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23rd February 2023
In a press release by manufacturer CSL, it is reported that Hemgenix (etranacogene dezaparvovec) has been granted a conditional marketing authorisation by the European Commission for the treatment of severe and moderately severe haemophilia B (congenital Factor IX deficiency) in adults without a history of Factor IX inhibitors.
Haemophilia B is an inherited and life-threatening rare disease affecting 1 in 40,000 live males which is about 15% of cases of haemophilia. It is a caused by missing or defective clotting protein, factor IX and sufferers are particularly vulnerable to bleeds in joints, muscles, and internal organs leading to pain, swelling and ultimately joint damage.
Patients with haemophilia B require lifelong treatment with intravenous infusions of Factor IX to maintain sufficient levels, which can have a significant impact on their quality of life and wellbeing. HEMGENIX® is an adeno-associated virus five (AAV5)-based gene therapy that is given as a one-time treatment for moderately severe to severe haemophilia B patients. HEMGENIX® uses a specific type of AAV, called AAV5, as its vector. The AAV5 vector carries the naturally occurring Padua gene variant of Factor IX (Factor IX-Padua), which generates Factor IX proteins that are 5 to 8 times more active than normal.
Hemgenix clinical data
The main clinical study with Hemgenix is the HOPE-B trial which is an ongoing, multinational, open-label, single-arm study, designed to evaluate the safety and efficacy of HEMGENIX®. Fifty-four adult haemophilia B patients classified as having a diagnosis of moderately severe or severe haemophilia B and requiring prophylactic Factor IX replacement therapy, were enrolled in a prospective, six-month observational period during which time they continued to use their current standard of care therapy to establish a baseline Annual Bleeding Rate (ABR). After the six-month lead-in period, patients received a single intravenous administration of HEMGENIX® with 53 patients completing at least 18 months of follow-up. The primary endpoint in the pivotal HOPE-B study was 52-week ABR after achievement of stable Factor IX expression compared with the six-month lead-in period.
Results from the pivotal HOPE-B study demonstrated that HEMGENIX® produced mean Factor IX activity of 36.9 IU/dL at 18 months post infusion. At 24 months follow-up, Factor IX activity remained stable at 36.7 IU/DL. After the six-month lead-in period post-infusion, the adjusted annualized bleeding rate (ABR) (1.51) for all bleeds was reduced by 64 percent (p = 0.0002) and all Factor IX-treated bleeds was reduced by 77 percent (3.65 to 0.83; p<0.0001) over months seven to 18. From day 21 through to months 7 to 24, 52 of 54 (96.3%) treated patients remained free of continuous routine Factor IX prophylaxis. The mean consumption of Factor IX replacement therapy significantly decreased by 248,392.6 IU/year/patient (96.52%; 1-sided p< 0.0001) between month 7 to 24 following treatment with HEMGENIX® compared to standard of care routine Factor IX prophylaxis during the lead-in period.
Fortunately, there were no serious adverse reactions identified. One death resulting from urosepsis and cardiogenic shock in a patient at 65 weeks following dosing was considered unrelated to treatment by investigators and the company sponsor. A serious adverse event of hepatocellular carcinoma was determined to be unrelated to treatment with HEMGENIX® by independent molecular tumour characterization and vector integration analysis. No inhibitors to Factor IX were reported.
In the press release, Professor Wolfgang Miesbach, Head of Coagulation Disorders at the Comprehensive Care Centre, University Hospital of Frankfurt, said “this approval marks an important step forward in the treatment of haemophilia B, which could be transformative for people who are debilitated by bleeds into their muscles, joints and internal organs, alleviating the burden of lifelong intravenous infusions of Factor IX products,” They added that “data from the HOPE-B study demonstrate the potential of HEMGENIX® to remove the need for routine prophylaxis, by providing durable Factor IX activity, as well as improved bleeding outcomes and quality of life for people with haemophilia B.”
5th December 2022
According to the manufacturer, Sanofi, sutimlimab (Enjaymo) has been approved for the management of adult patients who have haemolytic anaemia with cold agglutinin disease.
Cold agglutinin disease (CAD) is a rare, autoimmune disorder and which is characterised by premature haemolysis (i.e., destruction of red blood cells). The termed “cold” refers to the fact that the autoantibodies (termed ‘cold agglutinins’) cause haemolysis at cold temperatures, usually 3 to 4oC. Haemolytic anaemias are due to the production of autoantibodies (IgM) directed against surface antigens on red blood cells. This IgM-antigen complex is a potent trigger of the classic complement pathway, binds to the C1 complement complex and which in turn, activates C1s, a C1 complex serine protease. CAD affects about one person per million every year, and mostly develops between the ages of 40 and 80 years. The condition impacts the lives of an estimated 12,000 people in the US, Europe and Japan and is associated with profound fatigue and increased risk of thromboembolic events and mortality.
Prior to the introduction of sutimlimab, there have been no effective treatments for CAD and supportive therapy such as cold avoidance has been of limited value although there has been some benefit from rituximab. Sutimlimab is a first-in-class, humanised monoclonal antibody designed to target and block C1s and in doing so, inhibits the activation of the complement cascade in the immune system and C1-activated haemolysis.
Sutimlimab clinical efficacy
Two clinical trials have provided the evidence to support the EMA approval of sutimlimab. The first trial, CADENZA, was a 26-week randomised, placebo-controlled phase 3 study, to assess safety and efficacy of the drug in patients with CAD and without a recent (i.e., within 6 months prior to enrolment) transfusion history. Enrolled participants had a haemoglobin (Hb) level less than 10.0 g/dL and were randomised 1:1 to sutimlimab (6.5 g if body weight was <75 kg; 7.5 g if body weight was ≥75 kg) or placebo and which was administered by IV infusion over 60 minutes on day 0, day 7, and every 14 days thereafter through week 25. The primary endpoint was a composite of Hb increase from baseline of ≥1.5 g/dL at the treatment assessment time-point, absence of blood transfusions from week 5 to week 26, and avoidance of protocol-prohibited CAD medications from week 5 to week 26. Patients receiving sutimlimab had significantly greater odds of achieving the composite primary endpoint than placebo (odds ratio, OR = 15.9, 95% CI 2.9 – 88.0, p < 0.01). In the second, CARDINAL trial, which was also for 26 weeks, the primary end point was a normalisation of the haemoglobin level to 12 g/dL or an increase in Hb of 2 g/dL or more from baseline and no red-cell transfusion or use of medications prohibited by the protocol. A total of 13 patients (54%) achieved the primary endpoint.
Enjaymo received a marketing authorisation valid throughout the EU on 15 November 2022 and this follows an FDA approval in February 2022.
29th November 2022
According to a press release by the manufacturer, Sanofi, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion, recommending the approval of Dupixent (dupilumab) in the EU to treat adults with moderate-to-severe prurigo nodularis who are candidates for systemic therapy.
Prurigo nodularis (PN) is a skin disease that causes hard, pruritic nodules to form on the skin. The pruritus can be intense, causing people to scratch themselves to the point of bleeding or pain. It is categorised as a rare disease and one UK-based study estimated a prevalence of 3·27 patients per 10 000 population and the condition has a negative effect on patients’ quality of life.
Dupixent is a fully human monoclonal antibody that inhibits the signalling of the interleukin-4 (IL-4) and interleukin-13 (IL-13) pathways. The drug currently has several indications including the treatment of moderate-to-severe atopic dermatitis in adults and adolescents 12 years, as add-on maintenance treatment for severe asthma and as an add-on therapy with intranasal corticosteroids for the treatment of adults with severe Chronic rhinosinusitis with nasal polyposis.
Dupixent clinical data
The efficacy data for Dupixent which led to the CHMP approval came from two randomised trials, PRIME and PRIME 2. In both PRIME and PRIME 2 the primary objective was to demonstrate the efficacy of dupilumab on itch response in patients with prurigo nodularis and which was inadequately controlled on topical prescription therapy or when those therapies are not advisable. The PRIME trial included adults with PN and at least 20 nodules and severe itch who were randomly assigned to 300 mg dupilumab subcutaneously after a 600-mg loading dose or to matching placebo, every two weeks for 24 weeks. The primary endpoint was the number of patients who experienced at least a 4-point reduction in the Worst-Itch Numerical Rating Scale (WI-NRS) score from baseline to week 24. Overall, 60% of dupixent patients achieved the primary endpoint, compared to placebo patients (18%, p < 0.0001). In the second trial, PRIME 2, the primary endpoint was the proportion who experienced a clinically meaningful reduction in itch from baseline at week 12. This occurred for 37% of Dupixent patients compared to 22% of placebo patients (p = 0.0216).
The press release also reports that Sanofi and Regeneron (a partnering biotechnology company) are studying the use of dupilumab in a broad range of diseases including paediatric eosinophilic oesophagitis, hand and foot atopic dermatitis, chronic inducible urticaria-cold, chronic spontaneous urticaria and chronic obstructive pulmonary disease with evidence of type 2 inflammation.
28th November 2022
Trastuzumab deruxtecan (brand name Enhertu) been recommended for approval in the European Union (EU) as monotherapy for the treatment of adult patients with advanced HER2-positive gastric or gastro-oesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen according to a press release from the manufacturer, AstraZeneca.
Gastric cancer is the 5th most common cancer worldwide and there were more than 1 million new cases in 2020 and 719,523 deaths. If a gastric cancer is diagnosed and treated when localised, the 5-year survival rate is 70%. However, if the cancer has spread to surrounding areas and/or the regional lymph nodes, the 5-year survival rate is 32% and this rate reduces to 6% if the cancer undergoes metastases. Given this poor prognosis it is important to have gastric biomarkers one of which is the Human epidermal growth factor receptor 2 (HER2) protein. While over expression is increasingly recognised as a molecular abnormality in breast cancer, there is mounting evidence of the role of HER2 over expression in patients with gastric cancer, and it has been correlated to poor outcomes and a more aggressive disease. The frequency of HER2 over expression in gastric and gastro oesophageal cancer ranges from 4.4% to 53.4%, with a mean of 17.9%. Trastuzumab is a recombinant humanised monoclonal antibody that targets the HER2 protein. In fact, trastuzumab in combination with chemotherapy is a treatment option for patients with HER2-positive advanced gastric cancer. Data obtained from two clinical trials, suggests treatment with trastuzumab deruxtecan, improves both the response and overall survival in patients with metastatic gastric cancer.
Trastuzumab deruxtecan and gastric cancer outcomes
In an open label, dose-escalation and dose-expansion phase 1 trial, 44 patients with HER2-positive gastric or gastro-oesophageal junction cancer, who received Trastuzumab deruxtecan (T-Dx-T) had a manageable safety profile and showed preliminary activity in heavily pre-treated patients with HER2-positive patients. These findings prompted the authors to suggest that T-Dx-T should be further investigated for HER2-positive gastric or gastro-oesophageal junction cancer patients. In a second phase 2 trial with HER2-positive advanced gastric cancer patients, researchers compared T-Dx-T with a physician’s choice of chemotherapy. The results showed that an objective response was seen in 51% of T-Dx-T compared with 14% of those in the physician’s choice group. In addition, the median overall survival was also longer with T-Dx-T than with chemotherapy (12.5 vs. 8.4 months).
The most recent data on T-Dx-T comes from a study reported at the ESMO Congress 2022 and provided an update from a second trial, DESTINY-GASTRIC-02, a T-Dx-T monotherapy open-label, single-arm trial in HER2-positive, unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma patients. The results demonstrated after a median duration of follow up of 10.2 months, a confirmed objective response rate of 41.8% was seen in T-Dx-T patients with a median duration of response of 8.1 months a progression-free survival of 5.6 months.
These two trials provided the necessary data to enable CHMP to give a positive opinion for the drug and it follows on from FDA approval of the drug in 2021.
15th November 2022
According to a press release by the manufacturer Astra Zeneca, nirsevimab (brand name Beyfortus) has been approved by the European Commission for the prevention of respiratory syncytial virus (RSV) lower respiratory tract disease in newborns and infants during their first RSV season. The product represents the first and only single-dose RSV passive immunisation for the broad infant population, including those born healthy, at term or preterm, or with specific health conditions. Approximately two-thirds of infants are infected with RSV during the first year of life, and 90% have been infected one or more times by 2 years of age. Moreover, the rate of hospitalisation for primary infection is approximately 0.5% but can be as high as 25%
Nirsevimab is produced by a collaborative effort from Astra Zeneca and Sanofi which was agreed in 2017. Under the terms of this agreement, AstraZeneca leads all development and manufacturing activities, and Sanofi leads commercialisation activities and records revenue.
Nirsevimab is a long-acting, antiviral monoclonal antibody which binds to the RSV F (fusion) protein and effectively locks the protein into the pre-fusion conformation and thus inhibiting entry of free virions into cells, as well as inhibiting spread of cell-associated virus by cell fusion. The drug is designed for all infants for protection against RSV disease from birth through their first RSV season with a single dose.
Nirsevimab clinical efficacy
In a phase IIb trial, infants were randomised in a 2:1 ratio to receive nirsevimab, at a dose of 50mg in a single intramuscular injection, or placebo at the start of an RSV season. The results showed that the incidence of medically attended RSV-associated lower respiratory tract infection was 70.1% lower with nirsevimab prophylaxis compared to placebo. Further data came in a second trial in which infants who had been born at a gestational age of at least 35 weeks to receive a single intramuscular injection of nirsevimab or placebo (in a 2:1 ratio) before the start of an RSV season. The primary efficacy end point was medically attended RSV-associated lower respiratory tract infection through 150 days after the injection. Medically attended RSV-associated lower respiratory tract infection occurred in 1.2% of those given nirsevimab 5.0% in the placebo group, corresponding to an efficacy of 74.5% (95% CI 49.6 – 87.1, p < 0.001). Moreover, hospitalisation for RSV-associated lower respiratory tract infection occurred in 0.6% of those given nirsevimab compared to 1.6% in the placebo group. However, this was associated with a lower efficacy (62.1%), and which was not significant (p = 0.07).
According to the EMA, nirsevimab should be given before the RSV season or as soon as possible after birth for those infants born during the RSV season.
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