In the rush to develop new diabetes drugs, big pharma's focus has been mainly on anti-diabetic agents that prolong a patient's transition to insulin or on developing easier routes of administration for insulin that do away with the need for pesky needles.

But Pfizer's infamous blunder with the inhaled insulin Exubera led to just about every other player in that market throwing in the towel (Mannkind excepted). And now it appears FDA could be about to cast a wide safety net over diabetes drug developers - one to reel them in with, not keep them from sinking.

All in all, the development and regulatory hurdles are making injectable insulin - the hormone that helps diabetics regulate glucose - look as dependable as ever, like betting on the slow but steady tortoise to win a race instead of the unpredictable hare.

Novo Nordisk is betting on both. Investors certainly have their eyes on Novo Nordisk's oral, long-acting glucagon-like peptide-1 analogue Victoza (liraglutide), currently pending at FDA with an Endocrinologic and Metabolic Drugs Advisory Committee meeting scheduled for March 2 (¹ Also see "Novo’s Liraglutide Gets Advisory Committee Review; Is Byetta To Blame?" - Pink Sheet, 5 September, 2008.).

But the Danish drug maker's late-stage pipeline also includes two new-generation insulins. The company announced during its third-quarter sales and earnings release Oct. 30 that it is readying the two products, NN5401 and NN1250, both of which have a potential duration of action of more than 24 hours, for Phase III trials, targeted for the second half of 2009.

Insulin Sales On Upswing, Despite New Drugs

Novo Nordisk, along with Eli Lilly and Sanofi-Aventis, is a key player in the insulin market. Novo markets the short-acting insulins NovoRapid and NovoMix and long-acting Levemir (insulin detemir [rDNA origin]). Sanofi's leading insulin is the long-acting Lantus (insulin glargine injection), and Lilly sells the short-acting Humulin (human insulin [rNDA origin]) and Humalog (insulin lispro injection [rDNA origin]) franchises.

Insulin was a strong contributor to each of these company's top-lines in the first nine months of the year. Novo's sales of modern insulins - engineered analogs of naturally occurring human insulin - increased 22 percent, despite a negative impact from currency, to DKK 12.29 billion ($2.14 billion) for the first nine months of the year. Sales of Lilly's Humalog and Humulin were up 21 percent to $1.28 billion and up 12 percent to $800.8 million, respectively, for the nine months. Sales of Sanofi's Lantus jumped 29 percent to $1.75 billion.

Market growth is being driven by the increasing number of patients diagnosed with type 2 diabetes. Within the insulin segment, growth is coming from synthetic insulins as patients convert from human insulin, as well as more convenient prefilled delivery devices. Around 56 percent of the global insulin market had converted to modern insulins by the second quarter 2008, versus 50 percent in Q2 2007, Novo Nordisk reported, citing IMS data. In the second quarter 2003 only 25 percent of the market was in synthetic insulins.

Growth has continued despite the introduction of new drugs intended to delay a patient's progression to insulin, like Merck's dipeptidyl peptidase-4 inhibitor Januvia (sitagliptin) and Lilly/Amylin's Byetta (exenatide).

That's because, for now, disease progression ultimately leads to insulin. New guidelines issued by the American Diabetes Association and European Association for the Study of Diabetes, released Oct. 22, mention insulin or a sulfonylurea as preferred over a GLP-1 inhibitor or pioglitazone in second-line therapy in type 2 diabetes patients whose blood glucose levels are not maintained with lifestyle intervention and metformin.

Longer-term, however, a threat to brand marketers is waiting in the wings: biosimilars. Insulin is an old, simple protein, making it a target for biosimilar competition.

Novo Eyes Thrice-Weekly Dosing Regimen

Novo Nordisk's strategy, though, is to develop formula and delivery enhancements to continue to bring differentiated products to market. "Novo Nordisk is the only company with a new generation of insulins in full clinical development," Chief Scientific Officer Mads Krosgsgaard Thomsen said during an Oct. 30 conference call. "The ambition is to further improve the treatment success rate, tolerability and convenience of insulin therapy for people with type 1 and type 2 diabetes."

Novo's new insulins, which recently completed proof-of-concept, include a long-acting insulin analogue (NN1250) studied in both type 1 and type 2 diabetes and a soluble dual-acting insulin analogue preparation (NN5401) studied in type 2 diabetes.

Importantly, NN1250, dosed three times a week, every Monday, Wednesday and Friday, was found to be similar to the once-daily basal insulin arm. If similar results are seen in Phase III, it could be the first insulin to offer a thrice-weekly regimen.

Thrice-weekly dosing could offer a competitive advantage over Sanofi's Lantus, which is approved for use every 24 hours.

"This agent was so long-acting that we may indeed provide it to the patient on a Monday, Wednesday, Friday regimen, giving the patient a holiday off the drug at the weekend," Thomsen stated during a follow up analyst meeting in London Oct. 31.

In addition to offering patient convenience, the regimen also could help with compliance. Data have shown that compliance with insulin injection therapy in type 2 diabetes patients is only around 75 percent, the exec added, which translates to about every fourth injection not being taken.

"Even relative non-compliance will have less deleterious effects for this compound than for any other base," he said.

In four clinical studies, enrolling around 700 patients, NN1250 was evaluated against insulin glargine and NN5401 was compared to NovoMix 30 and insulin glargine. Patients were treated for 16 weeks.

Data from the trials showed both insulins were safe and offered long-lasting blood glucose lowering. Between 50 to 75 percent of people with type 2 diabetes treated with NN5401 achieved HbA1C levels below 7 percent with no incidences of hypoglycemia during the last four weeks of treatment, Novo Nordisk reported.

Around half of those treated with once-daily NN1250 achieved HbA1C levels below 7 percent without hypoglycemia in the last four weeks of treatment.

Novo Nordisk is initiating discussions with regulatory authorities to design the Phase III program.

Insulin Could Bypass CV Hurdles At FDA

One reason why the near-term insulin market looks more appealing these days is that diabetes drugs are under intense scrutiny at FDA as part of the fallout from the safety data that emerged around GlaxoSmithKline's Avandia (rosiglitazone). Potential regulatory hurdles for type 2 diabetes drugs - namely the threat that FDA could require large cardiovascular outcomes studies - has made the therapeutic area look far less attractive to drug makers than it did a year ago.

It's not yet clear if new FDA safety requirements for diabetes drugs, if adopted, would apply to insulin. Novo Nordisk speculates it's unlikely. The company expects to get more input from FDA on the topic during its end of Phase II meeting.

FDA currently is assessing the kinds of cardiovascular safety data that should be required for diabetes drugs, after its advisory panel concluded earlier this year that the agency's approval standards are inadequate to assess cardiovascular effects. The panel expressed concerns that sponsors are focusing too much on measuring blood glucose lowering effects without sufficiently testing cardiovascular risk (² Also see "Diabetes Therapies Need Cardiovascular Safety Data For Approval, Panel Says" - Pink Sheet, 7 July, 2008., p. 3).

"Our argument is that what was being discussed there was diabetes drugs as such and not insulins, because insulin is known to be good for the heart," Thomsen said. "My take of the cardiovascular discussion is that this is not an insulin-applicable phenomenon, but it is for all non-insulins, including those that have just entered the market."

Novo Pushes Victoza Outcomes Post-Approval

But any cardiovascular safety requirements to emerge from FDA could impact other diabetes drugs in development by Novo Nordisk, including Victoza, which would mark the company's entry into the GLP-1 market with a dosing benefit over Byetta.

Nonetheless, management said it remains confident it has sufficient data to address FDA's immediate questions on cardiovascular safety for Victoza, and indicated that larger outcomes studies will be conducted post-approval.

"Novo Nordisk is in a very good and productive dialogue with the agency concerning what to do to rule out that cardiovascular harm [may] be done to people," Thomsen said.

"It is my clear expectation that we can move to the March 2 advisory committee meeting with the FDA and their panel in good faith and with a discussion of, among other things, what to do with cardiovascular things post approval," he added.

Big Pharma Skittish On Diabetes

Big pharma has been jittery lately wondering if FDA will require larger, more expensive clinical trials for diabetes drugs prior to approval.

For Novo's part, Exec VP and Chief Financial Officer Jesper Brandgaard maintained, "A company that has a promising product in diabetes care will never drop it only because the FDA is getting tougher."

But some drug makers are taking a more cautious stance. Sanofi-Aventis announced Oct. 31 that it is halting development of a Phase II oral sodium-glucose cotransporter-2 inhibitor AVE2268 for type 2 diabetes, citing both increased regulatory hurdles for anti-diabetic drugs and product differentiation challenges.

Sanofi's decision to discontinue development of AVE2268 could raise some red flags with the class. Bristol-Myers Squibb and AstraZeneca are developing dapagliflozin, an SGLT-2 inhibitor that is nearing Phase III.

"Our understanding is that SGLT-2s are likely to be put through the FDA ringer in terms of what studies have to be done to get approval," Sanford C. Bernstein analyst Timothy Anderson said in a same-day research note. "This is likely to include cardiovascular outcomes trials and, given the SGLT-2 mechanism of action (increased glucose excretion from the kidney), clinical trials in renally compromised patients."

Byetta LAR May See Delay

GLP-1 analogues are facing their own safety scrutiny, however, after cases of pancreatitis emerged following treatment with Byetta (³ Also see "Byetta Safety Concerns Could Set Roadblocks Ahead For New GLP-1s" - Pink Sheet, 21 August, 2008.).

Lilly and Amylin also are developing an extended-release form of Byetta. The companies have been targeting a first-half 2009 NDA filing for Byetta, but in a ⁴ 10-Q filing Nov. 4, Amylin indicates that it may not meet that goal (⁵ Also see "Amylin Speculation Intensifies: Byetta LAR May Be Delayed" - Pink Sheet, 4 November, 2008.).

- Jessica Merrill (j.merrill@elsevier.com)

Don’t Forget Injectable Insulin, Novo Nordisk Says

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