The U.K.'s cost-effectiveness watchdog, the National Institute of Clinical Excellence, issued draft guidance on Feb. 15 recommending only limited reimbursement for Novo Nordisk's newly-launched diabetes drug Victoza (liraglutide), despite the GLP-1 analog's proven efficacy not only in lowering blood sugar, but also in promoting weight loss.
On the bright side for Novo: a very rapid U.S. launch means the drug is now available in 90 percent of U.S. pharmacies, just three weeks after its delayed approval by FDA (1 'The Pink Sheet' DAILY, Jan 26, 2010).
Limited Reimbursement Only
NICE's draft verdict wasn't nearly as damning as that dished up to cancer drugs Sprycel (dasatinib) and Tasigna (nilotinib) on Feb. 9 (2 'The In Vivo Blog', Feb 9, 2010), but Novo's VP-Europe Viggo Birch, nevertheless, declared he was "not happy."
NICE has recommended that liraglutide be reimbursed only a) as part of a triple-therapy regimen (that is, for patients already on metformin and a sulfonylurea, or metformin and a thiazolidinedione, where the above combos aren't quite doing the trick); b) among patients with a body mass index equal to or higher than 35 kg/m, which means obese; and c) only at the lower, 1.2 mg daily dose.
Patients whose BMI isn't quite 35kg/m could also qualify for liraglutide "if it is considered that the drug's use could help to achieve levels of weight loss that could be beneficial in treating other conditions caused by being obese," NICE3 concedes.
But the 4 full appraisal consultation document reveals that, even among those tightly-defined patient groups, drug treatment should only be maintained if the individual loses at least 3 percent of body weight after six months (that's not far off the 5 percent threshold for an actual weight loss drug) and sees a reduction in blood sugar levels of at least 1 percentage point.
Hence, it appears as if a favorable side effect of this diabetes drug - one which could lead to lower incidence of co-morbidities and associated significant cost savings - is being used to limit its reimbursement.
The guidance is only preliminary. NICE is showing its opening hand in what may become a poker game of sorts, as the agency concedes that liraglutide "may have some advantages over insulin ... in particular its effect on weight." But NICE appears to be ruling out the higher dose point-blank, and is asking for further analyses on the cost-effectiveness of liraglutide among patients with a lower BMI.
NICE was also unsatisfied with the extent of the data comparing liraglutide with other combinations of oral drugs in triple therapy, including DPP-4 inhibitors, and felt that Novo's LEAD-1 trial comparing liraglutide to rosiglitazone used an insufficiently high dose of the glitazone.
It's impossible to cover in clinical trials all the various permutations and combinations in diabetes therapy, however. Novo submitted to regulators data from six studies in over 4,000 patients. All except one of the trials showed that the drug reduced HbA1c levels significantly better than comparators, which included Avandia (rosiglitazone); the DPP-4 inhibitor Januvia (sitagliptin); Lantus (insulin glargine); placebo; and Lilly/Amylin's Byetta (exenatide), the only other GLP-1 out there. The exception was the LEAD-2 trial, comparing liraglutide with Amaryl (glimepiride). The trial showed no significant difference in the two drugs' ability to lower blood sugar, but strongly highlighted liraglutide's weight advantage.
Liraglutide Guidance Mirrors That Of Byetta
Perhaps NICE's conclusion isn't such a surprise, considering the fate of Byetta in the U.K. Approved in Europe in late 2006, Byetta was not given a standard technology assessment like liraglutide - an assessment which, if positive, generates compulsory reimbursement. Instead, Byetta's usage is covered under NICE's broader type 2 diabetes guidance document.
That document states that Byetta is "not recommended for routine use in type 2 diabetes," with the same six-month benefit hurdles as described above for liraglutide. The drug is deemed "expensive" and "not cost-effective for an unselected population as compared to commencing human insulin therapy."
That would explain Birch's admission to "The Pink Sheet" that "given what they [NICE] have done for exenatide, this [recommendation] is what you'd expect in the first round." But he's nevertheless convinced that the Danish group has "a much better product [than exenatide] and much better data."
Novo's goal is to achieve reimbursement in the U.K. as second-line therapy, "at least for important patient subgroups," and a relaxation of the BMI-based restriction, since this, Birch claimed, "isn't fair. It was plucked out of the sky."
There's a good-sized crack in the door, though. NICE will hold another meeting on March 18, allowing Novo and others in the interim to comment and submit further data supporting wider use of the drug. "This 'minded no' is an invitation [by NICE] to open up a debate," said Birch. He maintained the company has data to support all its arguments in favor of wider reimbursement, and is required to generate a satisfactory cost-per-Quality-Adjusted Life Year (QALY, the measure used by NICE to assess cost-effectiveness).
In its general type 2 diabetes guidelines, NICE does acknowledge, with regard to Byetta, some uncertainty as to whether GLP-1s would be deemed cost-effective if the health economic model "fully reflected the negative quality of life issues of insulin, including fear of hypoglycaemia, and the costs of support and patient education for modern intensity of insulin dose titration" and added that the "more obese require much higher insulin doses, such that insulin costs alone can easily exceed those of exenatide."
Is NICE Calling for a Cost-Share?
Still, reading between the lines, it appears this preliminary appraisal for Victoza is a call not just for more data analysis, but also for a 5 cost-sharing scheme of some description to help smooth the drug's passage past the cost-effectiveness watchdog.
Such schemes appear increasingly regularly, particularly around expensive biologics and/or cancer drugs. In some cases, they make the difference between a "no" and a "yes" from NICE (6 'The Cost-Sharing Solution: The New NICE Ticket,' IN VIVO, March 2009).
Novo's not about to put forward such a plan, however, according to Birch. "It [a cost-share scheme] is not really on the radar for this product right now." Perhaps with good reason: Victoza's hardly the most expensive drug to cross NICE's desk - the low dose costs £954 per year, compared to tens of thousands of pounds for some cancer treatments.
But given the growing prevalence of diabetes, thought to affect up to 3 million people in the U.K., "NICE is probably wary of giving free rein to something that [may become] so huge," comments one analyst.
The question is whether its hardball stance on Victoza ideally balances the concern over escalating drug costs with that of the escalating costs of the disease itself (plus consequences), estimated to eat up about 10 percent of the U.K. health care budget. "Seen in that light, [liraglutide at £954 per year] is not an unreasonable cost to society," Birch stated.
Speedy U.S. Launch Helps Soften The U.K. Blow
Meanwhile, the good news for Novo is that in the U.S., Victoza has become available in the vast majority of pharmacies just three weeks after it was finally approved by FDA, and despite the inclement weather affecting much of the East Coast.
Perhaps unsurprisingly given the long delays to the drug's approval, Novo's teams and distribution plans were waiting and ready to go. "We were on the edge of our seats in terms of preparedness," recounts Novo's Alan Moses, chief medical officer for North America. "We had drug on the ground in the U.S. three days after approval and it reached pharmacies within 11 days," he says. It was all down to "extraordinary planning" along the entire supply chain (liraglutide is manufactured in Denmark), with a few calculated risks in terms of assuming that approval would, eventually, come.
Victoza's reception by prescribers could also be eased by an unlikely source. FDA officials took an unusual step of explaining their approval decision - specifically how they resolved the widely publicized concerns about a potential risk of thyroid C-cell cancer and pancreatitis - in an article published online in the New England Journal of Medicine on Feb. 17.
NICE's final guidance isn't in Novo's hands in the way the U.S. launch is, but the Danish group will doubtless apply the same vigor in attempting to influence the U.K. agency towards a more favorable verdict in March.
- Melanie Senior ( 7 m.senior@elsevier.com )
This article also appeared in "The Pink Sheet" – Feb 22, 2010
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