Innovation that Matters

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Novira’s Novel Approach to Anti-HBV Drug Discovery

For this month’s Innovation That Matters feature, we interviewed Dr. Osvaldo (Lalo) Flores, CSO of Novira Therapeutics, a leading biotech based in Philadelphia, PA, which is testing novel approaches to anti-hepatitis B (anti-HBV) drug discovery.  Hepatitis B infection presents a significant unmet medical need.  An estimated 350 million people worldwide are living with chronic HBV infection, and many face a higher risk of developing cirrhosis and liver cancer.  Current drugs approved for the treatment of HBV can effectively suppress virus replication, but rarely lead to a cure.  As an antiviral drug discovery company, Novira Therapeutics is focused on the discovery of first-in-class antiviral therapeutics for the treatment of chronic HBV and human immunodeficiency virus (HIV) infections.  The company recently began a Phase 1a clinical study of NVR-1221, a small-molecule, direct-acting antiviral for treatment of HBV infection. Novira’s NVR-1221 is one of a new class of agents that targets the viral core. Can you explain why NVR-1221 is a promising approach for treatment of HBV? How would it work as a monotherapy versus in combination with existing therapies? Flores: The problem with current HBV therapy is that it rarely leads to cures or durable response.  NVR-1221 belongs to a new class of antiviral drugs that target the viral capsid or core protein.  The HBV core protein forms the protein shell called capsid that protects the viral genome. Until recently it was believed that capsid assembly was the only role of HBV core in the virus life cycle.  However, it turns out that HBV core is also involved in several processes that allow the virus to persist during antiviral therapy, which include: 1) formation and maintenance of the viral mini-chromosome or cccDNA copy number in the nuclei of infected hepatocytes; 2) maintenance of the cccDNA in a transcriptionally active state; and 3) suppression of the host antiviral innate immune response. NVR-1221 was discovered and optimized based on the ability of the drug to bind to core and disrupt capsid assembly in vitro and HBV DNA synthesis in hepatoma cell lines.  However, binding of NVR-1221 to HBV core has the potential to inhibit all the other HBV core functions I mentioned, which is likely to translate in potent durable antiviral response in patients. While we believe that NVR-1221 will be highly efficacious as monotherapy, the experience with other viral diseases such as HIV and hepatitis C virus (HCV) has taught us that cross-class combination regimes have usually proven to be more effective than monotherapy.  For that reason, we plan to study NVR-1221 both alone and in combination with Interferon and a first line nucleoside in the Phase 1b trial that we are about to start. Since this is a new class of therapeutic, what were some of the challenges in finding the lead candidate and how did you overcome those challenges? Flores: An easy path would have been to identify and optimize proprietary leads using as starting point capsid inhibitor compounds already described in the literature.  This is a common approach used by pharma scientists but one that we decided not to pursue for many reasons.  Instead, our goal was to identify completely novel chemical classes of HBV core inhibitors and to do that we performed high-throughput drug screens that allowed us to identify multiple novel, attractive chemical classes of HBV core inhibitors. The challenge was then to find the right CRO partner to help us prosecute an efficient and rigorous lead optimization program that could transform screening hits into viable drug candidates.  We were fortunate to partner with WuXi AppTec, who has been an outstanding partner.  WuXi’s ability to provide integrated medicinal chemistry, pharmacology, DMPK, ADME and toxicology support was essential for the rapid progression of the lead program and to the selection of NVR-1221 as the clinical candidate. Why did you pursue the clinical trial application filing in New Zealand over other locations? Flores: Pharma and biotech companies are increasingly going to New Zealand for their first-in-man studies.  New Zealand has established an efficient, independent regulatory body along with sophisticated, top-tier clinical development capabilities. Were there any unique regulatory challenges you faced in bringing this new class of agent into clinic? Flores: We do not expect regulatory challenges.  The regulatory path for HBV drugs has been established by HBV drugs approved over the last decade, including 5 nucleos(t)ides (Nucs) and 2 interferons.   Development of combination regimens with NVR-1221 and other HBV agents is expected to follow the path established for HIV and HCV, which is also helpful. Looking at the broader antiviral R&D landscape, do you see resurgence coming? What would be the most promising areas for innovations? Flores: Yes, I think that the HCV field has created a lot of excitement that has had a positive impact on antiviral drug development in general and on HBV in particular.  It is also apparent that many players in industry and academia are beginning to shift their focus from HCV into HBV. I think HBV drug development will become a very exciting and active area of R&D, and that core inhibitors such as NVR-1221 will become the cornerstone of future curative regimens for HBV.   Related links: Visit WuXi’s International Discovery Service Unit

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Imbruvica and Its Impact on Patients

For this month’s Innovation That Matters, we interviewed Heow Tan, Chief of Quality and Technical Operations at Pharmacyclics.  Tan joined Pharmacyclics in 2012 and has headed their Global Quality, CMC Development, Global Manufacturing, Supply Chain, and International Operations. Pharmacyclics lead product, ibrutinib, with the trade name Imbruvica™, is one of the early molecules to receive US FDA Breakthrough Therapy Designation for oncology and the only drug to receive three Breakthrough Therapy Designations from the US FDA.  The cooperation for manufacturing activities between Pharmacyclics and WuXi-STA intensified about one year prior to the first approval of Imbruvica in November 2013 for its use in mantle cell lymphoma patients.  Imbruvica received a second approval for use in chronic lymphocytic leukemia patients in February 2014. Currently Imbruvica is clinically advanced in 35 countries and being tested in eight different types of B-cell malignancies. Can you begin by outlining the therapeutic need IMBRUVICA addresses for patients? Tan: Imbruvica is approved for patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) who have received at least one prior treatment.  Imbruvica is the first-in-class orally dosed inhibitor of Bruton’s tyrosine kinase (BTK)—a signaling protein that is critically important for the activity of B-cells (immune cells that produce antibodies to help fight infection).  By inhibiting the signal, Imbruvica has shown clinical benefits for patients with these diseases.   Most recently we stopped our latest study, Resonate, at the interim analysis because of the significant advantage in overall survival and progression-free survival that Imbruvica provided against the standard of care ofatumumab. How smooth was the transition from clinical development to commercial production? Tan: It has gone very well.  When Imbruvica was still in development, we sought out partners with expertise in both clinical and commercial supply, such as WuXi’s subsidiary Shanghai Syn-The-All.  We took this approach to be more efficient and to ensure we maintain a reliable supply of Imbruvica to patients. What is Pharmacyclics’ mission? Tan: Great question!  Our mission is to build a viable biopharmaceutical company that designs, develops and commercializes novel therapies intended to improve quality of life, increase duration of life, and resolve serious unmet medical healthcare needs. We exist to make a difference for the betterment of patients, and we believe these are important times to do just that. What is next for Pharmacyclics and Imbruvica? Tan: We’re continuing to develop Imbruvica for multiple indications.  Between our partner, Janssen Biotech Inc., and ourselves, we are conducting 44 clinical trials, of which 11 are Phase III registration studies. By the end of this year we are looking for a full Phase III label in CLL in the US and also for our first European approval.  In the meantime, we continue to work diligently work on our development program. There are a lot of trials that will read out in the coming months and years.   Each will provide valuable data about the benefits Imbruvica can provide to our patients. Right now we have approximately 500 employees at Pharmacyclics.  We all are working hard to advance Imbruvica so it can potentially help all patients with B-cell malignancies (blood cancer).  We truly appreciate the relationship we have developed with our partners at WuXi, and we thank for your support in helping us to provide valuable care to patients in need around the world.   Related links: WuXi to Partner with Pharmacyclics Visit STA’s website

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Fighting Counterfeit Medicines with TruTag Technologies

Did you know that 10% of all medicines are estimated to be counterfeit? Counterfeit medicines are found everywhere in the world, putting lives at risk and undermining the credibility of pharmaceutical products.  Online pharmacies are proliferating, and 50% of prescription medicines that are bought from Internet sites that conceal their physical address are counterfeit.  Pharmaceutical counterfeiting is an increasing problem for companies and society at large, with patient safety and intellectual property both threatened by the criminal activity.  To help our customers protect their IP and patients, WuXi has invested in and will explore collaborations with TruTag Technologies to offer its anti-counterfeiting technology to WuXi’s global pharmaceutical customers. This week we sat down with TruTag Chief Operating Officer Peter Wong to discuss the partnership. Tell us more about TruTag Technologies. We have developed a leading edge technology platform to address the enormous global challenge of counterfeiting, particularly high-value, high volume products that are life critical, such as prescription drugs.  Our specially coded microtags can be coated onto medicine and serve as “covert, edible bar codes” that can be incorporated into the very fabric of the drugs themselves and reveal if a pill is authentic, as well as other product intelligence.  Our technology solution to address this massive health problem has garnered us worldwide recognition, such as being named a 2014 Technology Pioneer company by The World Economic Forum, joining previous award winners like Google, 23&Me, Twitter and Kickstarter. How does TruTag’s Technology work? We’ve developed a line of inert, edible microtags that can be incorporated into drug dosage forms.  Each microtag is about the size of a particle dust, is virtually invisible to the human eye, and is made of high-purity silica (SiO2), which is a well-known excipient for food and drugs and has been affirmed as “generally recognized as safe” (GRAS) by the U.S. Food and Drug Administration. A single gram of “TruTags” contains approximately 12 million micro-particles, each encoded with a unique optical pattern that allows people along the pharmaceutical  supply chain to scan a pill with our special readers and confirm its authenticity.   In addition, it also reveals other vital information such as the product strength, manufacturing plant, expiration date, and where is it authorized to be sold. Why do companies need anti-counterfeiting technology? We view it as an important part of patient safety.  Patients need to the know the drugs they take are safe, effective, and from authentic and trusted resources.  Sadly, without anti-counterfeiting technology this  is difficult to ensure.  Fake drugs are estimated to have generated sales of $75 billion in 2010, and despite increasing public awareness, the problem appears to be only getting larger. Every questionable pill represents a threat to public health.  As a result, there is a real need for advanced technologies  to counter well organized criminal enterprises, which regularly defeat existing anti-counterfeiting measures that are packaging based.  “On-dose authentication” is the next level of security for pharmaceutical companies, and forward-thinking manufacturers and brand owners are increasingly seeking such protections. How do you plan to work with WuXi? We are honored to be partnering with WuXi, who is committed to enabling innovation for its global partners and is very focused on the integrity and security of its customers’ products and processes.  We are exploring collaborations in which TruTag will help WuXi to incorporate the microtags into manufacturing processes for its pharmaceutical customers. Ultimately we all want the same thing: to guarantee that all patients always receive the safe, effective medicines they need, while the intellectual property arising from the innovative R&D of pharmaceutical companies is protected.   Related links: WuXi PharmaTech Corporate Venture Fund Invests in TruTag Security Platform for Drug Safety

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Advancing Global Innovation to Benefit Patients in China and Around the World

WuXi recently announced the appointment of Dr. Hua Mu as Senior Vice President of Operations and Global Head of the Product Development Service and Partnership Business Unit.  This week we sat down with Hua to talk about his role at WuXi and a career that has included positions at Roche, Abraxis Bioscience, Biogen Idec, and Genentech. What is the proudest achievement of your career? Just before coming to WuXi, I spent four years at Hutchison MediPharma, and it was incredible.  We obtained China Food and Drug Administration (CFDA) approval for five INDs and one Phase II/III Clinical Trial Application (CTA), advanced six new drug programs into Phase I – Phase III clinical development, and established strategic partnerships with multinational companies for co-development of three new drugs.  All of this was achieved within the span of four years.  It convinced me that China-based organizations not only can participate in global innovation, but are also capable of undertaking efficient and high-quality clinical development – including early-stage development, to benefit patients in China and around the world. What can you tell us about the new business unit you’re heading at WuXi? Our mission is to help our clients and partners bring in and advance global and China innovations through the development process for regulatory approval, benefiting patients in China and beyond. This can be achieved through effective, integrated product development services and partnerships based on WuXi’s world-class scientific expertise, R&D platforms, and professional capabilities.  Over the past decade, external collaborations and partnerships in product development have become increasingly important for pharmaceutical and biotech companies to build up/expand pipelines, mitigate risks, and increase the productivity and efficiency of new drug development.  We are embracing this industry-wide trend and exploring various collaboration models and service approaches to address the broad needs of our clients and partners in developing innovative and effective medicines.  In particular, we are building an exceptionally capable and productive team that will support clinical development of high efficiency and quality to pursue Chinese regulatory approval. How do you expect to create value for your collaborators? Drug development is a very complex, highly regulated and lengthy process.  It requires companies to pursue well-planned global, regional and local product development strategies and execution. WuXi has an open access R&D platform that is positioned to meet the broad global product development needs of our collaborators and clients.  In addition, we have deep knowledge of the complex and fast evolving local regulatory environment, health care system, and clinical research landscape, as well as extensive experience in undertaking highly efficient product development in China. I believe such a unique and powerful combination can help our collaborators maximize the value of their innovations and ultimately deliver effective new medicines to benefit patients in China and around the globe. What is the secret to a successful collaboration? It requires continuous efforts to pursue a thorough understanding of each other’s needs, set goals of mutual interest and agreement, employ effective communication and working processes, build confidence and trust, and -most important – provide solutions and deliver on the promises.

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An Interview with Dr. Mao Mao

We are delighted to announce that Dr. Mao Mao has joined WuXi AppTec as Senior Vice President of Translational Bioscience and Diagnostics. Prior to WuXi, he was a Research Fellow leading biomarker and molecular diagnostics efforts at Pfizer Oncology Research. He is also President of Asian Cancer Research Group (ACRG), an independent not-for-profit organization jointly established by Eli Lilly, Merck and Pfizer. This week we sat down with Dr. Mao to discuss his career and thoughts on the industry. What inspired you to study medicine and genetics? It’s cliched but I was trained as a physician so I could help people. And as I advanced through my training I realized genetics and oncology research, particularly into the cancer genome, was a way to help millions of people. Once I saw the potential of genomics, I knew I had to be involved. What are some of the proudest moments of your career so far? Early in my career I was fortunate to be part of the Rosetta Inpharmatics team that worked on a 70-gene breast cancer prognosis test. It became the first test of its kind to win US FDA approval.  Now I have a couple of cutting-edge and validated molecular diagnostic assays that I will develop at WuXi for China FDA approval. What attracted you to work at WuXi? Wherever I’ve worked it’s always been about the science. At WuXi I see the same commitment to cutting-edge science and technology that attracted me to Merck and Pfizer. Ultimately it goes back to where I think my work will make the biggest difference, and WuXi is at the top of that list. How do you see WuXi’s open platform reshaping R&D? It’s incredibly exciting.  In the past, cutting-edge drug discovery and development technologies were out of the reach of many startups. Now anyone can access the capabilities they need to discover drugs efficiently.  I think it’s democratizing drug discovery. What role will genomics data come to play in the development of new cancer treatments? In the near term its biggest effect will be in identifying actionable mutations. Once we understand which genetic changes are driving progression of cancer, we can make better use of existing drugs and begin to develop more targeted therapeutics. It’s about honing in on the causes of tumorigenesis. From a physician’s perspective, it’s about to truly apply personalized treatment based on each individual patient’s mutation profile.

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