The high sticker price paid last year by the French drug giant Sanofi for Genzyme, the preeminent rare disease company, was widely seen as a ringing endorsement for the Cambridge, Massachusetts–based biotech’s innovative business model. Although Genzyme had started to diversify—much to some analysts’ chagrin—at its core lay a deep pipeline of enzyme replacement therapies (ERTs) that served small patient populations but with steep reimbursement rates. “Genzyme leveraged their enzyme replacement therapies across multiple rare diseases and showed it could be profitable,” says Matthew Riordan, an analyst at Putnam Associates, a biopharma consulting firm based in Burlington, Massachusetts.

Now, a handful of small companies are trying to recreate what made Genzyme great, focusing exclusively on rare diseases, even at the expense of a more diversified portfolio. Here, in honor of Rare Disease Day, we profile five such companies—the ‘next Genzymes’—that are focused primarily on the rare-disease market and have products either on the market or in late-stage development.

Spin-off success

In 1997, three senior managers from the Swiss drug giant Roche split off to launch Actelion Pharmaceuticals, a Basel-based company now with 2,500 employees focused primarily on the treatment of pulmonary arterial hypertension (PAH), a blood pressure condition that affects just under 200,000 people in the US. “A lot of people forget that PAH falls under the orphan designation, but it’s a very lucrative market,” says Joseph Schwartz, an analyst at Leerink Swann in Boston.

Over the past decade, Actelion has ramped up its PAH portfolio with two acquisitions, first of Basel’s Axovan, the developer of an experimental endothelin receptor antagonist called tezosentan, and later of CoTherix, the South San Francisco company behind Ventavis (iloprost), an inhaled PAH drug that Actelion now markets in the US. With three approved drugs for PAH, Actelion is hoping to further tighten its grip on the market with its next-generation PAH treatments, macitentan and selexipag, both of which are currently in phase 3 clinical trials. “We are the undisputed leader in PAH, and with these new products we will continue to be the leader for the foreseeable future,” says Actelion’s head of investor relations and public affairs Roland Haefeli.

The company is also investigating whether some of its PAH drugs can be used to treat other rare diseases, such as idiopathic pulmonary fibrosis, systemic sclerosis and glioblastoma. In addition, Actelion is testing its Gaucher’s drug Zavesca (miglustat)—which is currently approved only for those who cannot receive ERTs owing to allergies or other complications—in people with cystic fibrosis and people with Niemann-Pick disease type C.

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Companies these days use crowdsourcing for everything from striking gold to marketing facial moisturizer. Now a new startup, Transparency Life Sciences, hopes to harness that collaborative power to make clinical trials more effective and efficient by asking the opinions of doctors as well as patients and their families. The company, launched last month and based in New York, is the latest in a string of so-called ‘open innovation’ drug development initiatives. But until now most of these efforts have only crowdsourced from a limited group: researchers.

Back in 2009 Indiana-based Eli Lilly launched its Open Innovation Drug Discovery program, an online platform for researchers to submit small molecules for drug screening. “The goal of this kind of program is to attract researchers with new molecules and ideas in an unbiased way,” says Alan Palkowitz, vice president of discovery chemistry research and technologies at Eli Lilly.

Other big pharmaceutical companies have also established a handful of open innovation platforms for preclinical drug development. New York-based Pfizer has been building partnerships with institutions through its Centers for Therapeutic Innovation program since 2010, and Britain’s GlaxoSmithKline funds the non-profit open innovation organization Tres Cantos Open Lab Foundation. Most recently, in October, the United Nations World Intellectual Property Organization partnered with seven major drug companies in an intellectual property sharing consortium targeting neglected tropical diseases.

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The latest twist in the saga of US drug shortages came today when the country’s Food and Drug Administration (FDA) announced that it had found alternative sources for the cancer drugs methotrexate and doxorubicin, two of the 220 drugs currently in short supply in the US.

Last week, the FDA announced that emergency supplies of an injectable, preservative-free form of methotrexate, which is used to treat the childhood blood cancer acute lymphoblastic leukemia, would be made available by the Ohio-based manufacturer Bed Venue Laboratories. And today, commissioner Margaret Hamburg reported that APP Pharmaceuticals, a drugmaker based near Chicago that specializes in injectable therapies, had received expedited approval to make a version of methotrexate that will be available next month.

Meanwhile, the agency is also importing shipments of both methotrexate and doxorubicin from abroad. An unapproved generic version of doxorubicin, which is marketed as Doxil by New Jersey’s Johnson&Johnson, will be temporarily imported from India by Caraco Pharmaceutical Laboratories of Detroit, and the Chicago area company Hospira is shipping 31,000 vials of preservative-free methotrexate—enough to last US patients for one month—from its plant in Australia. “We believe supplies will continue to increase in the coming weeks,” Hamburg said in a press briefing this afternoon. “This should resolve the shortage.”

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The analytical fisticuff over how expensive research and development is for pharmaceutical companies flared up again today with a new estimate that pegs the cost of inventing a new medicine at well over the $1 billion price tag often tossed around in the industry. After factoring in money spent on drug failures, Bernard Munos of the InnoThink Center for Research In Biomedical Innovation says that the average cost to bring a drug to market closer to a staggering $4 billion.

Small firms that don’t go bust tend to be the most cost-effective. But among big pharma, some drugmakers manage to stretch their dollars further than others. Amgen, of Thousand Oaks, California, gets the most bang for its buck at just over $3.7 billion per approved drug—calculated by dividing the company’s total R&D spending by the number of approved agents—while UK-based AstraZeneca is the least efficient, spending closer to $12 billion per agent thanks to several recent late-stage clinical trial failures involving treatments for diabetes, depression, and ovarian cancer.

Experts remain divided about the accuracy of these new estimates, though. “A grand average doesn’t have much to do with the real world of cost,” Donald Light, a health policy researcher at the University of Medicine and Dentistry of New Jersey in Stratford, told Nature Medicine. Last year, Light used estimates of clinical trial costs submitted by pharmaceutical companies to the Internal Revenue Service to come to the conclusion that the overall cost to develop a new drug was closer to $60 million (see ‘Drugs development is cheaper than widely claimed, experts say’). He says that numbers as high as $12 billion are not useful measures of R&D costs because they do not take into account the cost that society bears on behalf of the drug company in the form of subsidies and tax credits.

Regardless of who’s right, “the high cost of developing drugs shouldn’t be a badge of honor for drug firms,” writes reporter Matthew Herper, who broke the story in Forbes. “There’s no reason it has to be this expensive.” Now, there’s one point all the experts can agree upon.

People with hemophilia have a lot of reasons to be hopeful these days. A December gene therapy study showed early success, and yesterday the Dublin-based pharmaceutical company Shire announced a partnership with the Richmond, California-based biotech Sangamo BioSciences. Together, the companies plan to develop hemophilia treatments that target defects in four clotting factor genes with the zinc finger DNA-binding protein technology developed by Sangamo. Shire will provide financial support to bring these therapies through clinical testing.

Sangamo’s gene-editing technology, which enables the alteration of any DNA sequence in any gene, first made hemophilia news last June. A team of researchers from the Children’s Hospital of Philadelphia (CHOP) showed that the technology could correct the genetic defect that causes hemophilia B in a mouse model of the disease without poisoning the liver, a perennial concern with treatments like these that are injected directly into the organ.

Current treatment for hemophilia involves adding clotting factors to a patient’s blood. A gene-editing therapy, such as the one Shire and Sangamo plan to pursue, would target the disease at its source in the genome rather than just alleviating symptoms.

Sangamo is not alone in pursuing gene therapy treatments for hemophilia. A host of researchers have made strides toward developing therapies using adenovirus-associated viral (AAV) gene delivery systems that target dysfunctional clotting factor IX in hemophilia B, one of the four factors Sangamo plans to target as well. A phase 1 trial published in December in the New England Journal of Medicine showed that an AAV treatment for hemophilia B improved clotting. A second phase 1 trial at CHOP is testing a slightly different AAV treatment that also targets factor IX. Katherine High, a hematologist at the University of Pennsylvania in Philadelphia, says she expects to see more trials being launched in the next couple years.

Although AAV factor IX therapy is farther along in development than the zinc finger nuclease technology, High says Sangamo’s approach should not be discounted. Because zinc finger nuclease therapy introduces a correction into the genome, which likely means the correction will be passed to daughter cells, this treatment may “have the advantage of being very long lasting,” High says. Whether AAV therapies could achieve such long-term results is not yet known. The immune system may clear clotting factors produced by the virus, causing the therapy to lose potency over time.

Photo courtesy of Bruce Wetzel via Wiki Creative Commons