There is a brand-new method to distribute medicine. The local post-sorting centre’s launch countdown just reached ‘one’.

A little while earlier, a purple package began its journey down a long, steeply sloping tube into the warehouse. About five minutes ago, it cleared a stringent set of checks and rechecks without sustaining any damage. At ‘zero’, a second tube peels away the formerly secure outer wrapping and fires its innards up and away to the waiting world. Someone’s medicine is out for delivery, blasting in a long arc through the pre-dawn twilight. Closer in, the sudden acceleration has triggered a pinch valve, precipitating a chemical reaction that pushes carbon dioxide into a small balloon attached to a carton of pills. Soon enough, the odd contraption is floating smoothly on the breeze. Then the balloon pops. This is meant to happen. No one carries medication to a patient’s doorstep on a tiny airship. But they do use the air pressure contained within the tiny airship to fling it there. And there it goes, skimming neatly through the letter box.

In this near-future scenario, the pack that lands on the doormat contains 30 RaniPills – devices that make it possible to orally administer biologic drugs. Here in the present day, Rani Therapeutics just announced the positive results of the first study into the safety and tolerability of the capsules in humans. However much it sounds like a Rube Goldberg space shuttle, the process described above is a general analogue for how each ‘pill’ works – just imagine it taking place inside you.

The first attempt to deliver a macromolecule drug (insulin) orally was abandoned in 1923. We’ve been failing to do so effectively ever since – biotechnology revolution notwithstanding. Made entirely of food-grade materials, RaniPill capsules have got this far because they bypass the stomach acid and gut enzymes that have waylaid the more than 100 previous attempts. They remain whole until the enteric coating dissolves in the intestines, which starts a chemical reaction that produces carbon dioxide. In turn, this inflates a small balloon. Finally, instead of depositing a box of pills, the balloon presses an absorbable sugar needle containing a solid form of the biologic payload into the intestinal wall, deflates, and is safely passed out. The user, meanwhile, feels nothing.

Although the lack of sensation wasn’t conclusively demonstrated until the recent in-human trial, Mir Imran, RaniPill’s inventor, had some idea of what the results would be. “I took more than half a dozen of the capsules before we tested them in subjects because I wanted a first-hand feel,” he says. “I was pretty confident going into the study.”

Patients would likely switch from Humira injections to a oncedaily biosimilar pill.
Rani Therapeutics

Inside out

Imran may have swallowed more examples of an important new drug delivery focus area than anyone else alive. RaniPill, which is supported by investments from Novartis, Takeda, and Alphabet’s venture capitalist arm, among others, is just one of numerous recent attempts to develop less invasive and more comfortable ways of injecting biologics and biosimilars. Indeed, shortly before Rani Therapeutics announced the results of its human safety and tolerability trial, Novo Nordisk-sponsored scientists at MIT published preclinical data from animal tests for an oral insulin delivery system that injects a solid form of the biologic into the stomach lining. If successful, these projects could have profound implications. By using the formfactor of pills to deliver an intramuscular injection to the intestinal wall, Rani Therapeutics increased the bioavailability of biologics in animal models by 10–20% over traditional subcutaneous injections. To put that in perspective, Israeli-based Oramed is running clinical trials for the most effective oral insulin formulation ever, which requires up to 69 times the amount of insulin per dose to achieve the same results as needle-based methods.

Even without the potential cost reduction, Oramed’s formulation still offers a great deal of value for diabetics. People will do a lot to avoid injecting their medicine. In a study commissioned by Rani Therapeutics, more than 62% of patients and 86% of physicians reported that patients either skip injections or consistently fail to inject the drug as prescribed. Even more starkly, over 20% of rheumatoid arthritis sufferers responding to a separate 2012 survey indicated that they would not consider using a medication that required them to self-inject.

Recently, two linked ethnographic studies into the lived experience of selfinjection have also shone a light on the personal struggle many patients face in meeting their biologic prescriptions. The combined review paper concluded that “patients viewed using a needle as an unnatural, transgressive act” and “did not consider the device part of the therapy, drawing a distinction between the drug, which helps them, and the device, which hurts them”.

Creating the conditions for patients to think otherwise is vitally important to improving their outcomes. The closer a patient comes to adhering to the prescribed dose at the prescribed frequency, the more slowly their condition will progress. Reasonably enough, a medicine’s effectiveness is determined by whether patients use it. Importantly, Rani Therapeutics’ study indicated that 70% of rheumatologists and 92% of gastroenterologists think that transitioning from injections to a pill would significantly increase patient compliance rates. It’s no surprise that a recent paper on the subject announced that, “oral delivery of biologics is considered a ‘panacea’ in drug delivery”.

From another angle, Imran thinks his product is part of a ‘perfect storm’ threatening reference biologics with expiring patents. Abbvie’s $19.9 billion blockbuster Humira is foremost among them.

As the world’s most profitable drug, Humira accounted for almost two thirds of Abbvie’s $32.75 billion revenue in 2018. Moreover, two thirds ($13.7 billion) of Humira revenue comes from the US market. Even there, where patients and physicians remain suspicious of biosimilars, Rani’s study indicates that 88% of patients and 86% of rheumatologists and gastroenterologists would likely switch from Humira injections to a once-daily adalimumab biosimilar pill if one existed.

That’s a stunning statistic. Compare it to this anecdote from biosimilars developer Professor Sarfaraz Niazi. While speaking at a recent Pfizer conference on off-patent biologics in the US, he asked the 500 primary care physicians present whether they trusted FDA decisions regarding the medicines’ safety. Responding on their phones, around 70% said no. “Some of the responses totally shocked me,” he recalls. “One said that without extensive clinical study, there’s no way to prove that biosimilars will not kill patients.”

Evidently, Rani Therapeutics and Niazi were not dealing with the same doctors, and any comparison between a peer-reviewed study and an impromptu conference survey is limited, to say the least. Still, it’s clear the connection between patient compliance and patient outcomes has the potential to reconfigure the ongoing debate around biosimilars in the US.

But for what cost?

Until now, arguments in favour of approving biosimilars to compete with reference biologics have focused on stressing that they offer equivalent safety and efficacy at far less cost. They’ve been directed at governments and payers over patients and physicians. As the US shows, that strategy has only been partially successful.

For Stephen Murby, biosimilars spokesman at the International Alliance of Patients’ Organizations, the drugs might actually be more controversial as a result. “The more you try to sell to government based on cost,” he says, “and the more government tries to force prescribers to prescribe based on cost, the more people’s backs get up, and the more people go, ‘I smell something rotten in Denmark’.”

Patients in the aforementioned ethnographic studies into self-injection seem to have sensed something similar. A number complained that rather than being treated and talked to as people, they were quickly issued with a prescription and left to work out how to use their injector pens by a painful, lonely process of trial and error. The paper concluded that this negatively impacted both the way they took their medicines and how they perceived their care. The healthcare professionals interviewed had “little understanding of how patients managed the fear and anxiety of self-injection”.

However, by competing in terms of patient experience, large molecule drug developers have a chance to refocus the discussion on care, rather than cost. “Engage the prescriber, the dispenser and the consumer early in your business plan,” urges Murby. “Patients’ organisations are not against biosimilars, but they are against being forced to take them on the grounds of cost.”

As well as collaborating with Novartis, Takeda and others, Rani Therapeutics has already bought some of their own biosimilars with this in mind. Later this year, the first patients will receive RaniPill octreotide injections. The clinical trial will be taking place in Australia, home to one of Murby’s least favourite biosimilar money-saving schemes. It’s a tough place to win back patient trust. Whatever happens, Imran’s still confident. “If we prove it with one drug molecule, we’ve really proved the platform for all drugs,” he says. “You don’t have to reapprove a syringe according to what medicine it’s carrying.”

Patients’ experiences of self-injection

“The device reminds me that I’m sick. I hate it for that.”
“I love my biologic, but I hate self-injecting. I hate it more than everything.”
“It’s a needle. It isn’t safe is it?… It is the kind of thing that you spend your life trying to avoid. Now it is part of my life. I still hate it.”
“It takes me about two days to work up the courage. I try to leave it off until I start to hurt. When the pain arrives, I know I have to inject and I spend a day or so circling the fridge. Once I have the courage, I have to just hold it in my hands for a few minutes to get over the feeling of wanting to run away.”

Source: ‘Chronic Disease and Self-Injection: Ethnographic Investigations into the Patient Experience During Treatment’