Taliglucerase Alfa Research Articles

Taliglucerase alfa in the longterm treatment of children and adolescents with type 1 Gaucher disease: the Albanian experience.

Enzyme replacement therapy is already recognized as the gold standard of care for patients with Gaucher disease. Taliglucerase alfa is one of the three alternatives recommended for treatment of Gaucher disease in children and adults. This study aims to evaluate the long-term efficacy and safety of Taliglucerase alfa in children and adolescents with Type 1 Gaucher disease. Over a six-year period, we monitored the efficacy of continuous treatment in 10 patients by assessing various parameters, including hemoglobin concentration, platelet count, liver and spleen volume, bone mineral density, glucosylsphingosine level, chitotriosidase activity, and growth parameters. Safety was evaluated by immunogenicity and adverse event monitoring. The mean age of patients was 13.4 ± 3.6 years and the treatment duration was 60.24 ± 13.4 months. From baseline to end line the parameters change as follows: hemoglobin concentration improved from 12.7 (±1.3) to 14.6 (±1.5) and platelet count from 180 (±74) to 198 (±79). The spleen volume, was reduced by 46% (p = 0,007). The chitotriosidase activity decreased from 4,019.7 (±3,542.0) nmoles/ml/hr to 2,039.5 (±1,372.2) nmoles/ml/hr (46% reduction). Glucoylsphingosine level dropped from 119.2 (±70.4) ng/ml to 86.2 (±38.1) ng/ml, indicating a reduction of 28%. Bone mineral density Z-score, improved from -1.47 (±1.76) to -0.46 (±0.99) (69.7% reduction). Out of the 1,301 total administrations, our patients reported only 37 (2.8%) infusion-related adverse events which were mild and transitory. Taliglucerase alfa exhibits good efficacy and a safe profile in the treatment of children and adolescents with Type 1 Gaucher disease.

Real-world experiences with taliglucerase alfa home infusions for patients with Gaucher disease: A global cohort study

Real-world experiences with taliglucerase alfa home infusions for patients with Gaucher disease: A global cohort study

Skeletal Manifestations, Bone Pain, and BMD Changes in Albanian Type 1 Gaucher Patients Treated with Taliglucerase Alfa

Gaucher disease is a rare, genetic lysosomal disorder leading to lipid accumulation and dysfunctions in multiple organs. Bone involvement is one of the most prevalent aspects of Gaucher disease. Pain, disability, and reduced quality of life remain the most frequent characteristics of bone involvement in Gaucher patients. Patients and Method. In this study, we will take into consideration data from 24 patients diagnosed with type 1 Gaucher disease. We followed them closely for six years in progress. At baseline, all patients started therapy with taliglucerase alfa at a mean dosage of 45 UI/kg; later, during the study, two of them switched their cure toward velaglucerase alfa. Before baseline evaluations, 12 patients had been treated with imiglucerase at variable duration times. At baseline, we performed an X-ray of long bones and the spine, and each year, different standard assessments were performed, such as bone pain, MRI of the vertebral spine and pelvis, and DEXA for bone density. Four patients left the study for various reasons, two of them at baseline and two others during year 3 (FU3). Results. At baseline, we had 8 children and 16 adults. The average age was 28.7 ± 16.5 SD years. The most frequent skeletal manifestations in our patients were reduction of tibial femoral space (40%), osteonecrosis (36%), and body vertebral reduction (32%). At baseline, 15 patients presented with bone pain to different degrees. Over the years, bone pain in our patients had a gradual improvement. The most dramatic bone pain improvement was seen in a patient who presented bone crises. Another impressive finding was a significant BMD improvement during six years of treatment. Our study showed a significant improvement in BMD comparing FU5 and baseline values ( p = 0.0007). Especially children demonstrated a significant improvement in BMD ( p = 0.00061) compared to adults ( p = 0.3673). Mean BMD change was more indicative in switched patients ( p = 0.0142) compared to naïve patients ( p = 0.147). Conclusions. Skeletal manifestations are very different in Gaucher type 1 patients. In our study, as a result of long-term evaluations, it was noticed that the most frequent skeletal manifestation was a reduction of tibiofemoral space. Bone pain has gradually improved in all patients. Also, BMD values have been enhanced over six years of treatment, especially in children.

Real-World Experiences with Taliglucerase Alfa Home Infusions for Patients with Gaucher Disease: A Global Cohort Study.

Taliglucerase alfa is an enzyme replacement therapy approved for Gaucher disease. We assessed the duration/compliance/safety of such home infusions in commercial use in four countries where home infusion programs are available. The treatment duration/compliance study included 173 patients (Israel, 58; US, 61; Brazil, 48; Australia, 6) who received ≥1 taliglucerase alfa home infusion through 6/2021. The median age at home therapy initiation was 38 (range, 2-87) years; 58% were females. The median treatment duration (at home) was 2.7 (range, 0.04-9.0) years. The annual compliance rate was stable (≥95%) throughout the study period. A search of the Pfizer global safety database (through 6/2021), identified 19 adverse events (AEs) as related to "definite home use" and 14 to "possible home use" of taliglucerase alfa; 42.4% of these AEs were serious; none were fatal. Twelve serious AEs in five separate case reports were considered treatment related: one case of chest discomfort/pain and hypertension and one case of erythema associated with a toe blister, for which causality could not be excluded; pain in extremity; projectile vomiting and chills, alongside excessive eye blinking; and an infusion-related AE (pruritus). In conclusion, this real-life global study demonstrated that taliglucerase alfa home infusions are safe with high compliance rates.

The Bone Biomarker of Quantitative Chemical Shift Imaging in Patients with Type 1 Gaucher Disease Receiving Low-Dose Long-Term Enzyme Replacement Therapy

Quantitative chemical shift imaging (QCSI) is the most sensitive imaging biomarker to assess bone marrow involvement in Gaucher disease. Widespread QCSI use is limited by test availability. Anecdotal reports describe two patients demonstrating significant improvement in fat fraction (FF) assessed by QCSI following a switch from imiglucerase to taliglucerase alfa. This analysis evaluated bone marrow involvement in adults with Type 1 Gaucher disease receiving low-dose enzyme replacement therapy (ERT) with imiglucerase and/or velaglucerase alfa. We report baseline data for 30 patients meeting eligibility criteria. Median (range) duration and dose of ERT were 18 (5-26) years and 30 (30-60) U/kg/month, respectively. Low FF scores (<0.30) were observed for seven patients (23%; 95% confidence interval, 10-42%) and were more common in females (n = 6) versus males (n = 1; p < 0.025); one female was menopausal. These baseline data demonstrate that prolonged low-dose ERT with imiglucerase or velaglucerase alfa led to an adequate bone response, assessed by QCSI, in the majority of patients. A minority of such patients with suboptimal bone response require therapeutic change. The next phase of the study will address the effect of switching to taliglucerase alfa on bone status for patients with less than optimal QCSI scores (<0.30).

A Systematic Review and Meta-analyses of Longitudinal Studies on Drug Treatments for Gaucher Disease.

Gaucher disease (GD) is a rare disorder linked to the absence/deficiency of glucocerebrosidase. GD can be treated by enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). The aim of this systematic review (SR) is to assess the effectiveness of drugs used for GD treatment. Searches were conducted in PubMed and Scopus, in April 2021. The search strategies encompassed the name of the disease and of the drug treatments. Manual search was also conducted. Observational and interventional longitudinal studies evaluating ERT and SRT for GD were included. Single mean meta-analyses were conducted for each drug using R. The initial search retrieved 2246 articles after duplicates were removed. Following screening and eligibility assessment, 68 reports were included. The studies evaluated imiglucerase, velaglucerase alfa, taliglucerase alfa, miglustat, and eliglustat. The results showed that ERT is effective as a treatment in both naïve and experienced patients. Miglustat did not significantly improve blood outcomes in naïve patients and resulted in a decrease in the platelet levels of experienced patients. Eliglustat was mainly assessed for experienced patients and resulted in stable outcome values. This extensive SR confirms the effectiveness of GD treatments in short- and long-term follow-ups. The results were favorable for all ERTs and for eliglustat. Based on the assessed evidence, miglustat did not achieved expressive results. However, all evidence should be interpreted considering its limitations and does not replace well-conducted randomized trials.

The budget impact of enzyme replacement therapy in type 1 Gaucher disease in the United States

Aim Gaucher disease (GD) is a rare autosomal recessive condition. Type 1 GD (GD1) is the most prevalent form of GD in Western countries; enzyme replacement therapy (ERT) is a treatment option for patients with GD1. To understand the economic value of the GD1 ERT velaglucerase alfa, a budget impact model (BIM) was developed from a United States (US) payer perspective. Methods We estimated the budget impact of velaglucerase alfa for a 10-million-member US health plan by comparing the annual total costs of therapy between a scenario using current velaglucerase alfa uptake to a projected scenario with increased velaglucerase alfa uptake. Total drug costs for both scenarios were estimated as the sum of the product of the number of eligible patients on each treatment and the annual per-patient cost of each medication. Average per-patient costs for ERTs were calculated by adding the yearly drug acquisition, drug administration, and site-of-care markup costs. The budget impact was measured over years 1–3. Results An estimated 65 patients would receive velaglucerase alfa treatment in year 1, increasing to 90 patients by year 3. Across analyses, cost savings were realized with velaglucerase alfa compared with imiglucerase ($115,909) and taliglucerase alfa ($80,401). An annual total budget savings of $8.67 million could be realized for a hypothetical 10-million-member US health plan with increased velaglucerase alfa uptake. The per-member per-month costs decreased by $0.0241 across years 1–3. Conclusions BIM results show that increased velaglucerase alfa uptake for GD1 treatment is cost-saving for US health plans.

Safety and effectiveness of taliglucerase alfa in patients with Gaucher disease: an interim analysis of real-world data from a multinational drug registry (TALIAS)

BackgroundLimited real-world data from routine clinical care are available on the safety and effectiveness of treatment with taliglucerase alfa in patients with Gaucher disease (GD).MethodsTaliglucerase Alfa Surveillance (TALIAS), a multinational prospective Drug Registry of patients with GD, was established to evaluate the long-term safety (primary objective) and effectiveness (secondary objective) of taliglucerase alfa. We present an interim analysis of the data from the Drug Registry collected over the 5-year period from September 2013 to January 2019.ResultsA total of 106 patients with GD (15.1% children aged < 18 years; 53.8% females) treated with taliglucerase alfa have been enrolled in the Drug Registry, as of January 7, 2019. The median duration of follow-up was 795 days with quartiles (Q1, Q3) of 567 and 994 days. Fifty-three patients (50.0%) were from Israel, 28 (26.4%) were from the United States, and 25 (23.6%) were from Albania. At the time of enrollment, most patients (87.7%) had received prior enzyme replacement therapy (ERT). Thirty-nine of the 106 patients had treatment-emergent adverse events (AEs). Twelve of the 106 patients experienced serious AEs; two patients experienced four treatment-related serious AEs. Four patients died, although none of the deaths was considered to be related to taliglucerase alfa treatment by the treating physicians. Nine patients discontinued from the study, including the four who died. At baseline, patients with prior ERT had a higher mean hemoglobin concentration and platelet counts than treatment-naïve patients, likely reflecting the therapeutic effects of prior treatments. During follow-up, the hemoglobin concentration and platelet counts increased in the treatment-naïve patients and remained relatively constant or increased slightly in patients with prior ERT. Spleen and liver volumes decreased in treatment-naïve patients.ConclusionsThe interim data showed no new or emergent safety signals. The overall interim data are consistent with the clinical program experience and known safety and effectiveness profile of taliglucerase alfa.

Efficacy and Safety of Taliglucerase Alfa for the Treatment of Gaucher Disease: A 9-Year Experience

Efficacy and Safety of Taliglucerase Alfa for the Treatment of Gaucher Disease: A 9-Year Experience

Plant-Based COVID-19 Vaccines: Current Status, Design, and Development Strategies of Candidate Vaccines.

The prevalence of the coronavirus disease 2019 (COVID-19) pandemic in its second year has led to massive global human and economic losses. The high transmission rate and the emergence of diverse SARS-CoV-2 variants demand rapid and effective approaches to preventing the spread, diagnosing on time, and treating affected people. Several COVID-19 vaccines are being developed using different production systems, including plants, which promises the production of cheap, safe, stable, and effective vaccines. The potential of a plant-based system for rapid production at a commercial scale and for a quick response to an infectious disease outbreak has been demonstrated by the marketing of carrot-cell-produced taliglucerase alfa (Elelyso) for Gaucher disease and tobacco-produced monoclonal antibodies (ZMapp) for the 2014 Ebola outbreak. Currently, two plant-based COVID-19 vaccine candidates, coronavirus virus-like particle (CoVLP) and Kentucky Bioprocessing (KBP)-201, are in clinical trials, and many more are in the preclinical stage. Interim phase 2 clinical trial results have revealed the high safety and efficacy of the CoVLP vaccine, with 10 times more neutralizing antibody responses compared to those present in a convalescent patient’s plasma. The clinical trial of the CoVLP vaccine could be concluded by the end of 2021, and the vaccine could be available for public immunization thereafter. This review encapsulates the efforts made in plant-based COVID-19 vaccine development, the strategies and technologies implemented, and the progress accomplished in clinical trials and preclinical studies so far.

Impact of Long-Term Enzyme Replacement Therapy on Glucosylsphingosine (Lyso-Gb1) Values in Patients with Type 1 Gaucher Disease: Statistical Models for Comparing Three Enzymatic Formulations

For three decades, enzyme replacement therapy (ERT), and more recently, substrate reduction therapy, have been the standard-of-care for type I Gaucher disease (GD1). Since 2012, three different ERTs have been available. No clinical trial or academic study has ever compared these ERTs beyond one year. Herein we compare the impact of the ERTs on repeated measurements of glucosylsphingosine (lyso-Gb1; the most sensitive and GD-specific biomarker). A total of 135 adult patients (77 (57%) female) with GD1, followed from July 2014 to March 2020 and treated with a single ERT (imiglucerase (n = 41, 30.4%), taliglucerase alfa (n = 21, 15.6%) and velaglucerase alfa (n = 73, 54.1%)), were included. Disease severity was defined by genotypes (mild: N370S (c.1226A>G) homozygous and N370S/R496H (c.1604G) compound heterozygous; severe: all other genotypes) and by the severity score index (SSI; mild: <7; severe: ≥7). Lyso-Gb1 testing was performed at Centogene™ on dry blood spot samples collected during routine visits. Patients treated with imiglucerase had higher lyso-Gb1 levels at different time points. A huge variation in lyso-Gb1 levels was noticeable both inter-individually and intra-individually for all three ERTs. A steeper and faster decrease of lyso-Gb1 levels was shown in velaglucerase alfa. Nevertheless, the differences between medications were not very large, and bigger numbers and more pretreatment data are required for more powerful conclusions.

Cellular engineering of plant cells for improved therapeutic protein production.

In vitro cultured plant cells, in particular the tobacco BY-2 cell, have demonstrated their potential to provide a promising bioproduction platform for therapeutic proteins by integrating the merits of whole-plant cultivation systems with those of microbial and mammalian cell cultures. Over the past three decades, substantial progress has been made in improving the plant cell culture system, resulting in a few commercial success cases, such as taliglucerase alfa (Elelyso®), the first FDA-approved recombinant pharmaceutical protein derived from plant cells. However, compared to the major expression hosts (bacteria, yeast, and mammalian cells), plant cells are still largely underutilized, mainly due to low productivity and non-human glycosylation. Modern molecular biology tools, in particular RNAi and the latest genome editing technology CRISPR/Cas9, have been used to modulate the genome of plant cells to create new cell lines that exhibit desired “traits” for producing therapeutic proteins. This review highlights the recent advances in cellular engineering of plant cells towards improved recombinant protein production, including creating cell lines with deficient protease levels or humanized glycosylation, and considers potential development in the future.

Pharmacoeconomic analysis of taliglucerase alfa used in the Russian Federation for Gaucher’s disease

<h3>ЦЕЛЬ ИССЛЕДОВАНИЯ</h3> Определить предпочтительную схему ферментозаместительной терапии (ФЗТ) с точки зрения клинико-экономического анализа и оценить возможную экономию бюджета программы при широком внедрении в клиническую практику препарата талиглюцераза альфа для лечения болезни Гоше. <h3>МАТЕРИАЛ И МЕТОДЫ</h3> Клинико-экономический анализ проводили с использованием минимизации затрат, поскольку сравниваемые препараты талиглюцераза альфа, имиглюцераза и велаглюцераза альфа обладают сопоставимой эффективностью. В анализе влияния на бюджет текущая клиническая практика (без талиглюцеразы) сопоставлялась с моделируемой клинической практикой, подразумевающей перевод на талиглюцеразу 40% пациентов в первый год, 60% — во второй и 80% — в третий. Исходный бюджет программы ВЗН, предназначенный для обеспечения пациентов с болезнью Гоше препаратами ФЗТ, оценивали, исходя из объема препаратов, закупленных в 2019 г. Учитывали только лекарственные затраты. Анализ проводили с использованием двух вариантов цен на сравниваемые препараты: предельные отпускные цены производителей с учетом 10% НДС и средневзвешенные цены, согласно результатам государственных торгов, в 2019 г. В завершение исследования проведен анализ чувствительности в отношении изменения цен на сравниваемые препараты, разовой дозы препаратов и объемов потребления лекарственных препаратов. <h3>РЕЗУЛЬТАТЫ</h3> При использовании цен государственных закупок годовая стоимость терапии препаратом талиглюцераза альфа у взрослых пациентов массой 70 кг на 23—28% ниже таковой для препаратов сравнения, у детей массой 35 кг — стоимость меньше на 26—32%. Таким образом, в рамках фиксированного бюджета программы ВЗН, достаточного для обеспечения 7 пациентов применяемыми сегодня схемами ФЗТ, возможно обеспечить до 10 больных препаратом талиглюцераза альфа в эквивалентной дозе. При использовании зарегистрированных цен с 10% НДС у взрослых пациентов снижение затрат достигало 23—41%, у детей — 26—43%. Анализ влияния на бюджет показал, что при постепенном переключении на препарат талиглюцераза альфа (в первый год 40%, во второй — 60% и в третий — 80% пациентов), суммарное снижение нагрузки на бюджет программы за 3 года составит 770,6 млн руб. (12,26%) при использовании цен государственных закупок и достигнет 932,0 млн руб. (13,82%) при использовании зарегистрированных цен с 10% НДС. Анализ чувствительности продемонстрировал устойчивость полученных результатов к изменению входных параметров в широком диапазоне. <h3>ВЫВОДЫ</h3> Применение препарата талиглюцераза альфа для ферментозаместительной терапии при болезни Гоше вместо применяемых в настоящее время лекарственных средств фармакоэкономически обоснованно и целесообразно. При сопоставимой эффективности и безопасности применение талиглюцеразы альфа позволит значительно снизить затраты на ферментозаместительную терапию.

Bone involvement in Gaucher disease type 1: a differential diagnosis of multiple fractures in a young patient. Case report

Gaucher disease type 1 (GD1) is a rare inherited disease caused by mutations in the GBA1 gene, which encodes the lysosomal enzyme glucocerebrosidase, leading to decreased enzyme activity and the consequential accumulation of its substrate, glucosylceramide, within macrophages. Bone involvement in GD1 may include avascular necrosis, bone infarcts, fragility fractures, lytic or sclerotic bone lesions and osteomyelitis. Bone pain can manifest as an acute and very painful bone crisis or a chronic pain that might vary in intensity, usually caused by fractures or avascular necrosis with progressive collapse of bone and joints. Hence, this report aims to describe a case of Gaucher disease type 1 and discuss its diagnosis, bone involvement and management, since late diagnosis or inadequate therapy can lead to clinical worsening, irreversible mobility impairment and increased morbidity. AGR, a 32-year-old male patient, was admitted to the Rheumatology Service with a previous history of diffuse bone pain, episodic hyperemia in the lower limbs since the age of 9 and two low-impact fractures. He had an initial non-confirmed diagnostic hypothesis of chronic recurrent multifocal osteomyelitis and was taking dipyrone and tramadol to reduce pain. His physical examination evinced overweight (body mass index: 29.7 kg/m2) and hepatosplenomegaly. Laboratory tests shown thrombocytopenia, with platelet count 103,000/mm3 (reference value [RV]: 140,000-450,000/mm3), serum phosphorus 4.7 mg/dL (RV: 2.7-4.5 mg/dL), C-reactive protein 88.8 mg/dL (RV: &lt; 5 mg/dL) and ferritin 1336 ng/mL (RV: 30-400 ng/mL). Biochemical and bone turnover markers were normal, including serum total calcium and magnesium, parathyroid hormone, 25-OH vitamin D, alkaline phosphatase, procollagen type-I N-terminal propeptide and C-terminal telopeptide of type I collagen. Conventional radiographies and magnetic resonance imaging were performed and confirmed previous fractures in the right humerus and the right acetabulum. They also showed sclerotic lesions in the left femur and Erlenmeyer flask deformities in the distal femurs and the proximal tibias. Bone scintigraphy indicated a bone infarct area in the left tibia. Areal bone mineral density (BMD) evaluated by bone densitometry showed a left total femur Z-score of +4.3 and left femoral neck Z-score of +4.5. Differently, the bone microarchitecture and volumetric BMD, evaluated by a high-resolution peripheral quantitative computed tomography (HR-pQCT) at distal radius and distal tibia, demonstrated an impairment of cortical compartment with lower cortical thickness and lower cortical volumetric BMD, possibly contributing to the low-impact fractures. Considering the compatible radiological findings, associated with hepatosplenomegaly and thrombocytopenia, Gaucher disease type 1 became the major hypothesis. It was confirmed after enzymatic dosage, which showed low residual glucocerebrosidase activity and high serum chitotriosidase. Enzyme replacement therapy was started with taliglucerase alfa, a recombinant enzyme preparation that aims to supply the lacking glucocerebrosidase in lysosomes. After 6 months of treatment, patient reported a significant improvement in bone pain and general quality of life. Therefore, clinicians should be alert to young patients with multiple low-impact fractures and further evaluate other possible bone involvement, as GD1 may be a differential diagnosis. Since it needs specific treatment, early diagnosis can be crucial to avoid permanent bone damage and morbidity.

Open-label, expanded access study of taliglucerase alfa in patients with Gaucher disease requiring enzyme replacement therapy

A multicenter, open-label, expanded-access study followed the safety of taliglucerase alfa, a plant cell–expressed recombinant enzyme replacement therapy (ERT), in adults with Gaucher disease previously treated with imiglucerase. Patients received taliglucerase alfa every 2 weeks for 9 months at a dose equivalent to their previous imiglucerase dose (Part A); patients were offered treatment for up to 33 months (Part B), and a later amendment allowed treatment-naïve patients.Fifty-eight patients received taliglucerase alfa (55.2% male; mean age, 46.1 years; mean bi-weekly dose, 35.2 U/kg; mean duration, 17.8 months); 51 patients previously received ERT, seven were treatment-naïve, and 36 completed the study. Most adverse events were mild or moderate; treatment-related adverse events were mild and transient. In previously treated patients, increases from baseline to last follow-up were observed for mean ± SE hemoglobin concentration (13.0 ± 0.3 g/dL to 13.4 ± 0.2 g/dL) and platelet count (179,242 ± 15,344/mm3 to 215,242 ± 17,867/mm3). Findings were similar in treatment-naïve patients (mean ± SE hemoglobin concentration and platelet count, 12.8 ± 0.3 g/dL to 13.5 ± 0.2 g/dL and 168,821 ± 14,368/mm3 to 204,641 ± 16,071/mm3, respectively).Taliglucerase alfa was well-tolerated for up to 33 months and demonstrated a durable therapeutic effect.

Bone Marrow Involvement in Patients with Type 1 Gaucher Disease Receiving Low-Dose Long Term Enzyme Replacement Therapy (median 18 years)

Bone complications are the most dramatic and life-impairing outcomes of type 1 Gaucher disease (GD1), a common lysosomal storage disorder. Bone marrow infiltration by Gaucher cells substantially decreases the bone marrow fat fraction (FF), and the extent of this reduction correlates with the overall severity of skeletal manifestations in this disorder. Previous studies have demonstrated that the degree of infiltration can best be estimated by magnetic imaging resonance (MRI)-based quantitative chemical shift imaging (QCSI) and that the fat fraction (FF) score so derived can predict the risk of clinically important bone events. The aim of this study was to evaluate bone marrow involvement in GD1 patients who had received enzyme replacement therapy (ERT) for at least 5 years. Methods: Patients from SZMC Gaucher unit, ≥ 18 years, who were treated with ERT for ≥ 5 years, with a stable dose in the previous 6 months, were recruited. Patients taking another experimental drug, with past exposure to taliglucerase-alfa, presence of any medical, emotional, behavioral or psychological condition were excluded. Energy x-ray absorptiometry (DEXA) was performed at SZMC and the QSCI was performed at the Academic Medical Center in Amsterdam, Netherlands as previously described [Mass et al, Am J Radiol 2002:179:961-965]. A QCSI score of &lt;0.30 was indicative of bone at risk. This investigator initiated clinical trial was approved IRB at SZMC and AMC and sponsored by Pfizer. Study number registration- MOH-2017-04-000351. Results: Thirty patients (13 females) at a median (range) age of 46 (19-71) years consented to participate in this study and to perform the QCSI test. GBA mutations of study patients included N370S homozygote (n=12), N370S compound heterozygote (n=17), and T431 homozygote (n=1). The median (range) duration of ERT was 18 (5-26) years. Thirteen patients were receiving imiglucerase as the primary ERT [median (range) duration, 19 (9-26) years], five patients were receiving velaglucerase alfa [median (range) duration, 11 ( 5-12) years], and 12 patients converted from imiglucerase to velaglucerase alfa [median (range) duration, 7 (6-10) years]. The majority of patients received low-dose regimen, i.e. 15 Units/kg/2 weeks (Table 1). The median (range) T score for lumbar spine from DEXA scans, available for 26 of 30 patients, was −1.3 (−2.8-0.0). The median (range) QCSI score was 0.42 (0.24-0.66). Seven patients, 23% (95% confidence interval 10%-42%), had abnormal QCSI FF scores (&lt;0.30). Abnormal QSCI score was more common in female compared to male (Table 1) (p=0.025). Only one of these was menopausal. No differences were found in age, gender, genotype, history of splenectomy, duration and type of ERT and GD-related parameters between those with QSCI score of bone at risk to those with normal score (Table 1). In summary, these findings demonstrate that, despite prolonged treatment with imiglucerase and/or velalgucerase alfa, 23% of patients still had QCSI scores indicative of an inadequate response in bones. Nevertheless, most patients with prolonged low-dose ERT maintain a normal QCSI, indicative of a positive bone status. The higher prevalence of women in the cohort with low FF is not related to menopausal phase and remains unexplained. As no other patient-related nor GD-related parameter predicted abnormal bone marrow infiltration, a more widely available, quantitative measure of bone marrow infiltration is required for the assessment of response in bones to ERT for patients with GD1. The second phase of this study will evaluate the impact of a switch to a third ERT in those patients from this study with QCSI scores of &lt;0.30. These patients will be offered treatment with taliglucerase alfa at equivalent doses and subsequent reassessment of any impact on clinical symptoms and QCSI scores evaluated. Disclosures Revel-Vilk: Takeda: Honoraria, Other: Travel, Research Funding; Prevail therapeutics: Honoraria, Other: Travel, Research Funding; Pfizer: Honoraria, Other: Travel, Research Funding; Sanofi: Honoraria, Other: Travel, Research Funding. Szer:Alexion: Honoraria, Other: Travel, Research Funding; Amgen: Honoraria, Other: Travel, Research Funding; Celgene: Honoraria, Other: Travel, Research Funding; MSD: Honoraria, Other: Travel, Research Funding; Novartis: Honoraria, Other: Travel, Research Funding; Pfizer: Honoraria, Other: Travel, Research Funding; Takeda: Honoraria, Other: Travel, Research Funding; Sanofi: Honoraria, Other: Travel, Research Funding; Prevail Therapeutics: Honoraria, Other: Travel, Research Funding. Zimran:Centogene: Other: research grant; Shire: Consultancy, Honoraria, Research Funding; TAKEDA: Honoraria; Pfize: Honoraria, Research Funding; Bio-events: Honoraria; Targeted Cell Therapies: Consultancy; Prevail Therapeutics: Consultancy.

A Multicenter, Safety and Efficacy Study of Taliglucerase Alfa in Subjects With Type 3 Gaucher Disease

A Multicenter, Safety and Efficacy Study of Taliglucerase Alfa in Subjects With Type 3 Gaucher Disease

Critical Evaluation of Strategies for the Production of Blood Coagulation Factors in Plant-Based Systems.

The use of plants as production platforms for pharmaceutical proteins has been on the rise for the past two decades. The first marketed plant-made pharmaceutical, taliglucerase alfa against Gaucher’s disease produced in carrot cells by Pfizer/Protalix Biotherapeutics, was approved by the US Food and Drug Administration (FDA) in 2012. The advantages of plant systems are low cost and highly scalable biomass production compared to the fermentation systems, safety compared with other expression systems, as plant-based systems do not produce endotoxins, and the ability to perform complex eukaryotic post-translational modifications, e.g., N-glycosylation that can be further engineered to achieve humanized N-glycan structures. Although bleeding disorders affect only a small portion of the world population, costs of clotting factor concentrates impose a high financial burden on patients and healthcare systems. The majority of patients, ∼75% in the case of hemophilia, have no access to an adequate treatment. The necessity of large-scale and less expensive production of human blood coagulation factors, particularly factors associated with rare bleeding disorders, may be an important area for plant-based systems, as coagulation factors do not fit into the industry-favored production models. In this review, we explore previous studies on recombinant production of coagulation Factor II, VIII, IX, and XIII in different plant species. Production of bioactive FII and FIX in plants was not achieved yet due to complex post-translational modifications, including vitamin K-dependent γ-carboxylation and propeptide removal. Although plant-made FVIII and FXIII showed specific activities, there are no follow-up studies like pre-clinical/clinical trials. Significant progress has been achieved in oral delivery of bioencapsulated FVIII and FIX to induce immune tolerance in murine models of hemophilia A and B, resp. Potential strategies to overcome bottlenecks in the production systems are also addressed in this review.

Open-Label, Expanded Access Study of Taliglucerase Alfa in Patients with Gaucher Disease Requiring Enzyme Replacement Therapy

Taliglucerase alfa, an enzyme replacement therapy (ERT) approved in several countries for the treatment of adult and pediatric patients with Type 1 Gaucher disease, is the first FDA-approved plant cell-expressed recombinant therapeutic protein for humans. PB-06-004 (NCT00962260) was a multicenter, open-label, expanded access study designed to follow the safety of taliglucerase alfa in patients with Gaucher disease who required ERT and who were previously treated with imiglucerase but had a dose reduction or discontinued due to a shortage of imiglucerase. Eligible patients (aged ≥18 years) with Type 1 Gaucher disease received taliglucerase alfa every 2 weeks for ³9 months at a dose equivalent to their previous imiglucerase dose, before it was reduced or discontinued (Part A), and had the option of continuing treatment for up to 33 months (Part B); a later amendment allowed treatment-naïve patients. Fifty-eight patients received treatment (55.2% male, mean age 46.1 years, mean bi-weekly dose 35.2 U/kg, mean duration 17.8 months); 51 patients previously received ERT, 7 were treatment-naïve. Thirty-six patients completed the study. Hemoglobin concentration and platelet counts were also explored. Most adverse events (AEs) were mild or moderate in severity and not related to taliglucerase alfa; treatment-related AEs were mild and transient in nature. In previously treated patients, mean (SE) hemoglobin concentration was 13.0 (0.3) g/dL at baseline, 13.4 (0.2) g/dL at 9 months, and 13.4 (0.2) g/dL at last follow-up; mean (SE) platelet count was 179,242 (15,344)/mm3 at baseline, 209,727 (17,157)/mm3 at 9 months, and 215,242 (17,867)/mm3 at last follow-up. In treatment-naïve patients, mean hemoglobin concentration and platelet counts increased. In conclusion, taliglucerase alfa was well tolerated for up to 33 months of treatment and demonstrated a durable therapeutic effect, as evidenced by stable or improved hemoglobin concentration and platelet counts in this expanded access study. DisclosuresKuter:BMS: Research Funding; Bioverativ: Consultancy, Research Funding; Rigel: Consultancy, Research Funding; Protalex: Research Funding; Novartis: Consultancy; Principia: Research Funding; Amgen Inc.: Consultancy; Argenx: Consultancy; ONO: Consultancy; Syntimmune: Consultancy; Pfizer: Consultancy; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wajnrajch:Pfizer Inc: Employment. Hernandez:Pfizer Inc: Employment. Wang:Pfizer Inc: Employment. Chertkoff:Protalix Biotherapeutics: Employment. Zimran:Pfizer Inc: Honoraria; Shire: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Genzyme: Honoraria, Research Funding.

PSY51 - CLINICAL AND ECONOMIC ASPECTS OF ENZYME REPLACEMENT THERAPY IN RUSSIAN PATIENTS WITH GAUCHER DISEASE TYPE 1

To evaluate the pharmacoeconomic effectiveness of drugs for enzyme replacement therapy (ERT), i.e. imiglucerase, velaglucerase alpha and taliglucerase alfa, in adults with Gaucher disease Type 1 (GD1), who receive treatment in conditions of the Russian health care system. The analysis of the results of clinical trials revealed no statistically significant advantages of any of the considered drug for ERT. Therefore, cost-minimization analysis (CMA) was conducted. The budget impact model considered three scenarios of enzyme replacement therapy of Gaucher disease Type 1 in adults on the stage of stable disease development (imiglucerase, velaglucerase alpha and taliglucerase alfa). The costs of original ERT drugs were calculated from the maximum manufacturer's prices indicated in the list of vital and essential medicines of 1 March 2018. The accepted dosing regimen in ERT was 60 U/kg of body mass (4 200 U). The cost of one administration was 508,200 RUB for taliglucerase alfa, 1,017,014.44 RUB for velaglucerase alpha, and 1,025,530.71 RUB for imiglucerase. The considered drugs were administered once per two weeks, so the costs of one-year course of treatment were 12,196,800.00 RUB, 24,408,346.51 RUB and 24,612,737.00 RUB per patient, respectively. Therefore, the cost of ERT in patients with Gaucher disease in taliglucerase alfa group was two times lower compared to the alternative drugs. It is possible to say that taliglucerase alfa is efficient from the pharmacoeconomic point of view. The introduction of a treatment schedule with taliglucerase alfa can lead to 50% decrease of the cost of ERT in adult patients with Gaucher disease in conditions of the Russian health care system