Background
Biologics
Bimagrumab (BYM338)
The rationale of the use
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Amato et al. hypothesized that signaling of transforming growth factor β superfamily through ActRII, is implicated in the pathophysiology of s-IBM. [7]. They performed a small placebo-controlled study to prove their hypothesis. They recruited 14 patients, 11/14 in a treatment arm and 3/14 in a placebo arm. The patients (14/14) were tested for the inhibition of ActRII after receiving a single dose of Bimagrumab. Most of the patients (12/14) were followed for 16 weeks. The primary outcome measure was to show a change in muscle volume by an MRI of the right thigh muscles at the eight-week point. Secondary outcome measures included muscle strength, function, and lean Body Mass Index (BMI). The treated arm showed a 6.5% increase in right thigh muscle volume as compared to the placebo arm (p = 0.024) [7].
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Ioannis et al. performed a literature search and identified four research studies on bimagrumab including one phase III study, and one open-label trial series on alemtuzumab. Although the primary endpoints were not met in the studies, the bimagrumab still showed promising results. Further randomized control trials are needed to know its value conclusively in the treatment of IIM [8].
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A phase IIb/III double-blind, placebo-controlled multicenter study named RESILIENT (supported by Novartis Pharma) is now complete (NCT01925209). A total of 251 s-IBM patients were recruited. The intervention included bimagrumab (10, 3, 1 mg/kg) or placebo every 4 weeks for at least 48 weeks. Patients were evaluated at 52 weeks using the 6-Minute Walking Distance (6MWD) test and the s-IBM- Functional Assessment (sIFA) for muscle strength assessment. The study failed to reach the primary endpoint.
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A follow-up phase three study was performed (July 2015 till February 2017) on patients initially recruited in core study (CBYM338B2203) (NCT02573467) to assess the efficacy, safety, and tolerability after three doses of bimagrumab. They also looked at the long-term effects of bimagrumab. The results are not yet available.
Summary
Sifalimumab (MEDI-545)
The rationale of the use
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The results of the double-blind, phase 1b multicenter randomized control trial (RCT) involving 26 polymyositis and 25 adult dermatomyositis patients, are available. This study (NCT00533091) aimed to evaluate the ability of the anti-IFN-α monoclonal antibody (sifalimumab) to neutralize the type I IFN gene signature (IFNGS) in found in serum as well as in muscles at inception and after the therapy in adult myositis patients. This study looked at the pharmacodynamic and not necessarily a clinical aspect of sifalimumab therapy. The study did achieve its outcome measures, and the results confirmed that sifalimumab therapy significantly reduced the IFNGS in muscles as well as in serum of patients with myositis.
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As a sub-study of the above study, several T-cell related proteins were measured. These T cell-associated proteins included IL-18, TNF receptor 2 (TNFR2) and soluble IL-2RA. The researchers explored if these protein serum markers could be modulated by anti-IFN-α mA therapy. The results showed a significant reduction in the serum T-cell associated proteins in the treated arm vs. placebo arm and concluded that INF blockage could block the T-cell activation which in turn could reduce the T-cell infiltration of muscles in myositis patients. The researchers suggested that change in soluble IL-2RA levels may serve as a biomarker for response to therapy in patients treated with sifalimumab [24].
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Another phase-2, single group assignment, open-label study looking at the long-term tolerability and safety sifalimumab in adult patients with 118 SLE and myositis diagnoses was completed in 2016 (NCT00979654). Out of 118 patients screened, only 103 patients who fulfilled the criteria were recruited, 67/103 completed the study, and 36/103 withdrew because of side effects or other reasons, and one death was reported. A total of 101/103 of Treatment Emergent Adverse Events (TEAEs) and 27/103 Treatment Emergent Serious Adverse Events (TESAEs) were reported from the drug administration until week 182. A business decision to discontinue further development of the sifalimumab at the time was made. A restrictive agreement between the principal Investigators (PI) and the sponsor disallowed the PI to publish the results of the research outcome but some of that can be looked at the Clinical Trials website (NCT00979654).
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Sifalimumab blocked the IFNGS in blood and muscle tissue in myositis patients. A correlation between the IFNGS nullification and improvement in diseases activity has been reported in patients treated with sifalimumab [23].
Summary
Siponimod
The rationale for the use
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A multicenter, phase 2, double-blind, randomized, controlled trial (NCT02029274) was conducted to assess clinical efficacy and dose response of siponimod in adult (age 18–70 years) dermatomyositis patients who had failed or were intolerant to conventional therapy. In the study, 18 patients with adult dermatomyositis were recruited, and 16/18 received siponimod. The trial was completed in February 2016. The International Myositis Assessment Study (IMACS) definition of improvement was used. The peripheral blood absolute lymphocyte count was used to monitor drug pharmacodynamics (PD). The siponimod was well tolerated, and no significant side effects were reported in the observations. Unfortunately, the ineffectiveness of BAF312 in active DM was recognized early in the study and therefore the study was prematurely terminated.
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A similar study on 29 patients which involved DM as well as PM was conducted.Unfortunately, this study was also prematurely terminated (2012). Though, the observations of this study were submitted to clinical trials.gov (October 2018) but are not yet publicly available. (NCT01148810).
Summary
Apremilast
The rationale of the use
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A very small open-label, single-center study with a group assignment from a clinical practice was performed from 2010 to 2015. The primary endpoint was to evaluate the safety and efficacy of apremilast in refractory adult dermatomyositis skin disease patients (NCT01140503). The research period included 12 weeks of therapy (apremilast 20 mg PO BID), and 4 weeks follow-up for a total of 16 weeks. At least 30% reduction in the cutaneous disease activity and severity index (CDASI) (at the baseline and 12 weeks) were the two secondary outcome measures. All patients were between 18 and 65 years old and white femalesOnly five patients could be recruited and one patient withdrew. Because of poor recruitment and other technical difficulties, the study was prematurely terminated. Only 1/5 patient reached the threshold of achieving a 30% reduction in the CDASI while 4/5 patients had a mean change in CDASI-activity at 12 Weeks.Unfortunately, the observations collected were considered ‘unreliable and ‘uninterpretable’ due to measuring errors. A total of 16 mild adverse events was reported in the 12-week period. No serious adverse effects or fatality were observed [27].
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Bitar et al. reported three patients treated with apremilast. One was a 57-year-old woman with steroid dependent refractory skin-predominant DM (CDASI score 43). The patient had failed several DMARDs as well as rituximab and had developed drug-induced diabetes. The second patient was 65 years old woman skin refractory DM (CDASI score 41). The third patient was 62 years old woman with classic DM with a CDASIc score of 62. All the three cases were biopsy confirmed DM and malignancy had been excluded. All the three patients were started on apremilast (30 mg twice daily) as add on therapy while their steroids and DMARD doses were kept stable. They were rechecked at 1 month after the start and then every 3 months. The apremilast was tolerated well by the patients and no side effects were reported. All three patients showed clinical improvement and a steroid sparing effect starting at 1 month into therapy and at 3 months their CDASI scores were zero, seven and 18 respectively. All the three patients could be weaned off immunotherapy and steroids and maintained on apremilast monotherapy without any relapses [28].
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Another phase two, open-label, single group assignment, interventional study (2018–2019, NCT03529955) is recruiting currently for recalcitrant cutaneous DM patients. The study is assessing safety and efficacy of apremilast (30 mg twice daily) and clinical response at 1 month and 3 months from the initiation of the study. The estimated enrollment is 10 patients. The sustainability of the response will be assessed at the six-month visit [29].
Summary
Gevokizumab
The rationale of the use
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A proof-of-concept, randomized, double-blind, placebo-controlled trial was started (2013–2015) to look at the efficacy of gevokizumab (60 mg SC every 4 weeks for 24 weeks) in 27 adult IIM patients (age ≥ 18 to 65 years) who were recruited in multiple centers in Europe (EudraCT number: 2012–005772-34). Unfortunately, not only the study was prematurely terminated due to financial reasons, the technical and measurement errors were also identified which made the collected observations unreliable.
Summary
Eculizumab (h5G1.1-mAb)
The rationale for the use
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In a randomized, double-blind, placebo-controlled pilot study in DM patients, treatment with eculizumab did improve global physician scores for cutaneous diseases. This study involved the total of 13 DM patients with 10 in the treatment arm and 3 in the placebo arm. The study period was 8 weeks. No serious adverse effects were noted, and the incidences of minor adverse effects were the same in treated and placebo arm. The improvement in MMT (6%), physician global score (9%) and in skin disease score (37%) from the baseline was reported in the treatment arm. The placebo arm showed worsening [31, 32].
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Stanislas Faguer et al. (2018) reported successful treatment with eculizumab of a 19 years old refractory DM patient with thrombotic microangiopathy (TMA) as a comorbidity [33].
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A phase two, randomized, placebo-controlled, third-party-blind study evaluating the safety and efficacy of eculizumab in 17 adult DM patients was recently been completed (2000–2001, NCT00005571) but the results have not been reported [34].
Summary
Basiliximab
The rationale for the use
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Jing Zou et al. reported a case series of four adult amyopathic DM patients (positiveanti-MDA5 antibody) who had failed conventional therapy. Three of 4 patients with rapidly progressing ILD demonstrated improved survival, reduction in ferritin levels, and improved lung functions in with use of two doses of 20 mg IV basiliximab 7 days apart [35].
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An open-label, randomized, parallel assignment without masking, phase-2, single center study in China is currently enrolling. This study will be looking at the safety and efficacy of basiliximab as an adjunct treatment in amyopathic dermatomyositis (CADM) patients with interstitial pneumonia. The study duration is to be 52 weeks, and the target recruitment is 100 patients 18 years to 65 years old (NCT03192657). The primary outcome measure is survival at 52 weeks [36].
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The secondary outcome measures are forced vital capacity, total lung capacity and diffusing capacity, serum ferritin, serum KL-6, and semi-quantitatively assessed lung CT change at 52 weeks. The start date was to be July 2017, and the expected end date is June 2020, but as per clinical trials.gov website, they are not yet recruiting [36].
Summary
Emerging therapies
Anti–T-lymphocyte immunoglobulin (ATG)
Rationale for its use
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Lindberg et al. performed an open-label randomized single-center comparative study on 11 s-IBM patients, but only 10 patients completed the 12 months follow- up period. The primary goal of this study was to evaluate the safety and efficacy of ATG therapy in s-IBM [38]. The first group (6/11) of patients received oral methotrexate alone (7.5 mg/week for 12 months, the second group (5/11) received IV ATG for 7 days followed by methotrexate for 12 months. The ATG group showed an increase in mean muscle strength by 1.4% as compared to the methotrexate alone group in which muscle strength declined by 11.1% (p = 0.021).
Summary
ACTH analogs
The rationale for the use
Clinical trials
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Aarat Patel et al. reported their experience with 4 steroid-resistant and refractory myositis patients who were treated with RCI [42]. Malignancy was ruled out in all the four patients. The first patient was a 70-year-old white female with skin biopsy-proven amyopathic DM who failed conventional therapy including rituximab. She was treated with RCI 80 IU SQ twice weekly. She not only showed improvement in her muscle disease but also showed improvement in her bone density after RCI therapy. Unfortunately, her muscle disease relapsed later and a repeat course of rituximab was being considered at the publication of the case series.The second case was a 50-year-old white male with electromyography (EMG) and biopsy-proven, skin predominant DM who had failed conventional therapy including steroids and rituximab. He was treated with RCI (80 IU SQ twice weekly) along with azathioprine (AZA) and intravenous immunoglobulin (IVIg). The AZA was later replaced by methotrexate (MTX) as maintenance therapy. He partially responded to RCI, i.e., his muscle enzymes normalized but his severe skin disease continued to flare. The RCI treatment was stopped after 8 months. He later responded to repeat course of rituximab in combination with steroids and hydroxychloroquine. The third patient was a 52-year-old white female with refractory overlap syndrome (PM with Sjogren’s and ILD). She had an inadequate initial response to steroids. She was started on RCI (80 IU SQ twice weekly) as a steroid-sparing agent, before using any biologic agent. Her steroids could be discontinued on RCI therapy, her muscle enzymes returned to normal, and skin lesions improved. Unfortunately, her ILD continued to progress. The rituximab was added to her RCI treatment which appeared to help with her dyspnea. At the time of writing of the case series, her disease was under control on a small dose of oral prednisone, MMF and RCI. The fourth patient was a 57-year-old AA male with an anti-SRP-antibody positive PM who had an initial inadequate response to steroids and later failed conventional therapy including rituximab. The RCI (80 IU twice weekly SQ) was added to his regimen. He responded to RCI, and he could be weaned off his oral steroids. At the time of the publication of the case series, he was asymptomatic, he had normal muscle enzymes and had been on RCI monotherapy for 27 months. The authors stated that the patients did not show exacerbation in their comorbidities during the treatment with RCI. Muscle disease clinical and serologic improvement was seen in all four patients, but skin and lung components of the myositis disease did not appear to respond well. Improvement in the bone density was recorded in one patient and the feeling of general well-being was reported in all the four patients on RCI treatment. Side effects that are commonly seen with steroid therapy, such as hyperglycemia, abnormal weight gain, cushingoid features, hypertension, hyperosmolar states, and skin pigmentation were not reported in patients on RCI treatment.
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Another retrospective report on a case series in which RCI was used in the treatment of biopsy confirmed, refractory PM/DM showed similar results [43]. This case series included five female patients aged 25–68 years with myositis (1 JDM with calcinosis, 2 adult DM, 2 adult PM). All these patients were refractory to conventional therapy but had shown the initial response to steroids. In this series, three out of five patients had also failed rituximab therapy. Four out of five patients in this series were treated with RCI (80 IU twice weekly SQ) while one received only once a week RCI for 12 weeks. Interestingly, they also used RCI to control small flares when continuing on their maintenance treatments. In this series, the RCI was used as a short-term treatment, and therefore, long-term safety and efficacy could not be evaluated. Yet in the short-term, all patients in this series achieved reduced exacerbations over time, increased muscle strength, serologic improvements, reduced skin disease, a decrease in pain, an improved feeling of well-being, and better independent ambulation. Yet since RCI was used as an additive short-term treatment for flares on top of the ongoing maintenance therapy in these patients, any improvements due to RCI could not be conclusively proven, though the effects are very suggestive.
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RCI was used with the intention of treatment and evaluation of its safety, efficacy, and steroid-sparing activity in two myositis centers in the USA in an open-label, single group assignment, phase two study (NCT01906372, 2013–2015) on 11 adult refractory myositis (PM and DM) patients. These patients had active disease who failed to respond to steroids and/or one or more immunosuppressive therapy and were defined as refractory. These refractory patients received RCI (80 IU SC twice a week) for 24 weeks. The International Myositis Assessment and Clinical Studies (IMACS) criteria for improvement were used to assess primary endpoint. The safety, tolerability, and steroid-sparing effect were assessed as secondary endpoints. The 10/11 patients completed the study, the median time to reach primary endpoint was 8 weeks in 7/10 patients, and a significant steroid-sparing effect was objectively reported (P < 0.01). The RCI was tolerated well, and no significant side effects (infections, hyperglycemia, hypertension, abnormal weight gain) were reported [44].
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There is an ongoing treatment, open-label, phase 4, single group assignment, single-center study (2014–2019, NCT02245841) with an estimated enrollment of 15 refractory cutaneous DM/JDM/ADM subjects (age 18 or above and meet the Bohan and Peter or Sontheimer’s diagnostic criteria). All patients will receive Acthar (80 IU SC twice a week) for 24 weeks. The study is expected to finish by the end of the year 2019.
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An interim observational case study (NCT01637064) was designed to develop a registry aiming to collect long-term experience data on RCI use in refractory PM/DM patients. The primary outcome measure was to look at the safety profile and efficacy of RCI in refractory adult PM/DM patients for at least a year post-treatment. The secondary outcome measures are to see the response in all the subgroups/types of myositis patients with an intent to identify if a particular subgroup of patients responded better to RCI therapy than others [45, 46].
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In an interesting single center, observational ongoing phase 2 trial in which the recruitment is through invitation (2017–2019, NCT03414086). Researchers aim to look at the predictors of clinical response to Acthar in 20 subjects. The researchers are trying to look at the effect of the Acthar at the cellular and molecular level by collecting serum, white cells, pax gene samples and RNA samples from 10 previously Acthar-treated refractory patients (4 PM, 6 DM) from previous research studies and 10 healthy controls. Active myositis patients are not enrolled in this study, but rather patients in remission who were previously treated with Acthar are being recruited along with healthy controls. The study is still in progress.
Summary
Conclusions
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Bimagrumab to increase muscle mass in atrophied IIM muscles
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Sifalimumab for all inflammatory myositis diseases due to importance of interferon in IIM.
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Basilixumab for IIM amyopathic disease with interstitial pneumonitis, if not other things as well.
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Eculizumab or Apremilast for cutaneous predominant IIM
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Gevokizumab has theoretical usefulness as an anti-IL-1β therapy in IIM but is untested.
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ACTH analogs appear to be effective in some IIM patients and side effects are surprisingly mild to moderate thus far.