ABSTRACT
The Royal Chemistry Society/Society of Chemistry Industry (RSC/SCI) Medicinal Chemistry Symposium is a key symposium in the field of medicinal chemistry that takes place every 2 years at the University of Cambridge, U.K., under the auspices of the RSC and the SCI. This year, in its 21st edition, it was run as a hybrid event, simultaneously attended by both in-person and virtual attendees. Its theme was 'Improving Success', and 25 orals and 30 posters were presented. The scientific program covered recent medicinal chemistry achievements in major therapeutic areas, with a few first-time structure disclosure presentations and particular emphasis on emerging early-stage drug discovery and lead optimization strategies, including reports of successful case studies illustrating fragment-based screening and phenotypic target engagement approaches. Applications of artificial intelligence (AI), mass spectrometry and photochemistry in drug design and discovery were also highlighted. This report will cover some of the medicinal chemistry presentations delivered at the meeting.
ABSTRACT
Background: The impact of some medical decisions hurriedly taken during the COVID-19 first wave remains unknown. We tried to assess the consequences of one of these precautionary measures, namely the interruption of a 4/6 cyclin D-dependent kinase inhibitor (CDK4/6i) in metastatic patients with clinical benefit (complete response/partial response and patients with stable disease for at least 6 months) on endocrine treatment (ET). The main reason for this interruption was to limit the risk of myelosuppression (assumed as a serious risk factor for COVID-19) and other adverse effects that could overlap with symptoms and clinical signs described in the SARS-CoV-2 infection. Methods: We included 60 patients (median age: 64 years old) in whom the CDK4/6i was stopped during the first COVID-19 outbreak. It was a non-interventional, retrospective, multicentric study. A univariate analysis was performed to assess risk factors associated with disease progression: odds ratios (OR) were estimated along with their confidence intervals (CI). Key patient characteristics, all included in the statistical model, are presented in Table 1. Results: The average duration of a CDK4/6i interruption was 8 weeks. During this therapeutic break, 22 (37 %) patients Shad a radiological and/or clinical progression of the disease. Among them, CDK4/6i were taken back for the majority of patients (n=16/22;73 %) when the sanitary situation improved.For four patients (n=4/22;18 %), a new specific treatment (chemotherapy or targeted therapy) was initiated for rapid or symptomatic tumor progression. Two patients died while CDK4/6i was withdrawn. All the results of the univariate analysis are summarized in Table 2. During the CDK4/6i discontinuation, the risk of disease progression was significantly increased in the presence of liver metastases. This was the only variable with a significant effect in univariate analysis. Although not statistically significant, the risk of disease progression was higher when CDK4/6i withdrawal was longer, when patients had a more aggressive breast cancer (Luminal B) and when the tumor was considered as resistant to ET. Conclusions: The importance of maintaining the cell cycle inhibitor in addition to ET does not seem to be debatable as 36 % of patients progressed during CDK4/6i withdrawal. This is important in clinical practice when the question of CDK4/6i discontinuation arises for other reasons (analgesic radiotherapy or programmed surgery for example). Special attention should be paid to patients with liver metastases for whom stopping such a treatment seems to accelerate the natural course of the disease.
ABSTRACT
Introduction: Patients with relapsed or refractory malignant lymphoma (rrNHL) after chemoimmunotherapy often do not experience longterm disease control. Therefore, novel therapeutic options are urgently needed. CD19, a type I transmembrane glycoprotein widely expressed in B-cell-lymphomas, has raised interest as a therapeutic target. Tafasitamab (formerly MOR208) is a humanized Fc-modified cytolytic CD19 antibody which exerts its efficacy via enhanced antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellular phagocytosis, as well as direct cytotoxic effects on tumor cells. In a phase IIa study of tafasitamab in rrNHL patients and no curative option available, the antitumor activity and safety of tafasitamab was investigated. Patients received tafasitamab at a dose of 12mg/kg intravenously, weekly for 8 weeks. Treatment could be continued for additional 4 weeks when at least stable disease was reached. Patients who reached PR or CR after 12 weeks of treatment could extend their treatment until progression. Clinical outcome was promising, however the median follow-up was only 26 months and therefore, little is known about the long-term tolerability and safety of tafasitamab. Methods: We identified 5 patients from the database with rrNHL, namely FL, MZL and DLBCL, who are treated with single-agent tafasitamab for more than 5 years and performed a long-term analysis of its tolerability and safety. Only patients, for whom complete information was available concerning efficacy and toxicity and who consented for long-term evaluation of data, were selected. Results: Besides the ongoing long-term response, a very favorable safety profile was found. There were only a couple of non-severe adverse events (AEs) mostly within the first 2 years of treatment. Most common AEs were infections (45%) and neurological symptoms (14%). There were no grade 4 AEs or grade 4 late toxicities, only one episode of treatment-emergent hematological grade 3 AE and grade 3 dizziness, no late toxicities, or infusion related reactions. ECOG performance status was unimpaired. Discussion: Our data support the safety of the long-term use. Given the long-term tolerability of tafasitamab, it can be considered as a safe agent in combination with chemotherapy, kinase inhibitors, bispecific antibodies, EZH2-inhibitors, or other options. In a future project, we will analyse the response to Covid-19 vaccination in these patients.
ABSTRACT
Case report-IntroductionCoronavirus disease 19 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), has reached pandemic level and led to over 46,000 deaths in the UK. COVID-19 is primarily a respiratory illness and 10-20% of infected individuals develop severe disease with interstitial pneumonia or acute respiratory distress syndrome (ARDS). In this subgroup of patients, severe clinical manifestations are postulated to result from a hyperactive immune response. This has led to the proposal that immunomodulatory medications could be used for the treatment of COVID-19. Here, we report a case of COVID-19 that was treated with the IL-6 inhibitor, tocilizumab.Case report-Case descriptionA 54-year-old Middle Eastern woman presented to A&E with a one-week history of fever, cough, headache and ageusia. Her past medical history was significant for asthma, chronic headaches, gastro-oesophageal reflux syndrome and subarachnoid haemorrhage. On presentation, she had a low-grade temperature (37.8 °C) but her observations were otherwise normal, and her oxygen saturations were 99% on room air. Examination revealed right basal chest crackles. Bloods showed a mild lymphopenia (0.9x109/l) and a raised CRP (82mg/l) and a chest radiograph demonstrated bibasal shadowing. The patient was diagnosed with probable COVID-19 and discharged with a course of oral doxycycline and a plan for review in the ambulatory unit the following day. When reviewed the next day, her oxygen saturations had fallen to 90% on room air. At this point, her SARS-CoV-2 assay had been resulted as positive and a decision was made to admit her for oxygen therapy.The patient continued to deteriorate despite optimal supportive therapy and the addition of intravenous benzylpenicillin for possible superadded bacterial infection. On day 7 of admission, her respiratory rate was 32-38 breaths per minute, and she required 13l/min of oxygen. Her bloods revealed CRP 474mg/L, D dimer >6000 ng/ml, ferritin 224 μ g/L, neutrophils 9.5x109/l and lymphocytes 0.6 x109/l. There were no signs of superadded bacterial infection despite a thorough infection screen. Given her clinical deterioration, she was reviewed by the critical care team for consideration of transfer to higher-level care. The ward team decided to administer a single dose of the anti-IL-6 agent tocilizumab for the treatment of a cytokine storm secondary to COVID-19 infection. Within 24 hours of tocilizumab treatment, her oxygen requirements fell to 5l/min and her work of breathing significantly improved. On day 15 of admission, she was discharged with saturations of 92% on room air. Case report-DiscussionThe patient described in this case showed significant clinical deterioration with features suggestive of cytokine storm secondary to COVID-19. IL-6 is thought to be a key cytokine responsible for initiating the acute phase response and we postulate that IL-6 levels were raised in this patient. Unfortunately, we did not have the assay available to measure this. The treating clinical team decided to prescribe a single dose of tocilizumab on a compassionate use basis. This resulted in a rapid clinical improvement and the patient was subsequently discharged without the need for intensive care. In this case, we propose that tocilizumab inhibited further cytokine activation and prevented the positive feedback loop of inflammation that can otherwise result in rapid clinical deterioration.There are several interesting points to be noted from this case. In this patient, tocilizumab resulted in a rapid reduction in CRP levels. This is thought to correspond to the inhibition of IL-6 mediated release of acute phase proteins by the liver. Therefore, it should be noted that post-tocilizumab treatment, patients should be closely monitored for superadded bacterial infection as they may not mount a full immune response.Larger trials of tocilizumab for the treatment of COVID-19 are currently underway and are required to confirm the efficacy of IL-6 inhibition for COVID-19. The phase III COVACTA trial of toci izumab in COVID-19 patients did not meet its primary endpoint of improved clinical status however a trend towards shorter hospital admissions was seen. Further studies are ongoing to investigate the role of tocilizumab in other treatment settings, including in combination with an antiviral medication. Further information is required to determine which patients should receive immunomodulatory medications and at which point in their illness. Data is also needed to understand the most efficacious dosing regimen for tocilizumab and its side-effect profile in COVID-19 patients.Case report-Key learning pointsThe COVID-19 pandemic has affected millions of people worldwide and has led to an unprecedented effort from the scientific community to understand the pathophysiology of the disease and to find effective treatments. Emerging evidence suggests that SARS-CoV-2 can induce a hyperactive immune response in a subgroup of patients who develop highly elevated levels of acute phase proteins. It has been proposed that the overactive immune response is responsible for some of the severe clinical manifestations seen and this has led to the suggestion that immunomodulatory medications could be used for the treatment of COVID-19.Indeed, dexamethasone has been shown to be an effective treatment and other immunomodulatory medications including hydroxychloroquine, the IL-1 inhibitor anakinra and JAK-kinase inhibitors are currently being trialled for the treatment of COVID-19. This case highlights the clinical and biochemical features of a patient who developed features suggestive of a cytokine storm secondary to COVID-19 and who responded to treatment with the IL-6 inhibitor tocilizumab. Further work is required to understand the role of immunomodulatory medications for the management of COVID-19 infection.