NICE Snubs Novo With Draft Lira Guidance

You'd think that even NICE would have welcomed with open arms a new, effective treatment option for the UK's nearly 3 million diabetic patients--particularly one that not only lowers blood sugar, but also causes weight loss.

Nah. NICE is playing hardball (again). Its draft recommendation for Novo Nordisk's GLP-1 analog liraglutide (Victoza), although not nearly so damning as last week's preliminary guidance around Sprycel and Tasigna, suggests that the drug be used only in limited circumstances by the National Health Service. 'Limited' means a) as part of triple therapy regimens only (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 35kg/m2 (that's high) and c) only at the lower, 1.2mg daily dose.

Ok, so patients that aren't quite so obese as 35kg/m2 could also qualify for the drug, "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", the NICE press release concedes.

But a quick read of the 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% of body weight after six months (that's not far off the threshold for an actual weight-loss drug) and sees a reduction in blood sugar levels of at least 1 percentage point.

It seems, at first glance, to be a case of "damned if you do, damned if you don't" for Novo. After all, weight loss is supposed to be a nice side-effect of the diabetes drug--one that could lead to lower incidence of co-morbitidies--yet it's apparently being used to limit its reimbursement.

Although NICE concedes that liraglutide "may have some advantages over insulin...in particular its effect on weight," it appears to rule out the higher dose point blank, and is asking for further analyses on the cost-effectiveness of liraglutide on patients with a lower BMI, which it says were not presented.

NICE was also unsatisfied with the extent of the data comparing liraglutide in triple therapy with other combinations of oral drugs, including for instance DPP-4 inhibitors, and felt that the LEAD-1 trial comparing liraglutide to rosiglitazone used an insufficiently high dose of the glitazone.

It's impossible to cover all the various permutations and combinations in diabetes therapy, however--and Novo did submit data from six trials in over 4000 patients. All except one of the trials showed that the drug reduced HbA1c levels significantly better than comparators, which included rosiglitazone (Avandia), sitagliptin (Januvia, the DPP-4 inhibitor), insulin glargine (Lantus), placebo, and Lilly/Amylin's exenatide (Byetta, the only other GLP-1 out there). The exception: the LEAD-2 trial, comparing liraglutide with glimepiride (Amaryl), which showed up liraglutide's weight advantage although no significant difference in blood sugar lowering.

Perhaps NICE's conclusion isn't such a surprise, though, considering the fate of Byetta in the UK (which you can read about in NICE's Type 2 diabetes guideline document). In brief, Byetta's "not recommended for routine use in Type II diabetes", with the same six-month benefit hurdles as described above, deemed as "expensive" and "not cost-effective for an unselected population as compared to commencing human insulin therapy."

As such, Novo's VP Europe, Viggo Birch, admitted that "given what they [NICE] have done for exenatide, this is what you'd expect in the first round." Still, "I'm not happy with it," he continued. "We have a much better product [than exenatide] and much better data." Novo's looking for reimbursement as second-line therapy, "at least for important patient subgroups," and a relaxation of the BMI-based restriction, since this, Birch claims, "isn't fair; it was plucked out of the sky."

There's a crack in the door, though. NICE will hold another meeting on March 18, allowing Novo and others time to comment and submit further data supporting wider use of the drug. And in its full diabetes document, 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."

Still, reading between the lines, we suspect this preliminary appraisal for Victoza is a call not just for more analysis, but also for a cost-sharing scheme of some description to help smooth the drug's passage past the cost-effectiveness watchdog.

That's not likely, according to Birch. "It [a cost-share scheme] is not really on the radar for this product right now." Perhaps with reason: after all, Victoza's hardly the most expensive drug to cross NICE's desk--the low dose costs GBP 954 per year, compared to tens of thousands of pounds for some cancer treatments.

But given the growing prevalence of diabetes, "NICE is probably wary of giving free rein to something that [may become] so huge" comments one analyst.

The question is whether its hard-ball 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% of the health care budget.

image by flikrer Roland used under a creative commons license

Victoza Gets Past FDA, But....

There are a few caveats. First, a black box warning for the once-daily GLP-1 analog which includes a potential increased risk of thyroid cancer (despite Novo Nordisk's repeated claims that this applies only to rodents, not monkeys or humans). Second, no first-line usage allowed. Third, significant post-approval requirements, including a CV safety study, a 5-year epidemiological study to evaluate thyroid cancer risks, a 15-year cancer registry to monitor thyroid cancer cases, and a REMS.

As such, "it's a worst case label for the product," concluded Sam Fazeli, an analyst at Piper Jaffray in London. "Bittersweet" was how Jefferies' Jeffrey Holford put it, while Citigroup simply cut to the chase with "Commercial success far from certain."

Things could have been still bleaker, though. At least the US approval has finally happened (the drug was filed in May 2008). It might have been pushed out significantly further, given the regulators' apparent problem with the thyroid cancer risk. And on the up-side, there's no need for calcitonin monitoring during Victoza therapy (calcitonin is the marker used in humans for thyroid cancer) and there are no broad contra-indications for the drug. Only patients with a family history of medullary thyroid cancer, or multiple endocrine neoplasia syndrome, aren't allowed Victoza--and both those indications are very rare.

As such, Novo's management was upbeat during the analyst call announcing the news. The REMS is very remiscent of that recently imposed on Lilly/Amylin's twice-daily GLP-1 analog Byetta, said EVP & CSO Mads Thomsen, and certainly manageable. He added that many diabetes drugs (metformin, the sulphonylureas) have black box warnings, and most new products aren't awarded first-line treatment at their first pass at FDA. Thus, "we're perfectly happy with our monotherapy label," he said. (The product was denied approval as a monotherapy in Europe).

There a big 'but', though--and it's Byetta. That product has not only a five-year head start, but also hasn't got a black box, hasn't got a thyroid cancer risk warning, can be used as an initial therapy, and thus remains "first choice" treatment in this class, according to Fazeli, despite its more frequent administration.

This explains the generally (although not exclusively) down-beat analyst reaction to the news; "we see more room for disappointment than surprise on Victoza," writes Citigroup's Mark Dainty. Never mind the fact that Victoza outperformed Byetta in blood sugar lowering in a recent Phase III head-to-head trial.

Novo's management still thinks it can surprise, however. (They're a confident lot.) They re-iterated their forecasts that Victoza will reach sales of over $1 billion by 2015 (Byetta's currently at about $700 million and it has been on the US market since 2005).

Much will depend on whether follow-on GLP-1 analogs including long-acting Byetta (EQW) and Roche/Ipsen's taspoglutide are stamped with the same thyroid cancer warnings as Victoza. (Amylin's epidemiological study of Byetta is due March 31). Novo's Thomsen is adamant that the thyroid cancer signal seen among rodents is a class-effect among the long-acting GLP-1 analogs, and points to a forthcoming peer-reviewed scientific paper outlining what he claims is a similar pre-clinical effect on thyroid c-cells for Victoza, long-acting Byetta and taspoglutide. "We'll have to live with the notion that long-acting GLP-1 analogs cause c-cell proliferation in rodents," he told The In Vivo Blog. "But there's no reason to believe that these findings have any relevance to higher species," he added.

Whether or not the other long-acting GLP-1s get the same treatment, FDA is unlikely to remove Victoza's black box for several years at least, likely until the 5-year follow-up cancer study data is available.

Meanwhile, though, with its already-expanded US sales force and pricing in line with Byetta at about $8/day for the 1.2mg dose, Novo will be pushing Victoza with all its might and leveraging its wider diabetes franchise where possible. And let's not forget the fundamentals: Victoza is once-daily, can be taken anytime, prompts some weight loss, isn't associated with hypoglycemia or significant nausea, and is relatively easy to titrate.

Those elements may yet trump the worries about cancer in rats.

Novo Hopes Victoza’s EU Clearance Bodes Well for US

As the European Commission today gave its final green light to Novo’s much-anticipated GLP-1 inhibitor liraglutide (Victoza) (no surprise, given the CHMP’s positive recommendation back in April), the company’s still bullish on the drug’s prospects in the US—anticipating not only approval but a none-too-severe risk-management plan as well.

“Our expectation is that the whole post-marketing system that we’ll agree and adhere to in the US will not be of a severity that will be commercially destructive to the product, not prohibitive for easy daily use in the doctor’s surgery,” Novo’s CMO Mads Thomsen told us (but enough, one assumes, to give practitioners comfort and get a leg in versus Byetta…).

Thomsen’s taking heart, perhaps, from the squeaky clean EU approval, which came with no usage restrictions and no contra-indications—despite an earlier split vote from an FDA advisory committee in April over whether Victoza should be approved in the US at all, due to increased cases of thyroid tumors seen among rodents.

The European authorities apparently liked the sound of Novo’s commitment to undertake a global, 9000-patient, five-year post-approval cardiovascular outcomes trial, including not just the classical MACE analyses of CV risk, but also various thyroid-related parameters, according to Thomsen. “The plan is to have the study protocol negotiated with the FDA as well [as the Europeans] by year-end,” he told The IN VIVO Blog—and to start recruiting a couple of months later.

So does that mean US approval’s likely before year-end? Not all analysts are that bullish, given the challenges of monitoring any potential thyroid risk in humans (though the worst-case scenario for some, a black-box warning, doesn't necessarily kill sales--just look at Actos). But as far as Thomsen’s concerned, yes, “we’re assuming that either we have US approval by then, or that we’re so far down the regulatory process that the CV study design will be part of the discussions,” he continues.

Novo’s in a hurry because liraglutide is already late (speed-to-market hasn’t always been Novo’s strength, as we reported in more detail here, although product quality has more often than not made up for this). Lilly/Amylin’s long-acting Byetta (taken once-weekly vs once-daily for liraglutide) is close on Novo’s heels, and these companies, unlike Novo, have an existing GLP-1 platform to build on.

Still, Novo’s going to do its damnedest to leverage its own insulin sales force to get liraglutide out as quickly as possible to a broad prescriber base, says Thomson. Not unusually, the UK and Germany, two of Europe’s largest markets where up-front pricing is free, will be the starting points. “We’ll make some minor adjustments to sales force size in Europe,” he says, “but we’re only talking an additional 100 or so.” Thomson says that a “sizable” part of the insulin sales force will be re-allocated to liraglutide, at least during the launch phase, as the company tries to capture what it hopes will be “positive perception of innovation” at Novo among diabetes drug prescribers.

It won’t just be the specialists, though: since liraglutide is easier to use than insulin (it doesn’t require blood sugar monitoring or dose titration), “we anticipate a broader prescription base [than insulin] and moving into the GP market within several months,” says Thomsen.

Liraglutide will be positioned as “the natural second-line therapy after metformin failure,” explains Thomsen, given its “superior clinical profile, effect on body weight and lack of hypoglycemia.” In this regard, Novo’s racing not just against Byetta and family, but against the (oral, and thus highly convenient, and cheaper) DPP-IV inhibitors, too—like Merck’s Januvia and, shortly, AstraZeneca’s saxagliptin (Onglyza), which last week received a positive EU opinion. Indeed, “the question is whether second-line therapy is liraglutide, or another oral therapy,” summarizes Thomson.

Novo’s leading position in the insulin market means it isn’t about to admit that liraglutide’s success will eat into its core franchise. But even if it does delay progression to insulin somewhat, Novo’s hoping the drug allows to it capture patients earlier on in the course of their disease. The idea is that pre-insulin diabetics become loyal Novo followers, “using our services and devices, and…that later on, when they go onto insulin, they’ll add [Novo’s basal insulin] Levemir”—and not Sanofi-Aventis’ competing Lantus—on top of liraglutide, explains Thomsen.

That argument might well be boosted by recent data—albeit still controversial—linking Lantus to an increased cancer risk, a link Novo is trying hard to ring-fence as a Lantus-specific problem, not one that affects all basal insulins.

For the next chapter in Victoza’s US story, we’ll have to wait until August 6th and Novo’s half-year results. The company in early June met FDA to talk risk-management and to discuss Victoza’s victorious performance in a gutsy two-year head-to-head trial versus Byetta. FDA "didn’t have access to this material prior to the [April] advisory committee meeting,” clarifies Thomsen.

In this trial, liraglutide also showed itself as “drug squeaky clean with regard to calcitonin levels compared to comparator drugs…” hence “the [US] regulators will also believe, like us, that the benefit-risk profile of performing invasive procedures to monitor patients’ calcitonin levels is negative,” asserts Thomsen.

Are you listening, FDA?

At Least the Europeans Appreciate Novo's Victoza

It’s all smiles again at Novo Nordisk following yesterday’s news that EMEA has recommended approval of its GLP-1 agonist liraglutide (Victoza).

The positive opinion followed a decidedly lukewarm US advisory committee outcome earlier this month, where concerns were raised not over cardiovascular safety (a possibility, given FDA’s more stringent diabetes guidelines) but over a raised incidence of thyroid c-cell tumors in rodents during pre-clinical trials. (We cheekily suggested thereafter that Novo might not mind so much about GLP-1s anyway.)

The European regulators, however, appear to agree with Novo’s CSO Mads Thomsen that “the mechanism [behind the raised incidence of thyroid c-cell tumors] is one that mice and rats are sensitive to, but that monkeys and humans are not.”

The regulators haven’t even requested that the company take any additional measures—such as thyroid cancer screening—to rule out the potential risk. “There are no restrictions on usage” as a result of the pre-clinical thyroid cancer data, Thomsen told The IN VIVO Blog. “It was a clean approval.”

Well, a clean recommendation anyway; the European Commission must still issue the final marketing authorization, expected in about two months. With that in hand, Novo will begin to sell Victoza in various European markets over the summer.

This un-restricted European thumbs-up for Victoza matters not just for the drug’s EU commercial potential. China, for instance—a key emerging market for Novo--requires a sponsor to have home-market approval before it can even submit a new therapy. And there will be positive knock-on effects of a European approval in other markets, too, adds Thomsen, since "some countries simply base their approval decisions on the European outcome."

Unfortunately, the US is not one of them. FDA is due to decide late next month whether to approve Victoza, but based on the split advisory panel outcome and an almost entirely risk-focused (as opposed to benefit-focused) discussion, things don’t look good. Analysts including Matthew Osborne, SVP at Lazard Capital Markets, reckon that the best case would be that Victoza launches on time during the second half of the year but with a black box warning and/or monitoring for thyroid cancer. Other options: a 6-12 month-delay due to a request for additional data, or outright rejection. Not a great outlook for a drug predicted to become a blockbuster by 2012.

This isn't the first time European regulators have approved a drug that FDA has rejected or at least prevaricated over. Sanofi-Aventis' obesity candidate rimonabant (Acomplia; Zimulti in the US) was another. Given what happened to that (rejection in the US, withdrawal in Europe), it's interesting--comforting?--to see that FDA's ultra-risk-focused conservatism isn't rubbing off too hard on the Europeans just yet.

image by flikrer sean-b used under a creative commons licence

Whoops! Did We--and Novo--Speak Too Soon?

Did we—and Novo—speak too soon yesterday about Victoza’s chances at the FDA advisory committee next month? We reported Novo’s confidence that its GLP-1 analog liraglutide won’t be required to comply fully with the new FDA diabetes guidance issued last December.

Today, however, Takeda tells us that FDA has said its new diabetes treatment, alogliptin, will indeed be subject to the December guidance, even though it, like Victoza, was submitted earlier. It appears that Takeda will require more data, and, according to JP Morgan analysts, “this provides absolute clarity that FDA will now apply its new guidelines to all new diabetes drug applications.” Oh dear. Misplaced confidence? (Certainly Novo’s investors think so: shares were off about 3% today.)

But Novo’s position hasn’t changed. “Today is no different than yesterday,” Novo’s CMO Mads Krogsgaard Thomsen told The In Vivo Blog this afternoon. Liraglutide’s clinical trial program is more than double the size of alogliptin’s. And they’re completely different drugs: alogliptin is a DPP-IV inhibitor, a class that isn’t shown to improve blood pressure or reduce weight, as Novo claims is the case with Victoza. It’s conceivable, therefore, that FDA might hold DPP-IV inhibitors up to the new guidance—but not GLP-1 analogs, at least, not quite so strictly.

Thomsen also re-iterates that the company has done its MACE analyses (of CV events) with good results—indeed, the JP Morgan analysts appear to interpret this as Victoza actually meeting the new guidance requirements, despite the statistical powering issues (we couldn’t check as they don’t talk to journalists.)

Victoza’s other potential advantage: it’s clearly differentiated from the only other drug in its class, Lilly/Amylin's Byetta, on both efficacy and conveniece. Takeda can’t say the same.

Good for Novo. Why not hold a brave face? If one thing’s clear, though, it’s that victory next month is not a foregone conclusion. But even if Victoza does stumble—and, as one of you kindly pointed out yesterday, pancreatitis is another possible hurdle, given Byetta’s story so far, although Novo doesn’t think it will be more than a labelling issue—Novo might not mind that much (not that it would ever say so.) As mentioned, any delay would likely stall Byetta LAR, too. Which leaves Novo playing in the field where it’s strongest: insulin.

image from flikr user Mel B. used under a creative commons license