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Safety in Lactation: Drugs for obstructive airways disease

25 September 2020Additional information relating to breastfeeding To be used in conjunction with individual drug entries for specific information and guidance. Bronchodilators Most bronchodilators are considered to…
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Lactation Safety Information

Corticosteroids
Monoclonal antibody used for refractory eosinophilic asthma
No published evidence of safety
Low levels anticipated in milk due to the drug’s properties and likely to be degraded in infant’s GI tract, although long half-life increases risk of accumulation in breastfed infant
Although large protein molecules may appear in colostrum, risk to preterm infants and neonates is considered to be small and unproven
21 April 2017

New Medicines

NucalaEosinophilic granulomatosis with polyangiitis; (or Churg Strauss syndrome) in adults - add-on therapy

Information

Nucala
Licence extension / variation
GlaxoSmithKline
GlaxoSmithKline

Development and Regulatory status

Phase III Clinical Trials
Pre-registration (Filed)
Launched
Yes
Oct 20Filed in EU [13].
Jan 20No further development reported [10,11].
Dec 17Approved in US [7]
May 17Results of PIII NCT02020889 study published in NEJM. RCT (n=136) found mepolizumab resulted in more weeks in remission (28% vs 3% had ≥24 weeks; OR 5.91 [95% CI 2.68 to 13.03];p<0.001) and higher proportion in remission vs placebo (32% vs 3%; 16.74 [3.61 to 77.56];p<0.001), though only ~half had protocol-defined remission [6].
Nov 16GSK report both co-primary endpoints and all secondary endpoints were met in the PIII NCT02020889 study, which completed in Sep 16. GSK plan to submit regulatory applications in 2017 [5].
Nov 15PIII development continues [4].
Feb 14Phase 3 study in patients with Eosinophilic Granulomatosis with Polyangiitis [formerly known as Churg-Strauss syndrome] due to start [1].

Category

Fully humanised IgG monoclonal antibody specific for interleukin 5 (IL-5)
Incidence is approximately 2.5 cases per 100,000 adults per year. Males are affected slightly more frequently than females. The age at onset usually varies from 15-70 years although patients as young as 9 have been reported. [2] EPGA is characterised by widespread inflammation of small blood vessels (vasculitis), affecting many organs, e.g. heart, lungs, skin, GI tract, kidneys, with symptoms varying according to organ affected. [1]
Eosinophilic granulomatosis with polyangiitis; (or Churg Strauss syndrome) in adults - add-on therapy
Subcutaneous

Further information

Yes
Suspended

Trial or other data

May 17GSK reported positive efficacy and safety results of the trial NCT02020889 and announced publication in the NEJM. Both co-primary endpoints and all secondary endpoints were met. Full results are available at https://www.nejm.org/doi/full/10.1056/NEJMoa1702079?query=featured_home [8,9].
Feb 14PIII study MEA115921 = NCT02020889. The key outcomes focus on evaluation of clinical remission, defined as Birmingham Vasculitis Activity Score (BVAS) = 0 with a corticosteroid dose of ≤4 mg/day prednisolone/ prednisone, reduction in disease relapse and reduction in corticosteroid requirement. The study is being conducted as part of an agreement between GSK and the National Institute of Allergy and Infectious Diseases (NIAID). The study, which will enrol 130 patients, starts Feb 14 and is due to complete Aug 16 [3].
Feb 14IL-5 is a cytokine which regulates the growth, activation and survival of eosinophils (white blood cells) and provides an essential signal for the movement of eosinophils from the bone marrow into the lung and other organs. Mepolizumab binds to human IL-5, stopping it from binding to its receptor on the surface of eosinophils. Inhibiting IL-5 binding in this manner reduces blood, tissue and sputum eosinophil levels, which in turn reduces eosinophil-mediated inflammation [1].
Feb 14The pivotal Phase III study, MEA115921, is a randomised, double-blind study with the purpose to investigate the efficacy and safety of a 300mg dose of mepolizumab (administered subcutaneously every 4 weeks) compared with placebo over a 52-week study treatment period in patients with relapsing or refractory EGPA receiving standard of care therapy including background corticosteroid therapy with or without immunosuppressive therapy [1].
Feb 14The current approach to disease management is primarily based on reduction of active inflammation and suppression of the immune response through the use of corticosteroid therapy with concomitant immunosuppressive therapy (e.g., methotrexate, azathioprine, mycophenolate mofetil) and/or cytotoxic agents (e.g., cyclophosphamide). Although the use of these treatments can be effective for establishing remission, patients remain vulnerable to either the complications of the long-term use of these therapies, or to the risk of relapse, particularly if the dose of corticosteroid is reduced [1].
Feb 14A key goal of treatment of EGPA is to induce and maintain remission while reducing the use of corticosteroids and other immunosuppressive therapies [1].

NucalaSevere hypereosinophilic syndrome in adults

Information

Nucala
Licence extension / variation
GlaxoSmithKline
GlaxoSmithKline

Development and Regulatory status

Phase III Clinical Trials
Pre-registration (Filed)
Launched
Yes
Oct 20Withdrawn from the EU register of orphan medicinal products at request of the Sponsor [17].
Oct 20Filed in EU [16].
Sep 20FDA has approved mepolizumab for the treatment of adult and paediatric patients aged 12 years and older with Hypereosinophilic Syndrome for ≥ six months without an identifiable non-haematologic secondary cause [15].
Mar 20Filed in the US [14].
Nov 19GSK plan to file in 2020 [13].
Nov 19The drug has been granted fast track designation in US for treatment of hypereosinophilic syndrome [13].
Jul 09EU filing withdrawn as more clinical data needed [9].
Dec 04Mepolizumab receives orphan drug status for first-line treatment in patients with hypereosinophilic syndrome in the US and EU [5].
Dec 03MAA filing anticipated 2006 (2). Anticipated filing in EU Q2 2008 (3,4)

Category

Humanised IgG1 monoclonal antibody specific for IL-5
HES is rare in adults and tends to be under-diagnosed. There are no formal patient registers and lack of published data makes estimates of prevalence difficult. HES can present anywhere from the age of 20 to 50 years. HES has a preponderance in males (4-9:1) [6].
Severe hypereosinophilic syndrome in adults
Subcutaneous injection

Further information

Yes
To be confirmed

Trial or other data

Nov 19GSK reports positive results from PIII (NCT02836496) study. Mepolizumab met primary endpoint with 50% fewer patients experiencing a flare, defined as worsening of symptoms or eosinophil threshold requiring an escalation in therapy, when added to SOC and compared to placebo [13].
Dec 18Collection of primary outcome data for study NCT02836496 is now expected in March 2020 [12].
Apr 18PIII study (NCT02836496) is recruiting. Collection of primary outcome data is due to complete Oct 19 [11].
Nov 17PIII extension study to evaluate the long-term clinical efficacy and safety of mepolizumab, in patients with hypereosinophilic syndrome, who were enrolled in study 200622 starts (NCT03306043). Evaluation of the number of subjects with non-serious adverse events (AEs) as well as serious AEs and number of subjects with the presence of anti-drug antibody are the defined primary endpoints of the trial. The open-label trial intends to enrol approximately 80 patients in Germany, Belgium, Spain [8,10].
Mar 17PIII trial to evaluate the efficacy and safety of mepolizumab 300mg SC injection in patients (aged ≥ 12 years) with HES starts (NCT02836496). The 32-week, randomised 1:1, double-blind, placebo- and active (prednisolone or prednisone)-controlled, parallel trial will enrol approximately 120 patients. The primary endpoint of the trial is the proportion of patients who experience an HES flare (worsening of symptoms requiring escalation in therapy) during the 32-week study treatment period. Enrolment is underway in Germany, the US, Belgium, Spain and the UK and is expected to expand in Russia, Italy, Romania, Argentina, France, Mexico, Poland and Sweden [8].
Aug 05PIII compassionate use trial of mepolizumab in patients with hypereosinophilic syndrome in the US, Canada, Australia, Belgium, France, Germany, Italy, Netherlands, Norway, Spain, Switzerland and the UK starts (NCT00244686; MHE104317). The open-label, non-randomised trial will enrol approximately 75 patients aged 12 years and older [8].
Jan 05Published study indicates mepolizumab can reduce number of blood and sputum eosinophils and allow prednisolone sparing in pts with asthma and sputum eosinophilia despite prednisolone treatment (7).

Evidence based evaluations

NucalaChronic obstructive pulmonary disease (COPD); characterised by eosinophil level - add-on therapy

Information

Nucala
Licence extension / variation
GlaxoSmithKline
GlaxoSmithKline

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Not approved
Aug 19Listed as PIII in company pipeline. FDA asked for more clinical data; assume this is being collected [12].
Sep 18Complete response letter issued by the FDA confirming rejection of licence application [11].
Jul 18US FDA staff report, which was prepared for an FDA advisory panel, expresses concerns with regards to Nucala as a potential treatment for COPD; specifically over the drug’s “failure to meet a statistical threshold for effectiveness in one trial” and “uncertainty in defining groups of patients” who would benefit from treatment with Nucala. The report also questioned the recruitment method for COPD trials [8,9].
Jul 18Advisory committee of the FDA votes against approval [10].
Nov 17Filed in the US [7].
Sep 17Based on the results of the PIII METREX and METREO studies, GSK plan regulatory filings during 2017 [5].
Jan 17PIII development continues. Both PIII studies are now due to complete Jan 17 [4].
Nov 15PIII development continues [3].

Category

Humanised IgG antibody (IgG1, kappa) with human heavy and light chain frameworks
It is estimated that 3 million people in the UK are affected by COPD. Approximately 900,000 of these are diagnosed, whilst another 2 million are estimated to be affected but undiagnosed (www.nice.org.uk/CG101).
Chronic obstructive pulmonary disease (COPD); characterised by eosinophil level - add-on therapy
Subcutaneous

Further information

Yes
To be confirmed

Trial or other data

Sep 17Results from the METREX (NCT02105948) and METREO (NCT02105961) trials have been published, including a pre-specified meta-analysis of the combined data. Overall, the results showed a statistically significant improvement in exacerbations in patients with raised eosinophil counts: there was a clear association between blood eosinophil count and response, with no benefit found in patients who had <150 eosinophils per microlitre at pretrial screening; results for the 100 mg and 300 mg doses were similar [5,6].
Apr 14NCT02105948 (MEA117106) is a PIII multi-center, randomized, double-blind, trial evaluating mepolizumab 100mg vs placebo given every 4 weeks by subcutaneous injection in 800 subjects who are above and below the baseline blood eosinophil count of at least 150 cells/m and who have frequent exacerbations of COPD. The primary outcome is frequency of moderate /severe exacerbations (that require either systemic corticosteroids and/or antibiotics, hospitalization or result in death). The study starts Apr 14 and is due to complete Jun 16 [2]
Apr 14NCT02105961 (MEA117113) is a 1 year PIII study of two doses of sc mepolizumab ( 100 or 300mg) given every 4 weeks vs. placebo as add-on treatment for 660 patients with COPD who are at or above the baseline blood eosinophil count of at least 150 cells/mL who exacerbate despite regular use of maximal tolerated therapy, appropriate for severe COPD subjects, in the 12 months prior to study start. The primary outcome is frequency of moderate /severe exacerbations (that require either systemic corticosteroids and/or antibiotics, hospitalization or result in death). The study starts Apr 14 and is due to complete Jun 16 [1].

Evidence based evaluations

NucalaNasal polyposis - severe, bilateral, recurrent

Information

Nucala
Licence extension / variation
GlaxoSmithKline
GlaxoSmithKline

Development and Regulatory status

Pre-registration (Filed)
Pre-registration (Filed)
Pre-registration (Filed)
Dec 20Filed in US [7]
Oct 20Filed in EU [8]

Category

Monoclonal antibody to interleukin-5. Neutralisation of IL-5 has been shown to reduce blood, sputum and tissue eosinophils and mepolizumab is thus assumed to be a treatment option in a number of eosinophilic diseases including NP [1]
The population prevalence of nasal polyps is reported as 2-4%, with no racial predilection. The male to female ratio has been reported at approximately 2:1
Nasal polyposis - severe, bilateral, recurrent
Subcutaneous injection

Further information

Yes
To be confirmed

Trial or other data

Apr 21Results of PIII SYNAPSE study reported in The Lancet [9].
Apr 20PIII study SYNAPSE met both co-primary endpoints, with mepolizumab producing statistically significant improvements in both the size of nasal polyps at week 52 (p<0.001) and asal obstruction (p<0.001) during weeks 49-52, compared to placebo added to standard of care. Difference in median change from baseline for total endoscopic nasal polyps score: -0.73 (95% CI: -1.11, -0.34). The median change from baseline for nasal obstruction visual analogue scale score: -3.14 (95% CI: -4.09, -2.18). Key secondary endpoint of time to first actual nasal surgery up to week 52 was also statistically significant, with mepolizumab, added to standard of care, showing a reduction of 57% (p=0.003) versus placebo added to standard of care (hazard ratio [95% CI]: 0.43 [0.25, 0.76]) [6]
Jan 20 SYNAPSE study has ceased recruitment [4].
Dec 18The PIII study (SYNAPSE; NCT03085797) is ongoing and is recruiting subjects worldwide, including the UK and other EU countries [3].
Jun 17PIII study (SYNAPSE; NCT03085797) has begun recruitment in the US. This is a 52-week, randomised, double-blind, parallel group study. Adult patients (n=400 planned) will also receive standard of care for nasal polyps consisting of daily mometasone furoate nasal spray, and if required, saline nasal douching, occasional short courses of high dose oral corticosteroids and/or antibiotics. Severe bilateral nasal polyps are defined by an average nasal obstruction VAS symptom score > 5 and an endoscopic score of at least 5 (out of 8), with a minimum score of 2 in each nasal cavity. Patients must also have a history of at least one prior surgery for nasal polyps, have recurrent nasal polyps despite treatment with standard of care and be in need of nasal polyp surgery. The study will assess the efficacy and safety of mepolizumab 100mg vs placebo, every 4 weeks for 52 weeks, on top of standard of care. The co-primary endpoint of the study is the change from baseline in the total nasal polyps score (sum of left and right nostril score) assessed by endoscopy at week 52 and nasal obstruction, as measured using the visual analogue scale (VAS) symptom score during the four weeks prior to week 52. The key secondary endpoint is the time to first actual surgery for nasal polyps by week 52. The study is anticipated to complete in 2019 [1,2].

Evidence based evaluations