At the end of 2021, efgartigimod, a targeted biologic with good efficacy and safety, was approved by the US FDA, and this innovative therapy brought new hope to patients with generalized myasthenia gravis (gMG)! The new dosage form of efgartigimod subcutaneous injection (SC), which is currently in the research and development stage, has attracted the attention of scholars. What is the safety and clinical efficacy of Efgartigimod SC dosage forms? Is it not inferior to the pharmacodynamic dynamics of intravenous (IV) dosage forms? Can it be a new treatment option for patients with gMG? The 2022 American Society for Neuromuscular and Electrophysiological Diagnostic Medicine Annual Meeting (AANEM) held not long ago announced some of the latest research advances on efgartigimod SC dosage forms, let's take a look.
Long-term maintenance therapy for chronic diseases: SC versus IV, who is the better choice?
Currently, SC biologics have become an alternative to many disease area IVs. SC has been shown to be effective, safe, well tolerated, often favored by patients and healthcare providers, and reduces healthcare costs and resource use associated with drug delivery1. A study on anemia associated with chronic kidney disease (CKD) showed that the mean drug concentration-time curves of alfadabebopol drugs in SC and IV administration were comparable. The pharmacokinetics (PK), pharmacokinetics (PD), and safety profile of the two modes of administration are similar, and the two formulations are used interchangeably in clinical treatment2. At the same time, a study on the treatment of relapsed or refractory multiple myeloma showed that patients in the SC group with daratumumab had shorter SC administration times and fewer infusion-related reactions (IRRs), reduced patient burden and higher treatment satisfaction than patients in the IV group3. Therefore, for chronic diseases that require long-term maintenance therapy, SC is as effective as IV, but it is shorter and more convenient.
efgartigimod breaks the treatment dilemma and starts a new journey of comprehensive benefit breakthrough
MG is an autoimmune disease mediated by autoantibodies, with impaired transmission of acquired neuro-muscle junctions (NMJs). Acetylcholine receptor (AChR) antibodies are the most common pathogenic antibodies. At present, the treatment of mainland MG is still dominated by traditional methods such as cholinesterase inhibitors and glucocorticoids4. More recently, targeted immunotherapy has emerged as a treatment for myasthenia gravis, avoiding associated limitations (such as inadequate symptom relief and adverse events) compared to traditional treatments5. Recently, efgartigimod, a neonatal Fc receptor (FcRn) antagonist that targets the elimination of pathogenic IgG, has attracted much attention. On December 17, 2021, efgartigimod IV was first approved in the United States for the treatment of AChR antibody-positive (AChR-Ab+) adult gMG patients. On January 20, 2022, Japan approved efgartigimod IV dosage form for the treatment of adult patients with gMG who did not respond adequately to steroidal or non-steroidal immunosuppressive therapies (NSISTs). In August 2022, the European Commission (EC) approved the marketing application for VYVGART (efgartigimod alfa-fcab) for the treatment of adult gMG patients with AChR-Ab+ in combination with existing standard therapies. In addition to IV formulations, efgartigimod SC preparations based on recombinant human hyaluronidase are in the R&D phase and clinical studies are ongoing5.
The ADAPT study confirmed the long-term efficacy and safety of egartigimod IV dosage form
Efgartigimod is a human IgG1-derived Fc fragment, as an FcRn antagonist, its competitive blocking of endogenous IgG binding to FcRn, promoting IgG degradation in lysosomes, thereby reducing the recycling of IgG and achieving the effect of reducing pathogenic IgG levels. In 2021, The Lancet Neurology published its key study, the ADAPT study, a 26-week randomized, double-blind, placebo-controlled phase III clinical trial. The results of the study showed that the MG-ADL response rate of the Efgartigimod group in the first treatment cycle (8 weeks) was 68%; 84.1% of respondents responded in the first two weeks; The proportion of patients in the Efgartigimod group who achieved minimal symptom expression (MSE) (MG-ADL 0 or 1) in the first treatment cycle was 40%; The Efgartigimod group was well tolerated overall. The results fully confirm the efficacy and good safety profile of egartigimod IV in the treatment of gMG patients6.
Egartigimod IV dosage form is safe and effective, bringing new hope to MG patients. In order to provide patients with more convenient dosing methods, meet individual needs, and further save medical care resources, the search for new dosage forms has never stopped.
New dosage forms, new expectations: the ADAPT sc study of efgartigimod
The newly developed efgartigimod subcutaneous injection combines efgartigimod with recombinant human hyaluronidase PH20 (rHuPH20). rHuPH20 degrades subcutaneous hyaluronic acid to aid penetration and absorption of SC drugs, providing patients with additional treatment options7.
ADAPT sc is a multicenter, randomized, open-label phase III clinical trial and a non-inferiority study comparing the pharmacodynamic kinetics of SC efgartigimod PH20 with IV efgartigimod (NCT04818671). The study included 110 adult patients with gMG (inclusion criteria: patients diagnosed with gMG; MG-ADL score ≥ 5, with at least 50% of the score coming from the non-ocular type score; Patients receiving at least one stable dose of gMG therapy, including acetylcholinesterase inhibitors, corticosteroids, or nonsteroidal immunosuppressive drugs, and need to maintain this stable dose throughout the main trial.3 Patients were randomized in a 1:1 ratio to receive four weekly injections of 1000 mg efgartigimod PH20 SC or four weekly injections of 10 mg/kg efgartigimod IV. The total study duration was approximately 12 weeks, including follow-up of 7 weeks after the treatment cycle. The primary endpoint was the percentage reduction in total IgG levels in patients from baseline at week 4. Secondary endpoints were safety, clinical efficacy, immunogenicity, and PK.
Figure 1 ADAPT sc study design
At the AANEM conference, the results of the Phase III ADAPT sc study were presented in detail for the first time8:
- The primary endpoint of non-inferiority (p<0.0001) was achieved. The mean total IgG level at day 29 was reduced by 64.7% (SE: 1.95%) from baseline in the SC group compared to 62.3% (SE: 1.24%) in the IV group. Efficacy results were consistent across the population, including patients with positive acetylcholine receptor (AChR) antibodies and those with negative AChR antibodies.
- Other secondary endpoints were met and consistent with the clinical efficacy observed in Phase III clinical trials of IV formulations. Include:
a.69.1% of patients with efgartigimod SC achieved a myasthenia gravis activity of daily living (MG-ADL) score response. Responders were defined as at least 2 points improvement in MG-ADL scores for 4 weeks or more;
b. 65.5% of patients received efgartigimod SC and achieved a quantitative myasthenia gravis (QMG) score response. Responders were defined as a 3-point improvement in QMG score and a duration of at least 5 weeks during the first treatment cycle7;
- After one treatment cycle, 37% of patients treated with efgartigimod SC achieved MSE, a measure of asymptomatic status, consistent with the ADAPT study. At the same time, the effect is also consistent with the ADAPT study.
- Both dosage forms were well tolerated and consistent with the results of previous Phase III clinical trials of IV preparations; The incidence of headache was comparable in both treatment groups; Other common AEs in the SC treatment group were injection site reaction (ISR) and MG exacerbation. ISR is predominantly mild to moderate and does not lead to discontinuation.
These results demonstrate that the reduction in total IgG levels after administration of SC efgartigimod meets pre-set criteria of non-inferiority compared to IV preparations, with similar safety and efficacy profiles. The Efgartigimod SC dosage form offers additional treatment options for gMG patients.
As a targeted biologic that directly acts on the core pathogenic link of MG, Efgartigmod has shown good efficacy and safety in clinical studies. Efgartigimod SC dosage forms provide treatment options to meet the individual needs of patients, and the latest advances in the ADAPT sc study presented at the AANEM conference demonstrate the efficacy and safety of efgartigimod SC new dosage forms. On September 21, 2022, the Biologics License Application (BLA) for efgartigimod SC dosage form was accepted by the US FDA for the treatment of adult patients with gMG. Looking forward to more follow-up related studies of this new preparation to benefit more patients!
Expert profiles
Professor Li Zhijun
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Associate Professor, Deputy Chief Physician, M.D., Master Supervisor, Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology;
- From 2008 to 2011, he studied at the University of Heidelberg, Germany;
- Member of the Electromyography and Clinical Electrophysiology Group of the 8th Committee of the Neurology Branch of the Chinese Medical Association;
- Member of the Neurodegeneration and Repair Committee of the Neuroprosthetic Professional Committee of the Chinese Medical Doctor Association;
- Member of Neurology Branch of Chinese Geriatric Society;
- Vice Chairman of the Neuroimmunology Committee of Hubei Medical Bioimmunology Society;
- Deputy leader of the Neuroimmunomyopathy Group of the Neurology Branch of Wuhan Medical Association;
- Standing Director of Hubei Parkinson's Disease and Movement Disorders Society;
- Undertake the National Natural Science Foundation, Provincial Fund and Ministry of Education Fund;
- Research interests: neuroimmunological diseases, peripheral neuropathy, neuromuscular diseases and neuroelectrophysiological diagnosis.
Expert reviews
Compared with IV administration, SC biologics have the characteristics of simple and convenient administration, good tolerability, and few infusion-related reactions. In addition, SC administration often does not require hospitalization, and can also reduce hospitalization-related medical costs and reduce the burden of treatment for patients. These advantages make SC administration more acceptable to patients with chronic diseases who require long-term maintenance therapy, especially when IC and SC formulations of biologics are clinically equivalent. efgartigimod, a neonatal Fc receptor (FcRn) antagonist that targets the removal of pathogenic IgG, has been fully demonstrated in the ADAPT study The efficacy and good safety of IV dosage form in the treatment of gMG patients, and the United States, Japan and the European Union have also approved efgartigimod IV dosage form for the treatment of adult gMG patients. In 2022, AANEM announced the latest ADAPT sc study of efgartigimod SC dosage form, showing that the reduction of total IgG levels after administration of SC dosage form meets the pre-set criteria for non-inferiority, and has similar safety and efficacy characteristics to IV dosage form, including QMG score response, MG-ADL score response and other indicators are consistent with IV dosage form. Currently, the Efgartigimod SC dosage form has been applied to the US FDA for the indication of the treatment of gMG. There is reason to believe that the Efgartigimod SC dosage form will provide additional, individualized, and more convenient treatment options for gMG patients.
ZMCNNP2022112300 Expire Date 2023/11/23
Bibliography:
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2.Kim S,et al. BioDrugs. 2019 Feb;33(1):101-112.
3.Iwahashi M,et al. Lancet Haematol. 2020 May;7(5):e370-e380.
4. Neuroimmunology Branch, Chinese Society of Immunology. Chinese Guidelines for the Diagnosis and Treatment of Myasthenia Gravis(2020 Edition).Chinese Journal of Neuroimmunology and Neurology[J].2021,28(1):1-12.)
5.Young-A Heo,et al. Drugs. 2022 Feb;82(3):341-348.
6.Howard JF Jr,et al. Lancet Neurol.2021 Jul;20(7):526-536.
7.Argenx Announces Positive Topline Phase 3 Data From ADAPT-SC Study Evaluating Subcutaneous Efgartigimod for Generalized Myasthenia Gravis. Retrieved March 22, 2022, from https://www.businesswire.com/news/home/20220321005941/en
8.Howard J, et al. Efficacy, A pharmacodynamic noninferiority study comparing subcutaneous injections of efgartigimod PH20 with intravenous infusions of efgartigimod:result of the phase 3 ADAPT sc study. 2022 AANEM. 31.