Developing a therapeutic for a targeted population: Crizotinib
Oncology is the frontier of Precision Medicine and typically focus is on identification of gene fusions (e.g. crizotinib, an ALK inhibitor for ALK fusion proteins in lung cancer), mutations (as in the case of vemurafinib, a BRAF inhibitor for melanoma patients with the BRAF V600E mutation) and protein over- expression (e.g. Trastuzumab a HER2-targeted antibody for breast cancer). Crizotinib was identified in 2005 as a cMET (and ALK/ROS1) kinase inhibitor. In 2007, contemporaneously with dose escalation in Phase I studies, academic researchers in Japan found that about 5% of patients with non-small cell lung cancer (NSCLC), typically younger non-smokers, carry an EML4-ALK fusion gene leading to constitutive activation of ALK kinase. The Phase I protocol was amended to include patients with ALK-positive tumors, and within a few months of enrolling the first patients with the ALK mutation, objective tumor responses were seen in ALK-positive NSCLC patients. An impressive objective response rate (ORR) of over 60% and a disease control rate of over 80% which was significantly better than the expected ORR of less than 20% in matched, historical control patients were observed. Based on these data, a rolling submission in the first half of 2011 to the US FDA led to accelerated approval in less than 6 months following submission. The ability to respond quickly to the ALK rearrangement discovery in 2007, along with the successful development of a FDA-approved ALK companion diagnostic assay was instrumental in enabling FDA approval only five years after the start of the first clinical studies. Had the clinical trials been conducted in a non-selected NSCLC patient population, the strong clinical efficacy would likely not have been evident in Phase I/II studies, the therapeutic benefit likewise may not have been seen in a randomized Phase III study, and this compound might never have become a medicine. This success demonstrates the potential and value of Precision Medicine.
Leveraging insight from human genetics to create novel therapeutics: PCSK9
The breakthrough in high throughput human genetics has enabled easy identification of the genetic cause for many “extreme diseases phenotypes”. This insight may lead to treatment of affected individuals as well as broader patient populations. One example of such an extreme phenotype relates to individuals with a rare loss-of-function mutation in the PCSK9 gene – but who are otherwise normal. These individuals have very low LDL-cholesterol as well as a markedly reduced incidence of cardiovascular disease. Based on these genetic findings and the biological knowledge that normal PCSK9 protein in the blood inhibits cellular uptake of LDL cholesterol several companies have developed antibodies that binds to and reduces the function of PCSK9 protein. Early clinical data suggest that treatment with one such antibody RN316 results in very significant and long lasting declines in LDL- cholesterol in the majority of patients with elevated LDL cholesterol. If these preliminary data are confirmed in broader testing, RN316 therapy may be particularly useful for treating high risk patients who do not respond adequately to intensive statin therapy.
Leveraging information about cytokine signaling pathways to create novel anti-inflammatory drugs: Lebrikizumab and tofacitinib
Direct targeting of pro-inflammatory cytokines has delivered several therapeutics notably TNFα and IL-6 neutralizing antibodies. In the case of lebrikizumab, an anti- IL-13 antibody, the underlying biology (e.g., IL-13 stimulated bronchial proteins) was used to identify a biomarker (periostin) for identification of Phase II trial subjects who benefited the most from the agent. This may allow smaller phase III trials with better statistical outcome in the targeted population of patients with moderate to severe asthma. The oral JAK inhibitor Tofacitinib takes a novel approach, targeting the intracellular signaling pathways that operate as hubs in the inflammatory cytokine network. More specifically JAK3 mediates signaling through the common gamma chain of IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cytokine receptor complexes, explaining the broad action of tofacitinib. Tofacitinib is being investigated as a targeted immune-modulator and disease-modifying therapy for Rheumatoid Arthritis (RA) and has the potential to become an important new treatment for RA patients. Phase 3 data showed that patients who received 5 mg or 10 mg tofacitinib have a statistically significant and clinically meaningful improvement in disease scores (ACR20, ACR50 and ACR70) vs. placebo. Tofacitinib is also being explored as a potential treatment for psoriasis, and inflammatory bowel disease. Precision Medicine may further help define the positioning of tofacitinib in these diseases as it was in RA trials where patients were selected who had moderate to severe disease as measured by disease activity score to identify a population with significant disease burden and risk of progressive joint injury.
Understanding the molecular basis of adverse drug events to create safer therapeutics
Another aspect of Precision Medicine is the role safety plays in selecting patients for treatment to avoid drug-related adverse events. Analysis of the FDA Table of Pharmacogenomic Biomarkers in Drug Labels (96 drugs in total) demonstrated that 62% of the biomarkers are used to exclude patients or adjust dose based on safety-related concerns, and 31% are used for efficacy.[4,5]. The majority of safety biomarkers measure polymorphisms in genes encoding metabolizing enzymes and drug transporters with the objective of achieving adequate drug exposure. Other safety biomarkers focusing on idiosyncratic safety issues most often measure enzyme deficiencies and immune response (e.g. HLA genes). For Pharmacodynamic adverse drug events, cetuximab and panitumumab are monoclonal antibodies for colorectal cancer that target EGFR. Patients with activating mutations in the KRAS gene downstream of EGFR receive no therapeutic benefit from treatment. Therefore, in these patients, treatment skews the risk-benefit profile toward toxicity without benefit.