For the Novartis Institutes for BioMedical Research, the translational research model established in 2005 may yield its first big success in ACZ885.

Back in 2005, executives at NIBR, which is headquartered in Cambridge, Mass., were pointing out the success of ACZ885 in a proof-of-concept trial for Muckle-Wells disease, an inherited inflammatory condition characterized by chronic recurrent urticaria, periodical arthritis, sensorineural deafness, general sign of inflammation, and migraine headaches. At the time, Muckle-Wells, which is a rare disease, was chosen for the proof-of-concept trial because the condition has a clear inflammatory signal, interleukin-1 beta, that is present in other inflammatory diseases and ACZ885 demonstrated a clear action against IL-1 beta in the lab.

The active chemical in ACZ885 is the monoclonal antibody canakinumab and was approved in the United States in June and the European Union in October for the treatment of cryopyrin-associated periodic syndromes, including familial cold auto-inflammatory syndrome and Muckle-Wells syndrome. Canakinumab is marketed as Ilaris for these indications.

According to Trevor Mundel, head of global development at Novartis Pharma AG, the findings reinforce the potential of ACZ885 in a number of inflammatory diseases where interleukin-1 beta plays a role. The drug is in Phase II clinical trials for systemic onset juvenile idiopathic arthritis, cardiopulmonary obstructive disease, and gout. In Phase II data released in October 2009, ACZ885 provided pain relief and reduced risk of flares by 94% versus an injectable corticosteroid in hard-to-treat patients unable to use common gout medicines such as colchicines or nonsteroidal anti-inflammatory drugs.

Dr. Mundel was head of exploratory clinical development at NIBR back in 2005 when the results of the proof-of-concept trials for ACZ885 were announced. At the time, he pointed out that the dramatic results seen in the first patient in the proof-of-concept trial were not indicative of every proof-of-concept trial, adding, “It does point you in the right direction, it points out that one of the key things is actually selecting the right group of patients to get the maximum effect."

With ACZ885 showing positive results in other therapeutic areas in 2009, Dr. Tim Wright, head of translational science at NIBR, says the proof-of-concept trials for canakinumab in Muckle-Wells disease set the stage in a lot of ways. “If I had to look backwards, if we didn’t have these strong indications of positivity, we would not have gone into advanced study” with canakinumab, he says, adding that it was these proof-of-concept studies that allowed researchers to link the interleukin-1 beta pathway imbalance with the disease.

Dr. Jeff Porter, head of developmental and molecular pathways at NIBR, says signaling pathway imbalances – disruptions in the complex dance of proteins responsible for cellular function and reproduction – are at the heart of disease. At NIBR, the goal of research is to intervene in pathway imbalances with efficacy and safety. For some diseases, he says, it’s necessary to hit the pathway imbalances “high and low”; with other diseases such as colon cancer, the aim is to “tune it down a little.” “Think dimmer switches rather than precisely turning a pathway on or off,” he says.

Dr. Porter says when researchers find a way into a signaling pathway, they can find a way to go after a disease and other signaling systems. One of the signaling pathways being researched now at NIBR is the Wnt pathway, a network of proteins that play big roles in embryogenesis and cancer. In October, data were published in the journal Nature announcing that a team at NIBR, led by Feng Cong, had found a new part of the Wnt pathway, tankyrases, that could lead to the development of a small-molecule inhibitor for cancer, particularly colon cancer. The team found a small-molecule inhibitor, XAV939, as part of their research. Until the team’s discovery, the lack of druggable targets for the Wnt pathway hampered the research for a Wnt-blocking therapy.

At NIBR, there are 10 different pathway research programs, and the researchers talk to each other. “This cross-talk between pathways builds insights that they could not have come up with alone,” Dr. Porter says.

Additionally, every project at NIBR is started with a patient population in mind. “It can really galvanize the team to know where we’re going,” Dr. Porter says. “That pathway/disease connection is just the starting point. We’re aiming for openness and thinking across lines, from pathway to cell, tissue, and organism.”

It’s this ability to have researchers in different disciplines communicating with each other that is so important at NIBR. Traditionally in the pharmaceutical industry, research teams discover promising compounds that are then transferred to the development teams. This transfer creates a chasm between research and development, in which the research team is unsure of whether the compounds given to the development team have any effect on humans. The drug’s effectiveness is known only after the development team extensively tests the compound. By that time, the research team has already moved on to another project. This is the process that Dr. Mark Fishman, the head of NIBR, felt had to change when he founded the organization in 2002.

According to Dr. Porter, the NIBR way translates to clinical trials and more compounds in development. “There’s still a great deal of work to be done, but we get the sense that people are increasingly excited about the way it’s playing out,” he says.

When asked about up-and-coming pipeline possibilities from NIBR’s research, Dr. Wright named AFQ056 and AIN457. AFQ056 is a metabotropic glutamate receptor 5 (mGluR5) antagonist that has the potential to become the first approved treatment for Parkinson's disease levodopa-induced dyskinesia, or PD-LID. No therapy has been approved for this disease, which is a complication after dopamine-replacement therapy in Parkinson's patients and characterized by a variety of hyperkinetic movements. AFQ056 has shown positive results in a proof-of-concept trial in PD-LID and is proceeding in development with planned submissions after 2011.

“PD-LID is not the biggest indication, but the proof-of-concept trials have built up confidence in other therapeutic areas such as Huntington’s disease and Fragile X,” Dr. Wright says. A Phase II proof-of-concept study is under way for symptomatic treatment of adults with Fragile X syndrome. As of November 2009, a Phase II, multiple oral dose titration proof-of-concept study is being prepared for AFQ056 in Huntington’s disease chorea.

AIN457 is a biologic antibody to interleukin-17. NIBR had started a proof-of-concept trial in rheumatoid arthritis in late 2006, a single escalating dose study. In the middle of this trial, Dr. Wright says, results started coming back that indicated that the drug might have an effect on a key pathway in inflammation of the skin. Two genome-wide studies showed polymorphisms in rheumatoid arthritis, psoriasis, and inflammatory bowel disease. The rheumatoid arthritis study was continued, but the decision was made to do also a proof-of-concept study in psoriasis. The Phase IIa proof-of-concept study in patients with stable plaque-type psoriasis was completed in November 2007. Researchers are now recruiting patients for a Phase II regimen-finding study in patients with moderate-to-severe chronic plaque-type psoriasis, and there is an ongoing Phase II efficacy study in chronic plaque-type psoriasis patients.

Studies are being conducted for AIN457 in other indications: a Phase III trial for patients with Behcet’s disease with posterior or panuveitis; a Phase II trial for noninfectious uveitis; three Phase II trials for Crohn’s disease; a Phase II trials for psoriatic arthritis; and a Phase I/II trials for moderate-to-severe ankylosing spondylitis.

Dr. Fishman says AIN457 could be a very important drug, one that could change the treatment in autoimmune diseases based on IL-17.

Dr. Wright says researchers will continue to narrow down the best patients for AIN457. “We’re anticipating that not everyone will respond to it,” he says. “We will look at the genetics and determine the responders versus non-responders, and continue looking for biomarkers.”

Dr. Fishman continues to look to the future of drug discovery at NIBR, specifically a program called “the lab of the future.” “The lab of the future is a metaphor, a sociological concept, how we think the type of environment can encourage great science,” he says.

Specifically, he wants to do away with the traditional lab bench. “Benches are designed for the way the work was done 50 years ago,” Dr.Fishman says. “The space isn’t used well; at the same time, it’s not enough space.”

NIBR will be building labs along this concept in new buildings in Basel and Shanghai. The new Basel building will be completed in 2010, and construction of the Shanghai labs will completed three years later. The labs at the Cambridge headquarters will be retrofitted later, using the lessons learned from the Basel and Shanghai projects, Dr. Fishman says.

The goal of the retrofitting and new space creation is to have teams of scientists in different disciplines all using the same lab for a project. The space must not only encourage these scientists to work together, but also allow each of them the opportunity for private contemplation and different ways of accessing computers and data libraries through the lab. Dr. Fishman says part of this solution is new click-and-play, modular furniture designed to get the equipment off the bench as well as giving scientists more than one place to enter data into the computer. In the new Basel buildings, the goal is to get everyone together into their own campus, and figure out how to put various teams together on one floor and make them work with colleagues around the world through innovative video conferencing technology.

Another innovation will be a “just-in-time” inventory system that will allow scientists to order lab supplies from a central location in the building and have them quickly delivered via an electronic dumbwaiter system. This allows lab space to be devoted to research, not storage. “It’s similar to the system used by many hospital emergency rooms,” Dr. Fishman says.

“The key is to make it nicer for researchers,” Dr. Fishman says. “If we do open up more space, that’s more pleasant. If we allow people to do science more ergonomically, if we empower the team to be more productive, it will quickly have an impact on their projects.”

The first teams going into the new labs in Basel are volunteers, Dr. Fishman says. “What we learn from the first groups will give us an opportunity to make changes, allow for adjustments,” he says.

Surprisingly, there hasn’t been much protest from senior scientists about giving up their own benches, Dr. Fishman says. “There’s a lot of enthusiasm, a few are cautious, but others are looking forward to it. Of course, there’s always a pretty small group who want to hang on to whatever they had.”