Background

Hematopoietic stem cell transplant (HSCT) in IMDs prevents progression of fatal neurodegeneration. Cord blood as a preferred donor source is disadvantaged by delayed engraftment and graft failure due to low CD34+ cell numbers. Higher cell doses are correlated with improved outcomes and cross-correction of disease. MGTA-456 is a novel cell therapy which provides a high dose of CD34+ cells and is being investigated in an ongoing Phase 2 clinical study to assess the safety and long-term outcomes in IMD patients.

Methods

A Phase 2 trial (NCT03406962) is enrolling 12 patients <16 yo with a diagnosis of cerebral onset adrenoleukodystrophy (cALD), mucopolysaccharidosis type IH (MPS I), metachromatic leukodystrophy (MLD) or globoid cell leukodystrophy (GLD). Patients receive a myeloablative conditioning regimen. Patients are followed for 1 year after transplant and eligible patients may enroll in a long-term follow-up study (NCT04008849).

Results

2 patients with cALD and 3 with MPS I, have been treated per protocol and with follow-up up to 1 year. In patients with cALD, resolution of gadolinium enhancement on MRI occurred by one month and was sustained throughout the follow-up period (Fig 1). Loes scores, a measure of disease severity, and Neurologic Function Scores remained stable over this time period consistent with a halt in disease progression. Neurocognitive function remains stable to date with no deterioration in Wechsler IQ Scale and Vineland Adaptive Behavior Scales.

MPS I patients showed normalization of blood a-L-iduronidase and excretion of MPS I-specific urinary glycosoaminoglycans declined from baseline over the period of observation (Fig 2). Neurologic development and function scores as measured by Bayley Infant Development and Vineland Scales are being collected.

Patients received a median CD34⁺ dose of 110 × 10⁶ cells/kg and TNC dose of 26 × 10⁷ cells/kg with a median duration of neutropenia of 1 day (range 0-9) compared to a median of 8 days for historical controls. Myeloid chimerism was ≥98% donor in evaluable patients by day +14 and immune reconstitution of CD4 and CD8 T cell subsets were comparable or better than historical controls. Two steroid-responsive episodes of skin-only aGVHD were observed and no cGVHD developed. Data on additional patients receiving cryopreserved MGTA-456 will be reported.

Conclusions

Treatment with MGTA-456 in patients with IMDs shows early, robust engraftment and immune reconstitution, features that are highly associated with improved clinical outcomes. Disease-specific outcomes up to one-year post-transplant in MPS I and cALD patients show crucial, durable stabilization in biochemical, MRI and clinical/neurodevelopmental assessments. In summary, the high CD34+ cell doses delivered by MGTA-456 shows compelling potential to rapidly and durably improve outcomes in IMD patients.

中文翻译：

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Mgta-456细胞治疗遗传性代谢性疾病（IMD）在第二阶段试验中可快速，持久地长期改善疾病特异性结果

背景

IMD中的造血干细胞移植（HSCT）可防止致命性神经变性的进展。脐带血作为首选的供体来源，由于CD34 +细胞数量低，延迟了移植和移植失败，因此受到不利影响。较高的细胞剂量与改善的结局和疾病的交叉校正相关。MGTA-456是一种新型细胞疗法，可提供高剂量的CD34 +细胞，并且正在进行一项正在进行的2期临床研究中，以评估IMD患者的安全性和长期预后。

方法

一项2期试验（NCT03406962）正在招募12名<16岁的患者，诊断为脑发作性肾上腺皮质营养不良（cALD），IH型粘多糖贮积症（MPS I），异色性白细胞营养不良（MLD）或球状细胞性白细胞营养不良（GLD）。患者接受清髓治疗方案。移植后对患者进行1年的随访，符合条件的患者可参加长期随访研究（NCT04008849）。

结果

按照方案对2例cALD患者和3例MPS I患者进行了治疗，随访时间长达1年。在患有cALD的患者中，在MRI上MRI的增强作用消退了一个月，并且在整个随访期间一直持续（图1）。在该时间段内，Loes评分，疾病严重程度的度量以及神经功能评分均保持稳定，与疾病进展停顿相一致。迄今为止，神经认知功能保持稳定，而Wechsler IQ量表和Vineland适应行为量表均未恶化。

MPS I患者在观察期间显示出血液中aL-艾杜糖醛酸酶的正常化和MPS I特异性尿糖氨基氨基聚糖的排泄量从基线下降（图2）。正在收集由Bayley婴儿发育和Vineland量表测量的神经系统发育和功能评分。

患者接受的CD34 ⁺剂量中位数为110×10 ^6个细胞/ kg，TNC剂量为26×10 ^7个细胞/ kg，中性粒细胞减少症的中位持续时间为1天（范围为0-9），而历史性中性粒细胞减少为8天控制。到第14天时，可评估患者中的骨髓嵌合体供体≥98％，CD4和CD8 T细胞亚群的免疫重建与历史对照相当或更好。观察到两个仅皮肤的aGVHD的类固醇反应性发作，但未出现cGVHD。将报告其他接受冷冻保存的MGTA-456的患者的数据。

结论

MGTA-456对IMD患者的治疗显示出早期，牢固的植入和免疫重建，这些特征与改善的临床结果高度相关。MPS I和cALD患者移植后长达一年的特定疾病结局在生化，MRI和临床/神经发育评估中显示出至关重要的，持久的稳定作用。总之，MGTA-456所传递的高CD34 +细胞剂量显示出令人信服的潜力，可以迅速而持久地改善IMD患者的预后。