“Something unique from Novartis...”

The impetus for pro bono research at Novartis dates from the integration period following the 1996 merger that created the company in its present form. A key challenge facing management at the time was consolidation of the development pipeline: The new company had inherited more experimental drugs from the predecessor companies than it could afford to develop and expendable compounds had to be weeded out.

A promising medicine against malaria was a potential casualty because clinical trials hadn’t yet confirmed its safety and efficacy. “The pure commercial people wanted to kill the drug because there was no market,” recalls Dr. Herrling, who at the time headed research at the Pharmaceuticals Division. Novartis Chief Executive Officer Daniel Vasella intervened, however, and rescued the antimalarial treatment as a potential complement to an existing program to provide medicines against leprosy to poor patients at no cost.

“Our idea was to find diseases that were really neglected, where we could really make a difference,”
Dr. Herrling explains

That was only the beginning. “Dr. Vasella wanted to help improve access to treatment in developing countries – but not simply by paying for infrastructure or education like some companies in other industries. He wanted something unique from Novartis and drug discovery is obviously one thing nobody can do as well as a pharmaceutical company,” Dr. Herrling explains. “I suggested that Novartis could allocate some of our best drug discovery science, technology and talent to neglected diseases. Importantly, we didn’t want to duplicate efforts already being made in areas like HIV/AIDS. Our idea was to find diseases that were really neglected, where we could really make a difference.”

Discussions with physicians, public health officials and other experts underscored the need for scientific advances in both TB and dengue fever. The spread of drug-resistant strains of Mycobacterium tuberculosis and a rapidly escalating number of patients co-infected by HIV has added urgency to TB drug discovery and development efforts after decades of standstill. For dengue there had never been any drugs available and scant research was ongoing. Malaria was not initially targeted due to availability of Coartem, the Novartis medicine that had pioneered a new class of antimalarials known as artemisinin-based combination therapy.

Recruiting financial partners

The potential impact of unleashing industrial research prowess against neglected diseases has proven attractive to donors. Foremost among these is Singapore’s Economic Development Board (EDB), which supported the creation of NITD financially under an agreement that set a number of milestones for the institute during its initial five years of operations.

Singapore’s bold industrial policy to foster a national biomedical industry aims to complement electronics as the primary engine of economic growth. Philip Yeo, Chairman of Singapore’s Economic Development Board (EDB), outlined his vision in a speech in March 2001: “Singapore must be a player in this new era of molecular medicine,” he declared. “Our goal is to make Singapore a small but significant hub for the biomedical sciences in our part of the world.”

Along with aggressive investments in government-funded research institutes for molecular biology, genomics and bioinformatics, Mr. Yeo promoted close synergy between the public and private sectors. To that end, EDB set aside funds to invest in strategic projects or joint ventures that have economic spin-offs to Singapore.

Mr. Yeo conveyed that message personally during a visit to Novartis headquarters in Switzerland and found a receptive audience. “In addition to basic science infrastructure, Singapore had solid intellectual property protection that is a precondition for industrial research,” Dr. Herrling recalls. “Another thing that was very important was that Singapore is located right where the diseases are. That was crucial.”

Singapore offered to be a financial partner in the new Novartis tropical disease research institute but preferred a fully-fledged commercial research operation to the nonprofit approach. “But Philip Yeo is a man with vision – ultimately he left operational control in our hands,” Dr. Herrling recalls. NITD duly achieved its initial performance milestones and in 2007 EDB extended its financial participation for a further five-year period.

Other donor organizations have been instrumental as well. NITD was able to expand into malaria research under a five-year, USD 20 million collaboration funded by the EDB, the Wellcome Trust, a large British medical charity, and Medicines for Malaria Venture (MMV), a nonprofit foundation dedicated to the development of affordable antimalarial medicines. In all, NITD has garnered more than USD 30 million in external funding from major global donors, including the Bill and Melinda Gates Foundation.

Close collaboration

The Novartis Institute for Tropical Diseases (NITD) in Singapore

Many of NITD’s key scientific partnerships have been forged within Novartis, reflecting the intense focus on translating basic science into drug discovery. For example, close collaboration with other Novartis research units was instrumental in the discovery and early preclinical development of a promising compound against malaria.

When NITD launched its malaria program, the Natural Products unit of the Novartis Institutes for BioMedical Research (NIBR) agreed to screen its compound library for possible activity against Plasmodium falciparum, the parasite that cause the most severe form of the deadly disease. The assay used in the screening program was developed by the Genomics Institute for the Novartis Research Foundation (GNF), based in La Jolla, California.

Learn more about the Novartis Institutes for BioMedical Research

Learn about the Genomics Institute for the Novartis Research Foundation

A natural product-like molecule from a chemical class known as the spiroindolones showed activity against P. falciparum and preliminary evidence suggested that this so-called “pathfinder” compound might work through a novel molecular mode of interaction. NITD initiated a lead optimization program in December 2007 with the goal to further improve antimalarial activity and pharmacological properties of the spiroindolone class.

Back in Basel, Switzerland, chemists from the Natural Products unit dug more deeply into the unusual chemical structure of the pathfinder molecule. “It’s a synthetically derived molecule, but one that started from two natural precursors,” says Frank Petersen, Head of NIBR’s Natural Products unit. “It looks like a natural product which is why it wound up in our library.”

Interestingly, the pathfinder actually comprised a mix of so-called isomers, molecules with an identical number and types of atoms but mirror-image structures that can affect their activity. When the isomers were separated by a NIBR team in Basel, one turned out to be inactive but the other isomer was highly active against malaria parasites.

Now scientists at both GNF and the Basel-based Swiss Tropical Institute are racing to determine the exact mechanism of action of a lead compound – known by the research number NITD609 and synthesized by NITD chemists. So far, there has been no evidence of cross-resistance with other existing antimalarial drugs – an indication that the target is potentially novel.

NITD609 has passed several key preclinical checkpoints and if ongoing toxicology studies are successful, the drug could begin full development before the end of 2010. That would represent a significant milestone for NITD but years of clinical testing would still be required before the compound could reach patients. Nevertheless, NITD609 was named Project of the Year 2009 by MMV, which manages a portfolio of projects and provides funding for partners from academia and industry.

“NITD609 is a great example of how Novartis makes available the best resources from across the organization to support our programs,” says Manos Perros, a virologist who joined Novartis as new Head of NITD in March 2010. “It underscores the unique contribution a major pharmaceutical company can make to neglected disease research. I don’t know of any academic institution that could match the know-how and experience that Novartis collectively brings to NITD’s malaria program.”

Vaccines for the developing world

The acquisition by Novartis of Chiron Corporation in April 2006 was the springboard to expand pro bono research to vaccines.
Rino Rappuoli, Chiron’s Chief Scientific Officer and Head of Vaccines Research, had dreamed of channeling the same sophisticated technology and passion devoted to commercial research to vaccines for the developing world. “Vaccines are powerful and I knew we could really make a difference,” Dr. Rappuoli enthuses. “But because of the way companies are organized, we always ended up developing commercially viable vaccines, which meant ones that were needed in Europe and the US.”

Agreeing to remain with Novartis and head research at the new Vaccines Division, Dr. Rappuoli won support for a proposed not-for-profit vaccine research initiative from both Dr. Vasella and Joerg Reinhardt, at that time Head of the Vaccines and Diagnostics Division. The proposed creation of a new institute was endorsed at a meeting of key stakeholders and approved by the Novartis Board.

In September 2007, Allan Saul was appointed Chief Executive Officer of NVGH. A native of Australia, Dr. Saul had spent more than 20 years in vaccine research, most recently with the US National Institutes of Health. His career also included extensive fieldwork in countries ranging from the Philippines and New Guinea to Mali and other parts of Africa, where he was exposed to many of the disease problems that occur in developing countries and gained understanding of working with vaccines in the field.

One of his first steps at the new institute was to compile a list of diseases of significance in the developing world – ranked according to total disease burden as well as whether a vaccine could significantly reduce that burden and be delivered within a few years. The highest priority projects target diarrheal diseases that take a significant toll among children across the developing world.
According to the WHO and the United Nations Children’s Fund (UNICEF), an estimated four billion cases of diarrhea occur worldwide every year, resulting in more than two million deaths, mostly among children under the age of five in developing countries. By contrast to major infectious diseases like HIV/AIDS or tuberculosis that are caused by a single organism, multiple pathogens are responsible for diarrheal diseases.

Diarrheal diseases cause the vast majority of clinically important disease in the world.

The first vaccine projects selected by NVGH aim to protect have been vaccines against infections caused by Salmonella bacteria, a major source of diarrheal disease. Salmonella Typhi, the bacterium that causes typhoid fever, has largely disappeared from developed Western countries but it is still a major public health problem in the developing world, resulting in more than 22 million infections, resulting and an estimated 200 000 deaths every year. There are two existing vaccines for S. Typhi but neither works in young children, who constitute a sizable proportion of the incidence of disease victims. Moreover, because S. Typhi can only infect humans, these young children also represent a major reservoir of infection.

In 2010 – only two years after its formal opening – NVGH initiated clinical testing of its first vaccine, known as Vi-CRM197, against S. Typhi. Such rapid progress builds on prototype vaccines developed by leading academic groups as well as technology provided by the Novartis Vaccines and Diagnostics Division. “This is the first of what we hope will be many examples of what can be achieved by matching the experience and expertise of industry with potentially good solutions to pressing public health problems developed by an academic group,” Dr. Saul says.

Protecting infants and children

During a distinguished career, John B. Robbins, M.D., Head of the Laboratory of Developmental and Molecular Immunity at the US National Institute of Child Health and Human Development, has concentrated on problems of immunity in infants and developed breakthrough vaccines for diseases of infants and children.

The accomplishments of Dr. Robbins and his colleagues include the pioneering discovery that Vi, a polysaccharide found on the capsule of S. Typhi, induces immunity when used as an antigen, or active ingredient in a vaccine. The identification of Vi (the acronym is short for “virulence factor”) led to development of vaccines: most recently, a prototype “conjugate” vaccine in which the Vi antigen is combined with a carrier protein to enhance immune response and broaden effective protection beyond adults and teenagers to include infants under 2years of age.

“We know from published data that the vaccine works in young children and gives long-term protection,” Dr. Saul says. “But despite the promising results from trials done over 10 years ago we still do not have a commercial vaccine that is available for use in the public sector.”

That is a common dilemma for academic researchers, who lack the validated expertise in development and production possessed by companies with longstanding industry experience. As a case in point, the prototype Vi conjugate vaccine developed by the Robbins group left room for improvement. “We took a hard look at each of the steps involved in the process and found that, from a commercial perspective, there were several steps where significant improvements could be made in the manufacturing process,” Dr. Saul said.

For example, the Robbins group used Vi polysaccharide from the so-called Ty2 strain of S. Typhi – a strain so virulent that it can only be worked with in BSL 3 laboratories, the next highest of four levels of bio-containment security. Moreover, like many S. Typhi strains, Ty2 is difficult to cultivate, growing best in an expensive broth of mashed yeast. Unfortunately, that growth medium further complicates purification of Vi in production, involving highly toxic chemicals.

Instead, NVGH developed a method to grow Vi in different bacterium, called Citrobacter, that is safer to handle, requiring the lowest level of bio-containment safety, BSL1. The Citrobacter strain selected by NVGH grows to high cell densities, enhancing productivity compared to use of Ty2.

“We’ve been able to adapt methods originally developed by Novartis Vaccines for purifying polysaccharides from other organisms that completely avoid the need for the nasty chemicals used with Ty2,” Dr. Saul explains. “Overall, our process is cheaper and simpler – and easier to manufacture satisfactorily in developing countries.”

The Novartis Vaccines and Diagnostics Division will support NVGH with supplies of a different carrier protein than the one originally used by the Robbins group. Known as CRM197, the carrier protein is a unique, chemically inactivated variant of the bacterium that causes diphtheria. Dr. Rappuoli did pioneering work on development of CRM197 in the early 1980s and over the next two decades the protein became a vital component in vaccines against the leading causes of bacterial meningitis. CRM197 is a key component of Menveo, the conjugate vaccine from Novartis against four of the five main causes of meningococcal disease.
Novartis is one of a handful of vaccine manufacturers currently able to produce CRM197. “Novartis Vaccines has agreed to provide supplies of CRM197 to meet the needs of vaccines we are developing at a price that would make the vaccines affordable,” Dr. Saul says. “That has opened up a much faster route to develop our Vi-CRM197 vaccine.”

Learn about the Novartis Vaccines and Diagnostics Division

While an improved vaccine against S. Typhi alone would be an important contribution to public health, the Vi-CRM197 vaccine also represents a key component in a vaccine targeting Salmonella serotype Paratyphi A, the bacterium that causes paratyphoid fever. Long considered a “poor cousin” to typhoid fever, paratyphoid fever has emerged as an important disease in its own right. More than five million people are infected every year and the proportion of paratyphoid fever is rising rapidly in proportion to typhoid fever.

“We believe that what is really needed is a vaccine that is going to cover both S. Typhi and Paratyphi A,” Dr. Saul continues. “There is no vaccine anywhere in the world for Paratyphi A. It is completely new territory.”

Robust vaccine formulations

Development of the Vi-CRM197 vaccine mirrors the rapid evolution of NVGH. During 2009, the institute raced to assemble its technical development group responsible for setting up a manufacturing process for its maiden vaccine. This was critical in bringing production of Vi-CRM197 in line with requirements of Good Manufacturing Practices (GMP), the industry standard.

Expertise in technical development is the linchpin of NVGH strategy. In a 2008 letter to the Journal of Infection in Developing Countries, Dr. Saul and Dr. Rappuoli observed that while years of patient research have identified likely candidates for vaccine development, the critical missing link is often the production of pilot scale lots of the candidate vaccine. “This requires production methods to be scaled up; robust formulations to be developed; the vaccines to be produced in GMP conditions and tested for stability; toxicology studies to be performed and regulatory documents to be submitted and finally the vaccine to be tested for safety,” they outlined. “The place where this scarce knowledge is present is in a few large vaccine manufacturers that have the experience to conduct this obscure but essential work.”

As clinical trials of Vi-CRM197 commenced during 2010, the clinical development group has undergone dynamic growth. Many of the medical centers selected to participate in clinical trials also have a high prevalence of paratyphoid fever, meaning that the second part of that bivalent vaccine will slot in more easily than if an entirely new study site had to be found.

The Wellcome Trust, one of the largest medical charities in the world, has awarded NVGH a grant of Euro 5.15 million to fund the bivalent (S. Typhi and Paratyphi A) vaccine project from preclinical development through Phase II studies. Dr. Saul has also forged scientific partnerships with the Wellcome Trust Sanger Institute, a genomic research center located near Cambridge, England, as well as the University of Birmingham (England) for the Paratyphi A project. Financial grants from both the government of Italy’s Regione Toscana and the Fondazione Monte dei Paschi have supported preclinical work on the Vi – CRM197 vaccine.

The “Century of Vaccines”

Strong links with industry and public health authorities offer NVGH valuable insights into the needs of its diverse stakeholders. “You can’t really expect the public health official to understand some of the complexities of vaccine development and production,” Dr. Saul acknowledges. “The experience of Novartis enables us to explain choices that are available – and to recommend which alternative we believe will work best. That’s part of the equation.”

The cost of vaccination, for example, comprises the cost of the vaccine itself but also the cost of delivery. With the Vi-CRM197 vaccine, the institute is trying to design a vaccine that is both affordable to produce and offers economies in delivery. “Part of our rationale in going for a vaccine for 6-week-olds is that it is the age when babies are visiting the clinic anyway to get their regular infant vaccines,” explains Dr. Saul. The alternative would be a school-based campaign, or a stand-alone program in which parents would have to bring children to a clinic for no other reason than vaccinations against S. Typhi. “Either would add considerably to cost,” Saul stresses.

Such a grounded, pragmatic approach is reinforced by the institute’s scientific advisors. Sir Gustav Nossal and Ciro de Quadros – members of the NVGH advisory board – are pivotal figures who have helped shape policy and broaden use of vaccines in recent decades, saving millions of lives in the process through senior roles at international organizations such as the former Children’s Vaccine Initiative, the Global Alliance for Vaccines and Immunization (GAVI) and the Pan American Health Organization (PAHO). Their experience and advocacy will help ensure that vaccines from NVGH actually reach the people who need them most.

Dr. de Quadros began his medical career doing fieldwork in a small clinic in the Amazon rainforest of his native Brazil. Later, he joined the WHO smallpox eradication program in Ethiopia and then returned to the Americas to lead the landmark Expanded Program on Immunization (EPI) for PAHO – as well as successful regional eradication of smallpox, and later polio and measles.

Writing in the American Journal of Public Health in 2004, he predicted that enormous progress in research and development “encourages us to believe that this century will be the Century of Vaccines.” And when Dr. de Quadros was invited by Novartis to an international conference in Siena, Italy, last summer to discuss plans for NVGH, he left convinced that the institute was a timely initiative that could make crucial contributions in improving access to vaccines in the developing world.

“There is a whole array of things that need to be tackled,” Dr. de Quadros says. “What’s the most cost-effective way to deliver a product? How much can NVGH contribute in terms of looking at the installed capacity for diagnostics, and for disease surveillance? This idea of training is also brilliant – to have younger people being trained at the lab bench as well as doing studies in the field and looking at community acceptance. It’s fundamental. And it’s very encouraging to see that NVGH is looking at these downstream aspects of vaccine research and development at such an early stage of operations,” he adds. “This is something that will give added visibility to the field of neglected diseases.”