It was Thursday night when Lindsey Cowles learned Takeda Pharmaceutical was recalling all doses of her hypoparathyroidism medicine Natpara. She had taken her last dose that morning. By Friday, she was suffering symptoms from a rapid drop in her blood calcium. On Saturday, she was in the emergency room with muscle spasms, her right arm weak and useless.
It was a couple of days before doctors stabilized her calcium enough with infusions so she could begin to return to her life taking care of her five small children, working part-time and finishing nursing school—a life she was able to balance only with the help of Natpara. It is a drug some patients credit with keeping them alive.
“Natpara is a medication we in the hypoparathyroid community rely on to have a productive and full life,” Cowles, of Clearfield, Utah, said by email. “There are no other options that leave us feeling like a semi-normal human being. This recall has left many of us in a panic about our future!”
The recall illustrates one of the paradoxes of modern drug development. The FDA’s orphan drug label has become a godsend to patients with debilitating, sometimes fatal, diseases that were overlooked by drugmakers in the past. The program's financial incentives spur companies to develop meds targeted at such small patient groups that otherwise would make them infeasible.
But when manufacturing problems create an interruption in supply, as with last week’s recall of Natpara, the consequences for patients can be devastating—and it is a scenario that may play out more often as more and more specialized drugs are developed.
Natpara is a bioengineered replica of human parathyroid hormone (PTH) for those whose bodies can’t make enough PTH and for whom standard therapy alone is not enough. It is a rare, calcium-depleting, body-wrecking disease that affects an estimated 70,000 people in the U.S., of which more than 2,500 are taking Natpara because standard care can't manage their symptoms.
Takeda voluntarily recalled the drug because of the possibility that rubber particles were getting in the vials from the drug’s injector. But the recall came with a grave warning: Patients shouldn't just quit taking the drug. Instead, they would need to transition to supplements and have their blood calcium levels monitored to make sure they didn't drop dangerously low.
The situation forced some, like Cowles, to the hospital for emergency treatment in hopes of staving off painful “hungry bone syndrome.” It has left the rest wondering whether they’ll be next.
A Takeda spokeswoman in a statement said the company understands “discontinuing Natpara can have serious health consequences.” The company is working with the FDA and is committed to getting the drug back on the market as quickly as possible. But there is a big question about how long that will take.
“Replacing even a small component of a medical device requires a series of tests and, subsequently, review and approval from regulatory agencies to ensure the highest level of safety for patients,” she said, adding, "We are working with the FDA on several routes to bring Natpara back to the market for patients as quickly as we can."
The FDA said Wednesday it is “working with Takeda on possible solutions to the issue of this recall, and will continue to work closely with them to reduce any impact due to the recall.”
In some cases, the agency can recruit another drugmaker to pick up the supply slack or fast-track drug review for a competitor’s product. But these steps don’t apply in this situation. As the only approved treatment and a protected orphan drug, no one else makes a competing product or has one ready for approval.
Patients are frustrated by the fact that the medicine is fine and that it’s the injector that is faulty.
“At the urging of the FDA, they’re pulling a medicine that saves our lives daily, simply due to a route-of-administration problem, a problem that can be easily fixed by simply handing us a normal vial of Natpara, and a diabetic syringe," 45-year-old Jennifer Stewart says in a letter that she sent to the FDA and Takeda.
Neither the FDA nor Takeda responded to questions about whether that's a viable solution.
Michael Mannstadt, M.D., a Harvard researcher and doctor at Massachusetts General Hospital who works with patients suffering from hypoparathyroidism, has laid out on his webpage a few options he sees for patients.
For one, they could continue taking any Natpara they have on hand. European regulators decided the risk from the particles is small enough that they haven’t asked Takeda to recall the drug there, he pointed out.
He also says Natprara users might have their doctors transition them to Forteo, an Eli Lilly osteoporosis injection that has been used for hypoparathyroidism in clinical trials at the National Institutes of Health. But Forteo comes with its own challenges, and because it is not approved for hypoparathyroidism, insurers might not cover its $30,000 cost.
Patients also can move to calcium/calcitriol injections, he said. Some patients who used the treatment in the past will find they require much higher doses after having been on Natpara, he cautioned. Patients will need frequent blood tests to get their blood calcium regulated.
Many Natpara users are debating their options in a Facebook group, and some are speculating that it could take Takeda a year to roll out a replacement injector. Even though Takeda has committed to restoring supply, some worry that it might decide not to return to the market a drug that earned $230 million last year.
Stewart conveys the fears many have about the ravages of their disease before Natpara came along.
“First: Brain Fog rolls in. It becomes very difficult for us to think straight or make good decisions,” she says. This is followed by a series of painful muscle cramps and spasms that can vary for each. “The most unsettling symptoms happen when the body begins vibrating internally like a tuning fork, just before the heart goes into palpitations. It’s these heart symptoms that threaten our lives.”
“We absolutely cannot go over a year, waiting on Natpara’s return,” Stewart says.