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in their words“now, people treat us like we’re an overnight success. Twenty-five years of overnights is not quite an overnight success.” CEO and founder of Regeneron, Leonard Schleifer, explains how his company came to

make him a billionaire. (Forbes, 25 February 2014)

Mitochondrial medicineSpecialty firm Edison Pharmaceuticals of Mountain View, California, has entered a strategic alliance worth up to $4.3 billon with Dainippon Sumitomo Pharma (DSP) of Osaka, Japan, to develop drugs for inherited respiratory chain diseases of the mitochondria. Under terms of the deal, the companies will jointly expand Edison’s pipeline, bringing ten new compounds targeting redox pathways into clinical development over the next five years. Also in pursuit of mitochondria-related diseases is biotech firm Mitokyne of Boston, which in October 2013 struck a five-year agreement with Astellas Pharma of Tokyo, potentially worth $730 million, to discover and develop drugs that modulate mitochondrial function. After decades of disinterest from investors, the deals confirm that mitochondrial research is gaining more traction. Douglas Wallace, director of the Center for Mitochondrial and Epigenomic Medicine in Philadelphia, points to a wider acceptance that systemic, cellular-energy metabolism defects caused by mitochondrial mutations can result in organ-specific symptoms and multisystem disorders, such as diabetes and Alzheimer’s disease. Wallace, who showed that mitochondrial DNA is inherited exclusively from the mother, says: “I’m hoping we can [persuade other pharmaceutical companies] that mitochondrial bioenergetics is a good target.” Hopes of tackling mitochondrial disease were raised on both sides of the Atlantic in February, when the US Food and Drug Administration and the UK government discussed mitochondrial replacement. This in vitro fertilization technique involves placing nuclear DNA from a woman with defective mitochondria into a donated egg that has had its nuclear DNA removed and contains healthy mitochondria. In the UK, where there is broad support for such a therapy, the government’s Department of Health announced on February 27 that it was opening a three-month public comment period on draft legislation on the technique. At the US Food and Drug Administration, advisory panels discussed what controls might be used in clinical trials, but no decisions were made. Emma Dorey

Leptin therapy gains FDA approval

In February, the US Food and Drug Administration (FDA) approved AstraZeneca’s Myalept (metreleptin) to treat generalized lipodystrophy—a disor-der that affects under 200 people in the US. The approval marks a major milestone in a 20-year odyssey of a drug that almost never was. Myalept is a recombinant form of human leptin, a naturally occurring protein hormone secreted by fat cells. Leptin and its role in controlling satiety, first described in 1994 (Nature, 372 425–432, 1994), ignited a frenzied excitement over the prospect of using leptin replacement therapy to treat obesity. But attempts were abandoned in the late 1990s after studies with obese people failed to show any benefit. It is only thanks to investigator-funded clinical trials and a final push by current sponsor Bristol-Myers Squibb (BMS) of New York that recombinant leptin has wound its way through the FDA to become a lifesaving treatment for a largely neglected indication. “It has been a long and challenging path for metreleptin,” says Alex DePaoli, vice president of clinical research at NGM Biopharmaceuticals in San Francisco.

For all the promise once heaped on this hormone, the approval is for a dramatically circumscribed population. Generalized lipo-dystrophy is a rare disorder characterized by

absence of adipose tissue. With no adipose tis-sue to secrete the appetite-suppressant leptin, individuals with lipodystrophy eat vora-ciously. The consequences are catastrophic, says Stephen O’Rahilly, director of the University of Cambridge Metabolic Research Laboratories. Excess calories get stored as fat in liver and muscle cells leading to diabetes, high blood lipid levels and pancreatitis. “It’s a totally appalling double whammy of being constantly hungry but of food being your greatest enemy,” says O’Rahilly. The disease manifests either as generalized or partial lipodystrophy. Both forms can be inherited or induced by medications or result from autoimmune disease or unknown causes.

The generalized form of lipodystrophy is extremely rare. There are fewer than 200 people in the US and 1,000 at most with partial lipodystrophy of varying severity, says Abhimanyu Garg, chief of the divi-sion of nutrition and metabolic diseases at the University of Texas (UT), Southwestern Medical Center. Currently there is no treat-ment other than managing complications. Myalept treatment yields striking results in people with generalized lipodystrophy. It markedly reduces food intake, improves blood glucose and triglyceride levels, in some cases normalizing levels of both.

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Leptin, a hormone secreted by fat cells, is now in the clinic, but only a few will benefit from it.

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in their words“Ten years ago if you told anyone there were going to be trials of drugs to improve cognitive symptoms of Down’s syndrome, they would have laughed you out of town.” Roger Reeves, of Johns Hopkins University

in Baltimore, on Roche’s partnering with Balance Therapeutics of San Bruno, California, to test GABA-blocking drugs to improve memory. Similar drugs improved surrogates of memory in a Down’s syndrome mouse model. (Bloomberg Sustainability, 3 March 2014)

Epilepsy neurodevice approvedA new generation of surgically implanted neuromodulation devices is making regulatory headway with one recent approval from the US Food and Drug Administration (FDA) and a positive recommendation. In November, the FDA granted premarket approval to Mountain View, California–based NeuroPace’s responsive neurostimulation system (RNS), a pulse generator implanted in the brain that detects and disrupts epilepsy seizures by delivering normalizing electrical neurostimulation. The system is approved for individuals for whom two antiepileptic drugs fail to control seizures. More recently, in February, the FDA’s Anesthesiology and Respiratory Therapy Devices Panel recommended approval of the Inspire II Upper Airway Stimulator, developed by Inspire Medical Systems, of Maple Grove, Minnesota, to treat obstructive sleep apnea in individuals who have failed continuous positive-airway pressure treatment. The device implanted under the chest skin senses breathing patterns, delivering mild stimulation to the airway muscles and the hypoglossal nerve, which runs beneath the base of the tongue, to keep the airways open during sleep. These ‘closed-loop’ systems are a dramatic departure from previous neurostimulation devices as they rely on sensors to anticipate neurostimulation needs. Joseph S. Neimat, an associate professor of neurological surgery at Vanderbilt University in Nashville, Tennessee, says, “What we’ve done in the past is a one-way stimulation model…. You pretty much put the stimulator in, you turn it on, you let it fire X number of times in a particular pattern.” Instead, the closed-loop stimulators “listen,” he says. As knowledge of brain function continues to grow, “There are going to be more proposals in front of the FDA for devices like this,” Neimat predicts. Alli Proffitt

Such dramatic benefit compelled FDA to approve the drug, says Robert Smith, profes-sor of medicine at the Warren Alpert Medical School of Brown University in Providence, Rhode Island. In an open-label, single-arm study of 48 patients with congenital or acquired generalized lipodystrophy, Myalept decreased hemoglobin A1c levels, a measure of blood glucose, from an average of 8.7 to 6.7. “That’s a big effect,” says Smith, who chaired FDA’s Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC), which voted 11 to 1 in favor of approving the drug to treat generalized lipodystrophy. “A typical diabe-tes drug in a different setting might decrease HbA1c levels by half that much,” he says. Myalept also cut triglycerides by an average of 60%, a more powerful effect than with any other drug, he says.

The regulators also followed the commit-tee’s advice in rejecting Myalept for treating partial lipodystrophy. The EMDAC cited a lack of evidence proving the benefits out-weighed the risks in this indication. The two most troubling side effects are a potential ele-vated risk of lymphoma and the risk of devel-oping anti-leptin antibodies. During the trial, three patients developed T-cell lymphoma, although two might have had lymphoma before taking the drug. In theory, the drug could cause lymphoma, as leptin is thought to act on pathways that promote cell growth and inhibit apoptosis through activating the Janus kinase signal transducer and activator of transcription and other intracellular path-ways. But individuals with lipodystrophy may be predisposed to lymphoma anyway, so it was difficult to tease out the drug’s effects from the disease.

Equally troubling is the risk of inducing anti-leptin antibodies, says Smith. This is particularly the case in people who produce some leptin. “If anti-leptin antibodies develop in these patients, you run the risk of neutral-izing leptin they already have and inducing complete lipodystrophy.” Three patients out of about 500 in the earlier obesity trials expe-rienced health issues linked to anti-leptin antibodies, but it isn’t clear how harmful the antibodies are, says Smith. Nevertheless, because of the risks, Myalept will be available only through the Myalept Risk Evaluation and Mitigation Strategy (REMS) Program.

The path to approval has been a long haul. The initial discovery in 1994 by Jeffrey Friedman at Rockefeller University in New York City, who identified the gene for leptin and the hormone itself, was universally lauded as a breakthrough. The discovery launched a new scientific discipline, the biology of appe-tite control and obesity research. For the

industry, it pointed to a blockbuster weight-loss drug. Thousand Oaks, California–based Amgen licensed leptin from Rockefeller for $20 million and developed metreleptin, a 147 amino acid, nonglycosylated polypeptide with one disulfide bond, which differs from the human leptin sequence by the addition of methionine at the amino terminus.

But preliminary results with the drug on obese patients were disappointing. Obese people, already brimming with leptin, are leptin insensitive. Adding more leptin has no effect. By the end of 1999, Amgen had almost resigned the drug to the junk heap.

In the meantime, despite industry’s oppro-brium, researchers at the National Institutes of Health (NIH) continued to think of ways to help people with lipodystrophies. In 1997, Simeon Taylor and Elif Oral at NIH’s Institute of Diabetes and Digestive and Kidney Diseases were recruiting lipodystro-phy patients to take part in a clinical trial of Rezulin (troglitazone), a diabetes drug since discontinued. In some patients who were excluded owing to poor liver function, Oral measured leptin levels to figure out another way to help them. “At the time measuring leptin was all the rage, it’s what you did,” she adds. The sickest patients had very low leptin levels. The investigators wondered whether leptin supplements might alleviate metabolic complications. Oral approached Amgen with-out success. At the time, Amgen’s obesity stud-ies were ongoing and the company was still hoping for a blockbuster, she says.

Then research fingering leptin to treat lipo-dystrophy started to heat up. O’Rahilly and his colleagues at Cambridge published the first study identifying a rare group of chil-dren with a congenital form of leptin defi-ciency, who were morbidly obese (Nature 387, 903–908, 1997). Moreover, his group showed in 1999 that daily injection of recombinant leptin therapy (supplied by Amgen on a compassionate-use basis) helped dramatically (N. Engl. J. Med. 341, 879–884, 1999).

About the same time, Michael Brown and Joseph Goldstein, both Nobel laureates at UT Southwestern, were studying how the body regulates cholesterol. Led by Iichiro Shimomura, they had created a transgenic mouse that overexpressed sterol regula-tory element binding protein 1 (SREBP-1) and unwittingly developed a model of con-genital lipodystrophy (Genes Dev. 12, 3182–3194, 1998). Giving leptin to the transgenic SREBP-1 mice also improved metabolic bio-markers.

All the while, Oral kept bugging Amgen. “When you are dealing with a really sick patient and you don’t know what to do, you

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302 volume 32 NumBeR 4 APRIl 2014 nature biotechnology

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in their words“i remember when they said, ‘By 2014, we’ll have the whole human genome in 15 minutes’. At the time, you had to say, ‘no, you’re not, of course you’re not.’ They lost their way.” Tim Hunkapiller, genomics consultant and brother of Tom

Hunkapiller, CEO of PacBIO, commenting on overpromising in PacBio’s early days. (Xconomy, 3 March 2014)

keep calling,” she says. Finally DePaoli, who at the time was global team leader for Amgen’s leptin research, convinced higher-ups to supply the drug for trials in patients with lipodystrophy. NIH and UT Southwestern agreed to conduct a two-center study and collaborated with Amgen in writing the trial protocol, which resulted in a 2002 paper on nine patients who improved dramatically (N. Engl. J. Med. 346, 570–578, 2002).

Since then, the drug has changed hands several times. In 2006, Myalept was out-licensed by Amgen to Amylin Pharmaceuticals. Then it became part of the BMS portfolio when BMS acquired the biotech in 2012. Then in February this year, Myalept came under London-based AstraZeneca’s control, through a deal trans-ferring BMS’s diabetes portfolio to the big pharma.

Myalept works just like its natural coun-terpart leptin, which acts on hunger centers in the hypothalamus to regulate body weight within a defined range; when leptin is low, appetite increases and vice versa. Over the years leptin has emerged as the most impor-tant hormone regulating appetite. “The only hormone that you can obliterate and then you suddenly become an eating machine is

leptin,” says O’Rahilly.AstraZeneca plans to pursue drug

approval in partial lipodystrophy. One pri-mary limitation of studies to date is a lack of long-term data. “Nobody imagined this would go on for over a decade,” says Oral. Moreover, because a pharmaceutical com-pany was not in charge from the beginning, data from the investigator-initiated studies weren’t necessarily collected for the purpose of drug approval, she says. Indeed, money spent by companies to develop Myalept for lipodystrophy came largely at the end, she says. With the drug far from a blockbuster, industry’s lethargic approach to developing it is partly understandable.

In the future, there may be other condi-tions that could benefit from leptin therapy. Oral plans to study Myalept in nonalcoholic steatohepatitis, an aggressive form of non-alcoholic fatty liver disease. Based on the drug’s mechanism of action, it may also play a role in treating amenorrhea induced by stress or exercise and subtypes of obesity characterized by low leptin. As data builds up, “leptin may gradually realize a broader role in therapeutics,” says O’Rahilly. “The history of endocrinology has often been so.”

Gunjan Sinha Berlin

AAV gene therapy continues to woo investorsSyncona, the venture arm of London-based charity Wellcome Trust, in January invested £12 ($20) million in an Oxford startup, the first program of which is a gene therapy for inherited blindness. NightstaRx—pronounced ‘Nightstar’—is a spin-out from the University of Oxford and its research commercialization unit Isis Innovation. The company is pursuing a therapy for choroideremia (CHM), an inherited X-linked form of progressive blindness, caused by mutations to the gene encoding Rab-escort protein 1 (REP1). The first symptoms occur in childhood with reduced night vision as the retina degenerates. The gene therapy—an adeno-associated viral (AAV) vector encoding REP1 designed to deliver the correct version to the cells in the retina—was developed by Robert MacLaren at Oxford’s Nuffield Laboratory of Ophthalmology. Vision improvements achieved by six patients were published in the Lancet (doi:10.1016/S0140-6736(13)62117-0; 16 January 2014), and a 12-patient phase 1 trial is underway. If approved, the price for this one-time treatment could fall between $83,000 and $110,000 per quality-adjusted life year, says Sander van Deventer, managing partner for Naarden, The Netherlands–based Forbion Capital Partners, the investors who backed the first FDA-approved gene therapy UniQure. The figures paid out for gene therapies are likely to match those for severe, untreated, Crohn’s disease or rheumatoid arthritis, which are on a par with blindness for reduced quality of life, he says. Final payout will depend largely on whether the therapy brings full sight recovery or just restores light perception—and how long it lasts. Another gene therapy company Voyager Therapeutics of Cambridge, Massachusetts, raised $45 million in a series A round from investors Third Rock Ventures in February. Voyager’s lead gene therapy program, an AAV serotype 2 vector encoding the dopa decarboxylase gene, is currently in phase 1 trials for Parkinson’s disease. Barbara Cassasus

Cheerios alert

Original Cheerios will no longer contain any genetically modified organisms (GMOs) and will be clearly labeled as such, General Mills announced in January, while still claiming on their website that they support GMO ingredients as safe. Critics say that they bowed to pressure from anti-biotech group GMO Inside, which is now expanding their lobbying to include Honey Nut Cheerios. It remains to be seen whether consumers will pay for the nonmodified cereal if it comes with a heftier price tag in 2014. General Mills has not altered the formulations of any of its other best-selling cereals.

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