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Take a look at a selection of our recent media coverage:
21st April 2023
Urinary tract infections (UTI’s) have a lifetime incidence of 50-60% in adult women. While commonly treated with antibiotics, UTI’s often recur in 16% of women. An uncomplicated UTI is mainly due to Escherichia coli but recent data indicates antimicrobial resistance is on the increase.
In a recent press release by GSK, its novel and investigational, first-in-class, antibiotic, gepotidacin (GD) was non-inferior to nitrofurantoin in two phase III trials in women with an uncomplicated UTI (uUTI). The drug inhibits bacterial DNA replication by blocking two essential topoisomerase enzymes. Consequently, mutations in both enzymes would be needed for resistance to occur. While GD appears effective in uncomplicated UTI’s according to a phase 2 trial, there is an absence of phase 3 studies.
The press release describes the findings from two near identical, randomised, double-blind studies, EAGLE-2 and EAGLE-3. Both involved women and adolescents with an uUTI and had nitrofurantoin (100mg twice daily) as an active comparator. The primary efficacy endpoint was therapeutic success (TS) which was a combination of clinical and microbiological success. GD was given at a dose of 1,500 mg twice daily for 5 days. Participant assessment took place 10 – 13 days after initiation of treatment.
Gepotidacin and therapeutic success
In EAGLE-2 the TC was 50.6% with gepotidacin and 47% with nitrofurantoin. In EAGLE-3, a higher proportion of participants receiving gepotidacin achieved a TS (58.5% vs 43.6%). Furthermore, across both trials, 94% of gepotidacin patients did not receive an additional antibiotic for their uUTI through to the follow-up visit on day 28. The clinical cure rates were similar for gepotidacin and nitrofurantoin in both trials. However, the microbiological cure rate was higher with gepotidacin in EAGLE-3 (72.2% vs 57.2%).
The safety and tolerability profile of gepotidacin in the EAGLE-2 and EAGLE-3 phase III trials was consistent with previous trials of gepotidacin.
GSK expects to submit data to the FDA in the second quarter of 2023.
13th April 2023
According to press release by the manufacturer, UCB, bimekizumab provides a clinically meaningful benefit to patients with hidradenitis suppurativa.
Hidradenitis suppurativa (HS) is a chronic inflammatory disorder affecting intertriginous areas of skin. and affects around 1% of the population. Clinically, patients experience cutaneous inflamed nodules, abscesses and pus-discharging tunnels that develop in axillary, inguinal, gluteal and perianal body sites. There is often a diagnostic delay and which leads to more severe disease. Bimekizumab is a humanised, monoclonal antibody that selectively inhibits both IL-17A and IL-17F. A phase 2 trial found use of the drug led to clinically meaningful improvement in patients with HS.
The press release provides data from two phase 3, randomised, placebo-controlled trials in adult patients with moderate to severe HS. Both trials had a 16-week initial and 32-week maintenance treatment period. Bimekizumab was used at a dose of 320 mg every two weeks and 320 mg every four weeks. The Hidradenitis Suppurativa Clinical Response (HiSCR50) served as the primary outcome measure. This is defined as a 50% decrease in the total abscess and inflammatory nodule count, with no increase in abscess or draining tunnel count.
Bimekizumab and HS outcomes
There were 1,014 patients in the two trials. In both trials at week 16, more patients using bimekizumab achieved the primary outcome compared to placebo. For example, 45.3% vs28.7%, p = 0.030 (BE HEARD 1) and 53.8% vs 32.2%, p = 0.004 ( BE HEARD II). These improvements were seen for both drug regimens. In addition, over 75% percent of patients using bimekizumab achieved HiSCR50 and over 55% a HiSCR75 at week 48.
The company will submit data for global regulatory approval of the drug in patients with moderate to severe HS later in 2023.
15th March 2023
Acadia Pharmaceuticals announced that it has received approval for trofinetide as a treatment for adult and paediatric patients with Rett Syndrome from two years of age.
Rett syndrome is described as a neuro-developmental disorder characterised by typical early growth and development followed by a slowing of that development, loss of functional use of the hands, distinctive hand movements, slowed brain and head growth, problems with walking, seizures, and intellectual disability. The condition primarily affects females resulting in severe cognitive and physical disabilities and is estimated to affect about 1 in 12,000 girls and is only rarely seen in boys. Virtually all patients with Rett syndrome have one of > 300 distinct loss-of-function mutations in the MECP2 gene on the X chromosome, which encodes methyl-CpG binding protein-2, an essential transcriptional regulator in the brain required for normal neurodevelopment.
Before trofinetide, which is given orally, there were no recognised treatments for Rett syndrome and the drug is believed to work by normalising aberrant neural function resulting from MECP2 mutations. In an exploratory phase 2, multicentre, double-blind, placebo-controlled, dose-escalation study, trofinetide was found to provide a clinically meaningful improvement for patients with the syndrome. The approval by the FDA was based on the findings from LAVENDER, a phase 3 study of trofinetide for Rett syndrome.
According to the press release, LAVENDER evaluated the efficacy and safety of trofinetide compared to placebo in 187 female patients with Rett syndrome, five to 20 years of age. In the study, treatment with trofinetide produced a statistically significant improvement (compared to placebo) on both co-primary efficacy endpoints, measured by the change from baseline, in Rett Syndrome Behaviour Questionnaire (RSBQ) total score (p = 0.018), which is a caregiver assessment on a range of disease symptoms, and the Clinical Global Impression-Improvement (CGI-I) scale score (p = 0.003) at week 12, which represents a physician-based assessment. In the study, the most common side effects were diarrhoea (82%) and vomiting (29%).
The drug is likely to be available in the US from April 2023 although the press release provides no information on its release elsewhere.
In a press release, Pfizer has announced that zavegepant has become the first calcitonin gene-related peptide receptor antagonist nasal spray to receive approval by the FDA for the management of acute migraine.
According to a study using data from 2016, it was estimated that globally, migraine affects some 1·04 billion people and caused 45·1 million years of life lived with disability. Although there was a breakthrough in treatment of migraine during the early 1990’s with the introduction of triptans, it later emerged that the calcitonin-gene-related peptide (CGRP) pathway was important in the pathophysiology of migraine. While first generation drugs targeting this pathway, known as ‘gepants’ were effective, hepatotoxicity halted further development but did lead to new generation of gepants, which have been shown to be safe, efficacious and well tolerated.
Zavegepant clinical studies
Zavegepant nasal spray is a third generation gepant and the first, non-oral gepant. In a randomised, dose-ranging, placebo-controlled, phase 2/3 trial in adults aged ≥18 years with migraine, single doses of 10 or 20 mg, of the drug were shown to be effective for the acute treatment of migraine and with a favourable safety profile. Further data on the efficacy of zavegepant and which formed the basis for the approval, came from a double-blind, randomised, placebo-controlled phase 3 trial in adults with a history of two to eight moderate or severe migraine attacks per month. The results showed that among those assigned to zavegepant, two hours after the treatment dose, a statistically significant higher proportion of zavegepant patients had freedom from pain and freedom from their most bothersome symptom. In addition, twice as many patients (16% vs 8%) given zavegepant reported pain relief after only 15 minutes. There were also significant differences (compared to placebo) for 13 of the 17 pre-specified secondary outcomes.
The trial also found that the drug was well tolerated with the most common adverse reactions reported in at least 2% of patients and at a frequency greater than placebo, were taste disorders (includes dysgeusia and ageusia), nausea, nasal discomfort and vomiting.
14th March 2023
In a press release from Merck, it is reported that their investigative, oral, once-daily, PCSK9 inhibitor, MK-0616, gave rise to significant reductions in LDL cholesterol in adult patients with hypercholesterolaemia.
Increased levels of PCSK9 elevate plasma LDL cholesterol and conversely, lowering PCSK9 reduces LDL cholesterol. As a result, inhibition of PCSK9 represents a therapeutic target and drugs such as evolocumab have been recommended in the treatment of primary hypercholesterolaemia or mixed dyslipidaemia and in patients with a high or very high risk of cardiovascular disease, where LDL cholesterol levels remain above 3.5 mmol/l. However, to date all PCSK9 inhibitors are only available as an injectable form, whereas MK-0616 is an oral PCSK9 inhibitor.
In a study of healthy patients with hypercholesterolaemia, the use of once daily MK-0616 (dose 10 to 300 mg), exhibited a dose dependent increase in plasma exposure and a > 90% mean maximum reduction of free plasma PCSK9 levels from baseline at all dose levels studied. The current press release relates to the findings from a phase 2b clinical trial in which MK-0616 was given at varying doses (6, 12, 18 and 30 mg) to adult patients with hypercholesterolaemia and who were divided into one of three categories, in which fasting LDL cholesterol levels ranged from > 1.81 to < 6.48 mmol/l. In addition, participants were either stable on one or more lipid lowering therapies or who had not received any such treatments for more than 30 days before screening. Individuals were then randomised 1:1:1:1:1 (i.e., each dose and placebo) and the treatment continued for 16 weeks and the primary objective of the study was to evaluate the percent change in LDL cholesterol from baseline to week 8.
MK-0616 and reduction in LDL cholesterol
A total of 380 participants with a median age of 62 years (49% female) with hypercholesterolaemia and a moderate to high risk of atherosclerotic cardiovascular disease were included.
At week 8, all four doses of MK-0616 significantly reduced LDL-C compared to placebo and the placebo-adjusted reduction from baseline ranged from 41.2% with the 6 mg dose to 60.9% with the 30 mg dose (p < 0.001 for each dose).
The drug was well tolerated and the proportion of participants experiencing greater than one adverse event was similar (ranging from 39.5% to 44.2%) between the different doses and placebo (44%).
The findings of the phase 2b study have been published in the Journal of the American College of Cardiology.
6th March 2023
According to a press release by the manufacturer, Reata, omaveloxolone (brand name SKYCLARYS™) has become the first treatment to be approved for the treatment of Friedreich’s ataxia, an ultra-rare, genetic, progressive neurological disorder.
Friedreich’s ataxia represents an inherited autosomal recessive disease, that affects the nervous system, producing a progressive ataxia, weakness and sensory deficits. The disease has a median onset age of 10 to 15 years and affects approximately 1 in 50,000 people worldwide. Friedreich’s ataxia is due to a lack of function in a gene responsible for the production of frataxin, a protein involved in mitochondrial iron homeostasis. During conditions of cellular oxidative stress, there is activation of the transcription factor, NF-E2-related factor and which triggers a cellular antioxidant response, through induction of antioxidant response element driven genes. However, it appears that a lack of frataxin impairs NF-E2 signalling and this is though a contributory factor for the neuro-degeneration seen in Friedreich’s ataxia. Omaveloxolone has been shown to induce NF-E2 and thus protect cells from oxidative stress.
Omaveloxolone clinical efficacy
An initial dosing ranging study identified that a dose of 160 mg/day appeared to improve neurological function. Following on from this, a phase 2 randomised, placebo-controlled trial with 103 patients, demonstrated that omaveloxolone 150 mg daily, significantly improved the modified Friedreich’s Ataxia Rating Scale (mFARS) score after 48 weeks compared to placebo (p = 0.014). In an open label extension trial, after 72 weeks, the response to omaveloxolone compared to placebo was maintained.
Following the FDA approval, the company has created the Reata Education, Access, and Care Helpline (REACH), an integrated specialty pharmacy and patient services program, designed to help eligible patients access prescribed Reata medicines.
While yet to be approved, the press release reports that omaveloxolone has been granted Orphan Drug designation in Europe for the treatment of Friedreich’s ataxia and is currently under review by the European Medicine Agency.
17th February 2023
In a press release by the manufacturer, Ena Respiratory, a phase 2a clinical study of INNA-051, when delivered intra-nasally, significantly reduced the duration of flu infection and led to a dose-related trend towards a reduction in symptom duration.
The body’s innate immune system is designed to provide the first line of defence against microbial pathogens via the use of Toll-like receptors (TLR), i.e., microbe recognition receptors present on the surface of cells. There are several types of TLR produced by cells and evidence suggests that three, TLR2, TLR1 and TLR6 (together with an unknown co-receptor), interact with a large variety of microbial ligands. Moreover, any alteration or absence of TLR2 function, correlates with a reduced immune protection against pathogens that possess TLR2 ligands. Given the important role of TLRs in the earliest phase of a host’s immune response, the development of TLR agonists is a promising therapeutic strategy. In fact, work from 2012 showed that the use of a TLR-2 agonist in mice offered protection against influenza.
INNA-051 is a first-in-class, TLR2/6 agonist and was originally tested as a treatment for COVID-19. In earlier work with ferrets infected with the virus, intra-nasal administration of the INNA-51 significantly reduced viral RNA in both the nose and throat by up to 96%. However, with the introduction of COVID-19 vaccines, there was less need for such treatments but the company continued to explore the potential of the drug in the treatment of other viruses and have found that it induced innate immune priming in response to rhinovirus infection.
INNA-051 and influenza
The press release provides top-line data from a randomised trial in which 123 adults were randomised to either two doses of INNA-051 (low and high) or placebo and then challenged with a large dose of H3N2 influenza A virus. Unfortunately, the company reported that interpreting the results were complicated by the lower than expected infection rates in the placebo arm and a larger than predicted prior immunity across all groups. Nevertheless, in post hoc analysis, it was found that participants treated with the higher dose of INNA-051 had a statistically significant shorter duration of infection, as well as a non-significant reduction in the duration of symptoms.
Although INNA-051 is not currently licensed for use outside of clinical trials, the evidence appears to suggest that a prophylactic approach, based on boosting the innate immune system in the nose could be of clinical benefit for those exposed to respiratory viruses.
10th February 2023
The anti-diabetic drug, dapagliflozin (brand name Forxiga) has been approved in the EU for patients with heart failure across the full spectrum of ejection fractions its manufacturer AstraZeneca has announced.
It has been estimated that globally, 64.3 million people are living with heart failure and chronic heart failure represents a leading cause of hospitalisation among those 65 years and older. Although dapagliflozin, which is a sodium-glucose cotransporter-2 inhibitor, used in the management of type 2 diabetes, it also appears to reduce adverse outcomes in patients with heart failure. In fact, studies have shown how the drug is effective in type 2 diabetics and heart failure, with an ejection fraction of less than 40%. Furthermore, in pursuing the value of the drug in heart failure, more recent data show that dapagliflozin at a dose of 10 mg daily, was able to reduce the combined risk of worsening heart failure and cardiovascular death in patients with either a mildly reduced or preserved ejection fraction.
Dapagliflozin use across heart failure ejection fractions
In a patient-level pooled analysis of the only two trials which tested dapagliflozin in heart failure with ejection fractions either ≤40% or >40%, there was no evidence that the effect of the drug varied by ejection fraction. In fact, the combined analysis revealed how dapagliflozin reduced both the risk of cardiovascular death and hospitalisations for heart failure.
6th February 2023
A press release from manufacturer Sanofi, has described how their novel, investigative agent, efanesoctocog alfa, is effective in the management of patients with haemophilia A.
In those with severe haemophilia A, levels of endogenous plasma factor VIII are below 1% and such individuals can experience recurrent bleeds and which are treated using replacement therapy with clotting factor concentrates as prophylaxis or on-demand therapy for bleeding. Within the plasma, the majority of Factor VIII circulates attached to von Willebrand factor and this modulates its half-life and provides protection from degradation. However, coupling of both proteins imposes constraints on the half-life of factor VIII. Efanesoctocog alfa represents a novel form of factor VIII replacement that is physically decoupled from endogenous endogenous von Willebrand factor, thereby extending the half-life of factor VIII. Although not yet approved, the available data for efanesoctocog alfa and which was published in the New England Journal of Medicine (NEJM), concluded that it provided superior bleeding prevention compared to pre-study prophylaxis, as well as the achievement of near to near-normal factor VIII activity and improvements in physical health.
In the trial (XTEND-1) which is the subject of the press release, efanesoctocog alfa was able to deliver normal or near-normal (> 40%) factor VIII activity for the majority of the week with a single, once weekly dosing. In fact, the mean annualised bleeding rate (ABR) was 0.71 (95% CI 0.52 – 0.97) yielding a 77% reduction compared to prophylaxis with factor VIII (P < 0.001) based on an intra-subject comparison.
Other data showed that efanesoctocog alfa led to significant (compared to baseline) improvements in physical health, pain intensity and joint health after 52 weeks. Additionally, the product was well tolerated and inhibitor development to factor VIII was not detected and treatment-emergent adverse effects, in greater than 5% of participants were headache, arthralgia, fall and back pain.
Efanesoctocog alfa is currently under FDA review and regulatory submission in the EU is anticipated in the second half of 2023.
According to the manufacturer, Pilant Therapeutics, results from a phase 2a placebo-controlled trial, showed that bexotegrast at a daily dose of 320 mg, achieved a statistically significant mean increase in forced vital capacity (FVC) from baseline up to week 12 in patients with idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterised by scarring of unknown cause, giving rise to dyspnoea and a non-productive cough. The data comes from the INTEGRIS-IPF trial, a multi-national, randomised, double-blind, placebo-controlled trial designed to evaluate the safety, tolerability and pharmacokinetics of once daily bexotegrast in people with idiopathic pulmonary fibrosis. The study included four doses (40, 80, 160 and 320 mg) and patients were randomised 3:1 (active vs placebo). Although the primary outcomes for INTEGRIS-IPF were not related to efficacy, exploratory efficacy analyses included changes in FVC and biomarkers such as PRO-C3, which is raised in patients with IPF and associated with disease progression.
Bexotegrast and IPF outcomes
A total of 21 patients were assigned to the 320 mg dose and there was a mean FVC increase of 29.5ml compared to baseline at 12 weeks compared to a decrease of 110.7ml for those assigned to placebo (p < 0.05). Moreover, the mean increase was statistically superior to placebo at all timepoints. In addition, patients receiving 320 mg saw a significant reduction in PRO-C3 levels at both week 4 and 12 (p <0.01) compared to placebo.
The press release adds that 24-week data for patients treated with bexotegrast should be available in the second quarter of 2023.
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