By: Daniel Mathan, PharmD Candidate c/o 2016, Anita Kachappilly, PharmD Candidate c/o 2016, & Amrita Singh, PharmD Candidate c/o 2015

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Systemic lupus erythematosus (SLE) is a debilitating autoimmune disease that affects multiple organs in the body and can potentially become life threatening.¹ The incidence of SLE is about 50 cases for every 100,000 people; it is predominantly seen in women and is more common in African Americans, Hispanics, and Asians. Diagnosis is typically made between the ages of 15 to 45.  While the etiology of this disease is not completely understood, genetics and environmental factors, including exposure to certain medications, are thought to be the main causative factors.

Manifestation of symptoms and progression of disease severity is primarily patient specific. SLE involves the formation of antibodies against the patient’s own antigens as well as unusual immunologic function. The overabundance of autoantibodies results from hyperactive B-lymphocytes. These antibodies are generally formed against different nuclear components of the body such as RNA, DNA, and histones, which are essential parts of chromatin and nucleosomes. As a result, the body’s immune system attacks its own tissues and causes detrimental effects. Thus, disease presentation often depends on which areas of the body are affected and the extent of organ dysfunction.²

A highly definitive marker commonly used to diagnose SLE is the level of antibodies to double stranded DNA (dsDNA). Since leukopenia, anemia, and thrombocytopenia are common features of SLE, obtaining complete blood counts is also important when monitoring patients. Other pertinent labs include levels of general markers of inflammation such as C-reactive protein and erythrocyte sedimentation rate. Because significant protein loss may occur from complications such as nephrotic syndrome or enteropathy, serum albumin levels may also be obtained.¹ Since the progression of this disease is different for each patient depending upon which organ systems are affected by the autoantibodies, no set recommendations on how often blood tests should be performed exist. However, there are many other signs and symptoms that can be used to diagnose SLE.Some symptoms are nonspecific and include weight loss, fever, and fatigue. Other symptoms are mainly musculoskeletal , including arthritis, malaise, and myalgia. The most iconic sign is the butterfly rash, which spans over the bridge of the nose and cheeks. Other disorders precipitated by SLE include renal impairment, hematological disorders, oral ulcers, and cardiac and pulmonary problems.²

Since there has been no cure established for SLE, providers must create a treatment regimen aimed at symptomatic relief. The goals of these regimens are to prevent flares, treat the flares that occur, and to lessen organ damage and any associated complications. They also must personalize treatments according to each patient’s needs, health goals, age, gender, and lifestyle.³ A combination of immunosuppressive, supportive, and symptomatic drugs have been shown to provide the best therapeutic outcomes in preventing the worsening of this disease. As of now, only a few medications have been approved by the FDA for the treatment of SLE, namely aspirin, prednisone, hydroxychloroquine, and belimumab.⁴ Aspirin is an NSAID used as symptomatic relief to treat pain, swelling, and fever. Antimalarials, such as hydroxychloroquine, have been found to not only treat malaria, but also relieve many of the symptoms of lupus. Prednisone is a corticosteroid that helps to reduce inflammation associated with this disease process. Lastly, belimumab is a B-lymphocyte stimulator (BLyS) protein inhibitor approved in March 2011 that attenuates the number of abnormal B-cells present in the body. The major downside to this medication is that it has not yet been proven effective for African and African-American patients.³ This further substantiates the fact that this disease manifests differently in different patients.

Due to the debilitating effects of this disease state and the lack of sufficient medications for treatment, a new drug, rigerimod (Lupuzor^TM) was put on fast track approval status by the FDA. Rigerimod is a 21 amino acid long peptide fragment of the spliceosomal U1-70K small nuclear ribonucleoprotein. In clinical trials, this peptide has shown to significantly relieve signs and symptoms in patients with SLE. While the mechanism of action is not completely understood, rigerimod is known to regulate the immune system in patients with lupus by altering the activity of important inflammatory cells responsible for causing this disease. For example, rigerimod inhibits T cell response to self-peptides present on cell surface molecules, specifically major histocompatibility complexes (MHC).⁵

Phase II, open label, clinical trials conducted to establish the efficacy of rigerimod and further assess its safety profile were conducted in twenty patients across two centers in Bulgaria. The primary objective was to determine the association between rigerimod administration and disease markers of SLE, specifically anti-dsDNA antibody levels. Statistically significant reductions in this primary marker were observed in groups receiving both the 200 µg and 1000 µg dose every two weeks. Interestingly, more patients in the 200 µg as compared to the 1000 µg group saw a reduction in anti-dsDNA (7 out of 10 patients versus 1 out of 10 patients, respectively). In addition, statistically significant reductions in SLE Disease Activity Index scores and a decrease in the mean level of the acute phase reactant C-reactive protein by about 55% in the 200 µg group and about 2% in the 1000 µg group was also detected. In regards to safety analysis, no serious adverse events were documented during the study period and the incidence of non-serious adverse events was 45%, all of which were indicated to be mild in nature. The only drug related event was mild erythema at the injection site, which resolved within one hour.⁶

In addition, a randomized, double-blind, placebo-controlled Phase IIb clinical trial was conducted to evaluate treatment outcomes from rigerimod (Lupuzor^TM). This multi-center study was conducted in four countries and included over one hundred patients. Results from this study indicated that rigerimod dosed at 200 µg subcutaneously every 4 weeks significantly decreased the autoimmune disease activity in SLE patients being treated with standard of care (primarily steroids). Furthermore, a statistically significant increase in SLE Responder Index in the treatment group versus the placebo group was noted. Significant adverse events were not reported. ⁵

Rigerimod (Lupuzor^TM) is an innovative treatment for lupus 14 years in the making. So far it has completed Phase I, IIa, and IIb studies, and is now preparing for the final phase of testing, Phase III studies with Special Protocol Assessment and Fast Track designation.⁷ Special Protocol Assessment means that the FDA will approve the drug as long as the clinical trials are conducted exactly as promised with evident data as proof.⁸ Fast Track designation accelerates the process of development and reviews of the drug that treats a condition that has an “unmet medical need.” This protocol will allow for patients to have access to the new drug earlier than if the review process had gone at its regular rate.⁹

In summary, rigerimod has significant potential to improve treatment outcomes in patients suffering from SLE and its success following availability on the market is highly anticipated.

 

SOURCES:

1. Schur PH, Wallace DJ. Overview of the therapy and prognosis of systemic lupus erythematosus in adults. In: UpToDate, Pisetsky DS. (Ed), UpToDate, Waltham, MA, 2013.
2. Delafuente JC, Cappuzzo KA. Delafuente J.C., Cappuzzo K.A. Chapter 96. Systemic Lupus Erythematosus and Other Collagen-Vascular Diseases. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. DiPiro J.T., Talbert R.L., Yee G.C., Matzke G.R., Wells B.G., Posey L eds. Pharmacotherapy: A Pathophysiologic Approach, 8e. New York, NY: McGraw-Hill; 2011. http://accesspharmacy.mhmedical.com.jerome.stjohns.edu:81/content.aspx?bookid=462&Sectionid=41100875. Accessed April 14, 2014.
3. Handout on Health: Systemic Lupus Erythematosus. National Institute of Arthritis and Musculoskeletal and Skin Diseases. May 2013. http://www.niams.nih.gov/Health_Info/Lupus/#Lupus_6. Accessed April 14, 2014.
4. Resman-Targoff BH. Chapter 69. Systemic Lupus Erythematosus. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014.http://accesspharmacy.mhmedical.com/content.aspx?bookid=689&Sectionid=48811477. Accessed April 14, 2014.
5. Zimmer R, Scherbarth HR, Rillo OL et al. Lupuzor/P140 peptide in patients with systemic lupus erythematosus: a randomised, double-blind, placebo-controlled phase IIb clinical trial. Ann Rheum Dis. 2012;72(11): 1830-5. http://ard.bmj.com/content/72/11/1830.full.pdf+html. Accessed March 24, 2014.
6. Muller S, Monneaux F, Schall N et al. Spliceosomal peptide P140 for immunotherapy of systemic lupus erythematosus: results of an early phase II clinical trial. Arthritis Rheum. 2008;58(12): 3873-83. http://onlinelibrary.wiley.com/doi/10.1002/art.24027/pdf. Accessed March 24, 2014.
7. Lupuzor^TM-treatment for lupus. ImmuPharma Web site. http://www.immupharma.org/lupuzor. Accessed April 14, 2014.
8. Guidance for Industry Special Protocol Assessment. U.S. Food and Drug Administration. May 2002. http://www.fda.gov/downloads/Drugs/Guidances/ucm080571.pdf. Accessed April 14, 2014.
9. Fast Track, Breakthrough Therapy, Accelerated Approval and Priority Review. U.S. Food and Drug Administration. June, 26 2013. http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/speedingaccesstoimportantnewtherapies/ucm128291.htm. Accessed April 14, 2014.

[pubmed_related keyword1=”lupus” keyword2=”treatment” keyword3=”SLE”]

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