News: Fall 2015

Love of Teaching Yields Potent New Drug Candidate, Major Acquisition

Partners HealthCare spin-off, Adheron, is acquired by Roche for $580 million.

When pharmaceutical giant Roche announced plans to acquire Partners spinoff Adheron Therapeutics in September, immunologist Michael Brenner, MD, couldn't help but recall the unlikely events that inspired the spinoff. The original spark that ignited Adheron's promising therapy for inflammatory and autoimmune diseases, and fibrosis wasn't lit in a lab or a clinic. Rather, patients who ultimately benefit from the therapy can thank Brenner's love of teaching and his willingness to lecture on a topic he knew relatively little about. “I agreed to teach a class for Harvard medical students on rheumatoid arthritis. And because I didn't know that much about the underlying pathology in rheumatoid arthritis, I started reading chapters in books, and articles, and reviews so that I could help the students understand the pathology, the immunology, the pathways and how the drugs work,” recalls Brenner, the Theodore B. Bayles Professor of Medicine and Chief of the Division of Rheumatology, Immunology and Allergy at Brigham and Women's Hospital (BWH). Brenner's research at the time focused on immunology, but a very different topic – how antigens are presented to T cells. When he started to read about the pathology of rheumatoid arthritis, however, he suddenly realized that one of the most fundamental aspects of the disease was completely unknown. “The thing about rheumatoid arthritis is, it's an inflammatory arthritis,” and the entire inflammatory process is focused on a little membrane in the joints called the synovium” said Brenner. That membrane has a lining layer. But most membranes with lining layers are either epithelia or endothelia: your skin is an epithelium; your blood vessel linings are endothelium, and so on. This was neither.” Brenner began to wonder about the synovium – the site where inflammation unfolds in patients with rheumatoid arthritis. Realizing that the fundamental nature of the synovium's tissue type was unknown, Brenner began searching for a family of molecules that might underlie the development and the architecture of the tissue. That search led him to a class of molecules called cadherins. Back in the lab, Brenner set out to clone whatever cadherin might exist in the synovium. His lab designed a screen and searched for a cadherin that could mediate the tissue's architecture; they emerged with a molecule called cadherin-11. Brenner's lab found that this molecule was expressed by fibroblasts that formed the structure of the synovial membrane. Fibroblasts are the cells that lay down the connective tissue (made of collagen) that provides much of the structure between cells of the body. These cells regulate the processes by which the connective tissue is laid down and then digested away, ensuring a proper balance. In a 2007 report in Science, Brenner and colleagues showed that cadherin-11 steers the development of the entire synovial tissue by providing adhesion between the fibroblasts, allowing them to form the synovial membrane – and that mice lacking cadherin-11 were unable to develop rheumatoid arthritis. In rheumatoid arthritis, he found, these fibroblasts are overactive and digest too much connective tissue, thereby degrading the cartilage in the joint. That's when Brenner started to think about the discovery's commercial potential. He disclosed the invention to the group now known as Partners Innovation. In the years since, Brenner's team has shown that cadherin-11 regulates connective tissue remodeling in many organs. The implications of such a ubiquitous role are enormous: Targeting cadherin-11 could have implications for diverse diseases including fibrosis in tissues from lung to kidney and to inflammatory bowel diseases like Crohn's disease. Indeed, reports in 2012 and 2014 in animals, Brenner and colleagues found that blocking fibroblasts via cadherin-11 could prevent them from causing fibrosis in the lung and skin. “In these very different diseases, which seem to have nothing in common, it is the fact that the tissue injury is caused by fibroblasts that ties them together. And it is that fibroblasts express the same target – cadherin-11 – that is the common thread. Blocking cadherin-11 resets the overactive state of the fibroblasts,” Brenner says. “And that's a biomedical opportunity, targeting excessive fibroblast behavior that causes pathology, for which there is currently no drug on the market.” In 2008, Adheron Theraputics was among the first spinoffs to receive an investment from the Partners Innovation Fund (PIF). From the start, it was clear to investors that Brenner and his team stood out from the crowd. “The first thing that you think about when you look at Adheron is the quality of the science and the people involved,” notes Roger Kitterman, an experienced venture capital investor and Managing Partner at the PIF. “It was clear that Michael Brenner, as a clinician and a scientist, was aware of some major unmet needs.” The company proceeded cautiously along the pharmaceutical development path, opting to forgo bricks and mortar in favor of a virtual existence. “The cost of doing this, in terms of actual money spent has been very minimal. This has been probably one of the most cost-effective ways of bringing a compound to this stage,” says Hari Kumar, CEO of Adheron . “This cost-conscious approach means that everything we've received has been used for advancement of the program. Sometimes when people raise $50 million or $100 million, there's a temptation to say well, let's build a building, lots of glass. Because we have the money; might as well use it. But even to this day, we don't have a bricks and mortar office. We don't have a glass-fronted place with a big plaque in front saying Adheron Therapeutics. The company remains virtual.” The extended timeline – nearly 10 years have elapsed since the original discovery – worked in the company's favor. “We obviously were able to conduct all the studies in a diligent fashion. We were able to file patents around these compounds, and we've gotten actual granted composition of matter patents for the asset. All of that comes with time,” Kumar says. In the case of Adheron, time has paid off. In September Roche announced it would acquire the company for $580 million. The transaction closed last week. The company's technology has enormous clinical potential. “If you think about rheumatoid arthritis, there are good drugs available but they don't work for a lot of people,” says Kitterman. “But it's a very debilitating disease, so what do you do for the rest of the people who aren't responding to the existing treatments? This is a very different mechanism from anything else on the market, and it has a lot of potential to help people who aren't helped by anything available today.” Progress over the next year will be critical to the technology's long-term success. Brenner and Kumar will work closely with the Roche team to infuse passion and diligence into the next big challenge: testing the compound in a human disease population. “Roche is a great partner to bring this discovery all the way through clinical trials and to market because it's an area that they already have a lot of understanding in,” Kitterman says. For Brenner and Kumar, the Roche handoff is a time of keen anticipation. “Beyond all of the hypothesizing, at the end of the day you have to actually do the experiment,” Kumar says. “You have to put the drug in a disease population and ask, ‘Well, does it work?” For all involved, the collaboration with Roche has brought a profound sense of satisfaction. For Michael Brenner, the enormous resources of Roche and its global reach means that his classroom-driven inspiration has the potential to improve the lives of millions of patients. Reflecting on it Brenner noted, “Only time will tell. But if targeting cadherin-11 works to stop fibroblasts from damaging tissues, this will be a far reaching advance we can all be proud of having brought forward.” For the Partners Innovation Fund, this is the third company to be acquired – one spun out from MGH and two from Brigham – with an aggregate value of more than $1 billion. It further validates the Partners investment model and carries a powerful message in the investment world and throughout the Partners community – a demonstrated ability to go from discovery to acquisition, no matter the length of the journey.