Dermatomyositis and Polymyositis (DM/PM)

Aggarwal R, Marder G, Koontz DC, Nandkumar P, Qi Z, Oddis CV —Annals of the Rheumatic Diseases, 2018

Acthar Gel was studied in patients with refractory and active DM/PM who needed an alternative to glucocorticoids and/or conventional immunosuppressive agents¹

Study Design

Results

STUDY OBJECTIVE

An open-label, 24-week proof-of-concept study of 11 adults with refractory and active DM/PM^1,*

Refractory disease defined as:
- Failing an adequate glucocorticoid trial (≥2 months of high doses [0.75 to 1 mg/kg] or intolerance to such therapy) and/or ≥1 conventional immunosuppressive agent
Active disease defined as:
- Baseline Manual Muscle Testing (MMT-8) score ≤125/150 and ≥2 additional abnormal core set measures (CSMs), or
- DM with cutaneous 10-cm Visual Analogue Scale (VAS) score ≥3 cm on the Myositis Disease Activity Assessment Tool (MDAAT) and at least 3 other abnormal CSMs (excluding the MMT-8)
All patients received the same dose of Acthar Gel, 80 U twice weekly, for 24 weeks

*Ten of the 11 enrolled patients completed the study. One patient dropped out due to heart block unrelated to the study drug and was not included in the analysis, as he did not complete the minimum 8 weeks of the study drug required for outcome assessment as per study protocol.

Study Assessments

Primary Endpoint

Three of any of the 6 CSMs improved by ≥20%, with no more than 2 CSMs worsening by ≥25%, based on International Myositis Assessment & Clinical Studies Group (IMACS) definition of improvement (DOI)
- Worsening measure could not include the MMT
Primary endpoint was also separately evaluated on a subset of patients with severe muscle weakness (≤125/150 of MMT at baseline), as well as moderate to severe cutaneous DM rashes (≥2.5/10 of cutaneous VAS score at baseline)

Secondary Endpoints

Median change in 6 individual CSMs:
- MMT
- Physician global assessment of change (MD global)
- Health Assessment Questionnaire-Disability Index (HAQ-DI)
- Patient global
- Muscle enzyme
- Extra-muscular global
Median time to DOI from baseline
2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) myositis response criteria
Mean change in glucocorticoid dose at 24 weeks
Secondary safety and tolerability endpoints were measured by frequency and type of adverse and severe adverse events

Patient Characteristics

DM/PM patients had chronic and persistent disease activity and were previously treated with other regimens

Myositis	Mean age
6 patients with DM 4 patients with PM	49.2 years
Mean disease duration	Concomitant treatments (with baseline prednisone dose)^†
1.8 years	Prednisone Methotrexate Mycophenolate mofetil Hydroxychloroquine Azathioprine Tacrolimus

Myositis	Mean age	Mean disease duration	Concomitant treatments (with baseline prednisone dose)^†
6 patients with DM 4 patients with PM	49.2 years	1.8 years	Prednisone Methotrexate Mycophenolate mofetil Hydroxychloroquine Azathioprine Tacrolimus

^†Concomitant immunosuppressive agents or glucocorticoids were allowed as long as patients were on these therapies for ≥8 weeks (and ≥4 weeks for glucocorticoids) and on a stable dose for ≥4 weeks and ≥2 weeks, respectively, prior to the start of the trial. Not every patient was on the same concomitant treatments.

Study Limitations

Results are based on 10 patients who completed the study. This study may not be fully representative of outcomes in the overall patient population. Sample bias may exist, as this was an open-label study. All patients were on multiple therapies; therefore, the clinical outcomes may not be solely attributable to Acthar Gel. Acthar Gel has not been formally studied in combination with other treatments.

70% of patients (n=7) with myositis treated with Acthar Gel demonstrated clinically significant responses¹

Primary Endpoint

Seven out of 10 patients completing the study met the IMACS DOI by a median of 8 weeks (interquartile range=4 to 20 weeks) after treatment with Acthar Gel
DM and PM patients did not differ in their response to treatment

Clinical response over time in weeks in myositis patients treated with Acthar Gel

Secondary Endpoints

90% of patients (n=10) met the secondary outcome measure of minimal improvement using the new 2016 ACR/EULAR myositis response criteria, but 2 patients had significant worsening before the 24-week period
Median interquartile range total improvement score^‡ was 52.5 (30 to 65) at 24 weeks with 40%, 30%, and 20% of patients achieving minimal, moderate, and major improvement, respectively

^‡Metric derived from the 2016 ACR/EULAR myositis response criteria, which corresponds to magnitude of improvement.

Median changes in all CSMs for all 10 evaluated patients

	Start value	End value	Relative % change
MMT (all patients)	119 (106 to 131)	142.5 (132 to 150)	13.9% (6.6 to 19.8)
MMT (with muscle weakness)	116 (96 to 119)	139 (113 to 143)	19.3% (11.5 to 25.4)
Patient global	5 (4 to 7.5)	2.75 (1 to 5.5)	50% (25 to 60)
HAQ-DI	1.375 (1.125 to 1.375)	0.9375 (0.125 to 1)	5.6% (0 to 27.3)
Extra-muscular global (all patients)	2 (0.5 to 3.2)	0.2 (0 to 1.0)	83.2% (66.7 to 100)
Extra-muscular global (with moderate-to-severe skin rash)	3.5 (3 to 4)	0.2 (0 to 1.0)	86.4% (67.7 to 100)
Muscle enzyme	2.9 (1.5 to 5.8)	2.1 (1.3 to 4.7)	9.5% (-19 to 66)
MD global	5.3 (4.3 to 6.5)	1.1 (0.5 to 2)	81.5% (70.8 to 88.9)
	Absolute % change		P value
MMT (all patients)	10.7% (4.7 to 15.3)		.002
MMT (with muscle weakness)	15.3% (7.3 to 20)		.001
Patient global	22.5% (10 to 30)		.003
HAQ-DI	2% (0 to 13)		.098
Extra-muscular global (all patients)	10.7% (4.7 to 15.3)		.015
Extra-muscular global (with moderate-to-severe skin rash)	20% (19 to 40)		.01
Muscle enzyme	9.2% (-3.1 to 43.1)		.69
MD global	43% (15 to 50)		.001

	Start value	End value	Relative % change	Absolute % change	P value
MMT (all patients)	119 (106 to 131)	142.5 (132 to 150)	13.9% (6.6 to 19.8)	10.7% (4.7 to 15.3)	.002
MMT (with muscle weakness)	116 (96 to 119)	139 (113 to 143)	19.3% (11.5 to 25.4)	15.3% (7.3 to 20)	.001
Patient global	5 (4 to 7.5)	2.75 (1 to 5.5)	50% (25 to 60)	22.5% (10 to 30)	.003
HAQ-DI	1.375 (1.125 to 1.375)	0.9375 (0.125 to 1)	5.6% (0 to 27.3)	2% (0 to 13)	.098
Extra-muscular global (all patients)	2 (0.5 to 3.2)	0.2 (0 to 1.0)	83.2% (66.7 to 100)	10.7% (4.7 to 15.3)	.015
Extra-muscular global (with moderate-to-severe skin rash)	3.5 (3 to 4)	0.2 (0 to 1.0)	86.4% (67.7 to 100)	20% (19 to 40)	.01
Muscle enzyme	2.9 (1.5 to 5.8)	2.1 (1.3 to 4.7)	9.5% (-19 to 66)	9.2% (-3.1 to 43.1)	.69
MD global	5.3 (4.3 to 6.5)	1.1 (0.5 to 2)	81.5% (70.8 to 88.9)	43% (15 to 50)	.001

Start and end values for severe MMT, rash, and muscle enzyme were not reported.

All patients decreased prednisone doses by Week 24, with 50% (n=5) of patients discontinuing prednisone completely by Week 24

Prednisone dose reduction by patient

Prednisone dose chart in patients with myositis treated with Acthar Gel

Safety Findings

Many of the observed adverse events were similar to those seen with glucocorticoids. Other factors typically associated with high-steroid doses given for an extended period, such as significant weight gain, diabetes, or Cushingoid features, were not observed.

Summary of adverse events

Adverse events	n	Related to Acthar Gel^§	Severity
Serious adverse events
Herpes zoster	1	Yes	Moderate
Disseminated herpes zoster	1	Yes	Severe
Avascular necrosis^‖	1	Yes	Severe
Chest pain	1	Yes	Mild
Heart block^¶	1	No	Severe
Nonserious adverse events
Injection site bruising and rash	4	Yes	Mild
Diarrhea	1	Yes	Mild
Anxiety	1	Yes	Mild
Insomnia	2	Yes	Mild
Calcinosis	2	Yes	Moderate
Depression	1	Yes	Mild
Agitation	1	Yes	Mild
Herpes pneumonitis	1	Yes	Moderate
Sinus tachycardia	1	Yes	Moderate
High cholesterol	1	Yes	Mild
Hyperglycemia	3	Yes	Mild
Infection (sinusitis and upper respiratory tract infection)	2	Yes	Mild
Hypertension	2	Yes	Mild
Adverse events		Effect of Acthar	Resolution
Serious adverse events
Herpes zoster		None	Resolved
Disseminated herpes zoster		Interrupted	Resolved
Avascular necrosis^§		N/A	Resolved
Chest pain		None	Resolved
Heart block^‖		Withdrew	Resolved
Nonserious adverse events
Injection site bruising and rash		None	Resolved
Diarrhea		None	Resolved
Anxiety		None	Resolved
Insomnia		None	Resolved
Calcinosis		None	Continuing
Depression		None	Resolved
Agitation		None	Resolved
Herpes pneumonitis		Interrupted	Controlled
Sinus tachycardia		N/A	Resolved
High cholesterol		N/A	Resolved
Hyperglycemia		N/A	Controlled
Infection (sinusitis and upper respiratory tract infection)		None	Resolved
Hypertension		None	Controlled

Adverse events	n	Related to Acthar Gel^§	Severity	Effect of Acthar	Resolution
Serious adverse events
Herpes zoster	1	Yes	Moderate	None	Resolved
Disseminated herpes zoster	1	Yes	Severe	Interrupted	Resolved
Avascular necrosis^‖	1	Yes	Severe	N/A	Resolved
Chest pain	1	Yes	Mild	None	Resolved
Heart block^¶	1	No	Severe	Withdrew	Resolved
Nonserious adverse events
Injection site bruising and rash	4	Yes	Mild	None	Resolved
Diarrhea	1	Yes	Mild	None	Resolved
Anxiety	1	Yes	Mild	None	Resolved
Insomnia	2	Yes	Mild	None	Resolved
Calcinosis	2	Yes	Moderate	None	Continuing
Depression	1	Yes	Mild	None	Resolved
Agitation	1	Yes	Mild	None	Resolved
Herpes pneumonitis	1	Yes	Moderate	Interrupted	Controlled
Sinus tachycardia	1	Yes	Moderate	N/A	Resolved
High cholesterol	1	Yes	Mild	N/A	Resolved
Hyperglycemia	3	Yes	Mild	N/A	Controlled
Infection (sinusitis and upper respiratory tract infection)	2	Yes	Mild	None	Resolved
Hypertension	2	Yes	Mild	None	Controlled

^§In the opinion of the study's author.

^‖Total left hip arthroplasty.

^¶Transvenous pacemaker insertion.

NEXT: Retrospective Registry (Levine et al 2016)

References

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IMPORTANT SAFETY INFORMATION

Contraindications

Acthar should never be administered intravenously
Administration of live or live attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of Acthar
Acthar is contraindicated where congenital infections are suspected in infants
Acthar is contraindicated in patients with scleroderma, osteoporosis, systemic fungal infections, ocular herpes simplex, recent surgery, history of or the presence of a peptic ulcer, congestive heart failure, uncontrolled hypertension, primary adrenocortical insufficiency, adrenocortical hyperfunction, or sensitivity to proteins of porcine origin

INDICATIONS

Acthar^® Gel (repository corticotropin injection) is indicated for:

Treatment during an exacerbation or as maintenance therapy in selected cases of systemic lupus erythematosus
Treatment during an exacerbation or as maintenance therapy in selected cases of dermatomyositis (polymyositis)
Adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy); ankylosing spondylitis
Treatment of symptomatic sarcoidosis

Warnings and Precautions

The adverse effects of Acthar are related primarily to its steroidogenic effects
Acthar may increase susceptibility to new infection or reactivation of latent infections
Suppression of the hypothalamic-pituitary-adrenal (HPA) axis may occur following prolonged therapy with the potential for adrenal insufficiency after withdrawal of the medication. Adrenal insufficiency may be minimized by tapering of the dose when discontinuing treatment. During recovery of the adrenal gland patients should be protected from the stress (e.g. trauma or surgery) by the use of corticosteroids. Monitor patients for effects of HPA suppression after stopping treatment
Cushing’s syndrome may occur during therapy but generally resolves after therapy is stopped. Monitor patients for signs and symptoms
Acthar can cause elevation of blood pressure, salt and water retention, and hypokalemia. Blood pressure, sodium, and potassium levels may need to be monitored
Acthar often acts by masking symptoms of other diseases/disorders. Monitor patients carefully during and for a period following discontinuation of therapy
Acthar can cause GI bleeding and gastric ulcer. There is also an increased risk for perforation in patients with certain gastrointestinal disorders. Monitor for signs of bleeding
Acthar may be associated with central nervous system effects ranging from euphoria, insomnia, irritability, mood swings, personality changes, and severe depression to psychosis. Existing conditions may be aggravated
Patients with comorbid disease may have that disease worsened. Caution should be used when prescribing Acthar in patients with diabetes and myasthenia gravis
Prolonged use of Acthar may produce cataracts, glaucoma, and secondary ocular infections. Monitor for signs and symptoms
Acthar is immunogenic and prolonged administration of Acthar may increase the risk of hypersensitivity reactions. Neutralizing antibodies with chronic administration may lead to loss of endogenous ACTH activity
There is an enhanced effect in patients with hypothyroidism and in those with cirrhosis of the liver
Long-term use may have negative effects on growth and physical development in children. Monitor pediatric patients
Decrease in bone density may occur. Bone density should be monitored for patients on long-term therapy
Pregnancy Class C: Acthar has been shown to have an embryocidal effect and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus

Adverse Reactions

Common adverse reactions for Acthar are similar to those of corticosteroids and include fluid retention, alteration in glucose tolerance, elevation in blood pressure, behavioral and mood changes, increased appetite, and weight gain
Specific adverse reactions reported in IS clinical trials in infants and children under 2 years of age included: infection, hypertension, irritability, Cushingoid symptoms, constipation, diarrhea, vomiting, pyrexia, weight gain, increased appetite, decreased appetite, nasal congestion, acne, rash, and cardiac hypertrophy. Convulsions were also reported, but these may actually be occurring because some IS patients progress to other forms of seizures and IS sometimes masks other seizures, which become visible once the clinical spasms from IS resolve

Other adverse events reported are included in the full Prescribing Information.

Please see full Prescribing Information for additional Important Safety Information.

Acthar Gel was studied in patients with refractory and active DM/PM who needed an alternative to glucocorticoids and/or conventional immunosuppressive agents1

STUDY OBJECTIVE

An open-label, 24-week proof-of-concept study of 11 adults with refractory and active DM/PM1,*

Study Assessments

Primary Endpoint

Secondary Endpoints

Patient Characteristics

Study Limitations

70% of patients (n=7) with myositis treated with Acthar Gel demonstrated clinically significant responses1

Primary Endpoint

Secondary Endpoints

Median changes in all CSMs for all 10 evaluated patients

All patients decreased prednisone doses by Week 24, with 50% (n=5) of patients discontinuing prednisone completely by Week 24

Safety Findings

Summary of adverse events

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IMPORTANT SAFETY INFORMATION

Contraindications

INDICATIONS

IMPORTANT SAFETY INFORMATION

Contraindications

INDICATIONS

Warnings and Precautions

Adverse Reactions

Acthar Gel was studied in patients with refractory and active DM/PM who needed an alternative to glucocorticoids and/or conventional immunosuppressive agents¹

An open-label, 24-week proof-of-concept study of 11 adults with refractory and active DM/PM^1,*

70% of patients (n=7) with myositis treated with Acthar Gel demonstrated clinically significant responses¹