Extending the effect

24 May 2023

Chronic diseases often come with a burden of administering medication routinely throughout the week, or in many cases, the day. Proponents of long-acting injectables wish to change this to make life easier for patients and increase medication adherence. Kim Thomas speaks to Farshad Ramazani, a principal researcher at Novartis, and Professor Andrew Owen, co-director of the Centre of Excellence for Long-acting Therapeutics at the University of Liverpool, to learn about long-acting injectables and the challenges researchers face in trying to bring them to the clinic.

For patients managing a chronic illness such as diabetes or schizophrenia, the need for a daily dose of medication creates additional burdens: remembering to take it; ordering and collecting a new prescription when it runs out; and making sure that they have enough medication to take with them when they go away on holiday or for short breaks. As Professor Andrew Owen, co-director of the Centre of Excellence for Long-acting Therapeutics (CELT) at the University of Liverpool, points out, when a patient forgets to take their medication, “this can compromise the efficacy of their therapy”. But what if we could remove those burdens? If, instead of taking a tablet every day, a patient could have a single injection that would last for months?

The potential advantages aren’t difficult to imagine; their medication regime would be made easier, reducing the risk of harm caused by forgetting to take a dosage, or even forgetting one has already been taken and adding more of the active pharmaceutical ingredient to the body than it needs. On the other side of the equation, administering fewer injections would reduce the administrative load on doctors and pharmacists. In diseases that carry a social stigma, Owen points out, it would also provide patients with greater privacy.

Long-acting injectables (LAIs) first emerged in 1953, when a study described a long-acting injectable oestrogen. The principle is straightforward enough: When a long-acting formulation is used, the drug is contained inside a carrier, such as a liquid, that allows for the slow release of the medication when injected. Sometimes, a long-acting drug is delivered by an implant – this is particularly the case with contraceptives – and has to be surgically removed at a later date.

Renewed interest in LAIs

Yet for decades, the use of LAIs was confined largely to contraception and the treatment of a small number of chronic conditions. The barriers to wider adoption mostly relate to the technical challenges in repurposing oral medicines for use in a long-acting formation. As Farshad Ramazani, a principal scientist at Novartis, says: “The development of such a complex formulation is difficult and time-consuming, and it costs lots of money.” There has, however, been a renewed interest in LAIs in recent years. One sign of the changing landscape was the regulatory approval awarded in 2021 to Johnson and Johnson’s long-acting schizophrenia drug, Invega Hafyera, which can be injected every six months. Another was the launch of CELT, also in 2021, which is focusing its efforts on repurposing existing medicines as slowrelease formulations. Working with a number of academic and pharmaceutical partners, CELT plans to change, on a global scale, the way we treat both chronic and acute diseases.

Compared with 20 or 30 years ago, Ramazani points out, pharma companies are “better equipped”. Simulation technology and machine-learning have both helped to shorten the development timeline, he says. Another difference, Ramazani notes, is that LAIs are being used with different targets in the body. “We are, for example, injecting them in the knee, or in the back of the eye, or in different organs – directly in the place where the disease is.” This means there is a high drug concentration in the target site, rather than throughout the body, resulting in a lower likelihood of adverse effects. “This is why we are seeing more long-acting injectables in the pipeline,” he says, adding that he believes musculoskeletal conditions are a particularly promising target for LAIs.

Lower risk of attrition in repurposed drugs

Technological developments have helped address another historic problem. Traditionally, the polymerbased carrier system used to release the long-acting drug remains in the body, and in some cases may need to be removed surgically. An advantage of the latest carrier systems, Ramazani points out, is that they are based on a polymer called poly(lactic-coglycolic acid), or PLGA, which is fully biodegradable. Currently, pharmaceutical companies are working on repurposing existing oral formulation drugs rather than developing LAI candidates from scratch. This makes sound scientific and commercial sense, Owen says: “If a drug is compatible with long-acting technologies, then there are benefits to applying reformulation approaches, because for approved drugs the systemic safety is already well understood. This means that a repurposed drug has a lower risk of attrition due to an unpredictable safety concern and the speed at which a long-acting medicine can be translated is also accelerated.”

“If a drug is compatible with long-acting technologies, then there are benefits to applying reformulation approaches, because for approved drugs the systemic safety is already understood.”
Professor Andrew Owen, co-director at CELT

So what conditions are the most likely to benefit from LAIs? “Long-acting approaches lend themselves best to chronic diseases, or diseases where a cure can be achieved through a single administration,” says Owen. As an example, he adds that there is “a whole raft of long-acting HIV medicines in development by the pharmaceutical industry and by academic groups.” It is not only patients with chronic diseases who might be able to benefit from LAIs. Owen expects to see “great strides forward with infectious diseases” – and LAIs can also be used to prevent disease. The “most exciting development programmes in CELT,” he adds, are “for a long-acting medicine that protects from malaria infection after a mosquito bite, for a longacting prevention for tuberculosis in patients latently infected with the disease, and for a single shot cure for Hepatitis C Virus (HCV).” Owen believes that, if these medicines live up to their current promise, we will see human trials for each of them in coming years. He also believes there are “huge opportunities for non-communicable diseases.” They could be used to prevent cardiovascular diseases, for example, or for central nervous system conditions. Even so, there are challenges. “Changing the route of administration from oral to parenteral means that the safety at the site of administration needs to be carefully assessed,” Owen says. “Only highly potent drugs are applicable for these approaches, because low drug concentrations in the blood are easier to achieve for long periods of time. Also, repurposed drugs were often chemically designed specifically for oral administration, meaning the chemistry of the molecule may not be ideal for a long-acting approach.”

A risk of developing drug resistance

An added difficulty relates to implementation. While Ramazani believes that in the future, patients may be able to selfadminister the long-acting medication, at present, LAIs are generally administered by a healthcare professional. “The durations of drug exposure should optimally fit with routine clinic visits for the specific disease, so that additional clinic visits are not needed,” Owen says. There is always a risk, he adds, that if a patient has a chronic infectious disease, but doesn’t return to the clinic for their scheduled dose, there may be a higher risk of developing drug resistance – an eventuality Owen refers to as “the long tail of suboptimal exposure”. Education, he says, will be important, and any patient who decides to stop taking a long-acting medicine will need to return quickly to their oral regimens.

In future, we may see pharma companies investing in the development of LAIs from scratch. Currently, many are reluctant to do so, for understandable reasons. “If you have a new molecule and you don’t know if it will work, it’s a lot of investment,” says Ramazani. “Developing the long-acting injectable costs lots of money, especially in the early stages of development.” For instance, clinical trials need to run for longer to make sure the drug is safe and effective. “Then we have the high risk of failure for the project, maybe 80%, when they enter the clinical trial phrase,” he says. With injections, he adds, there can be “local tolerability issues,” including inflammation, or even, in the worst cases, necrosis and tissue damage, all of which means that a cautious approach is required. “It’s not easy to convince the managers to go in this direction,” he adds. An alternative approach, Ramazani suggests, might be to develop a molecule for oral administration and carry out clinical trials to test whether it works, while developing the long-acting formulation in parallel to save time and money.

There is good reason, however, to believe that the future of long-acting injectables is assured. The technical complexities, and the related higher costs, are likely to diminish as the scale of applications increases, Owen says. Because a lower overall drug dose is needed for a long-acting approach than for an orally-delivered counterpart, he adds, that is likely to reduce costs too. The main reason that they are likely to be adopted is that all stakeholders – pharma companies, patients and health care providers – see benefits. “Pharma companies are demonstrating their apparent appetite for the approach through the depth of investment they are making in development,” he says. “Patients overwhelmingly see the benefits for long-acting medicines, and surveys have consistently demonstrated high enthusiasm for the approaches from patients and providers.”

Targeted injections for musculoskeletal diseases are a particularly promising area for using long-acting injectables.
Often drugs have been designed for oral administration, so the ingredients of it may not be suitable for longterm injectables.

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