A future for RNA therapies? Inclisiran: a short interfering RNA for the lowering of LDL cholesterol

The New England Journal of Medicine published results of a phase 1 study investigating a novel method to reduce LDL cholesterol through a small interfering RNA (siRNA) targeting PCSK9 — inclisiran (Alnylam Pharmaceuticals and the Medicines Company). Being a phase 1 study, the safety, side-effect profile and pharmacodynamic effects of this novel therapeutic agent were assessed.

The reason I am reflecting on this study relates to the excitement that is held within the field of cardiology and PCSK9 inhibition. PCSK9 is a well-validated target that has been recently identified as a critical regulator of LDL cholesterol. PCSK9 achieves this by breaking down LDL cholesterol receptors within the liver; the more LDL receptors broken down, the higher the LDL levels within the bloodstream. PCSK9 inhibition therefore results in lower LDL levels. Individuals with raised LDL cholesterol are at risk of major adverse cardiovascular events such as myocardial infarction, and consequently developing therapeutic agents to successfully lower LDL has been a goal for many years. Achieved initially through the development of statins, more recently the FDA approved two monoclonal antibodies that inhibit PCSK9 (alirocumab (Praluent, Sanofi/Regeneron) and evolocumab (Repatha, Amgen)) to lower LDL cholesterol in patients refractory to statin therapy.

What differentiates inclisiran (an siRNA) from the currently FDA approved PCSK9 inhibitors (monoclonal antibodies) is the the mechanism through which PCSK9 inhibition is achieved. To briefly outline these differences: monoclonal antibodies of PCSK9 restrict PCSK9 from binding to LDL receptors across all extracellular tissues across all organs, whilst inclisiran specifically targets PCSK9 inhibition within the liver. This specificity relates to the design of inclisiran, with carbohydrate residues bound to the siRNA combining with a molecule specific to the liver (Asialoglycoprotein receptors), which enables uptake into the liver. Once in the liver, the siRNA binds with an RNA inducing silencing complex that allows the siRNA to interact and disrupt the mRNA that is required for PCSK9 protein production. This unique mechanism of action makes inclisiran a first in class therapeutic.

Inclisiran, administered as a subcutaneous injection, demonstrated no serious adverse events and was reported to provide a sustained reduction in LDL levels (~60% reduction). It will be fascinating to track the progress of inclisiran in subsequent trials — a global phase III trial has been suggested. Some analysts are already suggesting that sales of Inclisiran will reach ~1.3 USD in 2030, despite no cardiovascular outcome trial data.

Protective alleles and modifier variants in human health and disease

My recent review article, co-authored with Shalini Nayee and Eric Topol, was published in Nature Reviews Genetics in late October 2015.

The manuscript considers how drug developers can leverage nature’s evolutionary mechanisms that protect individuals from developing disease and how such biological processes can help promote health

A Handheld Convergence

Predictions suggest 50 billion Internet enabled mobile devices (IEMDs) – including smartphones, tablets and wearable devices – will be in use globally by 90% of individuals over the age of 6 years old by 2020. Already 61% of Americans own a smartphone.

An icon of our generation, and emblematic of the unrelenting advances that have occurred in transistor technology, IEMDs have the potential to upgrade current healthcare surveillance and delivery strategies worldwide. Furthermore, these initiatives are estimated to generate $6 billion in savings for companies in the United States, and partly explain why the mobile healthcare (mHealth) industry has been supported with financial investment despite a paucity of clinical evidence to date.

Although not a recent development, telemedicine is only now beginning to be recognized as an appropriate vehicle for healthcare surveillance and delivery. Benefitting from the increased penetrance of mobile phones throughout society, public health organizations have been capable of closely tracking communicable disease outbreaks through geographically tagged text-messages. Such strategies were successfully implemented in Haiti for cholera during 2012 and throughout Western Africa for ebola in 2014. However, it was not until 2015 that telemedicine was authenticated for healthcare delivery when the largest insurance company within the United States, UnitedHealth, announced that it would reimburse physicians for virtual-doctor appointments. This came in response to the growing popularity of numerous online portals, such as Doctor on Demand, which connect patients with thousands of medically qualified staff whenever required. It is notable however that there remain strict regulations restricting physicians from providing advice to individuals outside the federal state in which they hold medical licensure. Such policies impinge on telemedicine’s potential within the United States, and mean successful telemedicine strategies observed throughout the developing world are unlikely to be replicated in the USA. Take for instance, Narayana Hrudayalaya, a specialist cardiac unit based in Bangalore, India. The telemedicine program in Narayana Hrudayalaya extends across 150 telemedicine centers across Asia and Africa and facilitates specialist input into the care of hundreds of thousands of patients with cardiovascular diseases, irrespective of geographical location.

The current generation of IEMDs go far beyond the ability to simply text-message and video-network on demand. Vastly improved computational power and the ability to effortlessly connect with additional devices, has opened up a large armamentarium of possible mHealth interventions for patients, doctors and researchers.

Despite a poorly defined regulatory framework, a surfeit of medically-related apps have been developed. Providing an alternative to traditional disease prevention and chronic disease management strategies, IEMDs have enabled patients to take control of their health, should they wish. From tracking medication compliance, to the recording of an endless stream of physiological data – such as blood pressure, heart rate and blood glucose — transmitted in real-time via wearable sensors, a whole range of possibilities exist. And consequently those patients who commit to this approach appear more empowered, by generating their own data and questioning the paternalistic dogma regarding ownership of medical records. For doctors, IEMDs become the go-to-guide for hard-to-reach diagnoses, guidance or support. Furthermore, by combining IEMDs with adjunctive hardware a smorgasbord of diagnostic tools emerge, digitally recreating routine tools such as otoscopes and opthalmoscopes, and providing handheld equivalents of expensive equipment such as ultrasound. Point-of-care testing for biochemical and microbiological information, traditionally generated in laboratories, can also be derived following advancements in microfluidigm technology. Such versatility has enabled life-saving procedures to be performed in resource-deplete settings, from screening for obstetric and neonatal risks during pregnancy to diagnosing deadly parasites in blood. The current generation of IEMDs represents the swiss-army knife of clinical medicine, with the greatest value being seen within the developing world.

But ironically the individuals most likely to benefit from mHealth strategies often cannot access this technology. Affordability of IEMD is improving, with devices harboring most features present on top end models now available for ~$35, making acquisition of an IEMD possible, if not for patients for healthcare workers. However, the far larger issue is bringing over 58% of the world’s population, ~4.2 billion people, online. Efforts from Google and Facebook are attempting to resolve this issue, providing Internet access to previously neglected geographical areas through innovative solutions. These efforts so far have been remarkably successful, with estimates suggesting that ~10% of individuals are being lifted out of poverty as a direct result of these interventions.

Beyond the direct benefits for patients and doctors, IEMDs also provide exciting potential for the way clinical trials are performed. Escaping from the contrived one-off data points that are convention within clinical research, Apple’s ResearchKit enables users record their own data seemlessly, either manually or via a sensor. Over 11,000 individuals signed up for Stanford’s MyHeart Counts within the first 24 hours of launching, a cohort population that would usually take over a year to acquire from 50 medical centers. Now ResearchKit is open-source and having overcome early ethical concerns regarding patient recruitment, provides a platform for investigators to recruit from the hundreds of millions of iPhone users worldwide and silently monitor their activities accurately, overcoming challenges previously felt in traditional clinical trials. And whilst the average iPhone user may not necessarily represent the typical patient a clinical trial would recruit, the sheer volume of data available through ResearchKit makes this approach a game changer for clinical research. With such rapid advancements it is foreseeable that smartphone based genome sequencing will soon be available, a venture that could yield further insight into the composition of human health, but will no doubt face multiple legal and ethical obstacles.

With so many developments within telemedicine and mHealth it is easy to get overwhelmed by the hype. Importantly, we need to remain guarded until the efficacy of the latest generation of mHealth interventions is formally evaluated in well-constructed clinical trials. Undoubtedly there is a huge opportunity to revolutionize healthcare surveillance and delivery globally.