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Take a look at a selection of our recent media coverage:
15th March 2023
Pholcodine is an opioid that is approved for use in adults and children over 6 years of age as a treatment for a dry or non-productive cough, although it is also present in other products as a treatment for cough and cold symptoms. The MHRA in the UK has said that pholcodine containing cough and cold medicines are being withdrawn from the UK market as a precaution following a review and will no longer be available from pharmacies. This decision was based on the potential for an interaction, giving rise to anaphylaxis, with neuromuscular blocking agents (NMBAs). This possible interaction has already been mentioned in the summary of product characteristics for pholcodine.
The MHRA review published on the 14th March 2023, states that recently completed ALPHO study, showed that use of pholcodine during the 12 months preceding anaesthesia was significantly associated with an increased risk of peri-anaesthetic anaphylaxis to NMBAs (adjusted odds ratio = 4.2, 95% CI 2.5 to 6.9). While information on the risk from pholcodine use beyond 12 months was not available in the ALPHO study, evidence from a study in Norway, showed that IgE-mediated anaphylaxis to neuromuscular blocking agents, was still present, 3 years after withdrawal of pholcodine. However, the MHRA does add that while the risk of an anaphylactic reaction to NMBAs in less than 1 case per 10,000 procedures, it still believes that it is necessary to withdraw pholcodine as a precautionary measure.
The action by the MHRA follows a similar move by the European Medicines Agency in December 2022.
27th February 2023
The Medicines and Healthcare Products Regulatory Agency said it had initiated a review after regulators in France alerted the European Medicines Agency (EMA) about a small number of cases.
EMA officials first announced they were looking into the issue on 10 February 2023 following concerns about posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) related to use of the decongestant medicines.
Both conditions can lead to reduced blood supply to the brain and may cause major and life-threatening complications, including seizures, the EMA said.
There had been a small number of reported cases of PRES and RCVS associated with pseudoephedrine-containing medicines and a committee would look at the evidence to decide whether the marketing authorisation in the EU should be maintained, varied, suspended or withdrawn.
The MHRA stressed that the side effects that had been reported with use of the medicines were extremely rare.
The products, which include Sudafed, Actifed and Neurofen Cold and Flu, already include warnings about the rare side effects as well as more common ones such as headache and dizziness.
Officials said they had received two Yellow Card reports on this issue including one case of PRES where the person recovered and one for RCVS where the outcome was reported as unknown.
A spokesman said: ‘We keep the safety of all medicines under close review to ensure that the benefits outweigh any risks – the safety of the public is our top priority.
‘We are reviewing the available evidence regarding the use of medicines containing pseudoephedrine and the risk of posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS), which have been very rarely reported with these medicines. We will provide any further advice as appropriate.
‘We would also like to remind patients and parents/carers to report any suspected side effects to our Yellow Card scheme.
‘If you have any concerns about your medicine, please seek advice from a healthcare professional.’
This article first appeared in our sister publication Pulse
13th February 2023
The UKs Medicines and Healthcare products Regulatory Agency (MHRA) has now approved Rinvoq (upadacitinib) for use in patients with moderate to severely active Crohn’s disease and who have had either an inadequate response or were intolerant to, conventional therapy or a biological agent.
Crohn’s disease is a form of inflammatory bowel disease that affects any part of the gastrointestinal tract and which is thought to affect around 10 million people worldwide and has a major impact on health-related quality of life. Patients with Crohn’s will often receive oral corticosteroids to manage a disease flare although those with more severe disease receive biologics either with or without immunomodulators to induce and maintain remission.
Upadacitinib is a Janus kinase inhibitor and a Phase II trial, evaluating the efficacy of 3 mg, 6 mg, 12 mg 24 mg twice daily or 24 mg daily, concluded that the drug induced endoscopic remission in a significant proportion of patients in comparison to placebo.
The MHRA decision was based on the findings of three other clinical studies and are reported in the press release. In the first, U-EXCEED, a significantly higher proportion of patients treated with upadacitinib 45 mg daily achieved clinical remission per SF/AP at week 12 compared to placebo (40% vs 14%, p<0.001) and an endoscopic response compared to placebo (35% vs 4%, p<0.001). In the second trial, U-EXCEL, again more patients given a 12-week induction regimen of upadacitinib 45 mg daily achieved clinical remission (51% vs 22%, p < 0.001) and endoscopic response (46% vs 13%, p < 0.001) compared to placebo. In the third study, U-ENDURE which was a maintenance trial, patients who had responded to 12 weeks of upadacitinib 45 mg, were re-randomised to 15 mg, 30 mg or placebo and assessed at week 52. The results showed that clinical remission occurred in 36 and 46% respectively (i.e., for 15 and 30 mg) compared to 14% for placebo (p < 0.001). Similarly, endoscopic response occurred in 28 and 40% compared to 7% in the placebo group (p < 0.001).
Interestingly, a recently published real-world study of upadacitinib in patients with Crohn’s disease has shown that the drug induced subjective and objective responses in 25% and 42% of patients, respectively.
Updated information on the indications for rinvoq can be found in the summary of product characteristics.
16th August 2022
According to a press release from the MHRA, an updated version of the COVID-19 vaccine made by Moderna and which targets two coronavirus variants (known as a “bivalent” vaccine) has now been approved for use as a booster dose for adults in the UK.
In each dose of the updated vaccine, ‘Spikevax bivalent Original/Omicron’, half of the vaccine targets the original COVID-19 strain from 2020 and the other half (25 micrograms) targets Omicron. The current MHRA approval was based on the findings of a phase 2/3 trial, which is available as a pre-print in which the bivalent vaccine was compared to the authorised 50-µg mRNA-1273 booster in adults who previously received 2-dose primary series of 100-µg mRNA-1273. Earlier work with the bivalent COVID-19 vaccine had shown that it elicited a higher neutralising antibody response against the ancestral (or original) COVID-19 and the Beta variant than that after the second mRNA‑1273 dose (i.e., the original Moderna vaccine), as well as against the Omicron and Delta variants.
Clinical efficacy of the Bivalent COVID-19 booster
In the latest pre-print study, the bivalent COVID-19 booster was examined in a group of 437 individuals with a mean age of 57.3 years (41% male) and compared with a group of 377 patients (mean age, 57.5 years, 49.3% male), who received the mRNA-1273 (50 µg) vaccine. The interim analysis is based on data 28 days after the booster vaccine doses. The results showed that the bivalent COVID-19 booster dose neutralising geometric mean titres (GMT) against Omicron were 2372.4 compared to 1473.5 for the mRNA-1273. Additionally, the bivalent COVID-19 booster induced a more potent neutralising antibody response against omicron sub-variants BA.4/BA.5 and and higher binding antibody responses against alpha, beta, gamma, delta and omicron variants.
The authors of the pre-print concluded that the bivalent booster elicited a superior neutralising antibody response against omicron, compared to mRNA-1273, and potent neutralising antibody responses against the BA.4 and BA.5 omicron sub-variants, 28 days after immunisation.
Commenting on the approval, Dr June Crown, the MHRA chief executive said
“The first generation of COVID-19 vaccines being used in the UK continue to provide important protection against the disease and save lives. What this bivalent vaccine gives us is a sharpened tool in our armoury to help protect us against this disease as the virus continues to evolve.’
Although the bivalent COVID-19 booster is yet to be approved by the EMA, the organisation announced in June that has started a rolling review of the vaccine.
2nd August 2022
Upadacitinib approval has been granted by the MHRA for use in patients who have moderate to severe active ulcerative colitis according to a press release from the manufacturer AbbVie.
Ulcerative colitis (UC) represents a chronic idiopathic inflammatory bowel disorder of the colon that causes continuous mucosal inflammation extending from the rectum to the more proximal colon with an estimated prevalence of 7.6-245 cases per 100,000 persons/year. In the UK alone, ulcerative colitis has been estimated to affect 1 in every 420 people, amounting to around 146,000 people. Symptoms of UC will include abdominal pain, bloody diarrhoea, severe urgency for a bowel movement, weight loss and fatigue. Both the severity of symptoms and uncertainty surrounding flares give rise to a substantial burden and often disability among those living with the disease.
Treatment for UC includes amino-salicylic acid, oral steroids and immunosuppressive drugs such as azathioprine and 6-mercaptopurine. However, 20% to 40% of UC patients do not respond to conventional medications and various biologics that target specific immunological pathways have been studied as potential treatments. In a 2014 network meta-analysis, the authors concluded that compared to placebo, infliximab, adalimumab and golimumab are all effective for the induction and maintenance of remission in ulcerative colitis. In addition, data also supports the use of Janus kinase inhibitors in the management of UC, with a study of patients having moderately to severely active ulcerative colitis, finding that tofacitinib gave rise to a better clinical response and remission compared to those receiving placebo. The AbbVie press release describes how the approval of upadacitinib, was based on the results from three phase 3 clinical trials.
Upadacitinib clinical efficacy
The clinical efficacy comes from two induction trials, U-ACHIEVE induction and U-ACCOMPLISH and a single maintenance study U-ACHIEVE maintenance which are detailed in a single publication. Patients aged 16 -75 years and with moderately to severely active ulcerative colitis for at least 90 days, were randomly assigned 2:1 to oral upadacitinib 45 mg once daily or placebo for 8 weeks. Patients who achieved the primary outcome after 8 weeks, which was an adapted Mayo score ≥2 points and ≥30% from baseline, plus a decrease in rectal bleeding score ≥1 or an absolute rectal bleeding score ≤1, were re-randomised 1:1:1 to upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 52 weeks for the maintenance phase of the study. The results showed that significantly more patients achieved clinical remission with upadacitinib 45 mg, 26% and 34% in both the induction trials (p < 0.001 for both trials) compared to the placebo group (5% and 4% for the two trials). In the second phase of the trial, clinical remission was achieved by significantly more patients (p<0·0001) receiving upadacitinib 15 mg (42%) and 30 mg (52%) compared to those receiving placebo (12%).
The press release quotes Professor James Lindsay, Consultant Gastroenterologist at the Royal London Hospital Barts Health NHS Trust, who said that “in clinical trials, upadacitinib showed its ability to rapidly control symptoms in eight weeks for many participants and sustained responses at one year. I believe these results could make a positive difference for many people with ulcerative colitis for whom previous treatment options have not worked.”
25th March 2022
Tixagevimab/cilgavimab (Evusheld) is a combination of two monoclonal antibodies that has been approved by the UK’s MHRA for use before exposure to COVID-19 in order to prevent the disease. The drug would therefore be most suited to adult patients who are unable to mount a sufficient immune response after receiving a COVID-19 vaccination or alternatively, patients for whom vaccination is not recommended.
Evusheld was issued an emergency use authorisation (EUA) by the FDA in the US in December 2021 for the pre-exposure prophylaxis (prevention) of COVID-19 in certain adults and paediatric individuals (12 years of age and older weighing at least 40 kilograms. However, the combination would not be suitable for those currently infected with COVID-19 or who have had a recent and known exposure to someone infected with the virus. The two components of Evusheld are available as separate intramuscular injections and research has shown that these recognise non-overlapping sites and are simultaneously bound to the S protein and neutralise the wild-type COVID-19 virus in a synergistic manner. As a result, the manufacturer, AstraZeneca, has examined the value of Evusheld in three separate clinical studies.
Evusheld clinical efficacy
To date, none of the three major clinical studies have been fully published and the efficacy data has been made available in press releases from the manufacturer. Evusheld was examined in the PROVENT trial which was designed to assess the safety and efficacy of a single dose compared to placebo for the prevention of COVID-19. The trial included 5,197 participants and who were randomised 2:1 to a single 300 mg dose of Evusheld (AZD7442 in all press releases) or placebo and which was administered in two separate, sequential IM injections. The trial recruited individuals 18 years of age and over (including 43% who were older than 60 years of age) who would benefit from prevention and were defined as having an increased risk for an inadequate response to active immunisation or having an increased risk for COVID-19 infection. Participants at the time of screening were unvaccinated and had a negative COVID-19 test. The primary efficacy endpoint of the trial was the first case of any COVID-19 PCR confirmed, symptomatic illness occurring after the dose before day 183. According to a press release from the manufacturer, Evusheld reduced the risk of developing symptomatic COVID-19 by 77% (95% CI 46 – 90%) in comparison to those given a placebo.
A second trial, STORM CHASER, was designed to explore post-exposure prophylaxis of COVID-19 in Adult patients. The trial included 1,121 participants, randomised 2:1 as before to either Evusheld or placebo, all of whom tested negative for COVID-19 prior to receiving treatment. Again, in a press release from the manufacturer, Evusheld reduced the risk of developing symptomatic COVID-19 by 73% (95% CI 27 – 90%) compared with placebo among those who were PCR negative at the time of dosing.
The third trial, TACKLE, explored the value of Evusheld given to adults who were non-hospitalised with mild-to-moderate COVID-19 and symptomatic for seven days or less, but this time, given a 600 mg dose of the drug. The primary efficacy endpoint of the trial was the composite of either severe COVID-19 or death from any cause through day 29. According to the manufacturer press release on TACKLE, Evusheld given to participants within five days of symptom onset, saw a 67% reduced risk of developing severe COVID-19 or death compared to placebo.
On the basis of these findings, the MHRA has approved the drug and in Europe, the EMA is currently evaluating the combination.
4th February 2022
Atezolizumab (Tecentriq) has been approved by the Medicines and Healthcare products Regulatory Agency (MHRA) for patients with non-small cell lung cancer (NSCLC).
Around 85% of lung cancers in the UK are due to NSCLC and according to the World Health Organization, there were 2.21 million cases of lung cancer in 2020 and which resulted in 1.80 million deaths. Moreover, 5-year survival among those with NSCLC is poor, with data from England showing that only around 3 in 20 people survive to five years after their diagnosis.
Immunotherapy, which is a novel method of lung cancer treatment, uses monoclonal antibodies directed against immune-checkpoint molecules including the programmed cell death 1 (PD-1) receptor or its ligand (PD-L1). In the UK, NICE has approved atezolizumab (Tecentriq) as an option for untreated metastatic NSCLC in adults if their tumours have PD-L1 expression on at least 50% of tumour cells or 10% of tumour-infiltrating immune cells and where tumours do not have epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations. The MHRA has decided that atezolizumab (Tecentriq) can be used in whose have undergone surgery and chemotherapy as such patients are at risk of cancer relapse.
Atezolizumab (Tecentriq) clinical efficacy
Data on the effectiveness of atezolizumab comes from the IMpower010 clinical trial, a Phase III, global, multicentre, open-label, randomised study designed to compare the efficacy of atezolizumab treatment versus best supportive care in participants with Stage IB-Stage IIIA NSCLC following resection and adjuvant chemotherapy. The trial recruited 1005 patients who were randomised to atezolizumab (n=507) or best supportive care (n=498). After a median follow-up of 32·2 months, atezolizumab treatment improved disease-free survival compared to best supportive care (hazard ratio, HR = 0·66, 95% CI 0·50–0·88, p=0·0039), i.e., the risk of recurrence, new primary NSCLC, or death with atezolizumab was reduced by 34% compared to best supportive care. In a further trial, IMpower110, the efficacy of atezolizumab combined with cisplatin or carboplatin chemotherapy and with either pemetrexed (non-squamous disease) or gemcitabine (squamous disease) in PD-L1-selected, chemotherapy-naïve participants with Stage IV non-squamous or squamous NSCLC. The published results showed that the median overall survival was 7.1 months longer in the atezolizumab group than in the chemotherapy group (20.2 months vs. 13.1 months).
According to the NHS, more than 850 patients in England are expected to be eligible for the drug in the first year and this is predicted to rise to more than 1000 in the third year. Amanda Pritchard, chief executive of NHS England, said, “The NHS has a strong track record of securing rapid access to cutting-edge, new treatments for our patients, and this is the latest rapid access agreement that places an innovative treatment in the hands of frontline NHS staff, supporting them to continue to deliver world-class patient care.”
17th January 2022
Kaftrio has been granted an extension to its marketing authorisation by the European Medicines Agency (EMA) for children as young as age 6 who have cystic fibrosis (CF) and at least one F508del mutation in combination with ivacaftor.
Kaftrio is a combination treatment containing 75mg ivacaftor, 50mg tezacaftor and 100mg elexacaftor and is already indicated in a combination regimen with ivacaftor 150mg tablets for the treatment of CF in patients aged 12 years and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
CF is a rare, monogenic disease (i.e., caused by variation in a single gene) which is thought to affect at least 100 000 people worldwide. The condition is best described as a progressive, multi-organ disease that affects the lungs, liver, pancreas, GI tract, sinuses, sweat glands, reproductive tract and a reduced life expectancy. However, according to Cystic Fibrosis, the life expectancy of children born today is likely to surpass 50 years for the first time.
CF is caused by mutations in the genes responsible for encoding of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. This defect results in a reduced chloride secretion and increased sodium absorption through epithelial sodium channels and removal of water from secretions, which therefore become abnormally viscous. Although more than 2000 gene variants of the disease have been discovered, the most predominant is the F508del mutation.
The three drugs present in Kaftrio work in combination. For example, ivacaftor functions as a potentiator of the CFTR protein for common gating mutations, allowing for an increase in chloride ion flow. Tezacaftor ensures correct folding and presentation of the mature CFTR protein to the cell surface, improving CFTR function for the F508del mutation. Finally, elexacaftor is also helps to ensure correct folding of the CFTR protein but acts at an alternate binding site to tezacaftor on the CFTR protein. Overall, this triple combination increases the function of the F508del mutated CFTR protein at the cell surface resulting in increased chloride ion transport and ultimately help hydrate and clear mucus from the airways.
Clinical data already support the use of Kaftrio in children aged 12 years and over though a more recent study demonstrated the combination therapy was also effective in children from 6 years of age and enabled the EMA to extend its licensed usage. In addition to approval from the EMA, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) has also confirmed the same license extension for Kaftrio.
2nd December 2021
Skyrizi (risankizumab) has been approved by the UK regulator, the MHRA, for the use in adults with active psoriatic arthritis. This follows the EMA approval earlier this month.
The Summary of Product Characteristics (SPC) of the drug has been updated to reflect this change, stating that it is indicated either ‘alone or in combination with methotrexate (MTX), is indicated for the treatment of active psoriatic arthritis in adults who have had an inadequate response or who have been intolerant to one or more disease-modifying anti-rheumatic drugs (DMARDs).’
Skyrizi is a monoclonal antibody and blocks the action of interleukin 23, (IL-23), which is believed to play an important role in psoriatic arthritis. The approved dose for risankizumab is 150mg, administered by subcutaneous injection at week 0 and 4, and every 12 weeks thereafter.
The approval was based on data from two clinical studies, KEEPsAKE-1 and KEEPsAKE-2 and although both of the trials included patients with moderate to severe PsA, the populations were slightly different. For example, KEEPsAKE-1 included patients who had with an inadequate respond to one or more DMARDs whereas KEEPsAKE-2 recruited those with an inadequate response to other biologicals. However, both studies had the same primary endpoint of an ACR20 response at week 24. In addition, secondary outcomes included improvements in several clinical manifestations of psoriatic arthritis such as physical functioning (as assessed by the Health Assessment Questionnaire Disability Index [HAQ-DI]) and minimal disease activity (MDA) and both the primary and secondary endpoints were assessed after 24 weeks of therapy.
In KEEPsAKE-1 57.3% of patients receiving risankizumab achieved the primary endpoint at week 24 compared to 33.5% in the placebo group (p < 0.001). Similarly, in KEEPsAKE 2, 51.3% achieved the primary endpoint compared with 26.5% in the placebo arm (P< 0.001).
There were also significantly greater improvements in the secondary outcomes for risankizumab-treated patients. For example, in KEEPsAKE-1, there was a -0.31 change in HAQ-DI compared to -0.11 (placebo) and in KEEPsAKE 2, a change of -0.22, compared to -0.05 in the placebo group (for both differences, p <0.001).
Xevudy (sotrovimab) which is a monoclonal antibody, has been approved by the UK regulator, the MHRA, after data showing that it can reduce the risk of hospitalisation and death in people with mild to moderate COVID-19 infection and who are at an increased risk of developing severe disease.
According to a press release by the manufacturer, GSK who developed the drug in collaboration with Vir Biotechnology, Inc, Xevudy binds to an epitope on COVID-19 shared with SARS-CoV-1 (the virus responsible for SARS). This suggests that the particular epitope is highly conserved and may therefore be less susceptible to mutations and hence development resistance to the therapy.
The manufacturer has embarked on several clinical trials with Xevudy which have included COMET-ICE, which was a phase 3, multi-centre, double-blind, placebo-controlled trial investigated sotrovimab in adults with mild-to-moderate COVID-19 at high risk of progression to severe disease, who are not hospitalised and not requiring oxygen.
COMET-TAIL another phase 3 randomised, multi-centre, open label, non-inferiority trial for the early treatment of mild-to-moderate COVID-19 in high-risk non-hospitalised adult and paediatric patients (12 years of age and older).
Interim results from COMET-ICE have been published in which 583 non-hospitalised, symptomatic COVID-19 patients were randomised, 1:1, less than 5 days after the onset of symptoms and with at least one risk factor for disease progression. Treatment consisted of a single infusion of sotrovimab at a dose of 500 mg or placebo. The results showed that 3 patients (1%) in the sotrovimab group and 21 patients (7%) in the placebo group, had disease progression leading to hospitalisation or death, giving a relative risk reduction of 85% (95% CI 44% – 96%, p = 0.002).
The full results of the COMET-ICE, which included 1057 patients showed that all-cause hospitalisation lasting over 24 hours, or death was significantly reduced with sotrovimab (1%) vs placebo (6%), giving an adjusted relative risk reduction of 0.79 (95% CI, 50% – 91%, p <.001). In other words, Xevudy reduced the risk of hospitalisations for longer than 24 hours or death by 79%.
According to the SPC, Xevudy is indicated for ‘the treatment of symptomatic adults and adolescents (aged 12 years and over and weighing at least 40 kg) with acute covid-19 infection who do not require oxygen supplementation and who are at increased risk of progressing to severe covid infection.’ It should be given as a single 500 mg dose and the SPC adds that ‘It is recommended that Xevudy is administered within 5 days of onset of symptoms of COVID-19.’
In a statement by the MHRA, it is noted that currently, it is uncertain whether the drug is effective against the omicron variant.