Retrospective case series of Acthar treatment for proteinuria in 44 patients with various etiologies of nephrotic syndrome

Largest-to-date Acthar clinical experience in a majority of patients who received previous therapies

Results are based on a retrospective case series of 44 patients and may not be fully representative of outcomes in the overall patient population. Most patients were on multiple therapies. The clinical outcomes may not be solely attributable to Acthar. Of the 44 patients, 37 completed treatment and 7 terminated early.1,2

Madan et al, 2016

Presentation of study design, baseline characteristics, efficacy, and safety findings are based on content from Madan et al, 2016, where proteinuria reduction was evaluated as a treatment outcome. Impact on renal function as part of the outcome definition was not reported for the entire population.

A post hoc analysis was then conducted by Mallinckrodt that assessed treatment response to Acthar based on a compound primary outcome measure that included both reduction in proteinuria and stable or improved renal function (creatinine 125% of baseline or eGFR 75% of baseline). This compound outcome measure aligns with the KDIGO (Kidney Disease: Improving Global Outcomes) guidelines recommendations for assessing treatment response to nephrotic syndrome therapy.

The original research was performed under a grant from Mallinckrodt. The post hoc analysis, using the compound outcome measure for response, was reviewed and approved by the primary and senior authors of the original paper. All data needed to perform the analysis were presented in the original paper.

Review Results

Overview1

A multicenter retrospective review of 44 patients with various nephrotic syndrome (NS) etiologies examined the efficacy and safety of Acthar for the reduction of proteinuria. The majority (30/44) had received ≥1 previous cytotoxic or immunosuppressive therapy. The remaining 14 patients were treatment naïve.

Patients ≥18 years diagnosed with NS received Acthar treatment for ≥6 months and had an assessment of either 24-hour proteinuria level (mg/d) or UPCR (g/g converted to mg/d) prior to and following 6 months of Acthar therapy. Patients did not have to meet a prespecified level of proteinuria at baseline to be included in the study.

Cases included 44 patients across the following NS etiologies:

*Individual results of the 4 patients with DN are not included in this presentation. Acthar is not indicated to reduce proteinuria associated with DN.

Design1

*One patient with iMN was treated with Acthar 40 IU.

Patients were prescribed Acthar for a minimum of 24 weeks; actual treatment durations varied.

Acthar dosing regimen and concomitant medications, including angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, and immunosuppressive and cytotoxic drugs, were documented.

Dosing of Acthar (as stated in Prescribing Information): Dosage and frequency of Acthar should be individualized according to the medical condition, severity of the disease, and initial response of the patient.

  • The usual dose of Acthar is 40 to 80 units given intramuscularly or subcutaneously every 24 to 72 hours

Outcome Measures1

Outcome measures evaluated in the case series included:

  • Responses that were defined as:
    • Complete Remission (CR): stable or improved renal function (serum creatinine that did not worsen >25% from baseline) and final proteinuria <500 mg/d
    • Partial Remission (PR): stable or improved renal function (serum creatinine that did not worsen >25% from baseline) with ≥50% reduction in proteinuria from baseline and final proteinuria 500-3500 mg/d
    • Clinical Response (CL): ≥30% reduction in proteinuria from baseline that did not meet CR or PR criteria
    • No Response (NR): patients showing no response failed to meet remission or CL criteria
  • Frequency of adverse events and early discontinuation due to adverse events

Additional laboratory measures included change in serum creatinine, albumin, and total cholesterol if data were available.

Patient Baseline Characteristics1

Among the 44 patients, the majority (30/44; 68.2%) had received ≥1 prior immunosuppressive or cytotoxic therapy and 20 of 44 (45.5%) had received ≥2 prior immunosuppressive and/or cytotoxic treatments.

IST=immunosuppressive therapy. CT=cytotoxic therapy.

Characteristics of patients by NS etiology group

Over half of patients (26/44; 59.1%) showed impaired renal function prior to Acthar treatment.

*Values based on patients for whom data were available.

Median proteinuria adapted from reported proteinuria values given for each patient.

Study Limitations1,2

Results are based on a retrospective case series of 44 patients and may not be fully representative of outcomes in the overall patient population. While this review includes a diverse set of NS etiologies, a significant limitation is small patient numbers in several of the etiology subgroups and a retrospective design without a control group. Because initiation of treatment was based on the judgment of the treating clinician, excluding the IgAN group, 8 patients began treatment at a non-nephrotic proteinuria level <3500 mg/d. Most patients were on multiple therapies. The clinical outcomes may not be solely attributable to Acthar. Longer treatment duration and follow-up may be needed for meaningful treatment responses. The relapse rate following successful treatment with Acthar is not yet known.

Results1

There was significant proteinuria reduction from baseline to post-Acthar treatment for patients with pre- and post-Acthar proteinuria values (n=40; mean reduction 3984.8±4069.1 mg/d, P<0.0001).*

*Of the 44 patients, 4 patients did not have follow-up proteinuria values.

Response rates from the 37 of 44 patients who completed Acthar treatment

Results are based on a retrospective case series of 44 patients and may not be fully representative of outcomes in the overall patient population. Most patients were on multiple therapies. The clinical outcomes may not be solely attributable to Acthar. Of the 44 patients, 37 completed treatment and 7 terminated early.1,2

Outcome Measures

Treatment outcome definitions from Madan et al, 2016 publication1

Complete Remission=stable or improved renal function (serum creatinine that did not worsen >25% from baseline) and final proteinuria <500 mg/d. Partial Remission=stable or improved renal function (serum creatinine that did not worsen >25% from baseline) with ≥50% reduction in proteinuria from baseline and final proteinuria 500–3500 mg/d. Clinical Response=≥30% reduction in proteinuria from baseline that did not meet complete or partial remission criteria.

Treatment outcome definitions from the post hoc analysis2

A post hoc analysis assessed treatment response to Acthar based on a compound primary outcome measure that included both reduction in proteinuria and stable or improved renal function (creatinine ≤125% of baseline or eGFR ≥75% of baseline).

Treatment response rates across multiple etiologies of NS

Adapted from Madan et al, 2016. Figure reports results for all patients (n=40). Results from 4 patients with DN are not included. Acthar is not indicated to reduce proteinuria associated with DN. Other includes 1 patient with MPGN, 1 patient with FGN, and 3 patients with unbiopsied NS.

*Complete Remission=stable or improved renal function (serum creatinine that did not worsen >25% from baseline) and final proteinuria <500 mg/d. Partial Remission=stable or improved renal function (serum creatinine that did not worsen >25% from baseline) with ≥50% reduction in proteinuria from baseline and final proteinuria 500–3500 mg/d. Clinical Response=≥30% reduction in proteinuria from baseline that did not meet complete or partial remission criteria. No Response=patients showing no response failed to meet remission or clinical response criteria.1

Includes patient who terminated early but had post-Acthar proteinuria assessment.

Includes patients who terminated early and did not have post-Acthar proteinuria assessment.

Adapted from Madan et al, 2016. Figure reports results for all patients (n=40). Results from 4 patients with DN are not included. Acthar is not indicated to reduce proteinuria associated with DN. Other includes 1 patient with MPGN, 1 patient with FGN, and 3 patients with unbiopsied NS.

§Complete remission, partial remission, and clinical response included both proteinuria reduction, as defined by Madan et al, and stable or improved renal function (serum creatinine that did not worsen >25% from baseline).2

Results are based on a retrospective case series of 44 patients and may not be fully representative of outcomes in the overall patient population. Most patients were on multiple therapies. The clinical outcomes may not be solely attributable to Acthar.1,2

Changes in proteinuria levels from baseline across multiple etiologies of NS*1

Adapted from Madan et al, 2016

*Figure includes all patients with post-Acthar proteinuria values, with the exception of 4 patients with DN (n=36).

Includes a patient who terminated early but had post-Acthar proteinuria assessment.

Safety Findings1

Adverse events during Acthar treatment were reported by 30% (13/44) of patients, and 16% (7/44) had early termination due to treatment-related adverse events. These results are summarized below.

Individual FSGS Patient Results1

60% (9/15) of patients with FSGS achieved Partial Remission based on proteinuria reduction1

47% (7/15) of patients with FSGS achieved Partial Remission based on proteinuria reduction and stable or improved renal function2

*Complete Remission=stable or improved renal function (serum creatinine that did not worsen >25% from baseline) and final proteinuria <500 mg/d. Partial Remission=stable or improved renal function (serum creatinine that did not worsen >25% from baseline) with ≥50% reduction in proteinuria from baseline and final proteinuria 500–3500 mg/d. Clinical Response=≥30% reduction in proteinuria from baseline that did not meet complete or partial remission criteria. No Response=patients showing no response failed to meet remission or clinical response criteria.1

Complete remission, partial remission, and clinical response included both proteinuria reduction, as defined by Madan et al, and stable or improved renal function (serum creatinine that did not worsen >25% from baseline).2

Patient demonstrated Partial Remission before terminating treatment early.

Individual iMN Patient Results1

55% (6/11) of patients with iMN achieved Complete or Partial Remission based on proteinuria reduction1

55% (6/11) of patients with iMN achieved Complete or Partial Remission based on proteinuria reduction and stable or improved renal function2

CR=Complete Remission.

PR=Partial Remission.

CL=Clinical Response.

NR=No Response.

X=Early Termination.

*Complete Remission=stable or improved renal function (serum creatinine that did not worsen >25% from baseline) and final proteinuria <500 mg/d. Partial Remission=stable or improved renal function (serum creatinine that did not worsen >25% from baseline) with ≥50% reduction in proteinuria from baseline and final proteinuria 500–3500 mg/d. Clinical Response=≥30% reduction in proteinuria from baseline that did not meet complete or partial remission criteria. No Response=patients showing no response failed to meet remission or clinical response criteria.1

Complete remission, partial remission, and clinical response included both proteinuria reduction, as defined by Madan et al, and stable or improved renal function (serum creatinine that did not worsen >25% from baseline).2

Acthar is indicated to reduce proteinuria of nephrotic syndrome. The impact of Acthar on other relevant lab values has not been more formally assessed and is included here for clinical context only.

Results are based on a retrospective case series of 44 patients and may not be fully representative of outcomes in the overall patient population. Most patients were on multiple therapies. The clinical outcomes may not be solely attributable to Acthar.1,2

Individual Patient Results for IgAN and Other Etiologies1

CR=Complete Remission.

PR=Partial Remission.

CL=Clinical Response.

NR=No Response.

X=Early Termination.

*Complete Remission=stable or improved renal function (serum creatinine that did not worsen >25% from baseline) and final proteinuria <500 mg/d. Partial Remission=stable or improved renal function (serum creatinine that did not worsen >25% from baseline) with ≥50% reduction in proteinuria from baseline and final proteinuria 500–3500 mg/d. Clinical Response=≥30% reduction in proteinuria from baseline that did not meet complete or partial remission criteria. No Response=patients showing no response failed to meet remission or clinical response criteria.1

Complete remission, partial remission, and clinical response included both proteinuria reduction, as defined by Madan et al, and stable or improved renal function (serum creatinine that did not worsen >25% from baseline).2

Patient demonstrated Partial Remission before terminating treatment early.

Acthar is indicated to reduce proteinuria of nephrotic syndrome. The impact of Acthar on other relevant lab values has not been more formally assessed and is included here for clinical context only.

Results are based on a retrospective case series of 44 patients and may not be fully representative of outcomes in the overall patient population. Most patients were on multiple therapies. The clinical outcomes may not be solely attributable to Acthar.1,2

Acthar is used to induce a diuresis or a remission of proteinuria in nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus.

Important Safety Information

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Contraindications

  • Acthar should never be administered intravenously
  • Administration of live or live attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of Acthar

Important Safety Information

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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 origins

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-axis (HPA) 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, and 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 mask 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.

Indication

H.P. Acthar® Gel (repository corticotropin injection) is indicated to induce a diuresis or a remission of proteinuria in nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus.

References