Drug trial

1. Journal Club
Dr. Vaibhav Kr Somvanshi
SR Neurology
GMC, Kota

2. Safety, efficacy, and tolerability of EFGARTIGIMOD in patients
with generalised myasthenia gravis (ADAPT): a multicentre,
randomised, placebo-controlled, phase 3 trial
James F Howard Jr, Vera Bril, Tuan Vu, Chafic Karam, Stojan Peric, Temur Margania, Hiroyuki Murai, Malgorzata
Bilinska, Roman Shakarishvili, Marek Smilowski, Antonio Guglietta, Peter Ulrichts, Tony Vangeneugden, Kimiaki
Utsugisawa, Jan Verschuuren, Renato Mantegazza, and the ADAPT Investigator Study Group*

3. Introduction
• 85% pts generalised MG have IgG autoantibodies, directed against
nicotinic AchR and (MUSK) and (LRP4)
• Most AchR and LRP4 antibodies are of the IgG1 subtype, which can
activate complement but MUSK antibodies can’t - IgG4 subtype
• Efgartigimod (ARGX113) is a human IgG1 antibody Fcfragment, a
natural ligand of FcRn, that has been engineered for increased affinity
to FcRn compared with endogenous IgG

4. ADAPT trial

5. Need for study
• Therapeutic plasma exchange shown the effect of IgG reduction, but
no previous pharmacological approaches to achieving such a targeted
reduction in IgG.
• Some neonatal Fc receptor antagonists completed preclinical and
early-phase studies, but no phase 3 studies in generalised myasthenia
gravis.
• Treatment options available are - burdensome, have substantial side-
effects, do not alleviate symptoms, or are reserved for refractory
patients.

6. Methodology
Inclusion criteria
• Age > 18 years Generalised Myasthenia gravis regardless of AChR ab status
• Myasthenia Gravis Foundation of America class II to IV and they had a Myasthenia Gravis Activities
of Daily Living (MGADL) score of at least 5 (with >50% of the MGADL score due to nonocular
symptoms)
• Patients to be on a stable dose of at least one treatment for generalised myasthenia gravis (ie,
acetylcholinesterase inhibitors, corticosteroids, or NSISTs) before screening and through out the trial
Exclusion criteria
• Patients received rituximab or eculizumab in the 6 months before screening,
• undergone thymectomy within 3 months,
• had IVIG or plasma exchange within 1 month of screening,
• active hepatitis B, hepatitis C, seropositive for HIV with low CD4 count, had serum IgG levels less
than 6 g/L at screening, or were pregnant.

7. Myasthenia
Gravis
Foundation of
America

8. MGADL score

9. QMG score

10. Methodology
• Multicentre, randomised, double-blind, placebo-controlled, phase 3
trial done at 56 neuromuscular academic and community centres in
15 countries in North America, Europe, and Japan
• 2 groups
EF group – 10mg/kg four infusions per cycle (one infusion per week)
Placebo group – Placebo infusion similar fashion for 26 week
• 3 cycles over 26 weeks with observation period of 5 weeks after each
cycle.

11. Methodology - Outcome
Primary
• Proportion of AchR ab positive patients who were MGADL responders
in the first treatment cycle.

12. Methodology - Outcome
Secondary
• proportion of QMG responders (defined as a ≥3 point improvement)
• percentage of MGADL responders in cycle 1
• proportion of MGADL responders in the acetylcholine receptor
antibody positive population, up to day 126.

13. Methodology - Statistical analysis
• Two sided exact test using a logistic regression model used for both
primary and secondary outcome measure
• Power of study – 90%
• Alpha level – 0.05
• Drop out rate – 10%
• Sample size – 216 with 84 in EF group & 83 in placebo.
• Statistical analyses were done using SAS, version 9.2 or higher, and
the software package R

14. Methodology - Statistical analysis
• Main analysis - Comparison of primary outcome between two trial
group at the end of first treatment cycle.
Secondary outcome analysed using an ANCOVA model
Intention to treat analysis.
Time from day 28 to not having clinically meaningful improvement in
the acetylcholine receptor antibody positive population was
estimated using Kaplan Meier time to event analysis.

15. Methodology
Enrolment &
randomisation

16. Baseline
Demographic and
clinical
characteristics of
patients

17. Results

18. Primary Outcome
• Efgartigimod group [68%] were MGADL responders in cycle 1 (primary
endpoint) than in the placebo group [30%] p<0·0001;.
• efgartigimod group [63%] were QMG responders in cycle 1 than in the
placebo group [14%].

19. Primary Outcome

20. Secondary outcome
• Among cycle 1 MGADL responders, the duration of responder status
• 6–7 weeks - 14 (32%)
• 8–11 weeks- 10(23%)
• ≥12 weeks - 15 (34%) patients
• In patients who received a second cycle, efgartigimod group [71%]
were MGADL responders compared with the placebo group [26%].
• posthoc analysis of AchR ab negative patients assessed both MGADL
and QMG responders in cycle 1 - (47%) in efgartigimod group and
(21%) in placebo group.

21. Adverse events

22. Secondary outcome

23. Positives of the study
• Duration for drug to produce disease modifying effect was sufficient,
( previous studies – 26-40 weeks)
• 3 cycles – Ideal method to prove the effect of drug.
• Study enrolled a broad population of patients with generalised
myasthenia gravis, including both antibody positive and negative
patients, with no requirement for patients to have had specific
myasthenia gravis medication
Heckmann, J.M., Rawoot, A., Bateman, K. et al. A single-blinded trial of methotrexate versus azathioprine as steroid-sparing agents in generalized myasthenia gravis. BMC Neurol 11, 97 (2011).
https://doi.org/10.1186/1471-2377-11-97

24. Positives of the study
• efgartigimod administered in treatment cycles, with the frequency of
cycles defined by the duration of clinical effect in each patient.
individualised approach proved effective, with reproducible efficacy
after a second and third cycle.
• Strengths of this study - randomised placebo controlled design, using
validated scales incorporating physician and patient assessment, and
combination of clinically meaningful improvement and sustained
effect.
A randomized double‐blind trial of prednisolone alone or with azathioprine in myasthenia gravis J. Palace, J. Newsom-Davis, B. Lecky, Myasthenia Gravis Study Group Neurology Jun
1998, 50 (6) 1778-1783; DOI: 10.1212/WNL.50.6.1778

25. Positives of the study
• Strength of ADAPT trial is that the study included patients with
MUSK-positive myasthenia gravis, although the number of
participants was small.
• Rituximab is recommended as an early therapeutic option -> MUSK-
positive disease who have an unsatisfactory response to initial
immunotherapy.
• Further study is necessary to compare efficacy between rituximab
and efgartigimod for patients with MUSK-positive myasthenia gravis.
Narayanaswami P, Sanders DB, Wolfe G, et al. International consensus guidance for management of myasthenia gravis: 2020 Update. Neurology 2021; 96: 114–22.

26. Limitation of study
• Demographic distribution was not equal in study.
• only a few of AchR ab negative patients patients were recruited, and
the trial was not statistically powered to assess efficacy in this
population.
• 2 more arm of Steroid and NSIST alone could have been added.
Future studies can be planned including these points.

27. Oyama M, Okada K, Masuda M, et al. Suitable indications of eculizumab for patients with refractory generalized myasthenia gravis. Ther Adv Neurol Disord 2020; 13:
1756286420904207
Comparision with other Trial
• Comparing the ADAPT trial (efgartigimod) with the phase 3 REGAIN trial
(eculizumab)  both trials were similar in scale and in terms of the
baseline demographics of participants.
• Primary outcome (REGAIN trial ) change in the MG-ADL score from
baseline to week 26 was not significantly different between the eculizumab
and placebo groups (p=0·07).
• REGAIN trial (88%) patients achieved an improved status and (57%) of
patients achieved a minimal manifestations status after 130 weeks of
eculizumab treatment.
• eculizumab was effective both in patients with myasthenic crisis and in
those with thymoma-associated myasthenia gravis

28. Conclusion
• Three promising biological drugs are now used for refractory
myasthenia gravis - rituximab, eculizumab, efgartigimod
• Treatment with efgartigimod at a dose of 10mg/kg infusion 1/week
for 4 weeks in combination with baseline anti-myasthenia
medications had Morbidity decreasing effect as ADL in MG among
patients who were evaluated over the course of 28 weeks.
• Efgartigimod triggers ↓ total IgG levels,  considerable risks of
infection  Specific attention to infection risk is required for patients
with myasthenia gravis.

29. Implications
• Whether to start efgartigimod infusion in population other than
whites needs to decided on basis of wider population based RCT .
• As of now novel mechanism of selective IgG reduction through
blocking of FcRn with efgartigimod can be considered as treatment
for patients with generalised myasthenia gravis.
• Efficacy both in patients with myasthenic crisis and in those with
thymoma-associated myasthenia gravis should be assessed in future
studies

31. Introduction
• Alteplase has low fibrinolytic efficacyarterial recanalisation in less
than 50% patients.
• Therefore, the development of an alternative, more effective, and
safer thrombolytic therapy is necessary.
• Staphylokinase was first isolated by Lack in 1948.
• Amino acid substitutions—including Lys74Ala, Glu75Ala, and
Arg77Ala—resulted in a more than 200-times reduction in titres of
neutralising antistaphylokinase IgGs

32. FRIDA trial

33. Need for the study
• Alteplase has somewhat low recanalisation rates and an increased
risk of bleeding.
• Rapid single bolus administration with more efficacy and low adverse
event medicine is need of hour to save minutes for brain.

34. Methodology
• Study type
Randomised, open-label, multicentre, parallel-group, non-inferiority
experimental trial
• Inclusion criteria
Men and women aged 18 years and older
Verified diagnosis of ischemic stroke
The time from the onset of the disease is no more than 4.5 hours.
Informed consent received

35. Methodology
• Exclusion Criteria
time of the onset of the first symptoms of a stroke is not known
Simultaneous reception of oral anticoagulants
Prior stroke or severe head injury within 3 months.
Neoplasms with an increased risk of bleeding.
Aneurysms of arteries, malformations of arteries and veins
Large operations or severe injuries within the last 14 days
Blood glucose less than 2.7 mmol / l or more than 22.0 mmol / l
Pregnancy, obstetrics, 10 days after birth.

36. Methodology
• Primary Outcome-
 Good functional recovery on the 90th day (modified Rankin scale, 0-1 point).
• Secondary Outcome-
 Modified Rankin scale (0-1) + NIHSS (0-1) + Barthel (95-100) - 90 days after fibrinolysis
• Additional Secondary Outcome-
• NIHSS at 24 hours,
• Safety End Points-
• Mortality at 90 days
• Symptomatic hemorrhagic transformation
• Serious Adverse event

37. Methodology
• Categorical data – odds ratio, two-sided Fisher’s exact test
• Continuous data – Mann-Whitney U test
• Non – inferiority hypothesis tested by – Welch’s t- test
• P < 0.05 was considered significant.

38. Methodology
• 2 groups
Staphylokinase group – 10mg/kg i.v bolus for 10 sec
Alteplase group – 0·9 mg/kg; maximum dose 90 mg) was
administered as an intravenous bolus of 10% of the total dose for 1–2
min and the remaining dose by continuous intravenous infusion
within 60 min.
Patients were assessed by study investigators at the time of
enrolment and 1–24 h, 2 days, 7 days, 14 days, and 90 days after drug
administration.

39. Methodology - Statistical analysis
• Sample size calculation was based on findings of the Safe
Implementation of Thrombolysis in Stroke- MOnitoring STudy (SITS-
MOST) study done to confirm the safety and efficacy of alteplase
• Power of study – 80%
• Alpha level – 0.05
• Drop out rate – 0%
• non-inferiority margin - 16%
• Sample size – 336 with 168 in Each group.
• Statistical analyses were done using SAS, version 9.2 or higher, and
the software package R

40. Methodology - Statistical analysis
• Main analysis - Comparison of primary outcome between two trial
group at the end 90 days.
Drug use and the reduction of mRS score association investigated
using  ordinal logistic regression model
Intention to treat analysis used with per protocol analysis to give
strength to study.

41. Methodology
Enrolment &
randomisation

42. Baseline
Demographic and
clinical
characteristics of
patients

43. Results

44. Primary Outcome
• In the non-immunogenic staphylokinase group, 84 (50%) patients had
an mRS score of 0–1 compared with 68 (41%) patients in the alteplase
group (OR 1·47, 95% CI 0·93 to 2·32; p=0·10)

45. Primary Outcome

46. Secondary outcome
• Secondary endpoint met in (35%) patients in staphylokinase group
and (31%) patients in the alteplase group
• Additional secondary endpoint of the NIHSS score after 24 h median 6
in both the groups
• Post-hoc outcome of an mRS score of 0–2 on day 90  (68%) in
staphylokinase group and (63%) in the alteplase group

47. Safety outcome
• (10%) staphylokinase group and (14%) in the alteplase group had died
by day 90.
• (19%) staphylokinase group and (17%) in the alteplase group had
intracranial haemorrhage.
• Symptomatic intracranial haemorrhage occurred in (3%) in
staphylokinase group and (8%) in alteplase group.
• Serious adverse events (13%) in staphylokinase group (22%) in the
alteplase group.

48. Adverse events

49. Positives of the study
• FRIDA was indentical in trial design to the historical trials of alteplase
versus placebo in patients with acute ischaemic stroke, which met the
so-called constancy assumption
• FRIDA study is first to report use of non-immunogenic staphylokinase
in patients with acute ischaemic stroke
Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4·5 hours after acute ischemic stroke. N Engl J Med 2008; 359: 1317–29.

50. Positives of the study
• Incidence of symptomatic intracranial haemorrhage in the non-
immunogenic staphylokinase group was similar to that in the
alteplase group in ECASS III trial
• alteplase was administered as weight-dependent doses (0·9 mg/kg),
even in patients weighing more than 100 kg, who received the
maximum dose of alteplase of 90 mg. In the ECASS patients weighing
more than 100 kg were not included.
Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. JAMA 1995; 274: 1017–25.

51. Limitation of study
• Main limitation is the 16% non-inferiority margin
• more typical non-inferiority threshold of a 5% difference would have
required a sample size nearly ten times larger than the trial now reported
• manufacturer of the non-immunogenic staphylokinase was involved in
study design, data collection, data analysis, data interpretation, and
reporting of the trial
• aspects of trial methodology were suboptimal. For example, treatment
allocation was by numbered sealed envelopes in individual centres, and the
random allocation was known to the treating clinician.
• 8% rate of symptomatic intracranial haemorrhage (the main risk of throm-
bolysis) in the alteplase group was higher than in other studies.
Yaghi S, Eisenberger A, Willey JZ. Symptomatic intracerebral hemorrhage in acute ischemic stroke after thrombolysis with intravenous recombinant tissue plasminogen activator: a review of
natural history and treatment. JAMA Neurol 2014; 71: 1181–85.

52. Conclusion
• Treatment with non-immunogenic staphylokinase within 4·5 h after
onset of symptoms was found to be non-inferior to alteplase in
patients with acute ischaemic stroke with comparable outcome at 90
days with alteplase.

53. Implications
• Single bolus IV drug will help to curtail morbidity and mortality with
rapid and easy administration even in mobile stroke unit.
• Other thrombolytic drugs still under investigation include
tenecteplase, which has a higher fibrin specificity than alteplase, and
desmoteplase, which is a fibrin-specific recombinant plasminogen
activator.
• Larger Future studies with low non inferiority margin will further
strengthen the evidence.