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people with poor statin adherence. Together with Duke cardiologist Deepak Voora, Haga genotyped study participants for a particular variant in the SLCO1B1 gene that has been associated with a painful muscle disease known as statin-induced myopathy. This side effect is most pronounced in people taking simvastatin or atorvastatin, and it can usually be avoided by switching to alternatives such as pravastatin or rosuvastatin. In their pilot study, Haga, Voora and their team used the results of the pharmacogenetic test to advise participants whether swapping statins could help minimize their risk of myopathy. This intervention, they found, improved participants’ perceptions of statins and promoted higher drug adherence compared to controls. The Duke researchers presented their findings on 23 October at the American Society for Human Genetics Annual Meeting in Boston. In collaboration with medical staff from the US Air Force, they are now running a larger confirmatory trial involving 375 statin takers who live on the Travis Air Force Base in Northern California. Meanwhile, some pharmacogenetic studies are now starting to look at the issue of adherence outside the realm of statin usage. For example, Ohio-based Assurex Health, in collaboration with Medco/ Express Scripts, recently completed a one-year trial evaluating the potential of pharmacogenetic testing to change medication-taking behavior among people with mental illness—a group with some of the lowest rates of drug adherence. In that study, close to 2,200 people who

US Air Force

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A tour de force: This Air Force base clinic is using genetic testing to improve statin adherence.

had recently switched psychiatric drugs received a pharmacogenetic test called GeneSight, which evaluated five genes involved in the metabolism of and response to antidepressant and antipsychotic medications. Assurex’s senior vice president of medical affairs and clinical development, Bryan Dechairo, has done a first pass at crunching the numbers. He says that of 1,260 test recipients who changed their prescriptions again, presumably after the GeneSight test results suggested that an alternate medication might be more suitable, only 33% had stopped taking those drugs after six months, compared with 41% of matched controls who swapped drugs through an unguided process of trial and error. And of those who did drop their meds, this generally happened later among test recipients—after

58 days, on average, as opposed to 38 days for matched controls. Add on top of that the anticipated clinical benefits of the GeneSight test, and James Burns, chief executive of Assurex, sees these elements coming together to create a snowball effect toward better health outcomes and reduced healthcare costs. “If adherence does increase,” he says, “then all the other pieces should follow.” “This is one of those interesting parts of personalized information,” notes Dan Roden, a clinical pharmacologist and cardiologist at the Vanderbilt University School of Medicine in Nashville, Tennessee, who has pioneered the use of pharmacogenetics in routine care of cardiovascular disease. “It’s not just about genomics, that’s for sure.” Elie Dolgin

Small nanobody drugs win big backing from pharma After more than a decade of research into a new type of pared-down antibody, the Belgian pharmaceutical firm Ablynx has begun reaping rewards. On 23 September, the company inked a licensing agreement worth up to $840 million with Illinoisbased AbbVie to co-develop one of Ablynx’s so-called ‘nanobodies’, ALX-0061, which is currently in midstage clinical trials for the treatment of rheumatoid arthritis. And three days later, Ablynx entered into a four-year co-discovery and co-development pact with Germany’s Merck Serono—a deal that comes on top of similar ongoing partnerships Ablynx has with Merck, Novartis and Boehringer Ingelheim. The appeal of nanobodies stems from their

size, explains Ablynx chief executive Edwin Moses. Like standard antibody therapy, they can be engineered to specifically bind to target cells or proteins. But by shedding most of the common antibody structure, including both light chains and all but one section of a heavy chain, nanobodies—also known as single-domain antibodies—can reach more targets in the body and act with elevated potency, especially when further engineering tricks are applied. “The possibilities are endless,” Moses says. “Things that antibodies have difficulty binding to, nanobodies are able to.” The discovery—and naming—of nanobodies stems from the early 1990s. Researchers at Vrije Universiteit Brussel

NATURE MEDICINE VOLUME 19 | NUMBER 11 | NOVEMBER 2013

(VUB) in Belgium were studying the blood of camels, llamas and alpacas when they noticed that the immune systems of these species produced a unique type of antibody. Unlike most mammal antibodies, including human ones, the camelid antibodies consisted only of heavy chains, making them around a tenth of the size of usual antibodies—small enough that they were orally bioavailable, whereas conventional antibody drugs must be injected to enter the bloodstream. Ablynx, which is based in the city of Ghent, spun off from the university in 2001 to advance nanobody technologies for commercial therapeutic uses. According to Serge Muyldermans, the VUB bioengineer whose lab discovered 1355

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the camelid antibodies, the simpler structure “provides benefits not only for their applications but [also] when it comes to production.” In his lab, and at Ablynx, scientists start by exposing a handful of llamas to the compound against which an antibody is desired. Six weeks later, nanobodies are isolated from the animals’ blood and cloned into bacteria or yeast cells for production and screening. Since the nanobodies only have one variable domain, isolating the right products is easier than when multiple domains must be selected for. Moses points out another advantage. Whereas antibodies are relatively unstable and fall apart at high temperatures or in many formulations, nanobodies don’t have this limitation. “The fact that they’re very robust gives us more options for delivery techniques,” he says. Ablynx now has phase 1 trials ongoing of an aerosol version of a nanobody against respiratory syncytial virus, which causes a highly contagious and common illness among children. By using such a therapeutic mist, more of the antibody gets to the lungs than would be expected with an injection, notes Moses. Other researchers have developed skin cream and shampoo formulations of nanobodies. Work that nanobody With these production, performance and engineering advantages in mind, Ablynx has moved almost a dozen drugs through the preclinical and clinical stages of research for various indications, including cancer, Alzheimer’s disease and even snakebites (see ‘Nanobodies in motion’). The company has one drug—a nanobody called caplacizumab to treat a rare blood-coagulation disorder called thrombotic thrombocytopenia purpura—that, according to Moses, could hit the market as soon as 2017. In a baboon model of the disease, caplacizumab fully neutralized the protein that accumulates in the bloodstream to cause symptoms, without evidence of a severe bleeding risk (Blood 120, 3603–3610, 2012).

Design Pics Inc. / Alamy

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Over the hump: Nanobodies from camelids are now proving their clinical worth.

Meanwhile, the new license agreement with AbbVie will move forward a nanobody targeting the interleukin-6 receptor for treatment of both rheumatoid arthritis and systemic lupus erythematosus. In June, at the Annual European Congress of Rheumatology in Spain, Ablynx presented data from a 24-week study, reporting that the treatment led to remission of active rheumatoid arthritis in 18 of 31 patients tested. “The field has matured a lot,” says Michiel Harmsen of Wageningen University and Research Center in the Netherlands, who has studied nanobodies for veterinary applications and in animal models of disease. “There was this initial thought that nanobodies were these weird half antibodies that wouldn’t be as effective as conventional antibodies, and the opposite has turned out to be true in many cases.” At the same time as Ablynx’s nanobodies are showing their clinical potential, a handful of new pharma startups are hopping into the field. VHsquared, based in the UK, aims to develop single-domain antibodies

Nanobodies in motion: Ablynx’s drugs in clinical development. Drug

Lead indication(s)

Target

Phase

Caplacizumab

Thrombotic thrombocytopenic purpura

von Willebrand factor

2

Ozoralizumab

Rheumatoid arthritis

Tumor necrosis factor alpha

2

ALX-0061

Rheumatoid arthritis

Interleukin-6 receptor

2

ALX-0141

Osteoporosis; bone metastases

Receptor activator of nuclear factor-kappa B ligand

1

ALX-0171

Respiratory syncytial virus

Respiratory syncytial virus

1

ALX-0761

Inflammatory disease

Interleukin-6 receptor

1

Source: Ablynx

1356

for use in the gastrointestinal tract; Canada’s AbCelex Technologies is engineering small antibodies for diagnostic and environmental applications; and AgroSavfe, in Belgium, is applying nanobody technology to issues of food safety. Others are even harvesting similar single-domain antibodies from sharks, rather than relying on camelids as a source of the therapeutics. Meanwhile, Muyldermans, who has continued studying nanobodies even after passing the associated licenses for clinical development to Ablynx, is focusing on how to use nanobodies for more uses. “The nanobodies are small, but there are still questions about whether they can pass through the blood-brain barrier, so that is one issue we are looking at,” he says. Additional concerns revolve around whether the nanobodies produce unwanted immune activity, particularly when used long term. “Immunogenicity is still a big question, especially in applications where you to have to repeatedly dose the patient,” notes Harmsen. Of course, nanobodies must, on a caseto-case basis, still compete with traditional antibodies and small molecules, and the unique features of the smaller nanobodies don’t always add clinical efficacy. Two years ago, Ablynx ended a phase 2 study of caplacizumab for treating acute coronary syndrome, citing market reasons—in effect, the drug wasn’t any better than existing options. “It’s really just a matter of finding where nanobodies have the most advantage over classic technologies,” Moses says. Sarah CP Williams

VOLUME 19 | NUMBER 11 | NOVEMBER 2013 NATURE MEDICINE

Small nanobody drugs win big backing from pharma.

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