Finding Needles in Haystacks: First-in-class soloMER drug candidates as precision medicine for autoimmune inflammation diseases.

To date, there are over 150 drugs approved by the FDA for treating or preventing autoimmune and inflammatory diseases such as rheumatoid arthritis (RA), Crohn’s disease and ulcerative colitis. Despite what seems like a comprehensive arsenal of therapies, there remains huge unmet medical need for many patient groups. The aim of this fellowship in the face of lack of suitable drugs was to adopt a rationale multi-specific drug design approach with synergistic targets that would deliver broad reaching clinical efficacy. My FLF hypothesis was to design, for the first time Protein drug conjugate (PDCs) that were tailor-made for autoimmune and inflammatory diseases, an approach traditionally reserved for oncology indications. The outcomes from our initial research have achieved levels of drug potency even beyond our expectations and this FLF extension application is focused on driving our new PDC modalities towards first in man studies. Challenges I/we faced: Safety concerns: most approved therapies for autoimmune/chronic inflammation have an FDA black box warning, which is the highest level of safety warning for a marketed drug product. Patients on these therapies are predisposed to life-threatening adverse drug reactions such as reactivation of latent tuberculosis, new malignancies, etc. Treatment failures; at least 30 % of patients do not respond to treatments targeting a single disease pathway (mono-specific targeting). For the 50 – 70 % of patients that have an initial clinical response to monospecific treatment, ~ 70 % will fail to sustain this response after one year requiring a second and then a third drug strategy to be prescribed. Eventually many patients simply “run out” of effective treatment options. My original fellowship focused on tackling probelms 1, 2, by creating novel soloMER® PDC therapies with novel and multiple mechanisms of action to increase potency whilst at the same time improving safety profiles. The two most common drug classes currently used to treat autoimmune and inflammatory diseases are called anti-TNF biologics (proteins) and JAK inhibitors (JAKi - small-molecules). My aim was to join these two drug classes together (via chemical conjugation) to create one modality (PDC) capable of hitting two disease pathways at the same time. Firstly we developed our own in-house anti-TNF biologics soloMER that was 6x more potent than the “blockbuster” marketed anti-TNF drugs whilst at the same time we designed our anti-TNF to avoid many of the worst side effects of this drug class by encouraging it to recognse its target in a unique manner. To this new super-charged anti-TNF soloMER, via the development of novel chemistries, we “joined” JAKi. The resulting PDC drug (now greater than 10x the potency of existing clinical competitors) could control disease (in clinically predictive animal models) at very low dosing levels and minimised toxicity of the JAKis by the targetted delivery of this drug only to the point of need in the body. This fellowship renewal will focus on advancing the clinical development of these soloMER PDC drug candidates by next identifying key efficacy biomarkers utilising psuedonymised patients tissue biopsies, next generation RA synovial organoid and multi-omics approach. Identifying key biomakers of efficacy will help us identify patients who will achieve deep and sustained disease remission with our soloMER PDC. Our vision is a move towards personalised medicines enabled by companion efficacy biomarkers, instead of the conventional one-size-fits-all treatment approach that is now failing so many patients.