Nature Medicine | Spoonful of Medicine

Small biotechs raring to cash in on the orphan disease market

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.

In rare form

Headquartered in Novato, California, BioMarin is the most established up-and-comer in the rare disease arena, with four drugs approved by the US Food and Drug Administration (FDA) and five more in various stages of clinical and preclinical development. Rare disease research is often funded in large part by private advocacy groups who act as angel investors for small pharmaceutical companies. But, “unlike some of its competitors, BioMarin has been successful enough to fund its own development projects without seeking a lot of outside money,” says Riordan.

BioMarin’s diverse portfolio includes approved small-molecule drugs for phenylketonuria, a metabolic disorder, and Lambert-Eaton myesthenic disorder, an autoimmune disease, as well as two ERTs for different kinds of mucopolysaccharidosis, a lysosomal storage disorder (LSD). To expand its pipeline, in 2010 the 800-person company bought up two small biotechs with therapies for the muscle-disabling disorder Pompe’s disease and rare, genetically defined cancers.

Looking ahead, “2012 is going to be an important year for BioMarin,” says chief executive Jean-Jacques Bienaime. “We are confident in our pipeline and look forward to significant milestones in the next year.”

Escort service

With a staff of around 130, Amicus Therapeutics is following in the footsteps of Genzyme by going after rare LSDs. But, rather than developing injectable ERTs, the company is advancing pill-form chaperone proteins that can stabilize endemic enzymes and restore their function. “If they can prove the chaperones work, they will be able to treat multiple diseases, including Fabry’s and Pompe’s,” says Joseph Schwartz, an analyst at Leerink Swann in Boston.

If approved, the new treatments would put the Cranbury, New Jersey–based drugmaker in direct competition with Genzyme, which markets ERTs for several LSDs. But Amicus has faced setbacks. For instance, Plicera (afegostat tartrate), the company’s lead Gaucher’s drug candidate, failed in 2009 in phase 2 testing, leading critics to question the efficacy of the chaperone approach. Nonetheless, Amicus is pushing for success this year with three new chaperone therapies for three different diseases in clinical trials. Phase 3 results for their most promising candidate, a new treatment for Fabry’s disease called Amigal (migalastat hydrochloride), are expected by the end of the year. “This is the beginning of a disruptive paradigm shift in the approach to treating lysosomal storage diseases,” says chief executive John Crowley.

Lean and mean

Aegerion Pharmaceuticals of Cambridge, Massachusetts is betting it all on one compound: an inhibitor of the microsomal triglyceride transfer protein that helps prevent the formation of ‘bad’ cholesterol. The drug, lomitapide, is currently in phase 3 testing to treat a rare heritable lipid disorder called homozygous familial hypercholesterolemia (HoFH), which affects an estimated 7,000 people worldwide. Unlike the more common ‘heterozygous’ version of the disease, people with HoFH have blood cholesterol levels that are so high that they often have strokes and heart attacks while they are still in their teenage years. “With orphan drugs like this one where there is clearly an unmet need, the likelihood of approval is high,” says William Tanner, a senior analyst at Lazard Capital Markets in New York who expects the lomitapide will be approved by early 2013.

Aegerion chief executive Marc Beer freely admits that the company’s strategy has been influenced by his former employer—Genzyme. Specifically, he plans to minimize overhead costs by hiring physicians to identify potential patients in overseas markets in the hopes that their training will spare the 45-person company the need to hire hundreds of new sales representatives. “In three to four years, our goal is to get lomitapide to patients in 100 countries globally,” Beer says. By the end of the year, Aegerion also plans to initiate clinical trials testing the drug as a treatment for familial chylomicronemia, another rare genetic disorder in which large amounts of fat build up in the blood.

The price is right

Cheshire, Connecticut–based Alexion Pharmaceuticals had early success with its drug Soliris (eculizumab), on the market since 2007 for the treatment of paroxysmal nocturnal hemoglobinuria, a red blood cell disease that is estimated to affect fewer than 10,000 people in North America andEurope. In September of last year, Alexion also won expanded approval for Soliris for the treatment of another rare blood disorder, atypical hemolytic uremic syndrome (aHUS), and the company is currently running trials for its use in various diseases of the kidney, nervous system and eye.

Priced at more than $400,000 per year, Soliris—an antibody directed against the complement protein C5—is among the costliest drugs on the market today (see ‘Priced to $ell’ below). “Soliris is an extremely attractive asset for the firm,” says Lauren Migliore, an analyst at Morningstar in Chicago. “Alexion could have a blockbuster on its hands by the end of 2012.”

But Alexion is far from being a one-trick pony. The 1,000-person company has an antibody the blocks the CD200 membrane protein for the treatment of multiple myeloma currently in phase 1 testing, and it has four more preclinical drugs in the pipeline targeting rare conditions such as molybdenum metabolic disorder and rare solid cancers. Earlier this month, Alexion also completed a $610 million deal to acquire Montreal-based Enobia Pharma, developer of an ERT for the rare metabolic disorder hypophosphatasia that is currently in phase 2 development. Despite the company’s swelling pipeline, however, much focus remains on “continuing the global expansion of Soliris for the treatment of patients with aHUS in the US and European countries,” says Alexion chief executive Leonard Bell.


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