Small molecules drugs are typically by mouth, but recently, an increasing number of global pharmaceutical companies are turning their attention to long-acting injectable medications. It is commonly perceived that medicinal chemistry design of small molecules is a mature science at a bottleneck that is very difficult to break through. However, some pharma companies have taken a different route to successfully generate blockbuster drugs by converting small molecules into long-acting injectables. Based on traditional approaches of drug design, antibody drugs are slowly metabolized in the body and their efficacy can last for two weeks, one months, and as long as three months in some cases. In comparison, small molecule drugs are designed to be metabolized within one day and completely cleared out by the human body within one week. This traditional approach is thus unsuitable for the design of long-acting injectable drugs.
Indeed, there are over 3000 small molecule drugs approved by the FDA, but only 20-30 of them belong to the class of long-acting injectables. The majority of small molecule drugs are initially designed for oral administration with fast metabolism, so are not appropriate for injections that last for weeks and months. However, a new wave of anti-HIV drugs have been developed and approved, and these drugs are projected to reach multiple billion dollars of annual sales. These commercial success stories have rekindled the industry’s efforts to long-acting injectables as the next pillar for innovation.
For example, top pharmaceutical companies such as Gilead and Merck are developing anti-HIV drugs that deliver one month, two months, three months, or even six months of sustained viral suppression upon one single injection. Upon subcutaneous or intramuscular injections, these poorly soluble small molecule drug form crystals that are slowly dissolved by body fluids, and this dissolution cycle lasting multiple months is the key for the drug’s long-acting effects. In the past, one major hurdle for HIV suppression lies in drug fatigue by patients. Having to take multiple pills for multiple times per day for the whole life creates enormous emotional stress for patients, who sometimes just give up or simply forget to take the drugs. To address this problem, long-acting injectables can fill this treatment gap and provide un-interrupted viral suppression, which have become a vital tool for the global fight against HIV.
Other long-acting small molecule drugs rely on advanced drug delivery technologies including biodegradable polymers to achieve sustained release for weeks and months of duration. For example, Invega Sustenna by Johnson and Johnson is a modified version of an oral paliperidone encapsulated by bio-polymers, which demonstrates one to three months of sustained efficacy upon each intra-muscular injection. For the target indication of atypical schizophrenia, patients typically have trouble taking medications themselves, so periodic injections enable sustained control of their psychotic symptoms over the long term.
Leveraging the unique advantage of long-acting drugs, Avidence Therapeutics and founder, Dr. Ang Li, have invented a breakthrough new platform to create long-acting drugs for chronic arthritis pain. The team have developed a pipeline of novel formulations that optimized drugs with validated targets into long-acting local injections with three to six months of therapeutic efficacy. In the current treatment protocol for osteoarthritis, oral anti-inflammatory drugs, despite good efficacy, are accompanied by severe cardiovascular and gastro-intestinal side effects. In fact, the FDA has mandated a Black Box Warning that describes potentially fatal risks of myocardial infarction, stroke, gastric ulceration and bleeding. The FDA further emphasized that these drugs must be taken at the lowest possible dose for the shortest duration possible to lower the cumulative safety risks of these drugs. Due to these severe side effects, the addressable patient population that can benefit has seriously shrunk, and even for patients who are taking these drugs for arthritis pain, they cannot fully take advantage of the analgesic benefits due to the required lower dose.
The breakthrough approach taken by Avidence Therapeutics is an intra-articular long-acting injection, which solves the problems of these side effects. In a rat model of osteoarthritis, the novel intra-articular drug demonstrated similar analgesic effects as steroid injections. In pharmacokinetic studies in Beagle dogs, the novel drug showed sustained and steady release over three to six months, with systemic exposure one hundred times lower than existing oral medications. This miniscule blood exposure ensures little systemic safety risk of heart attack and stroke and demonstrates the best-in-class potential of the new delivery system. This product is currently undergoing GMP manufacturing and IND-enabling studies.
Notably, despite the severe side effects of traditional oral anti-inflammatory drugs, their revenues were still staggering. In 2003, COX-2 inhibitors including Bextra, Celebrex and Vioxx generated combined sales over 9 billion dollars. Even after the emergence of cardiovascular safety risks, the limitation of their use still has not hampered the growth of the osteoarthritis market. It is projected that the annual growth rate of the osteoarthritis market is 8.1% and the market size will reach 10.3 billion dollars by 2025.
The marvelous innovation of Avidence Therapeutics originates from the deep expertise of Dr. Ang Li in joint diseases and biomaterials. Dr. Li obtained his doctoral degree at Columbia University under the mentorship of Dr. Gordana Vunjak-novakovic, a member of National Institute of Health and National Academy of Engineering. In the doctoral research, Dr. Li discovered novel mechanisms by which the extracellular matrix of cartilage regulates cartilage growth and health and explored the interactions between various biomaterials and cartilage differentiation and degeneration. Avidence also takes advantage of the decades of experience by seasoned pharmaceutical experts to push long-acting injectables to the center stage of small molecule drug discovery.
In the future, Avidence Therapeutics will continue to focus on innovations in small molecule long-acting drugs, given their unique advantages in chronic diseases. By expanding the application from osteoarthritis to broader indications, Avidence strives to establish long-acting injectables as a new modality that can benefit a vast number of patients.