Drug delivery
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 slow- release 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 polymer- based 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-co-
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glycolic 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.”
Targeted injections for musculoskeletal diseases are a particularly promising area for using long-acting injectables.
“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 long- acting 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
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