FDA acceptance of new drug application and EMA MAA validation
- New drug application (NDA) for zilucoplan seeks approval for the treatment of generalised myasthenia gravis (gMG) in adult patients who are acetylcholine receptor antibody positive (AChR-Ab+)
- Acceptance by U.S. Food and Drug Administration (FDA) follows the recent European Medicines Agency (EMA) validation of Marketing Authorization Application (MAA) for treatment of adult patients with AChR-Ab+ gMG and who require treatment in addition to steroids or non-steroidal immunosuppressants
- Both NDA and MAA are based on pivotal Phase 3 RAISE study in gMG, which demonstrated treatment with zilucoplan resulted in clinically meaningful and statistically significant improvements in key MG-specific outcomes compared to placebo
- UCB expects to receive feedback from the agencies in Q4 of 2023
On 14th November 2022, UCB announced that the U.S. Food and Drug Administration (FDA) has accepted for review the New Drug Application (NDA) for its investigational treatment, zilucoplan.
Zilucoplan is a subcutaneous (SC), self-administered peptide inhibitor of complement component 5 (C5 inhibitor) for the treatment of adult patients with acetylcholine receptor antibody positive (AChR-Ab+) generalised myasthenia gravis (gMG).
In 2019, the U.S. FDA granted orphan drug designation to zilucoplan for the treatment of MG.1 The safety and efficacy of zilucoplan have not been established and it is not currently approved for use in any indication by any regulatory authority worldwide.
This acceptance follows the recent European Medicines Agency (EMA) validation of the Marketing Authorization Application (MAA) for zilucoplan for the treatment of adult patients with AChR-Ab+ gMG and who require treatment in addition to steroids or non-steroidal immunosuppressants. Validation confirms that the application is complete and the formal review process by the EMA’s Committee for Medicinal Products for Human Use (CHMP) can begin. Orphan designation was granted in 2022 by the European Commission to zilucoplan for the treatment of myasthenia gravis.2
gMG is a chronic and unpredictable auto-immune disease in which pathogenic autoantibodies can impair synaptic transmission at the neuromuscular junction by targeting specific proteins on the post-synaptic membrane. This disrupts the ability of the nerves to stimulate the muscle and results in a weaker contraction.4 People living with MG can experience a variety of symptoms, including drooping eyelids, double vision, and difficulty in swallowing, chewing and talking, as well as severe muscle weakness that can result in life-threatening weakness of the muscles of respiration.3 In the U.S. the prevalence of MG is estimated at 14 to 20 per 100,000 population; approximately 36,000 to 60,000 cases.4 In Europe, the prevalence is estimated at 10 per 100,000 population.5
People living with gMG experience high treatment burden, on top of the debilitating impact of the condition, and there is a clear need for additional targeted treatments to support the gMG community. Our goal is to provide a solution that can help meet these needs and transform lives. The acceptance of the NDA by the FDA as well as the acceptance of the MAA by the EMA, brings us one step further on our journey towards approval for this medicine. We look forward to working with the FDA and EMA to help bring this important new treatment option to patients.”Charl van Zyl, Executive Vice President Neurology Solutions & Head of EU/International Markets, UCB.
The NDA and MAA are based on data from the pivotal Phase 3 RAISE study (NCT04115293), which demonstrated at week 12 that treatment with zilucoplan (0.3 mg/kg daily) resulted in clinically meaningful and statistically significant improvements in key gMG-specific outcomes compared with placebo in patients with AChR-Ab+ gMG. The study met its primary endpoint with zilucoplan showing a placebo-corrected mean improvement of 2.09 points in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score at week 12 (p<0.001).6
Zilucoplan demonstrated a favorable safety and tolerability profile, showing a similar rate of treatment-emergent adverse events (TEAEs) between zilucoplan (76.7%) and placebo (70.5%). The most common TEAEs were injection site bruising, headache, and diarrhea. Rates of treatment discontinuation due to a TEAE were low and all patients who completed the 12-week treatment period have entered the ongoing RAISE-XT open-label extension study (NCT04225871).6,7
In the RAISE study, 174 adult patients were randomised to receive daily SC, self-administered doses of placebo (N=88) or zilucoplan 0.3 mg/kg (N=86). Patient demographics and baseline disease characteristics were generally balanced between treatment arms.6
As a complement C5 inhibitor, zilucoplan is a targeted therapy that inhibits key components in the underlying pathophysiology of gMG, addressing the underlying mechanism of neuromuscular junction damage.8,9
UCB anticipates making regulatory filings for zilucoplan in gMG in Great Britain, Japan, and rest of the world from Q3 2022 onwards.
Alongside zilucoplan, UCB is also investigating rozanolixizumab, a SC-administered, humanized monoclonal antibody that specifically binds, with high affinity, to human neonatal Fc receptor (FcRn), as a potential treatment for gMG. UCB anticipates filing regulatory submissions for rozanolixizumab later this year.
About the zilucoplan RAISE study 6,7
The RAISE study (NCT04115293) is a multi-center, Phase 3, randomized, double-blind, placebo-controlled study to confirm the efficacy, safety, and tolerability of zilucoplan in patients with AChR-Ab+ gMG. Patients were randomized in a 1:1 ratio to receive daily subcutaneous (SC) doses of 0.3 mg/kg zilucoplan or placebo for 12 weeks.
The primary endpoint for the RAISE study is change from baseline to Week 12 in the Myasthenia Gravis-Activities of Daily Living (MG-ADL) score. Secondary endpoints include change in the Quantitative Myasthenia Gravis (QMG) score, the Myasthenia Gravis Composite (MGC) and the Myasthenia Gravis Quality of Life 15 revised (MG-QoL15r) score from baseline to Week 12, time to rescue therapy, the proportion with minimal symptom expression (MSE) (defined as MG-ADL of 0 or 1), the proportion with a ≥3-point reduction in MG-ADL and the proportion with a ≥5-point reduction in QMG without rescue therapy, all measured at Week 12. The secondary safety endpoint is incidence of TEAEs. Patients who completed the 12 week RAISE trial had the possibility to enter the open label extension study, RAISE-XT.
For more information about the trial visit https://clinicaltrials.gov/ct2/show/NCT04115293.
- US Food and Drug Administration https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=699319. Accessed October 2022
- Data on file.
- Hansen JS, et al. Mortality in myasthenia gravis: A nationwide population-based follow-up study in Denmark. Muscle Nerve. 2016;53:73-77.
- Myasthenia Gravis Foundation of America. Clinical Overview of MG. https://myasthenia.org/Professionals/Clinical-Overview-of-MG. Accessed August 2022
- Salari N, et al. Global prevalence of myasthenia gravis and the effectiveness of common drugs in its treatment: a systematic review and meta-analysis. J Transl Med 19, 516 (2021). https://doi.org/10.1186/s12967-021-03185-7. Accessed September 2022.
- Vu T, et al. Efficacy and safety of zilucoplan in myasthenia gravis: Responder analysis from the randomized Phase 3 RAISE trial. Poster 200, AANEM 2022.
- Weiss MD, et al, Quality of life outcomes in RAISE: A double-blind randomized, placebo-controlled study of zilucoplan in gMG. Oral presentation. MGFA Scientific Session, AANEM 2022.
- Tannemaat et al. Emerging therapies for autoimmune myasthenia gravis: Towards treatment without corticosteroids. Neuromuscul Disord. 2020;30(2):111-119
- Howard J, et al. Clinical Effects of the Self-administered Subcutaneous Complement Inhibitor Zilucoplan in Patients With Moderate to Severe Generalized Myasthenia Gravis: Results of a Phase 2 Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial. JAMA Neurol 2022 1;77(5)
- ClinicalTrials.gov. 2022. A Study to Test Efficacy and Safety of Rozanolixizumab in Adult Patients With Generalized Myasthenia Gravis. https://clinicaltrials.gov/ct2/show/NCT03971422. Accesed October 2022
- Chen J, et al. Incidence, mortality, and economic burden of myasthenia gravis in China: A nationwide population-based study. Lancet Reg Health West Pac: 2020;5:100063.
- National institute of Neurological Disorders and Stroke. 2022. Myasthenia Gravis Fact Sheet. https://www.ninds.nih.gov/myasthenia-gravis-fact-sheet. Accessed October 2022.
- Dong D, et al. Gender differences in quality of life among patients with myasthenia gravis in China. Health and Quality of Life Outcomes 2020 18;296
- Myasthenia Gravis Foundation of America. MG Quick Facts. https://myasthenia.org/MG-Education/MG-Quick-Facts Accessed October 2022
- Smith B, et al. Generation and characterization of a high affinity anti-human FcRn antibody, rozanolixizumab, and the effects of different molecular formats on the reduction of plasma IgG concentration. MAbs. 2018;10:1111-30.
- Kiessling P, et al. The FcRn inhibitor rozanolixizumab reduces human serum IgG concentration: A randomized phase 1 study. Sci Transl Med. 2017;9(414:eaan1208).
- US Food and Drug Administration https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=669918. Accessed August 2022
- European Medicines Agency, EU/3/20/2272: Orphan designation for the treatment of myasthenia gravis https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3202272. Accessed August 2022