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Novo Nordisk (NYSE:NVO) has postponed pre-launch training sessions with US clinicians for diabetes drug liraglutide (Victoza), clinicians have said, and Novo Nordisk has confirmed, Pharmawire reports.
The Danish company has recently notified selected diabetes physicians that a speaker training meeting planned for 1 May in Miami, Florida, has been cancelled and would be rescheduled at a later date, according to a source claiming knowledge of the situation. The reason Novo cited for postponing the meeting was that the recent US Food and Drug Administration (FDA) action would require them to do additional studies, said the source.
“Novo Nordisk also said that they were definitely going to keep trying to get the drug approved in the US,” the source said, adding that the speaker training had been organised to teach selected physicians to go out and train additional health care professionals across the country about liraglutide ready for its launch, which had previously been expected by the company around mid year until the drug hit regulatory uncertainty earlier this month.
Liraglutide belongs to the GLP-1 class of injectable diabetes drugs, which are also associated with weight loss, and its novelty is that it is dosed once-daily, compared with Amylin/Eli Lilly’s already-marketed drug in the same class, Byetta (exenatide), which is dosed twice- daily.
In animal studies of liraglutide, C-cell/medullary thyroid tumours were seen in two species of rodents and increased calcitonin – a biomarker of human C-cells – was also seen in clinical data. This was flagged as a potential concern by the US regulator, but played down by the company. On 2 April an FDA Advisory Committee panel voted 1-12 against Novo Nordisk’s suggestion that this data was not relevant to humans. The panel was split (6-6 with 1 abstention) as to whether the available data on C-cell/medullary thyroid tumours permitted approval of liraglutide. Novo Nordisk has maintained the drug is still “approvable” in the near term, despite the set back.
Commenting on Novo Nordisk’s move to postpone the speaker training, a person with regulatory insight in the field said that usually a company would only go ahead with a speaker training session if there was expected to be an imminent launch. Another clinician noted that the “word on the street” is that Novo is now not expected to launch liraglutide in the US this year.
The person with regulatory insight noted that the FDA hearing on liraglutide was only held within the past month, so they do not think that the FDA will have issued any formal guidance yet. They speculated that Novo is assuming on the basis of informal contact with the agency that further studies are to be requested.
The person further speculated that these would likely be toxicology studies and said the company will also be required to submit a safety plan on this issue for post-licensing, although this is just normal practice when an issue - such as the C-cell tumours in rodents/raised calcitonin in humans, Novo’s case, arises.
Two other US clinicians said that it is their current understanding, “based on second hand information from a relatively reliable source” that Novo Nordisk may only have to design a post-marketing study on the C-cell/calcitonin issues and once Mary Parks, director of FDA’s Division of Metabolic and Endocrine Drug Products, is satisfied with the design, the company will get the go ahead and perhaps only incur a delay of a couple months.
Novo Nordisk’s chief science officer Mads Krogsgaard Thomsen confirmed the speaker training postponement and said that it is not something the company would do months in advance of a launch, but it would be something the company would do around two months in advance. He said: “In our mind gaining approval to launch is a question of months; which path the FDA requires us to take will determine whether it is a few or several, or many.”
Thomsen explained the FDA Advisory Committee did not have a chance to review the company’s two-year calcitonin data in humans as it was not part of the pre-reading materials they were given. This is because the data was generated after the FDA’s 120 day cutoff for submission of new data in the new drug application (NDA) process, so it was not included in the original submission, he said. In summing up, the chairperson of the Advisory Committee suggested the FDA look at calcitonin data longer than six months when making their decision, said Thomsen.
“The agency could allow us to present our long-term calcitonin safety data in one dedicated meeting, or it could require a more lengthy procedure involving resubmission of the data, which could result in a delay of half a year or more,” Thomsen said.
He added that this data includes a two year follow-up Phase IIIb study measuring calcitonin levels from the LEAD 3 liraglutide monotherapy study; the LEAD 2 liraglutide + metformin vs sulfonylurea study; a six month study of liraglutide vs exenatide; and a one year study of obese patients that were given “very high” doses of liraglutide (3mg) compared with placebo and orlistat (Xenical).
The long term clinical data shows “absolutely no tendency of an increase of calcitonin with liraglutide, or a trend towards moving from one range of calcitonin into a higher range,” said Thomsen.
In relation to the RISKMAP/REMS, designed to monitor potential safety concerns of new drugs after they are approved, Thomsen said that the company has long been in discussion and consultation regarding this and does not believe that there will be a requirement for pre-screening of patients for thyroid abnormalities, but instead a need to ensure that the label is relevant.
Novo intends to propose to the FDA a two-pronged approach. Firstly, there will already be a postmarketing study running to monitor cardiovascular safety in 8,000-10,000 patients for up to five years and the company believes that calcitonin monitoring in the form of a blood test can be incorporated into this postmarketing study as a secondary endpoint.
Secondly, Novo will propose that a C-cell/medullary thyroid cancer registry is set up to ensure that any serious adverse events (SAEs) related to this in patients on liraglutide are reported in a rational way. Currently there is no such registry established. “Based on the dialogue we are having with the FDA we think we’ll be able to proceed our formal discussions with them in the near future – within weeks,” said Thomsen.
On Thursday liraglutide moved a step closer to approval in Europe after a positive opinion was issued by the Committee for Medicinal Products for Human Use (CHMP). It is understood that the European Medicine’s Agency (EMEA) usually follows the opinion of the CHMP in issuing final approval for European marketing authorisation of drugs, but not always, although expert European diabetes physicians polled by this news service remain positive.
Novo Nordisk has a market cap of GBP 20.83bn.
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