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`Natpara sails through panel despite headwind; NPS Pharma gets an 85 'yes' vote in hypoparathyroidism | BioWorld
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`Natpara sails through panel despite headwind; NPS
`Pharma gets an 85 'yes' vote in
`hypoparathyroidism
`
`By Randy Osborne
`Staff Writer
`
`With briefing documents and history on its side, the biologic
`license application for NPS Pharmaceuticals Inc.'s Natpara
`emerged with success from a meeting of the FDA's Endocrinologic
`and Metabolic Drugs Advisory Committee (EMDAC) as expected,
`scoring eight votes in favor of approval and five against – but a
`handful of panelists said their ballots might have gone either way.
`
`NPS' recombinant human parathyroid hormone (PTH) for the potentially fatal disorder hypoparathyroidism,
`if approved, would be the first therapy cleared for U.S. marketing in that indication. Lee Weinstein, acting
`chief of the metabolic diseases branch of National Institute of Diabetes and Digestive and Kidney
`Diseases in the National Institutes of Health (NIH), voted for approval.
`
`"I would honestly say I was very much on the fence with this, and perhaps at another time or another
`moment, I could have made my vote the other way," he said, adding that he "was not overly impressed
`with the study that was done and some of the outcomes that were shown in the data. To be honest with
`you, as a physician, I think I would probably very rarely if ever even prescribe it." Still, he said, there
`appear to be a "small number of very difficulttotreat patients that, for whatever reason – and I'm not sure
`we totally understand why that is" – are helped by the drug.
`
`Thomas Weber from Duke University Medical Center went the other way, despite "compelling stories from
`patients" during the publichearing portion of the meeting because he wanted to see a "true reduction in
`urinary calcium" and better assurance that patients would not meet with renal complications. "In the
`absence of clear benefit, the bar for safety has to be much higher," he said.
`
`Panelists considered data from the pivotal trial called REPLACE, along with supportive outcomes from
`RELAY and RACE. NPS, of Bedminster, N.J., disclosed positive topline results from REPLACE in late
`2011. There was another study, too, smaller and singlecenter, called REPEAT, that didn't play much of a
`role. (See BioWorld Today, Nov. 8, 2011.)
`
`EMDAC verified expectations from briefing documents that questions would have mostly to do with the
`risks of such problems as hypo/hypercalcemia, hypercalciuria, and osteosarcoma with longterm use.
`
`Members seemed frustrated that many of their questions could not be answered in REPLACE data. In an
`intenttotreat analysis, NPS reported that 53 percent (48/90) of Natparatreated patients achieved the
`primary endpoint vs. 2 percent (1/44) of placebotreated patients (p < 0.0001).
`
`That endpoint was defined as a 50 percent or greater reduction in oral calcium supplements and active
`vitamin D therapy, along with a total serum calcium concentration that was normalized or maintained
`compared to baseline after 24 weeks of treatment.
`
`Not using calcium excretion as the primary endpoint bothered panelists such as Weber, while others said
`the trial was necessarily too small to capture the volume of data that would be required with a different
`primary goal. Others questioned the dosing regimen, wanting more frequent than once per day; one voter
`suggested an administration route other than an injection. "This drug would be perfect if it was a pump, or
`at least multipleday dosing, but that's not the option that was put in front of me today," said the NIH's
`Weinstein.
`
`LONGTERM OSTEOSARCOMA PERIL?
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`12/29/2015
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`Natpara sails through panel despite headwind; NPS Pharma gets an 85 'yes' vote in hypoparathyroidism | BioWorld
`
`Natpara was well tolerated in REPLACE. Thirteen of the 134 randomized subjects discontinued the study
`early, including seven on placebo. Overall, the incidence of adverse events and serious adverse events
`was similar in both groups.
`
`The good data were bolstered by EMDAC's past, as surveyed by Leerink Partners analyst Joseph
`Schwartz, who found the most recent 2.5 years voting history showed nine of 10 meetings ended with a
`positive vote. The meetings included two orphan drugs and eight massmarket indications. Since early
`2013, the only negative EMDAC meeting involved Vascepa (icosapent ethyl), the lipidlowering agent from
`Amarin Corp. plc, of Dublin. (See BioWorld Today, Oct. 17, 2013.)
`
`With Vascepa, the picture was nothing like that with Natpara. Not only were the briefing documents much
`more doubtful, but also the market for mixed dyslipidemia is much larger. What's more, the FDA "was (and
`still is) attempting to address a political question regarding special protocol assessments (SPA) and the
`emergence of new, conflicting information," Schwartz wrote in a research report. For the first time ever, the
`committee turned down an application submitted under an SPA agreement. (See BioWorld Today, Oct. 18,
`2013.)
`
`The issue at hand, though, was Natpara, for which analysts had predicted a win at EMDAC, with Schwartz
`– who maintained an "outperform" rating and $40 price target on the stock – pegging peak sales in 2025 of
`$1 billion. More conservative on the shares was Jefferies analyst Eun Yang, with a "hold" rating and a
`target price of $26. NPS (NASDAQ:NPSP) stopped trading at a price of $32.70 for the day of the panel
`meeting.
`
`Yang pointed out that the clinical significance of Natparainduced osteosarcoma in a preclinical rat model
`was unknown, similar to the PTH peptide Forteo (teriparatide, Eli Lilly and Co.) in osteoporosis. "It remains
`to be seen whether the FDA would place a black box for osteosarcoma in Natpara label (as a PTH class
`effect) and consider treatment duration limitation to less than two years, similar to Forteo (and Preotact
`[also from NPS] previously) despite the chronic nature of secondary hypoparathyroidism. The
`osteosarcoma matter cropped up in the EMDAC meeting, with panelists proposing risk evaluation and
`management strategies if the compound is approved.
`
`Last year, NPS regained full worldwide rights to Gattex (teduglutide) for short bowel syndrome and the
`recombinant PTH Preotact from Takeda Pharmaceutical Co. Ltd., of Osaka, Japan, in exchange for stock
`valued at $50 million, plus a milestone payment of $30 million in cash or stock in the first year that net
`sales of both products exceed $750 million. (See BioWorld Today, March 20, 2013.)
`
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