The Current Treatment of Rare Disease, Lysosomal Acid Lipase Deficiency (LAL-D) and Paroxysmal Nocturnal Haemoglobinuria (PNH)

O’Malley S; Tian F

Review Article

Austin J Clin Immunol. 2023; 9(2): 1059.

The Current Treatment of Rare Disease, Lysosomal Acid Lipase Deficiency (LAL-D) and Paroxysmal Nocturnal Haemoglobinuria (PNH)

O’Malley S*; Tian F

School of Food Science and Environmental Health, Technological University Dublin (TUD), Ireland

*Corresponding author: O’Malley S School of Food Science and Environmental Health, Technological University Dublin (TUD), Ireland. Tel: 0035312205673 Email: furong.tian@tudublin.ie

Received: June 27, 2023 Accepted: August 01, 2023 Published: August 08, 2023

Abstract

The Paroxysmal Nocturnal Hemoglobinuria (PNH) and Lysosomal acid Lipase Deficiency (LAL-D) are rare disorder disease. Ultomiris and Soliris for PNH and Kanuma for LAL-D are innovative treatments for PNH and LAL-D, respectively. These therapies can treat each ultra-rare condition by alleviating symptoms and lowering mortality rates for both diseases. The aim of this research is to investigate the rare diseases PNH and LAL-D, as well as the existing treatments for both. Each medicine should be safe and have a good therapeutic effect, with a wide range of benefits and few adverse effects. PRISMA (Preferred Reporting Items for Systematic Reviews) was used to evaluate three treatments: Ultomiris and Soliris for PNH and Kanuma for LAL-D. The search was limited to scientific research articles and clinical trials (Publication years between 2007 and 2022). In the analysis, 20 studies were chosen based on their treatment, concentration, population, year of publication, outcomes, and references. Extensive study on the present treatment of PNH and LAL-D was used to draw conclusions on the overall benefits, distribution, efficacy, and safety of the medicines. This study was also utilised to validate the overall improvement in the lives of people with PNH and LAL-D. Ultomiris has an average effect of 96.5% on PNH symptoms, including hemolysis events. Kanuma has a 90% typical impact against LAL-D by reducing symptoms such as LDL-C and normalising Aspartate Aminotransferase (AST) levels (LAL-D symptoms), whilst Soliris has an average 97% effect against PNH, by reducing the presence of lactate dehydrogenase, for example.

Keywords: Rare disease; Lysosomal acid lipase; Deficiency; Paroxysmal; Haemoglobinuria

Introduction

Paroxysmal Nocturnal Hemoglobinuria (PNH) and Lysosomal Acid Lipase Deficiency (LAL-D)

PNH (paroxysmal nocturnal hemoglobinuria) is a rare condition that causes a variety of vague symptoms. It mostly causes problems such as intravascular hemolysis, thrombosis, and bone marrow failure [1]. PNH is a rare blood illness in which blood cells are targeted by a component of the body's immune system. The process of destroying red blood cells is known as "haemolysis," and it is responsible for many of the disease's symptoms.

"Haemolytic PNH" affects approximately 5 persons out of every million in the general population, making it an ultra-rare disease [2]. PNH indications include red/brown/dark urine observed during late-night or early-morning bathroom visits. "Paroxysmal" means "sudden," and "nocturnal" means "at night,". Haemoglobinuria refers to the red blood cells breaking down in blood vessels which eventually appear in the urine [3].

Lysosomal Acid Lipase Deficiency (LAL-D) is an uncommon, chronic, and developing hereditary disease. It inhibits the body's ability to produce the Lysosomal Acid Lipase enzyme (LAL). LAL-D is an extremely rare genetic metabolic condition that causes multiorgan failure and premature infant death in newborns, children, and adults [4]. LAL-D is characterised by cholesteryl esters and triglyceride buildup, primarily in the liver and spleen, although it may occur in other organs [5].

A liver transplant or fibrosis, or both, arise in about 50% of adolescents and adults with LAL-D within three years after the onset of clinical symptoms. The median age of onset for both children and adults with LAL-D is 5.8 years. The LAL-D condition can be identified with a quick blood test [4].

Kanuma (Sebelipase alfa) is an ERT (enzyme replacement therapy). Kanuma's major ingredient, sebelipase alfa, is a synthetic version of the enzyme LAL. Sebelipase alfa substitutes LAL by helping in fat breakdown and avoiding fat accumulation in the body's cells, hence preventing LAL-D symptoms such as liver damage and mortality [6].

Registry and Diagnosis

PNH can be challenging to identify and make a diagnosis because it is an extremely rare condition. Less than 40% of PNH patients have a diagnosis within a year of their first symptoms, and 24% of PNH diagnoses can take five years or more [7].

PNH should be suspected in those who have symptoms of intravascular hemolysis, such as hemoglobinuria or an extremely high serum LDH concentration. A diagnosis may be made using a comprehensive clinical assessment, a complete patient history, and a range of specialty testing [8].

Previously, PNH was diagnosed using tests that sensitised the complement lysis activity on RBCs. In most countries, a Flow Cytometric (FCM) assessment of glycosyl phosphatidylinositol-anchored proteins has essentially replaced the once-common acidified serum lysis test (Ham test). (GPI-AP) [9].

To fully characterise PNH, both bone marrow analysis and flow cytometric detection of GPI expression on peripheral blood cells are required [8].

The Global PNH Patient Registry is a flexible online platform for safely gathering and storing data for medical research. Users of the database can fill out surveys about their own experiences with disease and additionally gain insight about other patients' experiences by viewing compiled survey data [10].

The differential diagnosis of metabolic liver disorders, for instance Lysosomal Acid Lipase Deficiency (LAL-D), can be problematic in clinical settings [11]. Given the disease's unpredictable development and the possibility of liver failure and/or accelerated atherosclerosis being factors in early mortality, there is evidence that LAL-D may be severely underdiagnosed or misdiagnosed [12].

Fortunately, given the availability of a simple diagnostic test and recently approved treatment, LAL-D should be considered in the differential diagnosis in relevant clinical circumstances. An LAL enzyme-based biochemical test can detect LAL-D, allowing for active patient monitoring to identify potential illness outcomes [11].

LAL-D is diagnosed by measurements of activity in the blood or other tissues, as well as assessments of lipid buildup on various organs using radiological techniques such as MRI [13]. The LIPA gene's mutations can also be found using genetic testing. Due to the low level of suspicion for the diagnosis and the commonality of the major clinical and biochemical abnormalities, biopsy findings and radiographic findings are not considered diagnostic, although they do aid increase the suspicion of LAL-D [12].

There are a number of registries for people with LAL-D that gather information, analyse it, and raise awareness of the condition. These registries serve as a catalyst for research that aims to better the lives of PNH patients. These include the Global LAL-D Registry, the LAL-D Alliance Patient Registry, and the LAL-D Registry [14].

Symptoms of PNH and LAL-D

When the immune system targets red blood cells and platelets, PNH occurs. If neglected, PNH can lead to thrombosis, chronic renal failure, or hemolytic anaemia [3]. Hemolysis causes PNH signs and symptoms such as fatigue, dysphagia, dyspnea, stomach pain, erectile dysfunction, haemoglobinuria, and anaemia [15].

Two antibodies, Ultomiris and Soliris, bind to and inactivate the complement protein C5 to prevent blood clotting. Both Soliris and Ultomiris improve PNH patients' quality of life while lowering hemolysis to terminate the symptoms and signs of PNH [16].

Lysosomal Acid Lipase Deficiency (LAL-D) is an uncommon, chronic, and progressive hereditary disease. It inhibits the body's ability to produce the Lysosomal Acid Lipase enzyme (LAL). LAL-D is an extremely rare genetic metabolic condition that causes multiorgan failure and premature infant death in newborns, children, and adults [4]. Sebelipase alfa acts as an LAL substitute by assisting in fat breakdown and limiting fat accumulation in the body's cells, hence preventing LAL-D symptoms such as liver damage and death [6].

Current Treatment

Ultomiris and Soliris as the current treatment for PNH: Eculizumab has been found to improve survival in people with paroxysmal nocturnal hemoglobinuria by decreasing intravascular hemolysis and thrombosis. The goal of raulizumab, a long-acting, second-generation complement component 5 (C5) inhibitor, is to reduce the burden of the eculizumab treatment regimen and the likelihood of breakthrough hemolysis [17]. Ravulizumab binds aggressively and preferentially to the complement protein C5, similarly to the first-generation C5 inhibitor eculizumab, preventing the formation of the terminal complement complex C5b-9, which causes cell lysis [18].

In PNH patients who had previously had eculizumab therapy and were clinically stable, investigations have shown that ravulizumab is noninferior to eculizumab. Nevertheless, Ultomiris may be preferred by patients since it only requires intravenous injections every 8 weeks as opposed to every 2 weeks with Soliris IV injections [19].

The function of ravulizumab and eculizumab in the modulation of complement. The C3 activation stage is the culmination of the complement alternative, lectin, and classical pathways. At this stage, CD55 often suppresses the production of the C3 convertase, preventing the formation of C3b [20]. The membrane assault complex is produced when C5b combines with C3b and other complement proteins after being split into C5a and C5b by the C5 convertase (MAC) [21].

Eculizumab and Ravulizumab both suppress the complement C5 activation [21]. The body's own red blood cells are typically not attacked by the Membrane Attack Complex (MAC), the terminal complement system's by-product, because CD59 inhibits this. Patients suffering PNH however, lack the CD59, allowing MAC to target red blood cells. [22].

The terminal complement system, which includes the synthesis of the MAC, is effectively shut down by both C5 inhibitors' interactions with complement C5 [22]. As a result, PNH patients experience much less hemolysis and a decrease in Neisseria clearance [23].

Kanuma as the Current Treatment for LAL-D

Alexion Pharmaceuticals, Inc developed Sebelipase alfa (Kanuma), a recombinant human Lysosomal Acid Lipase (LAL) for long-term enzyme replacement therapy in patients with LAL deficiency [24]. Kanuma was authorised as an ERT for LAL insufficiency in the European Union and the United States in 2015, respectively [25].

Preclinical research has demonstrated how the creation of an LAL Enzyme Replacement Treatment (ERT) permits the rectification of metabolic flaws cause by LAL-D [26]. In vivo studies in a mouse model, demonstrated how LAL replacement directs the enzyme to the intended compartment by LAL replacement, which decreases the damaging effects of LAL-D. The LAL-deficient invivo model revealed that treated mice outlived untreated animals and that hepatic lipid storage was dramatically enhanced [27].

Ultomiris and Soliris for PNH and Kanuma for LAL-D are innovative treatments for PNH and LAL-D, respectively. These therapies can treat each ultra-rare condition by alleviating symptoms and lowering mortality rates for both diseases. Each medicine should be safe and have a good therapeutic effect, with a wide range of benefits and few adverse effects.

This review is to demonstrate the effects of current PNH and LAL-D treatment by presenting correct data from scientific articles, studies, and clinical trials.

The object will be focus on PNH and LAL-D impact the patient, the efficacy and safety of the current therapeutics for PNH and LAL-D. The global approval of the treatments, and the benefits and drawbacks of the novel medicine will be discussed.

Method

Systematic Reviews and Meta-Analyses

A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 checklist was completed, and a flowchart was created in accordance with the PRISMA rules and registration information. The screening process was used to determine articles for inclusion and exclusion. Reasons for articles being excluded varied from; Studies that are not a Randomize Clinical Trial (RCT), Not relevant to the current treatment of PNH and LAL-D, and Language limitation. During the screening process, the eliminated articles, were recorded using the principles outlined in the PRISMA statement 2020 (Figure 2).

Figure 1: Graphical summary to describe the signs and symptoms of each rare condition, as well as the treatment for the disease.


    

    

    Figure 1: Graphical summary to describe the signs and symptoms of each rare condition, as well as the treatment for the disease.

Figure 2: PRISMA flowchart for finding literature.


    

    

    Figure 2: PRISMA flowchart for finding literature.

Global Approval of Ultomiris, Soliris and Kanuma

Ultomiris was authorised by the FDA for adult patients with PNH on December 21, 2019, and for children and adolescents with PNH on June 7, 2021 (Figure 3). Illustrates the nations where Ultomiris, Soliris, and Kanuma have received global approval. Ultomiris was approved in the US, EU, and Japan for the treatment of certain adults with PNH and for certain children with PNH in the US and EU [28]. The first medicine authorised to treat individuals with Paroxysmal Nocturnal Hemoglobinuria (PNH) and lessen hemolysis was Soliris. On Mar 19, 2007, FDA approved Solirs for PNH. In approximately 50 nations throughout the world, including the United States, the European Union, and Japan, Soliris has been given the go-approval for the treatment of PNH patients [29]. European Union, Japan, and the United States have all approved of Kanuma. The first medication authorised for LAL-D patients is Kanuma, which was approved by the FDA on Dec 8, 2015 [4].

Study Findings Following the Use of the Screening Procedure

The information in the table was compiled from key articles about Ultomiris, Soliris, and Kanuma as successful treatments for PNH and LAL-D, with Kanuma successfully reducing LAL-D related symptoms and Ultomiris and Soliris effectively alleviating PNH symptoms. Table 1 contained 20 papers. Treatment, Concentration, Disease, Number of People, Year of Publication, Description, Results, and References were listed in the columns from left to Right.

Each article's information included the number of cohorts that participated in the experiment or article, the amount of the treatment that was used in the clinical trial or article, the year the article or experiment was published, and the results of the treatment based on serious or adverse events. The first informational load focuses on Ultomiris's potential to treat PNH symptoms, including a decrease in plasma Lactate Dehydrogenase (LDH), involved a systematic review with doses ranging from 100 to 900 mg. The second therapy involves the drug soliris, and it involves weight-based dosing or concentrations ranging from 600 to 1,200 mg for the treatment of PNH symptoms such haemoglobin stability at a rate level of 48.8%. The third treatment is related to Kanuma and involved a systematic review with concentrations ranging from 0.35 to 3 mg, easing symptoms of LAL-D such as a reduction in LDL-C and a reduction in non-HDL-C.

Result and Discussion

Research Articles Distribution for the Three Medicines

Twenty publications totalling seven each regarding Ultomiris and treating PNH, six each about Soliris treating PNH, and seven each about Kanuma treating LAL-D were included in the results, as shown in table 1. The percentage of publications featuring Ultomiris, Soliris, and Kanuma is shown in Figure 3.

Figure 3: Global approval of Ultomiris, Soliris and Kanuma.


    

    

    Figure 3: Global approval of Ultomiris, Soliris and Kanuma.

Table 1: Experimental research on the Treatment of PNH and LAL-D.








  

    

    Concentration 

    Sample size 

    Year 

    Results 

    Reference 

  

  

    Ultomiris 

    PNH 

  

  

    1 

    100 -300 mg 

    42 

    2017 

    Half-life of 32 days 

    [20] 

  

  

    2 

    900mg or 1800mg /4 weeks 

    13 

    2018 

    Rapid and sustained LDH (73%-90% at end point vs    baseline). 

    [20] 

  

  

    3 

    30-mL IV 

    270 

    2018 

    Ravulizumab: 

    [29] 

  

  

    Affected/at risk at8.80% 

  

  

    Eculizumab; 

  

  

    Affected/ at risk at 7.4% 

  

  

    4 

    30-mL IV 

    246 

    2016 

    FACIT-F and EORTC-QLQ-C30 scores improved 

    [39] 

  

  

    5 

    2700mg-3000mg 

    191 

    2021 

    Common TEAEs for Ultomiris:  fatigue (n = 13 [13.5%]), 

    [40] 

  

  

    6 

    Weight-based doses 

    12 

    2018 

    Serious adverse events = 2/5 

    [18] 

  

  

    7 

    2400 mg / 8 weeks 

    201 

    2020 

    LDH percentage reduction ranging from 72.9% to    89.6%. 

    [41] 

  

  

    

    Soliris 

    PNH 

  

  

    1 

    600mg-1200 mg 

    345 

    2021 

    11 (3.2%) patients did not improve with Soliris. 

    [31] 

  

  

    2 

    N/A 

    59 

    2016 

    History of bone marrow disorder:  Yes 4 (7), 

    [9] 

  

  

    3 

    600 mg IV /week 

    176 

    2017 

    Death (3) 

    [42] 

  

  

    4 

    600 mg IV /week 

    153 

    2020 

    3 thrombotic events in 22 individuals. 

    [33] 

  

  

    5 

    900mg / 2 weeks 

    87 

    2007 

    Patients haemoglobin stability at a median rate    of 48.8%, 

    [32] 

  

  

    6 

    600 mg IV/week 

    123 

    2015 

    Eculizumab-treated patients with fewer thrombotic    events (TEs) 

    [43] 

  

  

    

    Kauuma 

    LAL-D 

  

  

    1 

    Sebelipase Alfa: 

    66 

    2015 

    TEAEs: 6     SAEs: 0 

    [34] 

  

  

    0.35 -3mg/kg 

    IRRS: 0      TEAES: 0 

  

  

    2 

    IV 0.35 -1 mg/kg     qow doses 

    9 

    2017 

    TEAEs: 8     SAEs: 1 

    [44] 

  

  

    IRRS: 2     TEAES: 0 

  

  

    3 

    IV 1 (mg/kg) qow 

    19 

    2022 

    A median ALT and AT levels decreased by 42.0%. 

    [35] 

  

  

    4 

    IV 1 (mg/kg) qow 

    66 

    2016 

    Changes from baseline of ARISE trial: 

    [45] 

  

  

    a reduction in LDL-C, a reduction in non-HDL-C 

  

  

    5 

    IV 1 mg/kg /2 weeks,. 

    21 

    2022 

    The first-in-human sebelipase alfa trial,    significantly lower ALT and AST values 

    [26] 

  

  

    6 

    IV 1 mg/kg /2 weeks,. 

    110 

    2022 

    Tachycardia (70%), pyrexia (60%), irritability    (50%), agitation (40%), urticaria (40%) 

    [25] 

  

  

    7 

    IV 1 mg/kg /2 weeks,.. 

    3 

    2018 

    Stiffness decreased from 8.6 kPa to 7.4 kPa 

    [46]






Table 1: Experimental research on the Treatment of PNH and LAL-D.

Table 1 lists the average drug efficacy and safety of this systematic review on Ultomiris, Soliris and Kanuma.

The concentrations per ingredient in each research were tabulated and shown in Figure 3. The figures with the title “concentrations” “drug efficacy” “safety” and “benefits and drawbacks” refer to the treatment concentrations and outcomes used in the experiment or article.

Table 2: Novel Therapies of PNH and LALD and it advantage.








  

    Treatment 

    Advantages 

    Reference 

  

  

    Ultomiris    (Ravulizumab) 

    1 

    Ravulizumab is an antibody that is thought to aid    the immune system avoid attacking red blood cells. 

    [48] 

  

  

    2 

    Developed into a phase 3 study of weekly    self-administered subcutaneous Ultomiris. 

    [48] 

  

  

    3 

    Ultomiris is designed to last longer in the body    than Soliris, therefore can help patients maintain C5 under control for 8    weeks between infusions, 

    [29] 

  

  

    4 

    Ultomiris successfully lowers LDH levels, without    needing red blood cell transfusions in patients with PNH 

    [23] 

  

  

    5 

    Ultomiris is a monoclonal antibody therapy 

    [29] 

  

  

    Soliris    (Eculizumab) 

    1 

    Patient’s experienced significant LDH reduction    and clinically noticeable improvement in fatigue compared to untreated    patients. 

    [49] 

  

  

    2 

    Throughout a course of 26 weeks Soliris treatment    resulted in stable haemoglobin levels in 49% of the patients (21 out of 43),    eliminating the need for red blood cell transfusions. 

    [37] 

  

  

    3 

    Patients treated with Soliris have an 82% chance    of surviving. 

    [50] 

  

  

    4 

    Safely used in pregnant PNH patients, which was    previously prohibited for PNH patients due to the danger of blood clots. 

    [51] 

  

  

    5 

    Soliris is a monoclonal antibody and an    immunosuppressant 

    [37] 

  

  

    Kanuma (Sebelipase    alfa) 

    1 

    Sebelipase alfa substitutes the lipase acid    enzyme, assisting in the breakdown of fats and preventing them from    accumulating in the body's cells. 

    [36] 

  

  

    2 

    Sebelipase alfa is well tolerated and resulted in    sustained improvements in liver and lipid parameters. 

    [35] 

  

  

    3 

    Improved survival in infants with LAL-D 

    [4] 

  

  

    4 

    Reduces the accumulation of fat that contributes    to medical issues like decreased growth, liver damage, and heart issues. 

    [52]






Table 2: Novel Therapies of PNH and LALD and it advantage.

The deepest blue segment indicates for Kanuma, and 35% of the sources were used to demonstrate how Kanuma affected LAL-D symptoms and signs. The lighter blue represents 30% of the sources utilised to indicate how Soliris affects PNH symptoms as you move clockwise around the image. 35% of the sources gathered were related to Ultomiris, which is represented by the lightest blue segment.

Novel Therapies of PNH and LALD and it Advantage and Disadvantage

Table 3 depicts the benefits and drawbacks of each treatment for each relevant condition, PNH or LAL-D. Each of the three therapies demonstrated a great deal of advantages with minimal drawbacks.

Table 3: Novel Therapies of PNH and LALD and it disadvantage.








  

    Treatment 

    Disadvantages 

    Reference 

  

  

    Ultomiris    (Ravulizumab) 

    1 

    Increased risk of serious and sometimes fatal    diseases such as meningococcal infections and sepsis. 

    [47] 

  

  

    2 

    Cost of treatment 

    [24] 

  

  

    3 

    Possible allergic reactions to acrylic adhesive 

    [54] 

  

  

    4 

    Prevalent side effects include upper respiratory    infection, diarrhoea, nausea, and elevated blood pressure. 

    [54] 

  

  

    Soliris    (Eculizumab) 

    1 

    Potentially life-threatening side effects 

    [35] 

  

  

    2 

    Variations in response profiles 

    [35] 

  

  

    3 

    Cost of treatment. 

    [35] 

  

  

    4 

    Potential life-long therapy, administered    intravenous infusion by a healthcare professional every 14 days. 

    [56] 

  

  

    Kanuma (Sebelipase    alfa) 

    1 

    Clinical data for the indicated populations were    sparse and ambiguous, limiting the amount of trust that can be placed in the    conclusions of the economic analysis. 

    [4] 

  

  

    2 

    Due to the limited duration of the current    trials, long-term safety and efficacy for sebelipase alfa are unknown and    cannot be proved throughout a lifetime. 

    [4] 

  

  

    3 

    Weight gain for patients under the age of 21    years 

    [4] 

  

  

    4 

    The utility values employed in the analysis were    not derived from LAL deficient patients. Changing the utility values in the    pediatric/adult presentations, on the other hand, had no discernible effect    on the outcomes. 

    [4]






Table 3: Novel Therapies of PNH and LALD and it disadvantage.

According to the benefits and downsides of Ultomiris, it helps the immune system and avoids attacking red blood cells. Ultomiris effectively reduced hemolysis in patients, and the drug has a longer dose interval than soliris, improving patient comfort and compliance to treatment. Ultomiris is currently in phase 3 clinical trials for a self-administered subcutaneous dose [29]. Consequently, Ultomiris is more accessible to PNH patients [18]. However, Ultomiris has several drawbacks, including an increased risk of serious and occasionally fatal diseases such as meningococcal infections and sepsis [3]. Upper respiratory infection, diarrhoea, nausea, and increased blood pressure are common adverse effects [30].

Eculizumab/Soliris is the most used medication to treat PNH (Soliris) [8,31]. The study demonstrated that Soliris is well tolerated and found no new safety issues [32,33] compared to untreated patients, Soliris patients exhibited considerable LDH reduction and clinically evident improvement in fatigue [9]. However, Soliris has the potential to be a life-long medication that must be administered intravenously by a healthcare expert every 14 days, which might be inconvenient for patients [33].

Kanuma works by replacing the lipase acid enzyme, assisting in fat breakdown, and improving the lives of people suffering with LAL-D [34,35] was discovered that Kanuma gives infants a better chance of survival. Sebelipase alfa is well tolerated and improves liver and lipid indicators over time [4].

[26]. Clinical evidence for kanuma, on the other hand, suggested some limited trust and ambiguous economic analysis outcomes, as well as long-term safety and efficacy [25]. This is due to the studies' brief duration and limited population size.

The Average Efficacy and Safety of Each Therapy Based on Research Articles and Clinical Trials

Figure 5 clarifies appropriate infusion volumes using weight-based dosing because several articles use weight-based dosing. Figure 5 demonstrates the average drug safety and efficacy, as determined by the findings of academic papers and clinical trials. It shows the method of treatment and the average drug efficacy and safety (%) associated with it. Safety (%) is illustrated dark blue and Drug efficacy (%) is illustrated a lighter blue.

This chart was used to determine the safety and efficacy of the current treatments of LAL-D and PNH. Ultomiris, Soliris, and Kanuma have drug efficacy rates of 96.7%, 97%, and 90%, respectively (Figure 4). Ultomiris has a 96.5% average impact on PNH symptoms, including hemolysis episodes. Kanuma has a 90% typical impact against LAL-D by reducing symptoms for instance LDL-C and normalising levels of AST (LAL-D symptoms) [36] whereas Soliris has an average 97% effect against PNH by, for example, reducing the presence of lactate dehydrogenase (symptoms of PNH) [37] Kanuma received a mean safety rating of 96%, which means that there was a 4% possibility of adverse events related to kauma. similarly, to Soliris which has a 95% average safety level with an average 5% chance of adverse or serious events caused by the treatment. Ultomiris however has a lower average safety of 77%. According to statistics from clinical trials and research papers, ravulizumab has a 23% probability of causing major adverse events on average. Ultomiris can induce more severe adverse effects, such as infusion-related symptoms, including back discomfort, fatigue, or drowsiness. Ultomiris increases patients' risk of contracting meningococcal infections, which can be fatal. Upper respiratory tract infection, diarrhoea, nausea, vomiting, headache, elevated blood pressure, and fever are among side effects related to ravulizumab

Treatment	Disease	Patient Body Weight (kg)	Infusion volumes per body weight	Reference
Ultomiris (Ravulizumab)	PNH	<40	2700mg	[23]
		<30	2100mg
		<20	600mg
		<10	600mg
Soliris (Eculizumab)	PNH	<40	600mg	[37]
		<30	600mg
		<20	600mg
		<10	300mg
Kanuma (Sebelipase alfa)	LAL-D	10-Jan	50 mL per 5mg/kg dose	[36]
		24-Nov	150 mL (5mg/kg dose)
		25-49	250 mL (5mg/kg dose)
		50-99	500 mL (5mg/kg dose)
		100-120	600 mL (5mg/kg dose)

The Current Treatment of Rare Disease, Lysosomal Acid Lipase Deficiency (LAL-D) and Paroxysmal Nocturnal Haemoglobinuria (PNH)

Abstract

Introduction

Paroxysmal Nocturnal Hemoglobinuria (PNH) and Lysosomal Acid Lipase Deficiency (LAL-D)

Registry and Diagnosis

Symptoms of PNH and LAL-D

Current Treatment

Kanuma as the Current Treatment for LAL-D

Method

Systematic Reviews and Meta-Analyses

Global Approval of Ultomiris, Soliris and Kanuma

Study Findings Following the Use of the Screening Procedure

Result and Discussion

Research Articles Distribution for the Three Medicines

Novel Therapies of PNH and LALD and it Advantage and Disadvantage

The Average Efficacy and Safety of Each Therapy Based on Research Articles and Clinical Trials

Recommended Infusion Volumes for Each Therapeutic, for the Treatment of PNH and LAL-D

Limitations

Conclusions

References