Pharma & drug development

A losing battle?

The idea of delivering insulin via inhaler has been around for some time, but with Pfizer and Sanofi dropping their pioneering products, has this form of delivery failed to live up to its promise? Abi Millar investigates.  

Diabetes is on the rise. In the UK, the number of people suffering from this chronic health condition is now estimated at over 4 million, and the figure is expected to surpass 5 million by 2025. Across the Atlantic, more than 29 million people have diabetes – a staggering 9.3% of the American population. A further 86 million have prediabetes, placing them at heightened risk of becoming ill.

For many sufferers, especially those with type 1 diabetes, regular insulin injections are a lifeline. On top of lifestyle measures and other medications, they may need to use their syringe or autoinjector as many as four times a day. This ensures the drug is administered directly into the bloodstream, rather than being metabolised like food, as would occur with an insulin pill.

Injections, however, are far from the most comfortable or convenient route of administration. For a number of years, the pharmaceutical community has been on a quest for alternatives, with many pondering whether insulin might be inhaled instead.

History repeats itself

In 2006, the world’s first inhalable insulin, Pfizer’s Exubera, was released to great fanfare. Forecast to draw in $2bn a year in sales, the drug was expected to revolutionise the diabetes treatment landscape. Unfortunately, in the face of mounting safety concerns, Exubera was pulled. As the hype died down, a number of similar products in development were quietly shelved.

It wasn’t until February 2015, with the release of Sanofi’s Afrezza, that the potential seemed to rise again. Developed by MannKind, this drug-device combination product comprises a dry formulation of insulin delivered through a small portable inhaler, and was also valued at around $2bn (around a tenth of the total global insulin market). It was intended to meet “a recognised need for an insulin that doesn’t require an injection”.

So when, in January 2016, Sanofi announced it would pull the plug on Afrezza, history appeared to repeat itself in the most dispiriting way.

“Sanofi did not spend as much on advertising for Afrezza as Pfizer had on Exubera,” says GlobalData analyst Jesus Cuaron. “Instead of spending on promoting initially, Sanofi waited to gain more insight on which patients would opt for such a treatment, while also collecting patient and physician feedback after using the product. However, despite the difference in advertising approach, along with the drug being more efficacious than Exubera, Afrezza ultimately met the same fate.”

Missed targets 

Sanofi originally struck its partnership with MannKind in August 2014, agreeing that Sanofi would be responsible for commercial, regulatory and developmental activities, while MannKind would focus on manufacturing. As per the terms of the deal, MannKind secured an upfront payment of $150 million, and stood to receive further payments up to $775 million alongside a share of profits. This, however, was conditional on meeting targets that did not come to pass.

With sales slow from the outset (reaching just $1.1 million in Q1 2015), it soon began apparent that Afrezza did not have blockbuster potential. And when subsequent quarterly sales ($2.2 million by Q2 and $5.4 million by Q3) proved similarly sluggish, the drug’s fate appeared to be sealed.

“Sanofi is a leader in the diabetes space, boasting the best-selling insulin in the world, Lantus. Thus, the company has extensive resources and experience to interpret that Afrezza has come to a dead-end,” explains Cuaron. “Although other strategies could be pursued to revamp potential uptake and sales, Sanofi is cutting its losses and reallocating its promotional resources to other products in the company’s diabetes portfolio, such as Toujeo, the successor of Lantus.”

With rights now due to revert to MannKind, the outlook for Afrezza seems shaky. MannKind has stated that it is investigating other uses and applications for its technology, and it is thought the company will try to salvage what it can. But with no licensing partners confirmed, and a 40% dip in shares, it may appear that the California-based drugmaker is fighting a losing battle. Is there any hope for Afrezza, or more broadly for inhalable insulin at all?

Doctors’ doubts

“If MannKind is able to continue its pursuit with Afrezza, the company will have to lower the cost in order to make it more competitive with incumbent insulins on the market,” says Cuaron. “This would result in payers being more willing to cover Afrezza, compared to coverage resistance seen when Sanofi had Afrezza priced at a premium.”

He believes there are several reasons Afrezza failed. To begin with, reimbursement has been lacking, making it less accessible for patients and harder for doctors to prescribe. Secondly, in order to be prescribed the drug, patients need to receive a pulmonary check, as it is not safe to use in those with existing lung problems.

Thirdly, a number of physicians have expressed doubts about Afrezza’s delivery method and overall safety, questioning whether patients would be receiving the correct level of insulin. Because the lungs contain enzymes that chew up proteins, a relatively small proportion of the molecules inhaled will be absorbed into the rest of the body. Compared to injected insulin, the precise dose is hard to judge.

“Although the drug has the potential to increase patient compliance, a variety of factors, including trust and cost, seem to have deterred its adoption,” Cuaron says.

Future blockbuster?

For the time being, Mannkind will be looking to adopt a new marketing and pricing strategy, in the hopes that it can still make Afrezza work. Despite the sizeable challenges that may lie ahead, it is selling a product that, notionally speaking at least, should hold widespread appeal. Through eradicating the need for injections, inhalable insulin could help thousands of needle-shy patients adhere to their treatment regimen. To date, this has been a large unmet need in the diabetes space.

The drug is also rapid acting, which makes it an attractive proposition for many users. Administered at the beginning of a meal, Afrezza dissolves rapidly upon inhalation and delivers peak insulin levels within 12-15 minutes.

However, it seems clear that a true blockbuster drug would need to tick more boxes than just convenience.

“Such a product would have to boast a superior clinical and commercial profile, which would include comparable efficacy to other insulins on the market, a cost-effective price, and an easy-to-use delivery device to ensure the correct dosage is being administered,” says Cuaron. “Pharmaceutical companies invested in inhalable insulin cannot forget that increased compliance does not only stem from an easier route of administration, but also from patients being able to afford and use the product correctly.”

It seems that hope is not entirely lost for inhalable insulin. That said, any drug company entering this space will need to keep a close eye on market conditions, ensuring their product makes it to the patients who need it most.

This article appears in the April 2016 edition of Pharma Technology Focus

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