Aventis: Building on a Base in Diabetes

Aventis is looking to the diabetes market to boost future growth. Lantus, the company's novel once-a-day injectable insulin, will spearhead the move. But can Aventis use an injectable to break into the fast growing Type II segment?

Since its formation in 1999 following the merger of Hoechst and Rhône-Poulenc, Aventis SA has been fuelled by its top three drugs, anti-histamine fexofenadine (Allegra), cancer drug docetaxel (Taxotere) and anti-coagulant enoxaparin sodium (Lovenox). But it cannot rely on this trio forever—Allegra is under pressure in the US market from OTC and generic versions of best-selling anti-histamine loratidine (Claritin) and Lovenox sales have weakened of late, leaving only Taxotere's growth prospects intact. Thus, to maintain growth longer term, Aventis is sharpening its focus on rapidly growing disease areas such as diabetes.

Diabetes is a disease of glucose metabolism characterized by damagingly high blood glucose levels. Type I diabetics depend on injected insulin to manage their blood glucose levels and indeed survive. The far more numerous Type II diabetics manage their blood sugar levels initially through diet and exercise regimes. When these measures fail, they take oral anti-diabetic drugs (OADs). OADs include the sulfonylureas (for example, Pfizer Inc. 's glipizide (Glucotrol/Glucotrol XL) and Aventis' glimepiride (Amaryl)) which promote insulin secretion in the pancreas, and the glitazones (such as GlaxoSmithKline PLC 's rosiglitazone maleate (Avandia) and Takeda Pharmaceutical Co. Ltd./Eli Lilly & Co. 's pioglitazone (Actos)), which increase body tissue sensitivity to insulin. When OADs fail, Type II diabetics must take insulin.

While there is still scope for developing safer and more efficacious insulin products for Type I diabetics, on the whole, their disease is effectively managed. In contrast, most Type II diabetics remain either undiagnosed or their disease remains poorly managed.

Hitting the Diabetes Highs

Clinical data provide compelling evidence for more aggressive treatment of Type II diabetes to more effectively control blood glucose levels. Two landmark clinical studies have shown that keeping blood glucose (HbA1c) levels at or below 7% leads to dramatic reductions in the risk of often-deadly diabetes-associated complications. "And often the only way to get this level of control is with insulin," points out Pierre Chancel, CEO and general manager of Aventis UK and Ireland. But convincing Type II patients to start insulin therapy is tricky.

Relatively few Type II diabetics are prepared to carry around the insulin and glucose testing paraphernalia and undergo the insulin injections that good disease management often requires. "Insulin-based therapy means pain and the inconvenience of lifestyle changes that many [Type II diabetics] aren't prepared to make," says Bank of America pharmaceutical analyst Mark Purcell.

Rather than fight human nature, most drug companies prefer to address this market with oral drugs—hence the explosion in competition in the OAD arena.

But oral drugs won't solve the problems for all Type II diabetics, thus a number of companies are trying to find more acceptable ways of inducing recalcitrant Type II patients to start using insulin to control their high blood sugar levels. GSK for example, already a leading player in the Type II market with Avandia, is working with Nobex Corp. to develop an oral insulin product to boost its diabetes offering [See Deal]. (See "A Coup for Nobex," IN VIVO, June 2002 (Also see "A Coup for Nobex" - In Vivo, 1 Jun, 2002.).) Similarly, Pfizer is attempting to move into the insulin market with inhaled insulin Exubera, in a three-way partnership with inventor Nektar Therapeutics and Aventis.

Pfizer turned to Aventis because it needed to: Aventis manufactures insulin, which Pfizer—with its small-molecule-only heritage—couldn't do. Moreover, Aventis also has some sales ties to the specialists who treat insulin-dependent diabetes, established through selling its Insuman recombinant human insulin products, as well as aging OAD Amaryl.

But Aventis is a distant number three in the diabetes and insulin businesses: its total diabetes sales in 2001 were only €742 million (then worth $657 million), compared with €2.2 billion from Novo Nordisk AS and $2.13 billion from Lilly. Still, Pfizer couldn't turn to those companies because they were developing their own pulmonary insulins.

Lantus Leads the Way

Aventis' first and biggest opportunity to move into the broader Type II market with an insulin hasn't come from Exubera, though (which is a rapid-acting insulin for control of mealtime elevations in blood glucose). It's instead come from an innovative new basal insulin product, Lantus (insulin glargine). Lantus is spearheading Aventis' strategy to establish a franchise strong enough to challenge the existing market leaders and capture a significant share of the Type II market.

Aventis' three-pronged plan of attack is based on offering innovative products that address unmet medical needs, aggressively marketing them to specialists and primary care physicians (PCPs), and educating doctors and patients about the clinical benefits of earlier insulinization in Type II diabetics.

Lantus fills the innovative product part of the strategy. Aventis scientists made just two amino acid modifications in the basic insulin structure to give the hormone a unique pharmacokinetic profile that releases steady amounts of the drug into the blood stream over 24 hours. Lantus avoids the peak or spike of insulin in the blood that NPH insulins (Neutral Protamine Hagedorn—the standard intermediate-acting insulin) cause, thereby reducing the incidence of life-threateningly low blood sugar levels that can be associated with those peaks. Moreover, the majority of users need only one injection of Lantus a day, whereas NPH insulins often require two or more.

Aventis' aggressive marketing support for Lantus—which has been launched in Germany (May 2000), the US (May 2001) and the UK (August 2002)—has helped make the product a hit. Lantus has been able to capture around 40% of the German basal insulin market and is performing equally well in the US, capturing 33% of the intermediate and long-acting insulin segment there, according to the company.

Marketing Might

In all three territories, Aventis has recruited and/or deployed more sales reps to detail the product than any of its competitors. Dirk Ullrich, head of the diabetology business unit of Aventis Pharma in Germany, confirms that the company has doubled its German sales force to allow it to increase its focus on marketing Lantus to PCPs. "We now have an advantage [in Germany] over our main competitors, especially Novo Nordisk," Ullrich claims.

In the UK, rather than recruit new sales reps, Aventis is redeploying reps from the promotion of other products to detail Lantus. And in the US the company now has more sales reps in the insulin space than any of its competitors. According to Purcell, the company has around 1100 reps detailing Lantus, principally to PCPs, compared to Lilly's 850 and Novo's 550.

And these reps have been particularly successful at getting the Lantus message across. According to c.baX GMBH, a collator of data on the impact of sales initiatives on German doctors' prescribing habits, physicians rate the Lantus product story as very convincing. Every 100 details generate 14 potential prescribers (the German average for a product that's been on the market for longer than one year is 8-10 potential prescribers per 100 details) and 95% of German doctors treating diabetics prescribe Lantus either regularly or occasionally.

Some analyst reports suggest that Lantus has gained market share in Germany primarily at Novo's expense. Novo's executive VP and CSO Mads Krogsgaard Thomsen, PhD, concedes "in basal insulin we have lost market share to Lantus in Germany, but we've captured market share in the premix and rapid-acting insulin segments so overall our insulin market share remains steady at 44%" of the total German market.

Thomsen contends that Lantus is having more of an impact on Lilly's insulin sales on both sides of the Atlantic. Bank of America's Purcell says Lilly is losing share to Lantus primarily because the two companies are targeting the same PCP audience; and with its bigger sales force, Aventis is winning the battle. Since Novo's sales force generally targets hospital diabetologists, the impact of Aventis' aggressive marketing campaign is weaker, according to Purcell.

Lilly declined to comment on Lantus' effect on its insulin franchise, except to say, through a spokesperson, that the product "is expected to have only a minimal impact on the company's European insulin market share."

The UK Test

Analysts expected Lantus would do well in Germany and the US. Aventis was already the strongest player in insulin in Germany, one of its home markets, and there was little real competition in the segment in the US, they say.

The UK will be Lantus's first real test. Since both Novo and Lilly have strong sales there, Lantus' UK performance "will be a pretty good indicator as to whether Novo and Lilly are likely to lose out in other markets," Lehman Brothers' Stewart Adkins says.

Despite the increased competitive pressure, however, Aventis' Chancel maintains that "the current ramp-up of Lantus is three times higher than the launch of any other insulin in the UK—which is completely consistent with what happened in Germany and the US."

UK retail pharmacy sales data from NDC Health UK support Chancel's comment. In its first three full months on the market, Lantus has captured over 29% of the long-acting insulin segment at the expense of both Lilly's Humulin range, whose market share has fallen from 33% to 23%, and Novo's Insulatard products, whose 64% share has fallen to 48%. Purcell sums up, "Lantus' performance to date has shown that with innovative products, you can capture market share."

Can Lantus Break into Type II?

Lantus will be rolled-out across the rest of Europe by the end of 2003, and judging by its performance in the German and UK markets, looks set to do well enough. But Lantus' long term success depends on whether it can grow the total basal insulin market. This is where the third prong of Aventis' diabetes plan--physician and patient education strategy of promoting earlier insulinization in Type II diabetics--becomes vitally important.

Many patients simply don't appreciate the serious consequences of not effectively treating their disease, opines Pascal Soriot, Aventis' senior VP global marketing and medical. "They think ‘ I just have a little bit of sugar in my blood—it's OK, I can live with that," he says. Soriot adds that patients need to be made more aware of the consequences of not treating their disease aggressively enough or not complying with their treatment regimes. To get the point across, to both patients and their treating physicians, Aventis has launched its "Treat-to-Target" campaign. The message: diabetes should be treated aggressively, employing earlier insulinization of type II patients where necessary, to ensure that they reach the recommended target blood glucose levels. In the US, the company will likely use DTC advertising to get that message out—and promote Lantus as the therapy to use. In Europe, which bans DTC ads, the message will be more discreetly promoted.

Exubera and Beyond

Lantus may have done well so far, but it's still just another injectable insulin, and no injectable product has yet succeeded in cracking the Type II insulin market. Purcell suggests that many of the Type II patients now using Lantus are "the low hanging fruit"—those already taking insulin, for whom once-a-day injection is preferable.

Aventis may have a second trump card, though: the inhalable insulin Exubera. "If Exubera is launched, it will be an amazing drug—a mega blockbuster—it will be a revolution in the treatment of diabetes," enthuses Jerome Berton of ING France.

But although Exubera has successfully completed Phase III trials, showing similar blood glucose control to injectable insulins, the drug is now bogged down in additional safety trials to investigate concerns over adverse effects on the lungs. Neither Aventis nor Pfizer has issued guidance on their expected filing dates. One analyst gives Exubera only a 50% chance of approval and, like many of his peers, has removed sales estimates for the product from his financial models for Aventis.

Even if it does make it to market, Exubera can only address mealtime blood glucose peaks, so insulinized patients will still need to inject basal insulins like Lantus for the time being.

Besides Exubera and some research and early development stage products that the company's not yet prepared to discuss, Aventis only has two other products in its diabetes pipeline. HMR 1964 is an injectable fast-acting insulin, currently in Phase III trials, that will be complimentary to Lantus in both Type I and Type II patients who need meal-time glucose control. But the insulin doesn't seem to offer any benefit over established fast-acting insulin analogs like Novo's NovoRapid/NovoLog and Lilly's Humalog.

Aventis' Diapep 277 is an immunomodulator in-licensed from Peptor Ltd. in July 2002 [See Deal]. The drug could prevent or delay the progression of pancreatic cell destruction in Type I diabetes and will likely have significant potential if it succeeds in the clinic. But neither Diapep 277 nor HMR1964 addresses the key Type II market. Moreover, Aventis has no OAD products in development to follow on from Amaryl, which will lose patent protection in the US in 2004 and in Europe in 2005.

"It's not exactly a pipeline to die for, is it?" concludes Lehman's Adkins.

As such, if Aventis is really committed to breaking into the Type II market in the near future as it claims, it's going to have to bolster its pipeline through in-licensing.

Like many of its Big Pharma peers, Aventis has been an aggressive in-licenser—winning DiaPep 277 in 2002, for example--and thanks to a number of divestments, such as the crop sciences business, it has plenty of cash. With Lantus, Exubera and a broader pipeline bolstered by further in-licensing, Aventis may well get the push it needs to become a more serious contender in diabetes.

--by Hazel Dawson

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