The diabetes pandemic (driven primarily by type 2 diabetes) has unfolded in conjunction with the ageing global population and rapid cultural changes such as increasing urbanization, dietary changes and decreased physical activity. However, despite the advent of aggressive health awareness campaigns that draw attention to the health problems associated with the key risk factor of type 2 diabetes - obesity - the prevalence of type 2 diabetes is expected to reach the 40 million mark by 2012.
Given the size of the patient pool, the chronic nature of treatment and the considerable unmet need, the promise of blockbuster revenue looms large and thus attracts the interest of major pharmaceutical companies. To be successful, a novel agent must improve glycemic control without causing hypoglycemia or weight gain.
One barrier to universal uptake of inhalable insulins is the effectiveness of other types of diabetic treatments. A variety of novel drugs are poised to be introduced to treat type 2 diabetes, including two dipeptidyl peptidase 4 (DPP-4) inhibitors in 2007, and two injectable Glucagon-like peptide 1 (GLP-1) agonists, which will likely enter the market by 2010. DPP-4 inhibitors are oral drugs which only provide a modest improvement on the efficacy of established oral drugs, but compensate by offering greater tolerability and weight neutrality.
The GLP-1 agonist class not only improves powerfully upon the efficacy of current non-insulin agents but also causes significant weight loss. Because Datamonitor does not believe that inhalable products will grow the market for insulins by advancing the initiation of insulin therapy in patients, it has not valued the commercial potential of inhalable insulins such as Exubera, as highly as other analysts.
Even in the medium term, inhalables will only increase the accessibility of insulin therapy for a limited number of very minor patient subsets, for example, hemophiliac diabetics. Presented to great fanfare to physicians and shareholders all over the world as a sure-fire blockbuster in the making, in Datamonitor's opinion, Pfizer/Nektar's Exubera is unlikely to revolutionize insulin therapy as some might expect. Datamonitor forecasts Exubera sales to stabilize at $207 million by 2015.
Insulin therapy is complicated and complex for both patient and physician alike. The patient is not only required to inject themselves but must also adhere to a complicated meal-dependent administration regimen. Meanwhile, the treating physician has to understand in detail a wide range of insulin products and translate this knowledge into patient-tailored treatment algorithm. The late-stage insulin pipeline is dominated by non-injectable insulins, and the most advanced preparations in terms of developmental maturity are inhalable formulations.
Exubera is expected to be followed, in 2010, by NovoNordisk/Aradigm AERx-iDMS, Eli Lilly/Alkermes AIR system and MannKind's Technosphere.
The next step forward
The pharmaceutical industry has long considered the development of inhalable rapid-acting insulins a significant advancement for diabetic patients who are postponing insulin therapy to avoid injections. However, although Exubera and its competitors would remove the need for injections, patients would still suffer from the usual trappings of insulin therapy. In fact, the lack of urgency associated with the unmet clinical need for non-injectable delivery formats is also reflected in the recent decisions by the UK's NICE and Germany's IQWiG not to reimburse Exubera, the first and so far only inhalable insulin launched in some of the major markets this year.
This is likely to apply to the other novel insulins as well unless they can be shown to address any of the two unmet clinical needs: an improved time-action profile and a reduction in intra-patient variability of insulins' metabolic effect. Cost of therapy will also be a key issue for patients, and any inhalable that does not garner reimbursement approval will simply not sell.
Moreover, the introduction of inhalable insulins has added a set of further potential side effects to insulin - on top of hypoglycemia and weight gain: the risk of carcinogenicity and long-term lung damage. Specifically, there is concern about the potential effect of insulin, a growth factor, on the pulmonary vasculature, such as pulmonary hypotension and pulmonary edema.
Indeed, physicians and patients are expected to be cautious in their use of inhalable insulins for fear of incurring lung cancer or long-term lung damage. Physicians will not be in any hurry to switch patients from injectables to inhalables until they have many more years of safety data, and getting these data may take up to ten years. How broadly Exubera, or indeed any other inhalable insulin, will be used is a matter of conjecture at this point. In Datamonitor's estimation, the level of unmet need for inhalable insulin is too low to fuel a multibillion dollar market. However, the market will be large enough to accommodate the four inhalables under discussion - Exubera, AIR, AERx, and Technosphere.
These will co-exist because their diversity in terms of formulation and device-handling is sufficiently pronounced to cater for the wide spectrum of end users that is characterized by differences in medical status and personal preference; the market will split accordingly.
There does appear to be one exception however. MannKind's Technosphere is distinguished by its ability to address a genuine unmet clinical need for a time-action profile that most closely mimics endogenous insulin dynamics. In fact, MannKind's candidate exhibits a time-action profile that resembles that of a healthy person more than any other rapid-acting insulin, injectable or otherwise. Moreover, phase II studies in patients with type 1 and type 2 diabetes have indicated that insulin therapy with Technosphere may also be weight-neutral.
Already forecast to become the best-selling inhalable insulin, with sales of $288 million by 2015, Technosphere's peak sales projection can still climb considerably - at the expense of its three competitors - depending on whether MannKind is able to acquire a much-needed marketing partner, but also on the degree to which Technosphere's superior time-action profile translates into superior clinical performance.
Although the emergence of new antidiabetics is definitely good news for patients, present and future, none of the new drugs will be the answer to the growing diabetes problem. Lifestyle changes and education are still needed. After all, the overweight child of today is the middle-aged diabetic of tomorrow. Compulsory school sport- ungraded and exercise-focused - for an hour a day in each country for example, would be a good start and shape the nations' bodies as much as their healthcare budgets.