Data on Use of Mallinckrodt's H.P. Acthar® Gel (Repository Corticotropin Injection) in Patients with Rare Cause of Nephrotic Syndrome Published in Transplantation

STAINES-UPON-THAMES, United Kingdom, Jan. 3, 2019 /PRNewswire/ -- Mallinckrodt plc (NYSE: MNK), a leading global specialty pharmaceutical company, today announced publication of a retrospective analysis assessing the efficacy of H.P. Acthar^® Gel (repository corticotropin injection) in kidney transplant recipients with treatment-resistant focal segmental glomerular sclerosis (FSGS). FSGS is a rare disease that can cause nephrotic syndrome, a serious kidney disorder that may raise the risk of progression to end stage renal disease (ESRD).[2] Results from the analysis, which included data from patients treated at two large U.S. transplant centers between April 2012 and December 2016, were published in the January issue of Transplantation.

"This is the first study of H.P Acthar Gel treatment in renal transplant patients who were previously treated with conventional therapy for FSGS, a rare and serious kidney disease with few available treatments," said Steven Romano, M.D., Executive Vice President and Chief Scientific Officer at Mallinckrodt. "We are pleased to share these valuable insights to better understand the potential applications of Acthar in treating patients who develop FSGS after their kidney transplant."

H.P. Acthar Gel is U.S. Food and Drug Administration (FDA)-approved to induce a diuresis or a remission of proteinuria (excess protein in the urine) in nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus. Clinical experience has shown reduction in proteinuria in multiple glomerular nephropathies, including FSGS.[3]

H.P. Acthar Gel in Resistant Focal Segmental Glomerulosclerosis after Kidney Transplantation[1]  
This retrospective study evaluated 20 kidney transplant patients (mean age of 49 years; range 22-80 years) who received H.P. Acthar Gel for the treatment of proteinuria due to new or recurrent post-transplant FSGS. Subjects had previously received conventional FSGS treatment with therapeutic plasma exchange (TPE) and/or rituximab and developed FSGS approximately three months after their transplant (median interquartile range [IQR] of three months; range 0.75-7.5 months).

• Forty percent of patients (8/20) received rituximab within 24 hours of the transplant surgery and twenty percent (4/20) received TPE before transplantation.
• Seventy-five percent of patients (15/20) were treated with TPE at the time of post-transplant FSGS; 50 percent (10/20) received rituximab as well which was started before the use of H.P Acthar Gel.
• Eighty percent (16/20) were treated with TPE and/or rituximab prior to initiating H.P. Acthar Gel therapy.
• All 20 patients in the study received thymoglobulin induction therapy (an immunosuppressive used in kidney transplantation).
• All patients were maintained on triple immunosuppression antirejection therapy of a calcineurin inhibitor (CNI), mycophenolate mofetil and prednisone. Tacrolimus (CNI) was used in 85 percent (17/20) of patients and cyclosporine (CNI) in 15 percent (3/20). One patient (5 percent) was switched from a CNI to belatacept because of CNI nephrotoxicity.

Subjects took H.P. Acthar Gel twice a week for approximately six months (median IQR of 24 weeks; range 8-32 weeks) and were evaluated for treatment response using the urine protein to creatinine ratio to determine complete or partial remission of proteinuria. Complete remission (CR) was defined as a decrease of proteinuria ≤1g/g with stable kidney function (creatinine within 30 percent from baseline after H.P. Acthar Gel treatment), and partial remission (PR) was defined as a decrease of proteinuria between 1 and ≤3.5 g/g with stable kidney function (creatinine within 30 percent from baseline after H.P. Acthar Gel treatment).

Key Findings

• The analysis found significant improvement in proteinuria after treatment with H.P. Acthar Gel from a mean ± Standard Deviation (SD) of 8.6 ± 7.6 g/g at baseline to a mean± SD of 3.3 ± 2.3 g/g at about six months (P=0.004).
• Fifty percent of patients (10/20) who received H.P. Acthar Gel had a complete or partial remission of proteinuria (four patients achieved CR and six patients achieved PR).
• The use of H.P. Acthar Gel did not significantly change mean serum creatinine levels (3.3 ± 2.7 vs. 2.8 ± 1.67 mg/dL, P=0.42) or estimated glomerular filtration rate (eGFR) (30.7 ± 19.3 vs. 34.4 ± 20 mL/min/1.73 m2, P=0.56).
• Three patients died, one during treatment and two in the post-treatment follow-up period.

Additional Observations

• During the observation period, 40 percent (8/20) of patients had transplant failure, with five cases attributed to new or recurring FSGS, while 60 percent of patients (12/20) reported no transplant failure.
• The analysis also assessed if patients on TPE (10/20) could discontinue therapy. Six patients were weaned off TPE. The remaining four were reported to require TPE less frequently.

Study Limitations

• This was a retrospective study with no control group.
• Not all patients were treated similarly; this included some subjects who received initial prophylactic TPE or rituximab as a preventative measure at their treatment center.
• A variety of factors may have influenced the improvement in proteinuria including TPE given with H.P. Acthar Gel.

The analysis was supported, in part, through the Mallinckrodt Investigator-Initiated Research program.

"The incidence of recurrent FSGS after kidney transplant has been reported between 20 percent to 50 percent but may exceed 80 percent in patients with a history of transplant failure from a prior FSGS recurrence. Further, transplant recipients with recurrent FSGS are two to five times more likely to have transplant loss compared to those with no recurrence. The goal of treatment is to reduce patients' disease activity or, ideally, achieve remission, but there are no real standards of care and challenges exist with current approaches," said Tarek Alhamad, MD, MS, FACP, FASN, Assistant Professor of Medicine, Medical Director of Transplant Nephrology at the Washington University School of Medicine in St. Louis, and the study's lead author. "This retrospective analysis – the first retrospective cohort review to date – provides data insights regarding H.P. Acthar Gel for physicians treating patients with post-transplant FSGS."

About Nephrotic Syndrome
Nephrotic syndrome (NS) is a collection of symptoms that occur when the blood vessels in the kidney begin to leak excess protein in the urine, a condition called proteinuria. A variety of diseases and underlying disorders may damage the kidneys and cause proteinuria in people with NS. These etiologies can include glomerular diseases such as: idiopathic membranous nephropathy, focal segmental glomerulosclerosis, minimal change disease, membranoproliferative glomerulonephritis, lupus nephritis, and IgA nephropathy. In these and other related disorders, the glomeruli, or small blood vessels that work as the kidney's filtering system, are damaged.

Proteinuria is one of the most important adverse prognostic factors for progression to end stage renal failure in patients with glomerular disease. One of the goals of treating nephrotic syndrome includes reducing or eliminating proteinuria.[4]

H.P. Acthar Gel (repository corticotropin injection) Indications
H.P. Acthar Gel is an injectable drug approved by the FDA for the treatment of 19 indications. Of these, today the majority of Acthar use is in these indications:

• Adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy)
• Monotherapy for the treatment of infantile spasms in infants and children under 2 years of age
• Treatment during an exacerbation or as maintenance therapy in selected cases of systemic lupus erythematosus
• The treatment of acute exacerbations of multiple sclerosis in adults. Controlled clinical trials have shown H.P. Acthar Gel to be effective in speeding the resolution of acute exacerbations of multiple sclerosis. However, there is no evidence that it affects the ultimate outcome or natural history of the disease
• Inducing a diuresis or a remission of proteinuria in nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus
• Treatment during an exacerbation or as maintenance therapy in selected cases of systemic dermatomyositis (polymyositis)
• The treatment of symptomatic sarcoidosis
• Treatment of severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: keratitis, iritis, iridocyclitis, diffuse posterior uveitis and choroiditis, optic neuritis, chorioretinitis, anterior segment inflammation

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 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.

ABOUT MALLINCKRODT
Mallinckrodt is a global business that develops, manufactures, markets and distributes specialty pharmaceutical products and therapies. Areas of focus include autoimmune and rare diseases in specialty areas like neurology, rheumatology, nephrology, pulmonology and ophthalmology; immunotherapy and neonatal respiratory critical care therapies; analgesics and gastrointestinal products. To learn more about Mallinckrodt, visit www.mallinckrodt.com.

Mallinckrodt uses its website as a channel of distribution of important company information, such as press releases, investor presentations and other financial information. It also uses its website to expedite public access to time-critical information regarding the company in advance of or in lieu of distributing a press release or a filing with the U.S. Securities and Exchange Commission (SEC) disclosing the same information. Therefore, investors should look to the Investor Relations page of the website for important and time-critical information. Visitors to the website can also register to receive automatic e-mail and other notifications alerting them when new information is made available on the Investor Relations page of the website.

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Mallinckrodt, the "M" brand mark and the Mallinckrodt Pharmaceuticals logo are trademarks of a Mallinckrodt company. Other brands are trademarks of a Mallinckrodt company or their respective owners. © 2019 Mallinckrodt. US-1900004 1/19

[1] Alhamad T, Dieck JM, Younus U, et al. ACTH gel in resistant focal segmental glomerulosclerosis after kidney transplantation.Transplantation. 2019;103: 202–209.
[2] Korbet SM. Clinical picture and outcome of primary focal segmental glomerulosclerosis. Nephrol Dial Transplant. 1999;14 Suppl 3:68-73.
[3] H.P. Acthar^® Gel (repository corticotropin injection) [prescribing information]. Mallinckrodt ARD, Inc.
[4] Troyanov et al. J Am Soc Nephrol. 2005;16(4):1061–1068.

SOURCE Mallinckrodt plc

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