An Orphan Gets Help

Marc Beer recognized an opportunity when he joined Cambridge, Mass.-based Aegerion Pharmaceuticals as chief executive officer in 2010. The prospect was called lomitapide. First developed by Bristol-Myers Squibb, the drug had failed as a general-purpose cholesterol treatment in Phase I clinical trials. Aegerion, which acquired rights to the molecule in 2007, wasn’t faring much better in its attempt to revive it as a drug for patients who can’t tolerate the cholesterol-lowering drugs known as statins. Beer, however, envisioned using it as a therapy for homo­zygous familial hypercholesterolemia (HoFH), a rare genetic disease that affects the liver and often causes heart failure.

Beer was looking for a challenge. A former executive at Abbott Laboratories and Genzyme, Beer had formed a stem cell research firm, ViaCell, and sold it in 2007. He then took three years off after his wife’s death because of a pulmonary embolism. Offered the CEO job at Aegerion, at the time a tiny company with no labs of its own, he saw a chance to get back in the game by launching an orphan drug that might address an unmet need for a small group of patients.

HoFH, which afflicts about one in 1 million people, makes the body unable to remove low-density lipoprotein, or “bad,” cholesterol from the blood. Lomitapide, a small molecule, inhibits the microsomal triglyceride transfer protein (MTP) necessary for bad cholesterol assembly and secretion in the liver.

But redirecting lomitapide as an HoFH treatment posed several challenges. The Food & Drug Administration had put a clinical hold on the molecule after problems arose with another drug candidate in the MTP inhibitor class. And Isis Pharmaceuticals was at work on another kind of therapy for HoFH. Getting lomitapide through clinical trials ahead of the competition, Beer knew, would require the company’s pharmaceutical services partner, Aptuit, to rapidly undertake process development, formulation, and scale-up.

Aegerion had contracted with Aptuit when it acquired lomitapide in 2007. When Beer arrived, he liked the fact that Aptuit offered a full range of services, from early development to commercialization, with assets in Europe as well as the U.S. He says he never considered switching service partners after redirecting the lomitapide program to HoFH.

Sticking with Aptuit has paid off, according to Beer. “In the last two-and-a-half years, Aptuit did critical process development work,” he says. No such work had been done under Aegerion’s previous management, he notes. “They were the classic private equity owner that takes the pill and proceeds to a number of clinical studies that would yield the big takeout.” Aptuit, he says, proved capable of dealing with a much more demanding client.

Kevin Duffield, senior director of active pharmaceutical ingredients (APIs) for Aptuit, says the company was ready to provide the research and manufacturing services required to take lomitapide into a more challenging drug development program. Its one-stop-shop approach and its ability to handle a potent compound such as lomitapide in fully enclosed production facilities were suited to the task, he says.

“This is fairly routine chemistry,” Duffield says. It is “convergent multistep synthesis with more than five stages. So it’s not particularly difficult.” Things get interesting in the final drug manufacture, however. “You need to get the correct polymorph and particle-size distribution.” Not a lot of contract service firms that manufacture high-potency APIs can also handle the finished product, according to Duffield.

But the clock was running. Aegerion was “under incredible time pressure to finish registration batches, to finish clinical trials, and to get to the point where they could file a New Drug Application,” he says. “They were trying to beat their competitor to an NDA, which they did by just a few weeks.”

Aptuit did most of the work in 2011 at its Harrisonville, Mo., facility. But the company also brought in resources from its sites in Oxford, England, and Verona, Italy, for analytical method development and validation. Particle-size and polymorph distribution issues were tackled at the company’s formulation services facility in West Lafayette, Ind.

While it coordinated work on the lomitapide project at various sites around the world, Aptuit was going through a transformation of its own by selling its clinical services business to another company, Catalent. Duffield explains that the deal included Aptuit’s drug formulation and packaging operations, breaking off one of the services that appealed to Aegerion from the start.

Even though the change meant that Aegerion was required to contract separately for final pill formulation and distribution with Catalent, Beer and Duffield say the dual contracting arrangement has caused no disruption. One key reason: Catalent’s formulation and packaging operations are located near Aptuit in Harrisonville.

FDA approved lomitapide, trade named Juxtapid, late last year, one month ahead of the Isis drug, which is called Kynamro and marketed by Genzyme. Aegerion and Aptuit recently announced a commercial supply agreement and are also working on approval in Europe.

Although Aegerion beat Genzyme to market, Beer says he never viewed the Genzyme drug as direct competition. “I believed that both products would be approved and that ours would be the first-line therapy.” A more important reason to get to the market quickly, he says, is because Aegerion’s drug targeted a patient population with an unmet medical need.

The company has gone public and now has a marketing and technical staff of more than 100, but it still relies on Aptuit for research and manufacturing services. Getting lomitapide approved and on the market so rapidly was a collaborative effort, Beer says. Duffield agrees, noting that Aegerion’s technical and regulatory staffers were frequently on-site in Harrisonville.

“This relationship is about close collaboration and the willingness on the supplier’s part to apply the resources to meet very difficult deadlines,” Duffield says. Although the chemistry was not particularly challenging, the project experienced the usual technical problems in process design and product formulation, he says. So despite the time pressure, the client needed to invest in a rigorous R&D regime that incorporates contingency plans such as multiple control procedures. Aegerion, Duffield says, has been a very cooperative partner as well as a customer.

Beer returns the compliment, saying he was confident early on that Aegerion and Aptuit were on the same page about the new direction for lomitapide. “We gave a presentation at Aptuit and told them our motto is, ‘The patient is waiting,’ ” Beer recalls. “They got it. And when we asked for seven-day weeks and double shifts, they did it. Their management team accepted the demands from a client that may not be its largest, but one who has a drug that can make a difference.”