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Antibodies Designed to Combat Ebola May Provide Protection from the Rare but Deadly Infection

New insights about experimental monoclonal antibody cocktails that recognize Ebola virus may soon help provide an effective treatment option.  Ebola virus disease (EVD) is a highly lethal illness in humans that is sometimes associated with bleeding. It is caused by a family of viruses (Filoviridae, genus Ebolvirus) linked to hemorrhagic fever. No approved medications exist to prevent or treat EVD. Investigators from The Scripps Research Institute (TSRI) and Mapp Biopharmaceuticals are developing 3 different monoclonal antibody (mAb) cocktails (or mixtures) that bind to Ebola virus and limit its spread to healthy cells. In past outbreaks—affecting mainly small, isolated human populations in African countries—the mortality rates ranged from 30 to 90%1,2. Currently, the 2014 outbreak in Western Africa is the largest on record, with more than 15,000 confirmed infections and 5,400 deaths as of November 20143. The experimental Ebola antibody cocktails, MB-003 and ZMAb have shown success in treating non-human primates. A small supply of ZMapp—the most effective of the 3 experimental therapies — was exhausted after treating 6 medical and religious workers (some of whom died) that contracted EVD1, 4. New information about the rationale for how the cocktails work may aid in developing a much needed treatment option; however, well-designed clinical trials must ultimately determine ZMapp efficacy. Dr. Charles Murin of TSRI and co-authors reported their findings in the October 2014 issue of the Proceedings of the National Academy of Sciences. 1 The researchers used electron microscopy and other methods to compare structural features and Ebola-specific binding capabilities of the antibody cocktails MB-003, ZMAb, and ZMapp.1 The results showed the antibodies fall into 3 groups based on the vulnerable viral region they bind (specifically, the mucin-like domain, the glycan cap, or the core glycoprotein). Analyses also revealed that while each of the cocktails contain some unique components, redundancies exist, and in some cases, the cocktails contain antibodies that compete for overlapping regions of the virus. It is hopeful that the new study will help identify the components of the cocktails that most effectively target distinct regions of the virus and aid in developing enhanced drug formulations. Fortunately, ebolavirus mutations thus far detected in Guinea and Sierra Leone have not altered the sites of the Ebola virus that are recognized by the ZMapp antibodies1—indicating that new supplies of ZMapp “would likely have efficacy against viral strains circulating in the ongoing 2014 outbreak.” The authors note, “This work provides clear next steps to determine if ZMapp can be honed for even greater potency, efficacy, or production.” This work by Murrin and colleagues provides direction for strategically selecting next-generation antibody cocktails that may be effective against existing ebolaviruses and mutated viral variants.1   References:   1Murin, C.D., Fusco, M.L., Bornholdt, Z.A., et al. 2014. Structures of protective antibodies reveal sites of vulnerability on Ebola virus. Proceedings of the National Academy of Sciences doi:10.1073/pnas.1414164111. 2World Health Organization. Accessed November 20, 2014. 32014 Ebola Outbreak in West Africa. Accessed November 20, 2014. 4Judging An Ebola Drug In The Middle Of A Crisis. Accessed November 20, 2014. 5Detailed Picture Of ZMapp Shows Room For Improvement. Accessed November 20, 2014.    

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Existing Medications for Erectile Dysfunction May Alleviate Symptoms of Duchene Muscular Dystrophy

Duchene muscular dystrophy (DMD) is a rare genetic disorder and is caused by a defect in the dystophin gene.  Insufficient levels of dystophin inhibit the function of nitric oxide, a chemical required for proper blood flow into muscles during exercise. The condition affects 1 in 3,600 male children globally and rarely affects females.  The disease causes devastating symptoms, including, progressive inability to walk or raise arms, weakened heart muscles and respiratory system, cognitive impairment and shortened lifespan[1]. Presently, glucocorticoids may be used to treat some symptoms associated with DMD; however, greater than 25% of patients treated with these medications experience significant side effects. A new study recently published in the journal Neurology indicates that medications historically prescribed for treating erectile dysfunction may help people diagnosed with DMD. Ronald Victor, M.D. with Ceders-Siani Medical Center in Los Angeles, CA, and colleagues reported their findings in the June 10, 2014 issue of Neurology[2]. The team investigated the effectiveness of sildenafil (Viagra) and tadalafil (Cialis) for treating DMD in boys between 8 to 13 years who were taking corticosteroids. One trial compared blood flow in 10 boys with DMD to healthy boys of the same age. The results confirmed that taking corticosteroids did not restore normal blood flow in boys with DMD. In a follow up study, boys with DMD received one alternating daily dose of both sildenafil and tadalafil two weeks apart. Following a handgrip exercise and a resting period, blood flow measurements were assessed. The results indicated that after taking sildenafil and tadalafil, blood flow in boys with DMD was similar to blood flow in healthy boys, even after exercise. The researchers also reported that higher doses of the drugs produced greater benefits in boys with DMD. Although these results are encouraging, additional studies are required to confirm the safety and efficacy of sildenafil and tadalafil for treating boys with DMD. The authors note, “this proof-of-concept study does not address the crucial issue question of whether restoring normal blood flow regulation will preserve dystrophic skeletal muscle and slow disease progression.” The investigators add that promising preclinical studies and results recently reported in the journal Neurology support moving forward with a larger clinical trial designed to determine if daily tadalafil preserves muscle function in boys with DMD. [1] [2] Nelson, M., Rader, F., Tang, X., et al. Neurology. 2014;82:2085-2091.

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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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