1 Limitations of ERT Oral GL-1 Synthase Inhibitor Therapy (SRT) - - PDF document

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MODULE 4 Management Strategies for Gaucher Disease Neal J. Weinreb, MD, FACP

Critical Conversations in Rare & Orphan Diseases: Challenges of Diagnosing and Caring for an Individual with Gaucher Disease

History

48 y/o woman with a 25-year history of “digestive problems” including periodic abdominal discomfort, bloating and early satiety also had chronic back and hip pain that was sometimes severe. She had easy bruising since childhood. When 38 y/o, PLT CT 72K was attributed to ITP but treatment was not needed. No other bleeding other than menorhagia. FH: “Pure” Italian. Other PH: hypothyroidism; one miscarriage.

Physical Exam

Spleen palpable 18 cm below LCM; liver 3 cm below RCM; scattered purpura arms and legs; thoracic kyphosis

Investigations

Hb 10.4 g/dL; MCV 83.3 fL; WBC 3600/µL; PLT 48,000/µL; LFTs wnl Ferritin 780ng/mL; serum iron 61 µg/dL; transferrin saturation 16% Polyclonal increase in IgG; PT, aPTT normal; Vit D 8 ng/mL L spine DEXA Z score: -2.8; Total L Femur Z score: -2.3 Abdominal ultrasound: Marked hepatosplenomegaly; cholelithiasis. MRI left and right lower extremities: Heterogeneous infiltration with medullary infarctions;

• steonecrosis and joint destruction left hip

WBC acid β-glucosidase activity: 8% of normal; consistent with GD GBA1 mutation analysis: N370S/unidentified allele

Case 4: GD1 Treatments and Treatment Goals Metabolic Pathway and Therapeutic Targets

Ceramide

Lactosylceramide Gangliosides

Galactosylceramide

Sphingomyelin

GL‐1

• Normal physiology: GL-1 synthesis balances GL-1 degradation
• GBA activity reduced by GBA mutations
• GCS activity increased in inflammation and GD mouse models
• GL-1 production increased in hypersplenism due to increased RBC and WBC turnover

Treatment Options

Pre-1991 Symptomatic Enzyme Replacement Therapy (ERT) Oral Substrate Reduction Therapy (SRT)

• Walkers,

wheelchairs

• Pain control
• Joint replacement
• Blood transfusion
• Splenectomy

FDA approved in US since 1991 IV infusions usually every 2 weeks

• Alglucerase*
• Imiglucerase
• Velaglucerase alfa
• Taliglucerase

FDA approved in US since 2003

• Miglustat
• Eliglustat

Summary: ERT Characteristics and Effects

• Recombinant, modified forms of glucocerebrosidase
• Specifically targeted for uptake by macrophage mannose receptors
• IV infusion every 2 weeks

– Imiglucerase – Velaglucerase – Taliglucerase alfa

• Results:

– Increased hemoglobin and platelet counts – Reduction in splenic and liver volumes – Increased bone mineral density – Less/no bone pain: slower response than viscera – Enhanced activity levels and lifestyle – Better responses with higher doses

Safety Issues with ERT

• ~10%-14% of patients experienced adverse events (AEs)
• Most are mild to moderate
• Mediated by IgG

– ~15% developed IgG antibodies, especially with imiglucerase and alglucerase*

• IgE reactions are severe—extremely rare
• <1% of AEs are related to route of administration: discomfort, pruritus, burning,

swelling, and sterile abscess at venipuncture site

• ~6.6%: pruritus, flushing, urticaria, angioedema, chest discomfort, dyspnea, coughing,

cyanosis, and hypotension

• ~6.5%: nausea, abdominal pain, vomiting, diarrhea, rash, fatigue, headache, fever,

dizziness, chills, backache, and tachycardia

• Prevention:

– Start IV infusion very slowly, and gradually increase rate – Pre-medicate with antihistamines if necessary

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Limitations of ERT

• Invasive and sometimes inconvenient or unavailable
• Ineffective for neuronopathic GD
• Not proven to prevent GD-associated Parkinsonism or malignancies
• Incomplete control of macrophage activation effects:
• Cytokines
• T and B cell stimulation
• Inflammatory manifestations including coagulation activation
• Incomplete control of skeletal manifestations:
• Marrow infiltration
• Bone mineral loss (osteopenia/osteoporosis)
• Osteonecrosis and fractures

Oral GL-1 Synthase Inhibitor Therapy (SRT) Miglustat

• Iminosugar that resembles glucose moiety of GL-1
• Efficacy: demonstrated non-inferiority in maintaining liver volume; also

maintained spleen volume, hemoglobin concentration, and platelet count in patients stable on ERT switching to miglustat

• FDA approved for patients with mild/moderate GD1 for whom ERT is not an
• ption
• Common AEs: GI issues, tremors, and weight loss
• Requires low-carbohydrate diet to minimize GI side effects

Eliglustat Clinical Trials

• The largest clinical trial program ever in GD
• Conducted over 14 years
• Included 395 patients in 34 countries
• Represents 1,400 patient-years of eliglustat exposure
• First to include a placebo-controlled phase 3 trial

‐80 ‐60 ‐40 ‐20 20 40 60 80 100 ‐2 ‐1.5 ‐1 ‐0.5 0.5 1 1.5 2 2.5 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 % Change from Baseline Change in Hemoglobin, g/dL Time on Eliglustat, years Platelets + 87%

Liver volume ‐23% Spleen volume ‐67% Mean ± SEM Hemoglobin +1.4 g/dL

ENGAGE: Long-Term Hematologic and Visceral Improvements at 4.5 Years in Previously Untreated Individuals with GD1

‐1.4 ‐1.2 ‐1 ‐0.8 ‐0.6 ‐0.4 ‐0.2 6 6.5 7 7.5 8 8.5 9 9.5 10 10.5 11 Mean Total BMB Score Time on Eliglustat, years I

I 0.75

I 1.5

I 2.5

I 3.5

I 4.5

Eliglustat ENGAGE Trial: Changes in BMD and BMB After 4.5 Years in Treatment-Naïve Patients

• Study design: Phase 3, placebo-controlled, randomized
• Population: adults with GD1 (N=40); duration: 9 months

Total BMB Score Spine T‐Score ‐0.5 ‐1 ‐1.5

Points to Remember About GD Treatment

• ERT effectively ameliorates most symptom-causing manifestations of GD1 in adults and

children, including splenomegaly, hepatomegaly, thrombocytopenia, anemia, bone crises, and chronic bone pain caused by GD1.

• Imiglucerase, velaglucerase, and taliglucerase appear to be similar in efficacy and safety.

There is no evidence for either superiority or inferiority to support a decision about which ERT to recommend. However, there are molecular differences, especially in glycosylation, that might impact efficiency of cellular uptake, transcriptome response in tissues and antigenicity.1

• Of the 2 oral SRTs (miglustat, eliglustat), eliglustat appears to have efficacy that is more

similar to that of the ERTs and can be prescribed for some treatment-naïve adult patients and for some patients currently or previously treated with ERT.2

• Eliglustat has a more favorable GI side-effect profile than miglustat.2
• 1. Brumshtein B, et al. Glycobiology. 2010;20:24-32; Tekoah Y, et al. Biosci Rep. 2013;33:pii:e00071; Dasgupta N, et al. PLoS One. 2013;8:e74912;
• 2. Mistry PK, et al. Blood Cells Mol Dis. 2018;71:71-4

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Points to Remember About GD Treatment (continued)

• Eligibility for eliglustat is limited by CYP2D6 genotype; pregnancy and lactation

status; severe chronic heart, liver, and kidney disease; and the potential for drug

• interactions. Eliglustat is not currently approved for pediatric use.2 Patients ineligible

for SRT should be treated with ERT.

• Neither ERT or current SRT are effective for neurological manifestations of GD2 or

GD3.

• The effect of ERT and SRT on long-term complications of GD1 (eg, Parkinsonism,

myeloma, and other malignancies) is currently unknown.2

• 1. Brumshtein B, et al. Glycobiology. 2010;20:24-32; Tekoah Y, et al. Biosci Rep. 2013;33:pii:e00071; Dasgupta N, et al. PLoS One. 2013;8:e74912;
• 2. Mistry PK, et al. Blood Cells Mol Dis. 2018;71:71-4

Domain Traditional therapeutic goals

Comprehensive assessments (adults and children)

• Annotate surrogate response indicators
• Evaluate treatment regimen

Hematologic

• Increase and maintain CBC at normal or near-normal values
• Eliminate symptoms associated with cytopenias

Visceral

• Achieve spleen volume <8 times normal
• Eliminate hypersplenism
• Achieve liver volume <1.5 times normal
• Alleviate abdominal pain and discomfort

Skeletal

• Eliminate bone crises
• Eliminate or alleviate GD bone pain
• Prevent osteonecrosis
• Correct osteopenia

Other

• Restore physical functional capacity
• Improve HRQOL scores

Short-term Management Goals for GD1

Management Goals for GD1 Relating to Long-Term Complications

• Early detection of hematological malignancies, including multiple myeloma, lymphoma

and amyloidosis (Sources: input from patients, national guidelines, literature search)

• Early detection of solid tumors, including hepatocellular carcinoma and renal cell

carcinoma (Sources: input from patients, national guidelines, literature search)

• Early detection of Parkinsonism/Parkinson disease (Sources: input from patients, national

guidelines, literature search)

• Early detection of insulin resistance and type 2 diabetes mellitus (Source: literature

search)

• Early detection of signs and symptoms indicative of GD3, such as eye movement

abnormalities (Source: consensus panel)

• General: Proper education of the patient and his family about the disease and therapy (Source:

consensus panel)

Points to Remember

• Several treatments are generally recognized as safe and effective for control of most

systemic manifestations of GD1, but none are curative. Treatment should be initiated with clear therapeutic goals. There is no standard international algorithm or guideline for when and in whom to initiate treatment.

• There is broad consensus that some patients may never require treatment but identifying

these individuals with a high degree of certainty has been problematic. They cannot be identified solely on the basis of genotype (e.g. N370S homozygotes) and apparently asymptomatic individuals may have a significant burden of disease (e.g. skeletal disease) after undergoing comprehensive evaluation. Late complications such as malignancies and Parkinsonism occur in these individuals, but there is little evidence that current treatments are preventative.

Points to Remember (continued)

• Evaluation of GD1 symptomatology may be impacted by concurrent illnesses, especially

as patients age. Manifestations such as mild to moderate osteopenia and thrombocytopenia may have greater significance in older untreated patients than in younger individuals, indicating the need for flexibility in treatment algorithms.