FDA Approves Orladeyo, 1st Oral Treatment to Prevent HAE Attacks

The U.S. Food and Drug Administration has approved Orladeyo (berotralstat) as an oral treatment to prevent swelling attacks in people with hereditary angioedema (HAE), ages 12 and older.

This approval makes Orladeyo, developed by BioCryst Pharmaceuticals, the first and only oral treatment available for these patients, for whom preventive treatment was only available previously via injections or infusions. The less burdensome oral route of administration is expected to improve the quality of life and independence of those with HAE.

BioCryst announced in August that it was prepared to launch the medication by the end of the year pending its approval.

“Orladeyo offers people with HAE and their physicians the first orally administered non-steroidal option for preventing HAE attacks and represents an important and welcome step in making more treatment options available to physicians and patients,” Anthony J. Castaldo, president and CEO of the US Hereditary Angioedema Association, said in a press release.

Orladeyo is a small molecule that blocks plasma kallikrein, a precursor of bradykinin — an inflammatory molecule produced in excess in HAE patients, leading to sudden and recurrent swelling episodes. By suppressing plasma kallikrein, the medication is expected to lower bradykinin levels, potentially treating and preventing angioedema attacks.

The FDA’s decision was based on data from the Phase 3 APeX-2 trial (NCT03485911) and the Phase 2/3 APeX-S trial (NCT03472040), both of which are evaluating Orladeyo’s safety and its ability to prevent swelling attacks in HAE patients ages 12 and up.

APeX-2 is testing two doses of Orladeyo versus a placebo in 121 HAE patients who had experienced at least two confirmed HAE attacks during an eight-week period before the trial started.

Both doses of Orladeyo significantly reduced the rate of monthly HAE attacks over a period of roughly six months, but the 150 mg dose showed the greatest benefits. While patients on a placebo experienced 2.35 attacks per month, the 150 mg Orladeyo dose lowered that rate by 44%, to 1.31 monthly attacks.

These reductions were sustained at least until week 48, at which point patients receiving the 150 mg had a mean of one attack per month, compared with 2.9 monthly attacks before starting treatment.

Patients treated with Orladeyo also reported meaningful improvements in quality of life and patient-reported satisfaction, along with a marked decrease in the need for standard on-demand medicines. These patients also experienced more days without any angioedema symptoms.

“Patients and physicians acknowledge that HAE treatments can add a burden to patients’ lives.  As an oral, once-daily option, Orladeyo can provide significant attack reduction and lessen the burden associated with injections and infusions,” said Marc Riedl, MD, an investigator in the APeX-2 trial.

“With this new treatment option, physicians and patients can continue to have collaborative discussions to choose the treatment that meets each patient’s needs, life circumstances and preferences,” added Riedl, who is also a professor of medicine and clinical director of the U.S. Hereditary Angioedema Association Center at the University of California, San Diego.

In the long-term, open-label APeX-S trial, participants who completed 48 weeks of treatment with the 150 mg dose had an average of 0.8 attacks per month after starting treatment.

The therapy was deemed safe and well tolerated, with the most common side effect being gastrointestinal reactions. These became less frequent with time and typically resolved on their own.

APeX-S is still recruiting participants at sites across the U.S.; sites elsewhere are no longer recruiting. More information is available here.

“The FDA approval of Orladeyo fulfills a promise BioCryst made to HAE patients that we were committed to helping them achieve the dream of an oral, once-daily medicine to prevent and reduce the burden of their attacks,” said Jon Stonehouse, president and CEO of BioCryst.

To support and accelerate patients’ access to Orladeyo, BioCryst launched a new program called EMPOWER Patient Services, which will connect patients with a dedicated care coordinator for financial and reimbursement assistance.

“Thank you to the HAE patients who participated in our clinical trials, to the investigators around the world who conducted these trials, to the HAEA for their patient advocacy and to our employees who never forgot that patients were waiting,” Stonehouse said. “We will stay focused on enabling access and providing personalized support to HAE patients and physicians.”

Orladeyo is also currently under review in Japan and in the European Union, with decisions expected in December and in March 2021, respectively.