Spotlight: Effect of the FcRn antagonist efgartigimod on protective antibodies and vaccination efficacy in vivo patients with pemphigus and myasthenia gravis

Systemic myasthenia gravis (gMG) and pemphigus (PV) are both autoimmune diseases mediated by immunoglobulin G (IgG) that continuously affect the health of patients and increase the burden on ^society1

Research background and methodology

The recently published study conducted a post-mortem analysis of data from two clinical studies of efgartigimod, namely the Phase II open-label trial of efgartigimod in PV patients (NCT03334058) ⁵ and the phase III randomized, double-blind, placebo-controlled trial (ADAPT, NCT03669588) of efgartigimod in gMG and its open-label extension study (ADAPT+, NCT03770403）⁶

In this post-mortem analysis study, the patient's level of protective antibodies associated with previous vaccinations or infections was assessed

Figure 1.

Results of the study

(1) For gMG patients

➤ gMG patients receiving efgartigimod treatment does not affect the immune response of T-cell-dependent vaccines

• COVID-19 vaccine: S-RBD (region of receptor binding of novel coronavirus spike protein) after vaccination IgG levels are not affected by efgartigimod therapy

  
  

  ✔ Patient 17 was not treated with efgartigimod and any other immunosuppressant drugs at the time of enrolment in the ADAPT+ study and sample collection

  
  
  
  

  ✔ Patient 16 was vaccinated with BNT162b2 1 week after the fourth infusion in the efgartigimod treatment cycle and received another cycle of efgartigimod after the second dose of BNT162b2

  
  
  
  

  ✔ Patient 12 received simultaneous prednisolone therapy (5 mg and 7.

  
  
  
  

Figure 2.
In individual patients with gMG receiving ADAPT+ therapy, the first dose and the second dose (day 1) BNT162b2 (A-C) before and after treatment with IgG levels

• Influenza vaccine: Patients with no significant reduction in IgG levels after vaccination, a clear immune response to all tests, and A/H1N1, A/H3N2, and/or B/Y antibody titers can meet or exceed the protection threshold

  ✔ Patients 10 and 11 were vaccinated between two treatment cycles of efgartigimod (Figure 3A
  ).
  
  Patient 10 (left panel) Total IgG levels were comparable to pre-vaccination levels, and the titer of anti-A/H3N2 and B/Y antibodies increased approximately 2-fold
  3 weeks after vaccination.
  
  In the efgartigimod cycle between hemagglutinous suppression (HI) titer measurements after 2 vaccinations, total IgG decreased, but titers of A/H1N1, A/H3N2, and B/Y reached or exceeded the protection threshold
  80 days after vaccination.
  
  Patient 11 (right) IgG levels were not significantly reduced and there was a clear post-vaccination immune response to all strains tested
  .
  
  

  ✔ Patients 7 and 9 took pre-vaccination samples during the efgartigimod treatment cycle (Figure 3B
  ).
  
  Patient 7 (left) received the flu vaccine near the end of the efgartigimod treatment cycle, with IgG near the lowest point
  .
  
  80 days after vaccination, the total IgG level was 2 times higher than at the time of vaccination, the A/H3N2 titer increased by 8 times, and remained above
  the protection threshold after another cycle of efgartigimod therapy.
  
  Patient 9 (right) was vaccinated 2 weeks after the efgartigimod treatment cycle, and after one month, the total IgG level was 2.
  5 times higher than the pre-vaccination level, the HI titer for A/H3N2 was increased by 8 times, and the titer for A/H1N1 was increased to the protection threshold; In subsequent efgartigimod treatment cycles, titers for both strains are at or above the protection threshold
  .
  

  ✔ Patient 6 did not respond to any of the tested strains, while the titer of other efgartigimod-treated subjects (patients 3, 4, and 8) remained >40 (protection threshold), although efgartigimod-induced IgG reduction
  .
  
  

  ✔ Of the flu vaccine recipients, only 5 patients reported flu-like illness
  .
  
  On day 127 of the study, influenza was diagnosed, at which point total IgG levels had returned to baseline and influenzae titers were above the protective threshold
  for all strains except Bacillus Victoria.
  

Figure 3.
Seven patients with gMG were vaccinated with influenza vaccine during double-blind treatment or during ADAPT+ with their individual HI titer

• PCV13: Antibody response is obvious, and most strains maintain antibody titers above 350 ng/mL

  ✔ In addition to the flu vaccine, patients 6 randomly assigned in the ADAPT study received two doses of PCV13 according to the guidance of the treating physician: the first dose was during the efgartigimod treatment cycle and the second dose was during the no-treatment period
  .
  
  Patients have a clear antibody response to all 13 strains
  .
  
  After the start of another treatment cycle, antibody titers were reduced against some strains, but 8 of the 13 strains still maintained antibody titers above
  350 ng/mL.
  
  

➤ GMG patients receiving efgartigimod treatment will also not affect the immune response of T cell non-dependent vaccines

✔ Patient 12 was vaccinated with the PPSV23 vaccine
during the fourth dose of the treatment cycle.

Overall, even during the decrease in total IgG levels, the antibody titer of the strain under test increased
significantly from baseline.

(2) For pemphigus patients

➤ Pemphigus patients receiving efgartigimod treatment for a long time, the total IgG level and protective antibody titer decreased, but it can recover after stopping the drug, and the pathological antibody is suppressed for a longer time

✔ According to the results of the previous phase II trial of efgartigimod for pemphigus, 28 (90%) of the reported 5^{, 7}, 31 participants achieved disease control, and 14 of the 22 subjects in the cohorts 3 and 4 (64%) achieved complete clinical remission
.

At 34 weeks of efgartigimod treatment and 10 weeks of post-treatment follow-up, patients with pemphigus had a 49% decrease in serum total IgG levels after the first transfusion compared to the baseline median and a 66%
decrease in the median on the 29th day after 4 weeks of infusion.

✔ Serum anti-Dsg-1 and anti-Dsg-3 autoantibody levels are reduced by 50-60% as long as efgartigimod is given, anti-VZV and anti-PCP antibodies reach their lowest point between days 22 and 36, while anti-TT antibodies decline more slowly
.

✔ Patients use efgartigimod every two weeks, and the total IgG and protective antibody titers remain stable and inhibited
.

After the last infusion (day 238), a gradual return of total IgG and protective antibodies to baseline levels
was observed.

Pathogenic anti-Dsg autoantibodies show longer inhibition times
compared to total IgG and protective antibodies.

✔ 12 out of 15 patients had baseline anti-TT IgG titers > 0.
1 IU/mL
.

Except for two patients who showed a brief titer drop below 0.
1 IU/mL, the remaining 10 patients remained within
the range of protection throughout the study.

No clinical signs
of infection were observed at the time of maximum antibody suppression.

Figure 4.
In 15 patients treated with efgartigimod for 238 days (34 weeks), the mean percentage change in anti-VZV, anti-TT, anti-PCP, anti-Dsg1, anti-Dsg3, and total IgG antibodies compared to baseline

Conclusion of the study

➤ The FcRn antagonist efgartigimod did not impede the production of the IgG immune response, but did briefly reduce all specific IgG titers
.

➤ In pemphigus populations, reductions in TT, VZV, and PCP protective antibody titers were parallel to reductions in total IgG levels ^{by 6, 8-10}
.

Returning to normal levels after discontinuation of efgartigimod indicates no negative effects
on long-lived plasma cell (LLPC) responses.

➤ In ADAPT, efgartigimod is well tolerated, with most infections (reported in 46% of efgartigimod-treated patients and 37% of patients receiving placebo) mild to moderate ^severity6
.

➤ Analysis showed that gMG patients retained the vaccine's ability to stimulate the production of protective antibody titers when receiving efgartigimod treatment, regardless of the timing of vaccination or the type of vaccine
.

➤ Efgartigimod can more selectively target the immune system, lowering IgG levels without significant inhibition of T lymphocytes, B lymphocytes or other components necessary for the immune system to establish a significant immune ^response11
.

brief summary

All in all, in the patients analyzed, regardless of the vaccine and at what time of vaccination, receiving efgartigimod treatment did not impair the ability to
produce a new specific IgG response.

Although vaccine-specific IgG levels may decrease in proportion to total IgG levels after receiving efgartigimod treatment, in general, they remain above pre-vaccination levels and/or above protection thresholds
.

After treatment is stopped, total IgG levels return to baseline and protective antibody titers increase
.

These findings suggest that the FcRn antagonist efgartigimod does not prevent the production of IgG, has no effect on LLPC, and maintains levels of protective antibodies after vaccination even if efgartigimod minimizes total IgG levels
.

Therefore, from the existing research results, it can be seen that efgartigimod is a safe and effective therapy for the treatment of IgG-mediated autoimmune diseases such as gMG and pemphigus, and does not increase the patient's risk of infection, nor does it affect the titer of existing protective antibodies and the ability to
establish an immune response after vaccination.

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ZMCNNP20220923006 Expire Date 2023/09/23