Positive CHMP opinion for generalised myasthenia gravis treatment

Posted on 29 September, 2023 - Myasthenia Gravis

UCB receives CHMP positive opinion of zilucoplan for the treatment of adults with generalised myasthenia gravis in Europe

  • The Committee for Medicinal Products for Human Use (CHMP) positive opinion1 is based on the pivotal Phase 3 RAISE study in generalised myasthenia gravis (gMG) in adult patients which demonstrated that treatment with zilucoplan resulted in statistically significant and clinically meaningful improvements in gMG-specific efficacy outcomes2
  • If approved by the European Commission, zilucoplan will be the first once-daily subcutaneous (SC) targeted peptide inhibitor of complement component 5 (C5 inhibitor) and the only gMG-targeted therapy for self-administration by adult patients with AChR antibody positive gMG
  • CHMP positive opinion in Europe follows recent FDA approval of rozanolixizumab-noli for the treatment of generalized myasthenia gravis (gMG) in adult patients in the U.S. who are anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive3
  • UCB’s two different medicines for gMG, each with a distinct mechanism of action, aim to offer a unique portfolio of treatments that embody our commitment to addressing the gMG community’s unmet needs

15 September 2023 – UCB, a global biopharmaceutical company, has announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion recommending granting marketing authorisation for zilucoplan in the European Union (EU) as an add-on to standard therapy for the treatment of generalised myasthenia gravis (gMG) in adult patients who are anti acetylcholine receptor (AChR) antibody positive.1

The CHMP’s positive opinion is now being reviewed by the European Commission, which grants centralised marketing authorisations for medicinal products in the EU. Feedback from the commission is anticipated before the end of the year. 

Following approval, zilucoplan will be the first once-daily subcutaneous (SC), targeted peptide inhibitor of complement component 5 (C5 inhibitor) and the only self-administered gMG therapy for use by adult patients with AChR antibody positive gMG.

As a C5 inhibitor, zilucoplan inhibits complement-mediated damage to the neuromuscular junction through its targeted dual mechanism of action.2 Benefits of SC self-administration can include reduced traveling time to and from hospitals, decreased interference with work obligations, and increased independence. Unlike monoclonal antibody C5 inhibitors, as a peptide, zilucoplan can be used concomitantly with intravenous immunoglobulin and plasma exchange, without the need for supplemental dosing.2

UCB’s RAISE study2, published earlier this year in the Lancet Neurology journal, demonstrated that zilucoplan delivered rapid, consistent, statistically significant and clinically meaningful benefits in different patient-and-clinician-reported outcomes – Myasthenia Gravis-Activities of Daily Living (MG-ADL) score, Quantitative Myasthenia Gravis (QMG) score, Myasthenia Gravis Composite (MGC) score and Myasthenia Gravis Quality of Life 15-item scale (MG-QoL15r)* – at week 12 in a broad population of mild to severe adult patients with AChR antibody positive gMG. Additionally, rapid improvements in fatigue were observed as an exploratory endpoint. 

Until now, people living with gMG have only had access to C5 therapy intravenously, which can be inconvenient and time-consuming. This positive CHMP opinion for zilucoplan is a significant step towards our goal of delivering a treatment to address the unmet needs of people living with gMG. If approved, we hope zilucoplan, a self-administered, once daily, subcutaneous targeted C5 inhibitor, will be able to help a broad population of mild to severe adult patients with AChR-antibody positive gMG. We would like to extend our thanks to the patients, care partners, and investigators who participated in the RAISE study, and to our employees and collaborators, whose dedication and commitment to the gMG community made this important milestone possible.

Iris Loew-Friedrich, Executive Vice-President and Chief Medical Officer at UCB.

gMG is a rare, chronic, heterogeneous, unpredictable autoimmune disease characterised by dysfunction and damage at the neuromuscular junction (NMJ).4,5,6 gMG has a global prevalence of 100–350 cases per every 1 million people.5 

The CHMP positive opinion recommending the approval of zilucoplan is supported by safety and efficacy data from the Phase 3 RAISE study (NCT04115293), published in The Lancet Neurology in May 2023.2 The primary endpoint for the RAISE study was change from baseline to Week 12 in the Myasthenia Gravis-Activities of Daily Living (MG-ADL) score. A statistically significant and clinically meaningful difference favouring zilucoplan in comparison to placebo was observed in the MG-ADL total score change from baseline: least squares mean change −4·39 [95% CI –5·28 to –3·50] vs −2·30 [–3·17 to –1·43], least squares mean difference −2·09 [−3·24 to −0·95]; p=0·0004. Secondary endpoints included change from baseline to Week 12 in QMG, MGC and MG-QoL15r. A statistically significant and clinically meaningful difference favoring zilucoplan compared to placebo was observed in the QMG total score change from baseline to Week 12 (p<0.0001), least squares mean change −6.19 [95% CI −7.29 to −5.08] vs −3.25 [−4.32 to −2.17]. Change from baseline to Week 12 in MGC in comparison to placebo was clinically meaningful and statistically significant. MG-QoL 15r change from baseline to Week 12 compared to placebo was also statistically significant.2 Change from baseline to week 12 in the Neuro-QoL short-form fatigue scale was an exploratory end point, therefore, p value was nominal, not multiplicity controlled.

The most common adverse events (reported in at least 10% of patients treated with zilucoplan) were injection-site bruising, headache, diarrhea and MG worsening.2

Zilucoplan is also currently under review by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), the U.S. Food and Drug Administration (FDA), the Australian Therapeutic Goods Administration (TGA) and Health Canada for the treatment of adults with gMG. Responses from the PMDA and FDA are expected by the end of Q4 2023. Responses from the TGA and Health Canada are expected by H1 2024. Orphan designation was granted by the European Commission in 2022 to zilucoplan for the treatment of myasthenia gravis.7 
    
The CHMP positive opinion of zilucoplan follows the recent FDA approval in the U.S. of rozanolixizumab-noli for the treatment of generalised myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive3. Rozanolixizumab-noli is currently only approved in the U.S. and is under review by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) and the European Medicines Agency (EMA) for the treatment of adults with gMG. Responses from regulatory agencies to these submissions are expected during H2 2023 and H1 2024.

* The threshold for clinical meaningfulness for MG-QoL 15r has not be established

References

  1. EMA CHMP Confirmation. Data on file, UCB September 2023.
  2. Howard JF Jr et al. Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Neurol. 2023;22:395-406. 
  3. US Food and Drug Administration. Novel Drug approvals for 2023. https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2023. Accessed September 2023.
  4. National Institute of Neurological Disorders and Stroke. 2022. Myasthenia Gravis Fact Sheet. https://www.ninds.nih.gov/myasthenia-gravis-fact-sheet. Accessed September 2023.
  5. Punga AR, et al. Epidemiology, diagnostics, and biomarkers of autoimmune neuromuscular junction disorders. Lancet Neurol. 2022;21(2):176-88.
  6. Howard JF. Myasthenia gravis: The role of complement at the neuromuscular junction. Ann N Y Acad Sci. 2018;1412:113-128.
  7. European Medicines Agency. EU/3/22/2650: Orphan designation for the treatment of myasthenia gravis. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-22-2650. Accessed August 2023
  8. Myasthenia Gravis Foundation of America. MG Quick Facts. https://myasthenia.org/MG-Education/MG-Quick-Facts. Accessed September 2023.
  9. Juel VC, Massey JM. Myasthenia gravis. Orphanet J Rare Dis. 2007;2:44.