Delivering novel therapies in the 21st century

Over the last few days I was fortunate enough to attend the Royal Society’s conference on “Delivering novel therapies in the 21st century” and have summarised a few of the key themes: –

Big Picture

Lots of high-level statements were presented at the meeting, but three in particular stuck with me.

  1. Rare disease is not as rare as you might think, as there are over 25 million individuals with one of 7,000 rare diseases, with 30% of individuals with a rare disease dying before they reach 5 years old.
  2. Multi-morbidity a growing issue: simulation studies suggest diabetes and concomitant depression will be present in 35% of females and 21% of males by 2028. By 2035, 68% of over 65s will have 2 or more long term conditions.
  3. By 2022, biologics will deliver 52% of the top 100 product sales, at the expense of traditional small molecule medicines.

    NHS, academia and business

    The United Kingdom is well position to be a leader within the life sciences sector. In part this is due to established partnerships between the NHS, academia, industry, and regulators, but it is evident that with uncertain political times looming, more is required to secure this leading position, particularly for the NHS and academia. Throughout the 2 day event the NHS was praised for its electronic patient records, that offers unparalleled opportunities to follow up patients’ health records. It was also stated that it was the responsibility of the NHS and academia to advance our understanding of disease pathophysiology. However, there is a real threat that our global advantage might be lost. The NHS struggling with a supply and demand issue: the lowest average annual real growth rate ever recorded (1.2% per year extra), coupled with a huge increase in demand over the last 10 years, with a 40% increase in Emergency admissions and 79% increase in outpatient appointments since 2005. Furthermore, Brexit remains a considerable threat to academia, as outlined by 29 Nobel laureates.

    Drug discovery

    90% of drug discovery efforts fail, however, when genetic information is used, the success rate doubles. This well known statistic was repeated throughout the conference and several examples were given for how genetics can be leveraged, and why drug discovery efforts fail. This included Prof Peter Donnelly discussing the efforts of Genomics PLC, where a matrix comparing ~14 million genotypes with ~7,000 phenotypes (and gene expression information) for over 3 million individuals, from prior genome-wide association studies, has been assembled to help guide target discovery efforts. Of course, this is only one side of the coin. Whilst having genetic support for a target will be increasingly important, we know there is heterogeneity in efficacy, and designing a drug for mass adoption for a single phenotype may be an oversimplification. I suggested an experiment that could leverage individual level data from the UK BioBank to generate a polygenic risk score for drug efficacy — something that they have not performed yet, but will look into.
    Accompanying the high failure rate are the large costs associated with running a clinical trial, resulting in the expensive drugs for patients. One view was that the high cost of running a clinical trial was pathognomonic of something far more unsettling: that either the drug was a poor candidate, or the wrong patient population was being selected (as the underlying biology was relatively unknown).
    The cost of therapeutics to payors was highlighted, particularly for oncology drugs, which have steadily increased in price, but are poorly correlated to overall survival.

    Drug delivery

    This considered not only the increased range of therapeutic modalities — such as PROTACs and bicyclic peptides —  that unlock a broader spectrum of possible biology amenable to intervention, but also manufacturing considerations for the production of individualised therapeutics tailored to an individual’s immune system — with processes having to change from a manufacturer to stock model to a manufacturer to order model.
    A range of presentations highlighted the current advances made by using various carrier materials to treat disease, both systemically and targeted towards a specific organ. From exosomes for the treatment of pancreatic cancer,  heat-sensitive liposomes that can be activated using ultrasound to treat liver tumours, viral delivering of a CRISPR system to treat tyrosinemiaadeno-associated virus delivery of gene therapy for duchenne muscular dystrophy and antisense oligonucleotide therapy for Huntington’s disease.


    Sir Michael Rawlins, from the Medicines and Healthcare products Regulatory Agency, outlined how data for the safety and efficacy of new therapeutics need not be solely derived from a randomised clinical trial. He discussed the various advantages with taking a Bayesian approach to study design and walked through the alternative study designs, including: adaptive trials, mendelian randomisation, umbrella trials, step-wedge trials and ring trials.
    There was also further discussion regarding basket trials within the health economics section of the conference, with respect to histology independent cancer drugs such as Larotrectinib, and the challenges such a trial design poses for health technology assessment bodies, such as NICE (National Institute for Health and Care Excellence).

Drug discovery and genetics

A loss-of-function genetic variant that protects against chronic liver disease was reported in the The New England Journal of Medicine on 22nd March 2018. This finding adds to a series of previously established protective variants and appears to have stimulated efforts to advance treatment options within chronic liver disease — Regeneron Pharmaceuticals, Inc. have subsequently announced a collaboration with Alnylam Pharmaceuticals, Inc. to develop RNAi therapeutics for non-alcoholic steatohepatitis.

Such reports tend to generate excitement. To understand why requires analysis of the underlying genetics, biology, drug discovery challenges and opportunities within clinical medicine. My goal is to provide context to this intersection between science, medicine and business.

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