DNTH103 for Myasthenia Gravis
(MAGIC Trial)
Recruiting in Palo Alto (17 mi)
+58 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Dianthus Therapeutics
Must not be taking: Rituximab, IVIg, PLEX
Disqualifiers: HIV, Hepatitis B, Thymoma, others
Prior Safety Data
Trial Summary
What is the purpose of this trial?The purpose of this Phase 2 study is to evaluate the safety, tolerability, pharmacometrics, and efficacy of DNTH103 in participants with generalized myasthenia gravis (gMG).
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but you cannot have used Rituximab within 6 months or IVIg and plasma exchange within 4 weeks before starting the trial.
What data supports the effectiveness of the drug DNTH103 for treating myasthenia gravis?
Recent advances in drug therapy for myasthenia gravis have significantly improved the quality of life for many patients, reducing complications and hospitalizations. While specific data on DNTH103 is not provided, the approval of similar treatments like complement and FcRN inhibitors by the FDA suggests potential effectiveness in managing the condition.
12345How does the drug DNTH103 differ from other treatments for myasthenia gravis?
DNTH103 is unique because it is an antisense oligonucleotide that targets acetylcholinesterase (AChE) mRNA, potentially reducing AChE activity and improving muscle function in myasthenia gravis. This mechanism is different from other treatments like pyridostigmine, which directly inhibits AChE, and eculizumab, which targets the complement system.
678910Eligibility Criteria
Adults aged 18-75 with generalized myasthenia gravis (gMG), a muscle weakness condition, can join this trial. They must have an MG-ADL score of 6+, be AChR antibody positive, and fall within the MGFA Class II-Iva. Participants need to agree to contraception if applicable and should weigh between 40-120 kg.Inclusion Criteria
Must have given written informed consent before any study-related activities are carried out
My weight is between 40 and 120 kg.
I am between 18 and 75 years old.
+6 more
Exclusion Criteria
Prior history (at any time) of N. meningitidis infection
I have a significant health condition or had major surgery recently.
Positive test results for active human immunodeficiency virus (HIV-1 or HIV-2), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibodies during Screening
+5 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
up to 10 weeks
Randomized, blinded, controlled treatment (RCT)
Participants receive either DNTH103 or placebo to evaluate safety, tolerability, pharmacometrics, and efficacy
13 weeks
Open-label extension (OLE)
Eligible participants may opt into continuation of treatment with DNTH103 long-term
52 weeks
Safety follow-up
Participants are monitored for safety and effectiveness after treatment
40 weeks
Participant Groups
The study is testing DNTH103's safety and effectiveness for gMG patients compared to a placebo. It will look at how well the drug works, its side effects, and how it moves through the body.
3Treatment groups
Experimental Treatment
Placebo Group
Group I: DNTH103 low dose Q2WExperimental Treatment1 Intervention
Group II: DNTH103 high dose Q2WExperimental Treatment1 Intervention
Group III: PlaceboPlacebo Group1 Intervention
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
West Texas Neurology ClinicLubbock, TX
Clinical Study SiteStamford, CT
Texas NeurologyDallas, TX
Clinical Study SiteBradenton, FL
More Trial Locations
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Who Is Running the Clinical Trial?
Dianthus TherapeuticsLead Sponsor
References
Baseline Decrement in Patients with Mild Myasthenia Gravis Predicts Immunomodulation Treatment. [2020]To explore whether higher degrees of electrophysiological abnormalities are associated with a more frequent exposure to a more aggressive treatment regimen, we performed a retrospective chart review of patients attending the neuromuscular clinic from June 2012 to December 2015 and included 87 patients. We compared treatment regimens during the follow-up period between patients with high and low jitter and decrement. Myasthenia gravis patients with high jitter or decrement at baseline were more frequently treated with intravenous immunoglobulins (IVIG) and/or plasma exchange (PLEX) during the follow-up period. In patients with mild disease, IVIG or PLEX treatment was associated with high decrement.
Myasthenia Gravis. [2022]The treatment of patients with myasthenia gravis should be individualized according to the extent (ocular versus generalized) and severity (mild to severe) of disease, the presence or absence of concomitant disease (including but not limited to other autoimmune diseases and thymoma), and, to a lesser degree, the age of the patient. Thymectomy should be performed in patients with generalized disease, especially those who have detectable levels of circulating antibodies to acetylcholine receptor (anti-AChR), as it should be in all patients thought to have an operable thymoma (observed on imaging studies of the chest). Symptomatic therapy consists of anticholinesterase drugs (usually pyridostigmine); occasionally, other drugs are required to reduce the muscarinic side effects. At times, patients need immunosuppressive or immunomodulatory therapy with glucocorticoids, azathioprine, cyclospor-ine or cyclophosphamide, plasma exchange, and intravenous immunoglobulin. Remission, whether spontaneous or pharmacologically induced, or significant improvement can be achieved in most patients, but some treatments entail significant side effects and considerable cost.
The best and worst of times in therapy development for myasthenia gravis. [2023]Within the last 5 years, the US Food and Drug Administration (FDA) has approved complement and neonatal Fc receptor (FcRN) inhibitors for treatment of generalized myasthenia gravis, and several other therapies are in late-stage clinical trials or under regulatory review. However, questions about which patients are most likely to benefit from which therapies, and the relative effectiveness of these very expensive drugs, has resulted in uncertainty around the place that they should occupy in the existing therapeutic armamentarium. MGNet (a Rare Diseases Clinical Research Consortium funded by the National Institute of Neurological Diseases and Stroke) held two meetings during the 14th International Conference of the Myasthenia Gravis Foundation of America to discuss the most critical needs for clinical trial readiness and biomarker development in the context of therapy development for myasthenia gravis. Herein we provide a summary of these discussions, but not a consensus opinion, and offer a series of recommendations to guide focused research in the most critical areas. We welcome ongoing discussion through comments on this work.
Myasthenia gravis: subgroup classification and therapeutic strategies. [2022]Myasthenia gravis is an autoimmune disease that is characterised by muscle weakness and fatigue, is B-cell mediated, and is associated with antibodies directed against the acetylcholine receptor, muscle-specific kinase (MUSK), lipoprotein-related protein 4 (LRP4), or agrin in the postsynaptic membrane at the neuromuscular junction. Patients with myasthenia gravis should be classified into subgroups to help with therapeutic decisions and prognosis. Subgroups based on serum antibodies and clinical features include early-onset, late-onset, thymoma, MUSK, LRP4, antibody-negative, and ocular forms of myasthenia gravis. Agrin-associated myasthenia gravis might emerge as a new entity. The prognosis is good with optimum symptomatic, immunosuppressive, and supportive treatment. Pyridostigmine is the preferred symptomatic treatment, and for patients who do not adequately respond to symptomatic therapy, corticosteroids, azathioprine, and thymectomy are first-line immunosuppressive treatments. Additional immunomodulatory drugs are emerging, but therapeutic decisions are hampered by the scarcity of controlled studies. Long-term drug treatment is essential for most patients and must be tailored to the particular form of myasthenia gravis.
Pharmacological Management of Myasthenia Gravis: A Century of Expert Opinions in Cecil Textbook of Medicine. [2021]Advances in drug therapy for myasthenia gravis have had a significant impact on the quality of life and work potential of a substantial majority of affected persons and has contributed to a remarkable decrease in the frequency and severity of complications, hospitalizations, and mortality.
Further developments with antisense treatment for myasthenia gravis. [2013]We present further developments in the study of the antisense oligonucleotide EN101. Ongoing in vitro and in vivo studies demonstrate that EN101 is a TLR9-specific ligand that can suppress pro-inflammatory functions and shift nuclear factor kappa B (NF-κB) from the pro-inflammatory canonical pathway to the anti-inflammatory alternative pathway, which results in decreases acetylcholinesterase (AChE) activity. Preliminary results of a double-blinded phase II cross-over study compared 10, 20, and 40 mg EN101 administered to patients with myasthenia gravis. Patients were randomly assigned to one of three treatment groups in weeks 1, 3, and 5 and received their pretreatment dose of pyridostigmine in weeks 2 and 4. Thus far, all doses show a decrease in QMG scores, with a greater response to higher doses.
Stimulated-single fiber electromyography monitoring of anti-sense induced changes in experimental autoimmune myasthenia gravis. [2007]The neuromuscular weakness associated with myasthenia gravis (MG) can be transiently relieved by pharmacological inhibitors of acetylcholinesterase (AChE). Here, we expand the anticholinesterase repertoire to include 2'-O-methyl-protected antisense oligonucleotides targeted to AChE mRNA (EN101). Using stimulated-single fiber electromyography, we show that EN101 treatment of rats with experimental autoimmune myasthenia gravis (EAMG), improved the mean consecutive difference (MCD) and blocking for 24h. This treatment was more efficient than pyridostigmine and was accompanied by marked improvement in stamina and clinical profile.
Suppression of experimental autoimmune myasthenia gravis by oral administration of acetylcholine receptor. [2019]Experimental autoimmune myasthenia gravis (EAMG), which to some extent represents an experimental counterpart of human myasthenia gravis, can be induced by inoculation of various animal species and strains with acetylcholine receptor (AChR). The oral administration of Torpedo AChR to Lewis rats prior to immunization with Torpedo AChR and complete Freund's adjuvant resulted in prevention or delay in the onset of EAMG. Levels of anti-Torpedo AChR antibodies in serum measured by radioimmunoassay were lower in orally tolerant compared to control animals. The model might have a relevance for studying the pathogenesis and immunotherapy of human myasthenia gravis.
Discovery of functionally distinct anti-C7 monoclonal antibodies and stratification of anti-nicotinic AChR positive Myasthenia Gravis patients. [2022]Myasthenia Gravis (MG) is mediated by autoantibodies against acetylcholine receptors that cause loss of the receptors in the neuromuscular junction. Eculizumab, a C5-inhibitor, is the only approved treatment for MG that mechanistically addresses complement-mediated loss of nicotinic acetylcholine receptors. It is an expensive drug and was approved despite missing the primary efficacy endpoint in the Phase 3 REGAIN study. There are two observations to highlight. Firstly, further C5 inhibitors are in clinical development, but other terminal pathway proteins, such as C7, have been relatively understudied as therapeutic targets, despite the potential for lower and less frequent dosing. Secondly, given the known heterogenous mechanisms of action of autoantibodies in MG, effective patient stratification in the REGAIN trial may have provided more favorable efficacy readouts. We investigated C7 as a target and assessed the in vitro function, binding epitopes and mechanism of action of three mAbs against C7. We found the mAbs were human, cynomolgus monkey and/or rat cross-reactive and each had a distinct, novel mechanism of C7 inhibition. TPP1820 was effective in preventing experimental MG in rats in both prophylactic and therapeutic dosing regimens. To enable identification of MG patients that are likely to respond to C7 inhibition, we developed a patient stratification assay and showed in a small cohort of MG patients (n=19) that 63% had significant complement activation and C7-dependent loss of AChRs in this in vitro set up. This study provides validation of C7 as a target for treatment of MG and provides a means of identifying patients likely to respond to anti-C7 therapy based on complement-activating properties of patient autoantibodies.
A Novel Approach to Reinstating Tolerance in Experimental Autoimmune Myasthenia Gravis Using a Targeted Fusion Protein, mCTA1-T146. [2019]Reinstating tissue-specific tolerance has attracted much attention as a means to treat autoimmune diseases. However, despite promising results in rodent models of autoimmune diseases, no established tolerogenic therapy is clinically available yet. In the experimental autoimmune myasthenia gravis (EAMG) model several protocols have been reported that induce tolerance against the prime disease-associated antigen, the acetylcholine receptor (AChR) at the neuromuscular junction. Using the whole AChR, the extracellular part or peptides derived from the receptor, investigators have reported variable success with their treatments, though, usually relatively large amounts of antigen has been required. Hence, there is a need for better formulations and strategies to improve on the efficacy of the tolerance-inducing therapies. Here, we report on a novel targeted fusion protein carrying the immunodominant peptide from AChR, mCTA1-T146, which given intranasally in repeated microgram doses strongly suppressed induction as well as ongoing EAMG disease in mice. The results corroborate our previous findings, using the same fusion protein approach, in the collagen-induced arthritis model showing dramatic suppressive effects on Th1 and Th17 autoaggressive CD4 T cells and upregulated regulatory T cell activities with enhanced IL10 production. A suppressive gene signature with upregulated expression of mRNA for TGFβ, IL10, IL27, and Foxp3 was clearly detectable in lymph node and spleen following intranasal treatment with mCTA1-T146. Amelioration of EAMG disease was accompanied by reduced loss of muscle AChR and lower levels of anti-AChR serum antibodies. We believe this targeted highly effective fusion protein mCTA1-T146 is a promising candidate for clinical evaluation in myasthenia gravis patients.