May Spotlight May 2017

Welcome New Editorial Advisor

David Rabuka is global head of research and development in chemical biology at Catalent Biologics, with overall responsibility of overseeing continued research and development of SMARTag technology. He also oversees strategy, resource allocation, and scientific oversight of preclinical and clinical studies. David joined Catalent Biologics following Catalent’s acquisition of Redwood Bioscience Inc., where he was founder, president, and chief scientific officer.

David’s scientific areas of expertise include chemical synthesis; drug delivery; translational research; chemistry, manufacturing, and control (CMC) activities; animal studies; and preclinical and clinical testing. He received a 2008 PhD in chemistry from the University of California at Berkeley in 2003, having served as a Chevron fellow in the laboratory of Professor Carolyn Bertozzi. There, his research included developing and applying Redwood’s platform technology to cell-surface modification. Before pursuing his PhD, David worked first at the Burnham Institute synthesizing complex glycans and later at Optimer Pharmaceuticals, which he joined as an early employee focused on development of glycan- and macrolide-based antibiotics.

David graduated in 1997 with an honors BS in chemistry and biochemistry from the University of Saskatchewan in Canada, where he received the Dean’s Science Award. He also holds a 1999 MS in chemistry from the University of Alberta. He is an author of more than 40 major journal articles as well as numerous book chapters and patents.

Personalized Medicines Top FDA Approvals

The Personalized Medicine Coalition (PMC) reports that in 2016, for the third year in a row, personalized medicines accounted for >20% of new molecular entities (NMEs) approved for market by the US Food and Drug Administration (FDA). PMC president Edward Abrahams says this trend reflects the drug industry’s commitment to personalized medicine despite the lack of a successful business model. Persistent barriers stand in the way of a model that delivers the right medicines to the right patients at the right time.

“Science shows that using diagnostic tests to determine which medical treatments work best for each patient produces better outcomes,” Abrahams explains. “It also helps some patients avoid ineffective and unnecessary therapy, thereby saving the healthcare system expense. The pharmaceutical industry is responding to this emerging understanding by developing personalized medicines, despite the fact that the regulatory pathway for molecular diagnostics remains unclear. And reimbursement policies are more often than not still based on statistical averages.”

Personalized Medicine at FDA: 2016 Progress Report highlights six personalized medicines approved in 2016 and suggests that nearly one in four drugs approved from 2014 to 2016 qualifies. That ratio is sharply increased from 2005, when personalized medicines accounted for just 5% of NME approvals. In a 2016 Journal of Precision Medicine article, Abrahams and Stephen Eck (PMC board chair, vice president of oncology medical sciences at Astellas Pharma Global Development) cite data from the Tufts Center for the Study of Drug Development showing that personalized medicines account for >40% of all drugs in development.

“The era of personalized medicine is upon us,” Abrahams says. “Now is the time to clear the path by putting in place regulatory and reimbursement policies that support its development and adoption.” For more information, visit www.personalizedmedicinecoalition.org.

Oncology Companion Diagnostics Market Will Approach US$414 million by 2023

According to research and consulting firm GlobalData, the companion diagnostic testing market for oncology in 10 major countries could rise from $260 million in 2016 to nearly $414 million by 2023, with a compound annual growth rate (CAGR) of 6.9%. GlobalData’s MediPoint: Companion Diagnostic Tests in Oncology — Global Analysis and Market Forecast report covers the United States, France, Germany, Italy, Spain, the United Kingdom, Japan, China, India, and Brazil. It states that the Asia–Pacific (APac) region should see the highest growth rate in this area, with China and Japan expected to see CAGRs of 9.4% and 7.9%, respectively.

Companion diagnostics detect the presence of a specific biomarker linked to a disease condition to help ascertain how a patient will respond to particular treatments. To lower expenditures, hospitals are moving to such evidence-based care and treatment programs — all part of personalized medicine.

GlobalData analyst Nadia McLurcan says, “It is widely recognized that not all drugs are effective for all individuals. The most ineffective drugs (such as those for cancer) also are the most expensive and have the most profound and debilitating side effects.” Companion diagnostics improve physicians’ ability to predict how patients will respond to treatment, allowing them to prescribe the best possible dose from the start. This could reduce overall costs by reserving expensive treatments for populations who will respond to them.

Reimbursement is a significant challenge. Adoption of new technologies depends on reimbursement policies of insurers and government health authorities. Approval of new tests does not necessarily lead to their immediate adoption. If a molecular test cannot be reimbursed, few patients will get it.

McLurcan notes that emergence of new companion diagnostic tests also depends on the success of the drugs related to them. Companion diagnostics are developed in parallel with drugs, which ties their fates to each other’s success. “Diagnostic test manufacturers can eliminate the risk associated with this process through multiple partnerships,” McLurcan says, “or by developing new tests to stratify patients for existing therapies.”

Melanoma Pipeline Is Robust

The melanoma pipeline has 579 programs in all stages of development, with 226 first-in-class programs in the pipeline acting on 138 distinct first-in-class molecular targets. According to business intelligence provider GBI Research, this accounts for 38% of all programs with a disclosed molecular target and reflects a high degree of innovation in melanoma therapeutic research.

GBI’s Frontier Pharma: Melanoma Therapeutics — Cytokine Multiple Targeted Small Molecules and MAbs Dominate Pipeline and First-in-Class Innovation report states that factors driving that innovation include a significant level of unmet need because of melanoma’s poor prognosis and high therapeutic resistance, as well as a paucity of effective approved options (especially among chemotherapeutics). Researchers are improving their understanding of the disease pathophysiology, thus facilitating development of novel treatments.

GBI associate analyst Callum Dew says, “Despite a high attrition rate in oncology indications, it is highly likely that numerous first-in-class products in the melanoma pipeline, many of which are supported by promising preclinical data, will reach the market over the coming decade.” They could transform the clinical and commercial landscape, with far-reaching strategic implications.

Targeted therapies such as Bristol-Myers Squibb’s Opdivo (nivolumab) and Merck’s Keytruda (pembrolizumab) have made a strong impact. But unmet needs remain for safer and more effective therapies and for patients with noncutaneous melanoma.

Dew suggests that the greatest promise in addressing those needs could be in combining novel therapies with those already marketed for improved patient survival rates. Such combinations might include an immunotherapeutic and a targeted drug or multiple targeted therapies. “As attention shifts toward combining drugs, companies with the most promising novel developmental programs may seek strategic consolidations with other companies that have current developmental or marketed products.”

C10 Antibodies Can Neutralize Zika

A team of researchers at Duke-NUS Medical School (Duke-NUS) collaborating with scientists from the University of North Carolina have discovered the mechanism that C10 uses to prevent Zika infection on the cellular level. It is a potent human antibody that reacts with the Dengue virus and also neutralizes Zika infections.

Viruses infecting a cell typically undergo docking and fusion — both common disruption targets for viral therapeutics. A virus particle finds a specific site to bind to on the cell surface, from which point an endosome will bring it into the cell. Viral coat proteins change structurally to fuse with the endosome’s membrane, and the virus genome is released inside the cell. Using cryoelectron microscopy, professor Lok Shee-Mei’s team could see C10 binding to the main protein that coats the Zika virus and locking it in place, thus preventing structural changes necessary for endosome fusion. That keeps viral DNA from entering cells.

“These studies provide further support for the idea that this antibody will protect against Zika infection, potentially leading to a new therapy to treat this dreaded disease,” says Ralph Baric (a department of epidemiology professor at UNC’s Gillings School of Global Public Health). Using C10 to disrupt fusion could be more effective in preventing Zika infection than using therapies that disrupt the docking process.

Lok hopes that these results will accelerate further development of C10 as a Zika therapy. “This should emphasize the need for further studies of the effect of C10 on Zika infection in animal models.” For more information, see the paper online at doi:10.1038/ncomms13679.

HIV Vaccine To Be Tested in South Africa

The US National Institutes of Health (NIH) is cofunding a human immunodeficiency virus (HIV) vaccine efficacy study of 5,400 South African adults. The study is enrolling uninfected, sexually active men and women 18–35 years old. Experts estimate that >1,000 people become infected with HIV in South Africa every day. This study is testing a new version of a vaccine candidate that provided some protection against the virus in Thailand.

“A safe and effective vaccine could be the final nail in the coffin for HIV,” said Anthony Fauci (director of the NIH’s National Institute of Allergy and Infectious Diseases, NIAID). “Even a moderately effective vaccine would significantly decrease the burden of HIV disease over time in populations with high rates of HIV infection.”

This vaccine candidate is based on a collaboration of the US Military HIV Research Program and the Thai Ministry of Health RV144 clinical trial, which produced landmark 2009 results. That was the first time an HIV vaccine prevented infection. The new regimen is adapted to the predominant HIV subtype in southern Africa and redesigned to improve protection.

Over 3.5 years after vaccination, the RV144 regimen proved to be 31.2 % effective at preventing infection. The new regimen is modified to improve the magnitude and duration of protective immune response. A previous clinical trial of 252 individuals found this new version to be safe and induce comparable immune responses to those reported in Thailand. As the regulatory sponsor, NIAID is overseeing operation of the Phase 2b–3 trial, conducted through the HIV Vaccine Trials Network (HVTN) at 15 sites across South Africa. Results should be available in 2020. Study volunteers will be randomly assigned to the investigational vaccine regimen or a placebo and receive five injections over one year.

All these studies are part of a research endeavor led by the Pox-Protein Public–Private Partnership (P5), a collaboration of organizations building on RV144’s success. P5’s goal is to produce a vaccine that would benefit southern Africa and eventually the world while advancing scientific understanding of preventing HIV infection.

“HIV has taken a devastating toll in South Africa, but now we begin a scientific exploration that could hold great promise for our country,” said protocol chair Glenda Gray. “If an HIV vaccine were found to work in South Africa, it could dramatically alter the course of the pandemic.” She is also president and chief executive officer of the South African Medical Research Council as well as a research professor of pediatrics at the University of the Witwatersrand in Johannesburg and a founding director of the Perinatal HIV Research Unit at Chris Hani Baragwanath Hospital in Soweto.

Niche Disease: Tauopathies

by Alison Center

According to the Institute for Neurodegenerative Diseases, tauopathies are diseases caused by misfolding of tau proteins in a patient’s brain. The resulting prions replicate spontaneously in the frontal lobe and form abnormal protein aggregations. Tau prions have been found in patients diagnosed with frontotemporal dementia (FTD); posttraumatic stress disorders (PTSD); dementia pugilistica; and chronic traumatic progressive supranuclear palsy (PSP) and chronic traumatic encephalopathy (CTE) in boxers, football and hockey players, and soldiers after traumatic brain injuries. The main problem in Alzheimer’s disease is formation of plaques by amyloid fibers; however, misfolded tau proteins also play a role, collecting in fibers that tangle up inside neurons.

Because so many different maladies fall into this category, the epidemiology of tauopathies is complex. For example, a 2013 study in JAMA Neurology (doi:10.1001/jamaneurol.2013.114) examined the incidence and distribution of specific types of Parkinsonism and related proteinopathies. Among 542 incident cases, 409 (75.5%) were classified as proteinopathies. The incidence rate of tauopathies was just 1.1% overall (20 cases), and the most common tauopathy was progressive supranuclear palsy (16 cases).

Early Therapeutic Research: At the Mayo Clinic, Dr. Leonard Petrucelli and colleagues are investigating cellular mechanisms of neurodegeneration diseases and looking for ways to prevent or reverse neurodegeneration (www.mayo.edu/research/labs/neurodegenerative-diseases/targeting-tau-treatment-tauopathies). They are working with heat-shock proteins, which regulate protein quality and can recognize and remove abnormally folded proteins from cells. Hsp90 forms multicomponent complexes with other chaperone proteins to regulate folding/degradation of proteins such as taus. Hsp90 can move between different multichaperone complexes, one of which directs the refolding of abnormal proteins whereas another removes abnormal proteins through degradation.

Drs. Erin Congon and Einar Sigurdsson are researching immunotherapies to treat tauopathies with antibodies (https://blogs.biomedcentral.com/on-biology/2016/09/02/new-insights-tau-immunotherapies-alzheimers-disease). Two key findings suggest that it is possible to use a therapeutic antibody against intracellular proteins: One study found that neurons can take up antibodies from the extracellular fluid; another showed that tau proteins are released from cells and taken up by neighboring cells, thus spreading through a brain (doi: 10.1186/s13024-016-0126-z). Antibodies that clear misfolded tau proteins could block their spread by binding to them outside the cells. Those working both inside and outside cells would be ideal therapeutics.

Treatments in Development: In a March press release, Akiko Fukui (GlobalData healthcare analyst), said that biomanufacturers are pursuing Alzheimer’s disease and tauopathies concomitantly. Because they share common disease pathways, progress and insight gained in researching one disease can be applied directly to the other. “A very common strategy in the tauopathies market is that companies are entering into licensing partnerships for codevelopment of products. Examples include Anavir and Otsuka’s AVP-796, Sellas Life Sciences Group and Catalent’s zolpidem, C2N Diagnostics and AbbVie’s ABBV-8E12, and Alectos Therapeutics and Merck’s MK-8719. This strategy enables companies to join efforts and resources, and share the costs and risks of R&D.”

Discovery of potential tauopathy treatments commonly is conducted by academic researchers (e.g., at the Mayo Clinic) and small specialist biotechnology companies, then transferred to larger and more established companies more experienced with the later stages of development. “For smaller companies,” Fukui says, “the main advantages of entering into licensing agreements with larger companies include access to resources for larger trials and teams with capabilities to market and bring products through the regulatory process.”

Organizations: Many organizations are involved in patient support and research on and for a cure for Alzheimer’s disease (www.alzheimers.net/alzheimers-dementia-research-centers-organizations). The CurePSP support group funds research for PSP (www.psp.org). Information on current clinical trials is posted online at www.clinicaltrials.gov. All studies with US government funding (and some supported by private industry) are listed there. For information about clinical trials in Europe, see www.clinicaltrialsregister.eu.