Chronic spontaneous urticaria shows clinically meaningful improvement with remibrutinib

11th August 2023

The use of remibrutinib leads to rapid, clinically meaningful improvements across urticaria disease activity scores in patients with chronic spontaneous urticaria (CSU), according to the top-line results of two trials by the manufacturer Novartis.

The identically designed phase III trials REMIX-1 and REMIX-2 were undertaken in adult patients (≥ 18 years) who had experienced CSU for six months or longer and who found the condition to be inadequately controlled by second-generation H1-antihistamines.

The primary endpoints include absolute change from baseline in the weekly urticaria activity score, absolute change in itch severity score and hive severity score at Week 12.

Remibrutinib was found to have a fast onset of action, with patients seeing an improvement as early as two weeks after treatment initiation.

Patients currently enrolled in REMIX-1 and REMIX-2 will continue to receive treatment up to Week 52, and will have the opportunity to continue in a long-term extension trial.

Shreeram Aradhye, president, global drug development and chief medical officer at Novartis, said: ‘CSU is a distressing and unpredictable disease, and patients urgently need effective, convenient and well-tolerated treatments that can provide rapid and sustained relief from the relentless itching and deep tissue swelling that greatly impact their daily lives.

‘These positive top-line results from the Phase III REMIX studies confirm that remibrutinib, a highly selective BTK inhibitor, has the potential to be a first-in-class, oral treatment for people living with CSU whose symptoms are refractory despite use of antihistamines.‘

CSU and remibrutinib

CSU affects approximately 40 million people worldwide and is characterised by the sudden appearance of pruritic wheals and/or angioedema, persisting for more than six weeks. In addition, CSU causes significant emotional distress, with the majority of patients suffering from sleep deprivation and high rates of mental disorders, such as anxiety or depression.

There are limited effective treatments available for CSU, although recently it was found that the monoclonal antibody dupilumab is effective when used in conjunction with antihistamines.

Remibrutinib is a highly selective, oral Bruton’s tyrosine kinase (BTK) inhibitor that blocks the BTK cascade and prevents the release of histamine that causes itch, hives/welts and swelling. In Phase II studies, remibrutinib demonstrated fast onset of action and sustained efficacy in patients with moderate to severe CSU. The drug has been shown to be well-tolerated across all doses studied in Phase II.

Esketamine nasal spray superior to quetiapine XR for treatment-resistant major depressive disorder

3rd April 2023

An Esketamine nasal spray achieved remission from week 6 onwards compared to extended-release quetiapine in treatment-resistant depression

Data presented at the 31st European Congress of Psychiatry (EPA 2023) showed that in patients with treatment-resistant major depressive disorder, esketamine nasal spray achieved significantly higher rates of remission as early as 6 weeks after starting therapy compared to the use of extended-release (XR) quetiapine.

In the World Health Organisation European Region, depression is estimated to affect roughly 4.3% (or 40 million people) of the population. In addition, a US study of 36,309 adults reported that the 12-month and lifetime prevalence’s of major depressive disorder were 10.4% and 20.6%, respectively. 

Treatment-resistant depression (i.e., failure to respond to ≥2 treatments) affects 10-30% of those with major depressive disorder, and is associated with considerable morbidity and mortality. Esketamine nasal spray has been found when used in conjunction with an antidepressant to induce a significantly higher reduction in the Montgomery-Åsberg Depression Rating Scale (MADRS) score compared to placebo and an antidepressant.

Furthermore, antipsychotics are a potentially useful adjunct in treatment-resistant depression with a 2019 Cochrane review concluding that addition of an antipsychotic such as quetiapine to current antidepressant therapy, improved depressive symptoms over the short-term. But how esketamine compares to agents such as quetiapine is unclear and the subject of the study presented at EPS 2023.

The findings presented at EPA 2023 are from the ESCAPE-TRD trial which directly compared esketamine with quetiapine XR in addition to a selective serotonin re-uptake inhibitor/serotonin-norepinephrine re-uptake inhibitor (SSRI/SNRI), in patients with treatment-resistant major depressive disorder, over 32 weeks.

In the trial patients were randomised 1:1 to either esketamine or quetiapine plus an antidepressant and examined the effect of both on remission (defined as a MADRAS score < 10) and response (defined as a > 50% improvement in MADRAS score from baseline).

Esketamine nasal spray and treatment outcomes

A total of 676 patients were randomised to either quetiapine (340) or esketamine.

At Week 32, 55% of esketamine and 37% of quetiapine patients achieved remission. However, a significantly higher proportion of patients given esketamine achieved remission from week 6 (p = 0.008) onwards and a response from day 15 (p < 0.001).

The most common adverse effects from esketamine leading to treatment discontinuation were dizziness, dissociation and vomiting.

The authors concluded that an esketamine nasal spray use in patients with treatment-resistant depression led to a higher response and rate of remission over time compared to quetiapine XR.

Citation
Reif A. et al., Esketamine nasal spray shows higher remission and response rates over 32 weeks of treatment compared with quetiapine extended-release in patients with treatment resistant depression: Results from ESCAPE-TRD, a randomised, phase IIIb clinical trial. Presented at EPA 2023, March 25-28. Poster PO0067 (under oral communication 8).

Ide-cel provides 51% reduction in the risk of progression or death in R/R multiple myeloma

23rd March 2023

Use of Ide-cel in refractory or relapsed multiple myeloma after two to four prior regimens more than halved the risk of progression or death

Ide-cel therapy for with relapsed and refractory multiple myeloma who had received between two to four previous regimens, significantly prolonged progression-free survival compared to a standard-regimen group, according to a recent and international, open-label, phase 3 trial.

A 2020 study found that the global incidence of multiple myeloma was 160,000 and which led to l106,000 deaths. While autologous stem cell transplantation has been a backbone of therapy for newly diagnosed patients with multiple myeloma eligible for high-dose therapy for decades, nearly all patients will eventually experience disease relapse. Although the introduction of CD38-targeting monoclonal antibodies (MCA), daratumumab and isatuximab, have significantly impacted the management of patients with multiple myeloma, patients who are refractory to CD38 MCA have a poor prognosis. In an earlier, phase 2 trial, ide-cel induced responses in the majority of heavily pre-reated patients with refractory and relapsed multiple myeloma.

In the current study, researchers undertook a phase 3 trial of ide-cel in adults with relapsed and refractory multiple myeloma who had received two to four regimens previously (including immunomodulatory agents, proteasome inhibitors, and daratumumab). Individuals were randomised 2:1 to ide-cel or one of five standard regimens. The primary end point was set as progression-free survival, whereas secondary endpoints included the overall response and survival.

Ide-cel and progression-free survival

A total of 386 patients with a median age of 63 years (60.5% male) underwent randomisation, with 254 assigned to ide-cel and 132 to a standard regimen. A total of 66% of the patients had triple-class-refractory disease, and 95% had daratumumab-refractory disease.

At a median follow-up of 18.6 months, the median progression-free survival was 13.3 months in the ide-cel group, compared to 4.4 months in the standard-regimen group (Hazard ratio, HR for disease progression or death = 0.49, 95% CI 0.38 – 0.65, p < 0.001). A response was seen in a significantly higher proportion of patients who received ide-cel compared to the standard regimen (71% vs 42%, p < 0.001) and a complete response occurred in 39% and 5% respectively. At the time of publication, overall survival data were immature.

Adverse events of grade 3 or 4 occurred more frequently in the ide-cel group (93% vs 75%) and cytokine release syndrome occurred in 88% of the ide-cel group although this was largely of grade 1 or 2 severity. Neurotoxic effects occurred in 15% of the ide-cel group, with 3% having an event of grade 3 or higher.

The authors concluded that ide-cel treatment gave rise to significantly prolonged progression-free survival and an improved response compared with standard regimens in patients with triple-class-exposed relapsed and refractory multiple myeloma. 

Citation
Rodrigeuz-Otero P et al. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N Eng J Med 2023

Lyme disease vaccine candidate VLA15 enters Phase III trial

19th August 2022

A Lyme disease vaccine Phase III study recruiting participants from age 5 is about to be launched in areas where the disease is highly endemic

Lyme borreliosis (Lyme disease; LD) is caused by spirochaetes of the Borrelia burgdorferi species complex, a bacterium, which are transmitted by ticks. The most common clinical manifestation is a gradually expanding erythematous rash (erythema migrans) together with more nonspecific symptoms including fatigue, fever, headache, mild stiff neck, arthralgia or myalgia.

However, the infecting pathogen can spread to other tissues and organs, causing more severe manifestations that can involve a patient’s skin, nervous system, joints, or heart. LD is the most common zoonotic disease transmitted by ticks in the USA and Europe and the incidence rate for Western Europe has been estimated at 22.05 cases per 100 000 person-years.

In the US, there are approximately 30,000 cases of LD are reported to CDC although the true annual incidence might be as high as 476,000.

According to a press release by Pfizer and Valneva, the two companies are about the launch a Phase III clinical study, Vaccine Against Lyme for Outdoor Recreationists (VALOR) to investigate the efficacy, safety and immunogenicity of their investigational LD vaccine candidate, VLA15.

There are currently no vaccines licensed for LD and VLA15 targets an outer surface protein OspA expressed by the bacteria when present in a tick. Blockage of the protein inhibits the bacterium’s ability to leave the tick and infect humans.

Early data from mice showed that VLA15 induced protection against challenge with four different clinically relevant Borrelia species (B. burgdorferi, B. afzelii, B. garinii and B. bavariensis) expressing five of the six OspA serotypes included in the vaccine.

In an earlier Phase II trial with VLA15, which enrolled 5 -17 year olds, the vaccine was found to be more immunogenic than in adults even though adults also generated a good immunogenic response.

According to the press release, the current Phase III study will be undertaken at up to 50 sites located in areas where LD is highly endemic, including Finland, Germany, the Netherlands, Poland, Sweden and the United States.

Participants will receive three doses of VLA15 180µg or saline placebo as a primary vaccination series followed by one booster dose of VLA15 or saline placebo (1:1 ratio).