After a debate-filled meeting today, the Endocrinologic and Metabolic Drugs Advisory Committee voted 8 to 5 in favor of approval for recombinant human parathyroid hormone, rhPTH I-84, to be known as Natpara, for long-term management of hypoparathyroidism.

Charles A. Stanley

Acknowledging the committee’s concerns for more optimal dosing and requests for better studies, Stanley compared current treatment of hypoparathyroidism to insulin in the 1920s.

“It took us many, many years to recognize that we needed longer acting dosing,” Stanley said.

Met primary endpoints

The drug, which was previously approved for osteoporosis treatment in Europe from 2006 to 2013, met the primary endpoints of decreased need for vitamin D and calcium in patients with hypoparathyroidism, as was shown by the manufacturer in their pivotal trial.

“A once-a-day injection provided a sustained increase in serum calcium lasting 24 hours, a decrease in urinary calcium excretion for 12 to 16 hours, the conversion of vitamin D to active vitamin D and a decrease in serum phosphate,” Hjalmar Lagast, MD, of NPS Pharmaceuticals, the drug sponsor and manufacturer, said during his presentation.

Though it was not a primary endpoint and the data was less remarkable than desired, the manufacturer presented data showing 1-84 improved long-term health in patients with hypoparathyroidism. Still, patients testified to its benefits in their daily lives.

Safety concerns

Hypoparathyroidism is considered an orphan disease and NPS Pharmaceuticals has conducted the largest clinical trial to date and maintains data for thousands of patients.

“We have a large safety database relative to an orphan disease,” Ralf Rosskamp, MD, a vice president at NPS said. “There are 3,343 unique patients in our efficacy and safety studies.”

He explained that though adverse events do occur, they most often occur early and are eventually resolved. He noted that the drug does have withdrawal effects and patients must be mindful of their daily dosing.

A concern presented by NPS and revisited by the committee was that of hypercalcemia.

“Treating endocrinologists will need to be introduced to frequent monitoring of serum calcium when using Natpara,”Roger Garceau, MD, chief medical officer of NPS, said.

Manoj Khurana, PhD, of the Office of Clinical Pharmacology, presented pharmacokinetic data in which he showed that urinary calcium excretion is still of concern.

“Initially there was a decrease in urinary calcium excretion,” he said. “However, with both doses by 10 to 12 hours, the excretion level returned to baseline levels.”

Kevin McBryde, MD, who is with the National Institute of Diabetes & Digestive & Kidney Diseases and voted against approval, expressed concern over the secretion levels.

Kevin McBryde

“I’m not sure I want to trade all the poor quality of life of hypoparathyroidism … for end-stage renal disease,” he said.

In the FDA presentations, Naomi Lowy, MD, showed the black box warning for Forteo (teriparatide,Lilly) and the committee took note of its treatment limitation of 2 years and caution of osteosarcoma due to occurrence in animal models.

“Both PTH molecules have the same intrinsic capacity to induce osteosarcoma,” Ronald Wange, PhD, supervisory pharmacologist with the Center for Drug Evaluation and Research, said in his presentation. “The clinical safety margin is low and does not permit a conclusion of negligible clinical risk.”

There was not a significant occurrence of osteoscarcoma seen with 1-84, though committee members said there is not yet enough data to justify or negate concerns.

“We’re discussing potentially treating patients with hypoparathyroidism for life,” Carola Arndt, MD, a pediatric oncologist at Mayo Clinic who voted yes, said. “If this is approved, there needs to be very close safety monitoring. These things might not show up for 10 years.”

Carola Arndt

Future considerations

Though these safety concerns were in the forefront of the committee debate, along with a discussion of other more applicable endpoints such as quality of life, those that voted in favor of approval of Natpara echoed Stanley’s statements.

“Having sat on many committees for orphan diseases … you’re not going to have a perfect clinical trial,” Julia Lewis, MD, a nephrologist from Vanderbilt University, said. “You have to change your perspective and wear your hat a little differently and it’s harder to make decisions.”

Julia Lewis

Lewis pointed to the patient testimonials in showing that the subcutaneous injection lessened their treatment burden and gave more stability and although that was not a primary endpoint, it should be weighed heavily.

“There are a lot of downstream positives that you don’t see with the current treatment,” she said. “This drug is doing something different that is more like the natural hormone than taking calcium and vitamin D.”

She and others questioned the FDA and Khurana, who in presenting the pharmacokinetic data suggested more frequent dosing may produce a more positive result. Though the FDA did not comment as to the agreed-upon primary endpoints, it was suggested that the manufacturer pursue further research in that direction.

“It remains an open question of whether there might be a subgroup of patients, perhaps a large subgroup, who might benefit from different administration, dosing or timing of treatment,” Robert J. Smith, MD, chair of the committee, said.

There is an ongoing trial, Trial 008, which is looking at safety and tolerability of varying doses of Natpara. Lowy said, “Data suggest that one can sustain the reduction in supplements along with maintaining a normal calcium beyond the 24 weeks seen in the pivotal trial.”

Upon explaining their votes, many of the committee members — both those voting for recommended approval and those voting against — admitted to being “on the fence” about their decision, acknowledging the definite need for a treatment in this arena but lamenting the lack of truly significant data to justify its approval.

For more information: See the Endocrine Today Twitter feed for a live update of the committee meeting:www.Twitter.com/EndocrineToday.