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).

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