DNTH103 for Myasthenia Gravis

(MAGIC Trial)

Recruiting at 59 trial locations

Overseen By Dianthus Clinical Contact Center

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Dianthus Therapeutics

Must not be taking: Rituximab, IVIg, PLEX

Disqualifiers: HIV, Hepatitis B, Thymoma, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

65 Participants Needed

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. ^{1 2 3 4 5}

How 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. ^{6 7 8 9 10}

Eligibility 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 either unable to have children or agree to use effective birth control and not try to get pregnant.

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

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

Treatment Details

Interventions

• DNTH103

Trial Overview 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.

Participant Groups

Group I: DNTH103 low dose Q2W Experimental Treatment 1 Intervention

Group II: DNTH103 high dose Q2W Experimental Treatment 1 Intervention

Group III: Placebo Placebo Group 1 Intervention

Who Is Running the Clinical Trial?

Dianthus Therapeutics

Lead Sponsor

Trials

3

Recruited

580+

Findings from Research

In a study of 87 myasthenia gravis patients, those with higher electrophysiological abnormalities (high jitter or decrement) were more likely to receive aggressive treatments like intravenous immunoglobulins (IVIG) and plasma exchange (PLEX).

For patients with mild disease, the use of IVIG or PLEX was specifically linked to high decrement levels, suggesting that these treatments may be prioritized based on the severity of electrophysiological symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Baseline Decrement in Patients with Mild Myasthenia Gravis Predicts Immunomodulation Treatment. Abraham, A., Lovblom, LE., Bril, V.[2020]

Treatment for myasthenia gravis should be personalized based on disease type (ocular vs. generalized), severity, and other health conditions, with thymectomy recommended for patients with generalized disease and detectable anti-AChR antibodies.

Most patients can achieve remission or significant improvement with treatments like anticholinesterase drugs and immunosuppressants, but these can come with serious side effects and high costs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Myasthenia Gravis. Lisak, RP.[2022]

The FDA has recently approved new therapies, including complement and Fc receptor inhibitors, for treating generalized myasthenia gravis, highlighting advancements in treatment options for this condition.

There is ongoing uncertainty regarding which patients will benefit most from these expensive therapies, prompting discussions on the need for better clinical trial readiness and biomarker development to guide future research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The best and worst of times in therapy development for myasthenia gravis. Benatar, M., Cutter, G., Kaminski, HJ.[2023]

Myasthenia gravis is an autoimmune disease characterized by muscle weakness due to antibodies affecting the neuromuscular junction, and patients can be classified into subgroups based on specific antibodies and clinical features, which aids in treatment decisions.

The prognosis for myasthenia gravis is generally good with appropriate treatment, including pyridostigmine for symptoms and immunosuppressive therapies like corticosteroids and azathioprine for those who do not respond well to symptomatic treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Myasthenia gravis: subgroup classification and therapeutic strategies. Gilhus, NE., Verschuuren, JJ.[2022]

The management of myasthenia gravis has evolved significantly over the past century, transitioning from basic care methods in 1927 to advanced pharmacological treatments, including immunosuppressants and monoclonal antibodies, which have greatly improved patient outcomes.

Key milestones include the introduction of anticholinesterases in 1937, standard immunosuppressants like prednisone and azathioprine in 1975, and newer therapies such as rituximab and eculizumab from 2012 onwards, highlighting the importance of understanding the autoimmune nature of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological Management of Myasthenia Gravis: A Century of Expert Opinions in Cecil Textbook of Medicine. Manu, P., Rogozea, LM., Roman-Filip, C.[2021]

EN101 is a TLR9-specific ligand that effectively shifts the inflammatory response from a pro-inflammatory to an anti-inflammatory pathway, which may help reduce acetylcholinesterase activity.

In a preliminary phase II study involving patients with myasthenia gravis, all doses of EN101 (10, 20, and 40 mg) resulted in decreased QMG scores, indicating improved symptoms, with higher doses showing a greater response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Further developments with antisense treatment for myasthenia gravis. Sussman, J., Argov, Z., Wirguin, Y., et al.[2013]

The study introduces EN101, a novel treatment using antisense oligonucleotides to target acetylcholinesterase mRNA, which significantly improved neuromuscular function in rats with experimental autoimmune myasthenia gravis (EAMG).

EN101 demonstrated greater efficacy than the traditional treatment pyridostigmine, leading to improved stamina and overall clinical outcomes for the rats over a 24-hour period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stimulated-single fiber electromyography monitoring of anti-sense induced changes in experimental autoimmune myasthenia gravis. Boneva, N., Hamra-Amitay, Y., Wirguin, I., et al.[2007]

Oral administration of Torpedo acetylcholine receptor (AChR) before immunization can prevent or delay the onset of experimental autoimmune myasthenia gravis (EAMG) in Lewis rats, suggesting a potential therapeutic approach.

Lower levels of anti-Torpedo AChR antibodies were observed in rats that received oral tolerance treatment compared to control animals, indicating that this method may help modulate the immune response in conditions similar to human myasthenia gravis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Suppression of experimental autoimmune myasthenia gravis by oral administration of acetylcholine receptor. Wang, ZY., Qiao, J., Link, H.[2019]

Eculizumab is currently the only approved treatment for Myasthenia Gravis (MG), targeting complement-mediated loss of acetylcholine receptors, but it missed its primary efficacy endpoint in the Phase 3 REGAIN study, highlighting the need for better patient stratification.

Research into C7 as a therapeutic target for MG shows promise, with a study indicating that 63% of a small cohort of MG patients (n=19) exhibited significant complement activation, suggesting that C7 inhibitors could be effective for a subset of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery of functionally distinct anti-C7 monoclonal antibodies and stratification of anti-nicotinic AChR positive Myasthenia Gravis patients. Lekova, E., Zelek, WM., Gower, D., et al.[2022]

The novel targeted fusion protein mCTA1-T146, administered intranasally in small doses, effectively suppressed both the onset and progression of experimental autoimmune myasthenia gravis (EAMG) in mice, indicating its potential as a tolerogenic therapy.

Treatment with mCTA1-T146 led to significant immune modulation, including increased regulatory T cell activity and production of anti-inflammatory cytokines, which correlated with reduced muscle AChR loss and lower anti-AChR antibody levels, suggesting a promising mechanism for treating autoimmune diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Novel Approach to Reinstating Tolerance in Experimental Autoimmune Myasthenia Gravis Using a Targeted Fusion Protein, mCTA1-T146. Consonni, A., Sharma, S., Schön, K., et al.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Baseline Decrement in Patients with Mild Myasthenia Gravis Predicts Immunomodulation Treatment. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Myasthenia Gravis. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

The best and worst of times in therapy development for myasthenia gravis. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Myasthenia gravis: subgroup classification and therapeutic strategies. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Pharmacological Management of Myasthenia Gravis: A Century of Expert Opinions in Cecil Textbook of Medicine. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Further developments with antisense treatment for myasthenia gravis. [2013]

7. Ireland pubmed.ncbi.nlm.nih.gov

Stimulated-single fiber electromyography monitoring of anti-sense induced changes in experimental autoimmune myasthenia gravis. [2007]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Suppression of experimental autoimmune myasthenia gravis by oral administration of acetylcholine receptor. [2019]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Discovery of functionally distinct anti-C7 monoclonal antibodies and stratification of anti-nicotinic AChR positive Myasthenia Gravis patients. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

A Novel Approach to Reinstating Tolerance in Experimental Autoimmune Myasthenia Gravis Using a Targeted Fusion Protein, mCTA1-T146. [2019]