large library of proprietary drug candidates that include SAGE-689 and SAGE-217. These two potent, selective second-generation GABAA modulators are optimized for oral and parenteral administration and expand the functionality of this class of molecules beyond allopregnanolone. What differentiates SAGE-547 and our proprietary family of neuroactive steroids from other potent GABAA modulators, for example benzodiazepines, is the ability to modulate not only the synaptic GABA receptors but also the extrasynaptic GABA receptors.  Defining the utility of this important characteristic of GABA modulation is something that underscores the potential value that the team at SAGE Therapeutics has brought to patients in several highly underserved indications,  such as refractory status epilepticus, a severe condition of chronic seizure, and several orphan genetic epilepsy conditions, such as Dravet and Rett syndrome.   The FDA designated status epilepticus as an orphan indication. The FDA also designated the SAGE-547 program for fast track development. What were the factors leading to that decision and what does it mean for SAGE Therapeutics’ development program? Albert: The receipt of orphan drug designation for status epilepticus and the fast track designation are both significant regulatory milestones for SAGE-547 and the potential patients who may benefit from it.  Orphan drug designation is intended to facilitate drug development for rare diseases, including diseases with small patient populations for which there are no approved therapies.  Status epilepticus is a life-threatening seizure condition that occurs in approximately 150,000 people in the U.S. each year, of which 30,000 will die.  Currently, there are very limited treatment options for these patients and no approved drugs. SAGE-547’s receipt of orphan drug designation in May 2014 has provided important benefits for the drug’s development, including market exclusivity for the product upon regulatory approval. Similarly, SAGE-547 was granted fast track designation by the FDA last July. Fast track designation is granted to expedite the review of drug candidates that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. This advancement has provided SAGE-547 a rapid path to market, fulfilling our mission to deliver treatment options to patients with SE as quickly as possible.   What are the clinical experiences to date with SAGE-547? Albert: We have been focused on advancing SAGE-547 as rapidly as possible to bring this NCE to patients in need.  We have reported positive results from our Phase 1/2 trial of SAGE-547 in refractory status epilepticus and plan to initiate the Phase 3 pivotal trial by-mid 2015.  In the Phase 1/2 trial, we observed an unprecedented 77 percent ORR, and SAGE-547 has been well tolerated with no drug-related SAEs.  Further, a number of patients who responded to SAGE-547 have since been able to go home and return to their daily activities. Based on the positive results, we are planning to initiate the Phase 3 STATUS Trial by mid-2015. In addition, we have been using SAGE-547 to establish proof of principle in exploratory Phase 2a clinical trials for additional CNS disorders, including postpartum depression and essential tremor.  In early June, we announced top-line data from the exploratory clinical trial in postpartum depression that indicated a statistically significant improvement from baseline in depression in four women with the disease within 24 hours after administration of intravenous SAGE-547.  The continued advancement of this important drug candidate serves as the basis of the rapidly evolving library of drug candidates SAGE Therapeutics is developing.   Can you share some insight on SAGE Therapeutics’ other portfolio programs and pipeline?  Albert: As mentioned at the outset, SAGE Therapeutics’ is focused on discovery and development of compounds focused on two receptor families – GABA and NMDA.  In addition to SAGE-547, our robust pipeline of proprietary second-generation product candidates in the GABA platform is led by SAGE-689 and SAGE-217. SAGE-689 is being developed as a potential follow-on IV product for second-line adjunct status epilepticus targeted for the ER, and SAGE-217 has been designed to be dosed orally, intramuscularly and intravenously, making it suitable as a potential oral, chronic therapy for a broad number of indications.  These products have the ability to provide greater efficacy, selectivity and utility, as well as fewer off-target effects.  Phase 1 trial initiations are anticipated for both SAGE-689 and SAGE-217 in late 2015. On the NMDA receptor front, we have an advanced discovery platform that has amassed a collection of selective NMDA allosteric modulators with excellent drug-like properties.  Our goal is to rapidly identify and advance clinical candidates with utility for therapeutic indications defined by glutamate deficiency.  Together with our understanding of the GABA pharmacology, the NMDA platform discoveries affords SAGE Therapeutics a leadership position in the CNS arena with the potential to advance NCEs for several key indications of unmet need.

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