High-dose influenza vaccine candidate deemed safe and effective

2nd August 2023

OVX836 is a universal influenza A vaccine which appears to be safe and has previously shown a preliminary signal of protection against influenza symptoms.

Now, in a study published in The Lancet Infectious Diseases, researchers sought to explore the safety and potential efficacy of higher doses of OVX836. This is a recombinant protein-based vaccine which targets the highly conserved influenza nucleoprotein (NP) and therefore potentially confers broad-spectrum protection against influenza.

Influenza viruses are associated with over five million hospitalisations every year across the world. Moreover, anti-viral agents such as oseltamivir do not appear to reduce influenza-related hospitalisations, highlighting the need for effective vaccinations.

OVX836 safety and efficacy

In the trial, a total of 137 healthy adults aged 18-55 years were randomly assigned to receive one single intramuscular administration of OVX836 influenza vaccine at three doses (180 μg, 300 μg or 480 μg) or placebo.

OVX836 had a favourable safety profile up to 480 μg without reaching the maximum tolerated dose and showed a good safety profile at all doses with only mild local and systemic reactogenicity.

Seven days after vaccination, there were no significant differences observed between the doses. Dose-dependent and poly-functional nucleoprotein-specific CD4 T-cell responses were observed, and CD8 T-cell responses were elicited at 300 μg and 480 μg.

In a planned further exploratory endpoint, the study also evaluated the protection level of the vaccine against RT-PCR-confirmed influenza A. During the influenza season, there were four RT-PCR-confirmed influenza A cases in the placebo group but only two in the OVX836 group. This resulted in an observed level of protection of 84% (95% CI 17–97) for OVX836 at the time of maximum exposure to influenza.

Study lead investigator Dr Paul Griffin said: ‘By combining OVX836 with the current standard of care, we expect to bring much-needed and critical additional protection against seasonal influenza, especially for high-risk populations, including the elderly.‘

Alexandre Le Vert, CEO and co-founder of the vaccine manufacturer Osivax, added: ‘The initiation of our multicenter Phase 2a trial marks an important milestone for Osivax as we continue optimising the development of OVX836 in combination with conventional influenza vaccines within a larger and more diverse population. We are eager to build upon the promising initial data from our previous study in an effort to provide improved and broad-spectrum protection, especially for at-risk populations.‘

CTX-009 shows promise in biliary tract cancer

27th January 2023

CTX-009 and paclitaxel improved the overall response rate in advanced biliary tract cancer when used as a second and third-line treatment

CTX-009 in combination with paclitaxel improved the overall response rate in patients with unresectable, advanced, metastatic or recurrent biliary tract cancer, according to findings presented at the 2023 ASCO Gastrointestinal Cancer Symposium in San Francisco.

CTX-009 is a novel, bispecific antibody which causes blockade of delta-like ligand 4 Notch-1 signalling, inhibiting tumour growth as well as an blocking vascular endothelial growth factors (VEGF), that are recognised as important factors in tumour biology with role in angiogenesis. Since the overall response rate to the use of a single VEGF inhibitor is often low, there is a need for additional angiogenesis-based therapies. In a previously reported release from the manufacturer, Compass Therapeutics, data from a phase 2 trial showed that when added to paclitaxel, CTX-009 demonstrated a 42% overall response rate based on data from 10 patients with partial responses.

The findings presented at ASCO 2023, relate to an open-label, multi-centre, single arm, phase 2 trial, in patients with unresectable, advanced biliary tract cancer. Individuals were given CTX-009 as either a second or third-line treatment at a dose of 10 mg/kg biweekly in combination with paclitaxel. The primary aim of the study was to assess the objective response rate (ORR) based on RECIST v1.1.

CTX-009 and overall response rate

A total of 24 patients (median age = 61.5 years, 58.3% male) were included and of whom, 11 were receiving CTX-009 as a second-line treatment and the remainder as a third-line agent. The median duration of follow-up was 12.1 months.

The ORR was 37.5% (95% CI 18.8 – 59.4%) and this was higher for patients receiving the drug as a second-line treatment (ORR = 63.6%) though lower when used third-line (ORR = 15.4%). In addition, the median progression-free survival was 9.4 months and the median overall survival 12.5 months.

In terms of safety, treatment-emergent adverse events > grade 3 occurred in 95.8% of patients and 6 patients discontinued treatment due to adverse events.

The authors concluded that CTX-009 showed promise in biliary tract cancer patients and called for further studies to examine the efficacy and safety of the regime.

Citation
Oh DY et al. CTX-009(ABL001), a bispecific antibody targeting DLL4 and VEGF A, in combination with paclitaxel in patients with advanced biliary tract cancer (BTC): A Phase 2 study. ACSO GI Cancer Symposium 2023

Infusion of novel agent reduces oral mucositis following chemoradiotherapy

25th January 2023

RRx-001 is a novel agent affecting the development of oral mucositis and reduced the duration of severe symptoms in a Phase II trial

Oral mucositis (OM) represents a common and highly symptomatic complication of cancer therapy which negatively impacts upon patient’s quality of life. OM affects virtually all patients undergoing radiation treatment for head and neck cancers and, given the inadequacy of pain relief offered by opiates, preventative rather than palliative measures are needed. OM represents a significant unmet need for patients undergoing chemoradiation (CRT) for head and neck cancers, affecting individual’s ability to eat, drink and swallow, yet there are currently there are no approved treatments for the condition. While the underlying cause of OM remains to be determined, it is thought to arise largely the consequence of cumulative CRT-induced biological changes overwhelming physiologic self-protective mechanisms.

RRx-001 is a white, crystalline, nitrogen containing small molecule with demonstrated anti-cancer activity affecting a number of pathways including nitric oxide. Moreover, data suggests that the compound is able to selectively protect normal cells, while inducing apoptosis within tumour cells.

In the current study, researchers randomised patients with squamous cell carcinoma and who received either definitive or postoperative cisplatin-based CRT, to three different dosing schedules of RRx-001 (arms 1 to 3) and a placebo arm. The severity of OM was assessed using the WHO grading scale and the incidence of severe OM was bases on WHO scores > 3.

RRx-001 and duration of severe OM

Although 53 patients were enrolled, only 46 contributed to the efficacy data. Overall, there were no severe adverse reactions attributed to the drug. Patients in arm 1 had the lowest median duration of severe OM which was 8.5 days compared to 17 days and 10 days in arms 2 and 3 respectively. Among those in the placebo arm, the median duration of severe OM was 24 days.

The authors concluded that these data supported both the safety and efficacy of RRx-001 while also highlighting the need for further studies to confirm these findings.

Citation
Bonomi R et al. PREVLAR: Phase 2a randomized trial to assess the safety and efficacy of RRx-001 in the attenuation of oral mucositis in patients receiving head and neck chemoradiotherapy Int J Radiat Oncol Biol Phys 2023

GSK3036656 shows bactericidal activity after 14 days in pulmonary tuberculosis

8th December 2022

GSK3036656 is a first-in-class antibacterial which has shown promise as a potential treatment for patients with tuberculosis

Preliminary findings suggest that GSK3036656 has the potential to be a component of future treatments to address the tuberculosis (TB) epidemic according the manufacturer GSK.

It has been estimated by the World Health Organisation that in 2021, tuberculosis affected 10.6 million people and led to 1.6 million deaths, so that globally, it was the 13th leading cause of death and the second leading infectious killer after COVID-19.

TB can affect bone, the central nervous system and many other organ systems, but is primarily a pulmonary disease and caused by Mycobacterium tuberculosis, which is carried in aerosol droplets onto lung alveolar surfaces. Current therapy involves the use of isoniazid and rifampicin for 6 months although both pyrazinamide and ethambutol are added during the first 2 months.

Given the need for prolonged treatment, the early findings for GSK3036656 are promising. The drug has a unique mode of action, targeting the aminoacyl-tRNA synthetase enzymes that mediate protein synthesis. Inhibiting these enzymes terminates protein synthesis and subsequently achieve an antibacterial action and GSK3036656 acts to inhibit one of these aminoacyl-tRNA synthetase enzymes, leucyl-tRNA synthetase.

GSK3036656 clinical efficacy

Data announced by GSK comes from a clinical trial designed to examine the early bactericidal activity, safety and tolerability of the drug in up to four sequential cohorts of subjects with rifampicin-susceptible tuberculosis. In the trial, participants were randomised in a 3:1 ratio to receive either GSK3036656 at doses 1 mg, 5 mg, 15 mg, and 30 mg or standard-of-care (SoC) regimen for drug sensitive TB.

The anti-mycobacterial activity was assessed in terms of its ability to reduce the number of viable TB cells which are able to multiply (i.e., colony forming units – CFU) and in the time to detect bacterial growth in culture (time to positivity – TTP). This latter marker indicates the time from the beginning of culture incubation to the detection of bacterial growth. Ideally, this marker should increase as a shorter TTP is likely to reflect a higher bacterial concentration in blood which may be associated with severe infection.

For the current study the primary outcome was the rate of change in log₁₀colony forming units (CFU)/ml in direct respiratory sputum samples from baseline to Day 14 (EBA CFU_0-14). The main secondary outcome was the rate of change in time to sputum culture positivity (EBA TTP) over the same timeframe (EBA TTP_0-14).

The results showed that after 14 days, of the four doses, GSK3036656 30 mg had the highest bactericidal activity with a decline in CFU of -0.138 log₁₀CFU/mL (95% CI -0.167 – 0.109) and an increase in TTP of 0.22 log₁₀CFU/mL (95% CI 0.019 – 0.024). Researchers also examined PET CT images of the lungs which showed a reduction in TB disease over 14 days in all participants taking GSK3036656 30mg. As well as proving to be effective, the treatment was generally well tolerated with no serious adverse events identified.

GSK will now be testing their oral therapy in Phase IIb/c studies as a part of different drug regimens to determine the appropriate partner agents and the optimal regimen durations. The overall aim is therefore to identify a GSK3036656-containing regimen with sufficient tolerability, efficacy and short enough duration to progress to Phase III with a high probability of success.