NEA Foundation

A scalable 8-step route for a key (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole intermediate for orforglipron was developed to support clinical trials. Highlights of process development results in this contribution include the following: (1) approximately 50% reduction of a key des-carbonyl impurity in the reductive removal of the Evans auxiliary by the introduction of MgCl2 as a chelating agent for the reduction with LiBH4, (2) a telescoped process for PTC alkylation with chloroacetonitrile and subsequent cyclopropyl ring formation with an asymmetric cyclic sulfate avoiding the problematic isolation of the alkylation product, and (3) significantly improved isolated yield and stereoselectivity of the cyclopropyl ring formation by replacing KHMDS with LiOt-Bu as the base for the reaction. The developed process was successfully scaled up to >400 kg scale for each step to deliver a high-quality product in an overall yield of 22%, demonstrating the robustness of the optimized process.

Dupilumab is an immunomodulatory medication blocking interleukins. This biologic drug is an injectable human monoclonal antibody targeting the α subunit of interleukin (IL)-4 which affects the IL-4 and IL-13 pathways. Since its approval by the United States Food and Drug Administration and Health Canada in 2017, it has been used extensively for the treatment of multiple diseases, including chronic rhinosinusitis with nasal polyposis, asthma, and most notably atopic dermatitis. In patients with moderate-to-severe atopic dermatitis (AD), dupilumab has significantly improved patients’ quality of life. In the pivotal SOLO 1 and SOLO 2 trials involving patients aged 18 years and older, dupilumab was compared with placebo and demonstrated a significant reduction in Investigator Global Assessment (IGA) atopic dermatitis score down to “clear” or “almost clear” (i.e., 0 or 1) and a ≥ 2-point improvement from baseline in that same score at week 16. This primary endpoint was achieved in 36-38% of patients on dupilumab compared with 8–10% of patients on placebo. However, these outcomes are not without drawbacks.
 The emergence of dupilumab-associated ocular surface disease (DAOSD) or dupilumab-induced ocular surface disease (DIOSD) is now commonly reported by both dermatologists and ophthalmologists who treat AD patients using dupilumab. Interestingly, dupilumab has not been associated with increased conjunctivitis rates in studies in other diseases, including asthma and chronic rhinosinusitis with nasal polyposis, which suggests that the increased rates of conjunctivitis in AD studies may reflect a unique interaction between AD and dupilumab-related mechanisms. The SOLO 1 and SOLO 2 trials were the first to detect a higher rate of conjunctivitis in dupilumab-treated patients with 3-5% of the dupilumab-treated patients developing “conjunctivitis of an unspecified cause” compared to 1% in the placebo groups, with 1 of 920 patients discontinuing dupilumab because of conjunctivitis in SOLO 1. The highest rate among dupilumab trials was in LIBERTY AD CAFÉ where conjunctivitis was reported in 16%, 28% and 11% of patients in the weekly dupilumab + topical corticosteroid (TCS), every two weeks + TCS and placebo + TCS groups, respectively; all but one event were mild or moderate. However, in those trials patients did not undergo complete ophthalmological examinations to characterize the type of ocular involvement that was reported. Subsequent research and real-world experience has since detailed the variety of findings associated with DAOSD. With more studies now published, including those which involve subjects examined by ophthalmologists, we have a better idea of the incidence of DAOSD. A recent Canadian study reported a rate of DIOSD at 37% over a 52-week follow-up period, with 19% of these patients requiring a consultation in ophthalmology. Most of the time, only the most severe cases will be referred to ophthalmologists, while milder cases will be treated by dermatologists or primary care providers through the use of artificial tears.
 The aim of this article is to provide a basic framework for clinicians to understand the pathophysiology of DAOSD, how to diagnose DAOSD, and the optimal treatment strategy for these patients.

AimsWe set out to identify risk factors for progression in untreated keratoconus patients from 34 centres across Australia, New Zealand, Spain and Italy.MethodsPatients were divided into ‘progressors’ and ‘stable’ patients for each clinical parameter: visual acuity (VA), steepest keratometry (maximum keratometry (Max-K)) and thinnest corneal thickness (TCT). Primary outcomes were the proportion of eyes with sustained progression in VA, Max-K or TCT within 3 years. Secondary outcomes included predictors of progression.ResultsThere were 3994 untreated eyes from 2283 patients. The proportion of eyes with VA, Max-K and TCT progression at 1 year were 3.2%, 6.6% and 3.1% respectively. Factors associated with VA loss were higher baseline VA (HR 1.15 per logMAR line increase in VA; p<0.001) and steeper baseline Max-K (HR 1.07 per 1D increase; p<0.001). Younger baseline age was associated with Max-K steepening (HR 0.96 per year older; p=0.001). Thicker baseline TCT, steeper baseline Max-K and younger baseline age were associated with TCT thinning: (HR 1.08 per 10 µm increase in TCT; p<0.001), (HR 1.03 per 1D increase; p=0.02) and (HR 0.98 per year younger; p=0.01), respectively.ConclusionsSteeper Max-K and younger age were the most clinically useful baseline predictors of progression as they were associated with worsening of two clinical parameters. Every 1D steeper Max-K was associated with a 7% and 3% greater risk of worsening VA and thinning TCT, respectively. Each 1 year younger was associated with a 4% and 2% greater risk of steepening Max-K and thinning TCT, respectively.