Can ToleRx Escape the Autoimmunity-Drug-Development Deathtrap?

“Like does not like like that is obnoxious.” Poet Marianne Moore wasn’t thinking of autoimmune diseases when she penned this line but it memorably captures the strife behind them—when our immune cells see their cellular kin as obnoxious, all hell breaks loose. Still, our immune systems are teachable. Early in life they learn to tolerate our own cells, forgoing attacks on genetically like tissues. Obviously, the lesson is sometimes forgotten. But if Cambridge, MA-based ToleRx is right, intolerant immune systems can be re-educated, revolutionizing the treatment of autoimmune diseases such as juvenile diabetes, rheumatoid arthritis, and psoriasis.

The idea isn’t new. For decades, drug developers have sought medicines to “tolerize” the immune system to selected antigens, molecules that trigger immune attacks. In principle, such drugs would have aspirin-like versatility and minor side effects, potentially quelling allergies, preventing rejection of transplanted organs, and dampening autoimmune diseases. But most attempts to intervene in our inner civil wars have gone poorly. In fact, two former Boston-area high flyers, ImmuLogic Pharmaceutical and BioTransplant, crashed and burned struggling to induce immune tolerance—ImmuLogic, known for seeking to curb cat allergies, was liquidated in 1999, and BioTransplant, focused on blocking organ-transplant rejection, went belly up in 2003.

So why have HealthCare Ventures, Skyline Ventures, Sprout Group, and other venture capitalists quietly bet $125 million on closely held ToleRx since it was founded in late 2000?

Its founders’ track record is clearly a factor. A decade ago, ToleRx CEO and cofounder Douglas Ringler helped guide development of a cancer drug named Campath at Leukosite, a Cambridge firm where he served as vice president of preclinical development. Campath, a monoclonal antibody drug now owned by Genzyme, was approved in 2001 to treat chronic lymphocytic leukemia, a blood-cell cancer. Its promise figured prominently in Millennium Pharmaceuticals’ 1999 acquisition of LeukoSite for over $600 million in stock.

LeukoSite’s success also bolstered the reputation of ToleRx cofounder Herman Waldmann, an Oxford University professor who chairs ToleRx’s scientific advisory board and is known for pioneering work in immunology: Campath originated in his lab in the 1980s. When Millennium acquired LeukoSite, Ringler and Waldmann moved on to form ToleRx. Sprung from research in Waldmann’s lab, the company’s main goal is to develop monoclonal antibodies and other drugs to suppress autoimmune attacks by revving up T regulatory cells, or T-regs—key mediators of immune tolerance. Secondarily, it’s developing drugs that do just the opposite: one is designed to break immune tolerance to cancer cells, inducing the immune system to wipe them out.

For years, T-regs—a subset of T cells, known mainly for fighting viruses and other invaders—were the dark matter of the immune system. Scientists knew they existed because of their effects. For instance, they continually check the activity of “autoreactive” T cells, which are primed to attack our own tissues and tend to become increasingly abundant as we age, raising the risk of autoimmune diseases. But their identifying traits and mode of action remained murky, only snapping into focus over the past decade. Now T-regs, and how to manipulate them to alleviate disease, are one of immunology’s hottest topics. Excitement about the immune peacemakers has stemmed partly from studies showing that pumping up their activity can actually cure autoimmune-induced diabetes in mice. The cells engender long-lasting tolerance for insulin-producing cells in the pancreas, which is lost in type 1, or juvenile, diabetes—the loss of tolerance leads to immune destruction of pancreatic cells that regulate blood sugar.

ToleRx’s flagship drug, dubbed TRX4, was developed in Waldmann’s lab to promote inner peace via T-regs. A monoclonal antibody, it works by glomming onto a molecule sticking out of T cells called CD3, triggering complex changes that culminate with increased numbers and activity of the tolerizing subset of the cells. That both suppresses ongoing autoimmune attacks and shifts the global immune response toward tolerance, says Ringler, yielding benefits that can last many months, and perhaps indefinitely, after a single course of therapy. The general tolerance induced by TRX4 means that it may alleviate many autoimmune diseases besides diabetes. ToleRx has already begun testing it in psoriasis patients and plans soon to begin another trial in rheumatoid arthritis patients.

But ToleRx’s main push with TRX4 has been against type 1 diabetes—the company is racing MacroGenics, a Rockville, MD, biotech, to develop the first CD3-targeted tolerizer for the disease. Both companies have reported promising preliminary clinical data. In a European trial, a six-day course of ToleRx’s drug in recently diagnosed diabetics significantly reduced the need for insulin shots over the following 18 months in many but not all of them: the ones who benefited were at an early stage of the disease, before nearly all their insulin-producing cells were destroyed. Last month, MacroGenics launched a “pivotal” trial in newly diagnosed diabetics with its drug, teplizumab. ToleRx plans to begin a pivotal trial with TRX4 within a few months.

If all goes well, TRX4 may reach the market in a few years to treat newly identified type 1 diabetics—those no more than 12 weeks from diagnosis. But the drug will probably also be used “off-label” for less recently diagnosed patients, says CFO Thomas Shea. Each year about 35,000 Americans, mostly youngsters, are diagnosed with the disease.

For all its promise, ToleRx has faced some harrowing moments. Just 48 hours before the planned launch of an initial public offering in 2003, an “abnormal event” in an animal study with TRX4 prompted it to cancel the stock sale, says Ringler. He declines to detail what went wrong but says “we now feel it was immaterial.” (Perhaps the main risk of tolerizing drugs is the chance that they will make T cells tolerant of pathogens—in ToleRx’s preliminary trial with TRX4, the drug was linked to transient symptoms of infection by the Epstein-Barr virus, which causes mononucleosis. At this point, though, the infection risk posed by drugs like TRX4 appears small.) ToleRx tried another IPO the following year, but investors soured on biotech before it could be completed, so the company canceled it. Still, in early 2003 ToleRx boosted its momentum by forming a collaboration with Genentech to develop its first tolerizing drug, dubbed TRX1, which has shown promise against several autoimmune diseases.

Another attempt by ToleRx to go public probably isn’t far off, says Ringler, as well as a major deal with a large drug company—the mounting reams of compelling data on T-regs and tolerance-inducing medicines have largely melted Big Pharma skepticism about their therapeutic promise. In theory, drugs like TRX4 “would be the closest thing to a cure” for autoimmune diseases that medicine has offered, says Ringler. Whether that’s borne out in practice remains to be seen. But clearly the odds are increasing that like can be made to like like.

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