Preliminary Safety and Efficacy Results from Precizn-1: An Ongoing Phase 1/2 Study on Zinc Finger Nuclease-Modified Autologous CD34+ HSPCs for Sickle Cell Disease (SCD)

Introduction Sickle cell disease (SCD) is caused by pathologic variants in both alleles of the β-globin gene, affecting ~100,000 patients in the US (Strouse. Handb Clin Neurol 2016;138:311-24). Elevated fetal hemoglobin (HbF) levels ameliorate symptoms and improve survival in patients with SCD (Hebert. Am J Hematol 2020;95:1235-45). SAR445136 (BIVV003) is a novel therapeutic product comprising autologous CD34+ HSPCs modified ex vivo by zinc finger nucleases (ZFN) and targeting the BCL11A gene erythroid-specific enhancer (ESE) to increase endogenous HbF production. Methods PRECIZN-1 (NCT03653247) is an ongoing first-in-human, open label, single arm, multi-site study evaluating safety and tolerability of SAR445136 (n=8; aged 18-40 years), with severe SCD across 6 US sites. Eligible subjects underwent mobilization and apheresis with plerixafor 240 ug/kg/day for up to 3 days to collect autologous CD34+ HSPCs to achieve a minimum of 10 × 10 6 CD34+ HSPC/kg for manufacturing of the SAR445136 dose. Additional apheresis cycles were allowed to achieve the minimum cell dose and rescue aliquots. Autologous HSPCs were transfected ex vivo with ZFN mRNAs targeting the ESE region of the BCL11A locus to manufacture SAR445136. A single IV infusion of 3-20 × 10 6 CD34+ HSPC/kg was administered at least 72 hours after the final busulfan myeloablation dose. Subjects were monitored for stem cell engraftment and hematopoietic recovery, adverse events (AEs), clinical and laboratory hemolysis markers, total Hb and HbF, percentage of F cells and sickle-cell related events post-SAR445136 infusion. Health-related quality of life (HRQoL) was assessed via the PROMIS-57 survey at screening, Weeks 26 and 52, and early termination visit. Results Of the 7 subjects that underwent mobilization and apheresis to date (25 June 2021), 5 achieved successful target yields ranging from 3.4-13.8 x 10 6 CD34+ HSPC/kg per apheresis day (mean: 6.49 x10 6 CD34+ HSPC/kg per apheresis day) in one apheresis cycle (4.45-10.9 x 10 6 CD34+ HSPC/kg per 2-day cycle). One subject failed to mobilize; one discontinued due to intercurrent cholangitis. Baseline patient characteristics of the 4 patients infused are in Table 1. Pre-apheresis peripheral blood WBC ranged from 23.2-36.9 x 10 3/μL (mean: 28.7 x 10 3/μL) and % CD34+ was 0.09-0.36% (0.22%) with absolute CD34+ counts of 20-80/μL (mean: 60/μL). Four of the mobilized subjects were successfully infused with SAR445136 at a single dose ranging from 3.2-9.7 x 10 6 CD34+ HSPC/kg (mean: 5.17 x 10 6 CD34+ HSPC/kg). All 4 subjects engrafted with a median time to neutrophil and platelet recovery of 21.5 and 24.5 days, respectively. No rescue doses were required. All 4 patients improved clinically since SAR445136 infusion, with no recurrence of previous vaso-occlusive crises (VOCs). Total Hb stabilized at 9-10 g/dL by week 26 post SAR445136 infusion along with improvements in the clinical markers of hemolysis in all 4 subjects. Percent HbF levels were 1-11% at screening, increasing to 15-29% by Week 13 in all 4 subjects, to 14-39% by Week 26 in the 3 subjects with at least 26 weeks follow up; and persisting at 35% in 1 subject with 65 weeks follow up (Figure 1). Percent F cells increased to 49-94% in 3 subjects with at least 26 weeks follow up, persisting at 90% in 1 subject with 65 weeks follow up. The fourth subject had 87.5% F cells at 13 weeks follow up. Although preliminary, a trend of improvement exceeding the proposed minimally clinically important difference in all PROMIS-57 HRQoL domains except sleep disturbance was observed in the 3 subjects with 26 weeks follow up, whose scores were "worse" than the norm at baseline (≤2 points per domain). SAR445136 was generally well tolerated with no infusion related reactions. The AEs reported were consistent with plerixafor mobilization and busulfan myeloablation therapy. No AEs or SAEs were reported as related to SAR445136. Conclusions As of 25 June 2021, these preliminary proof-of-concept efficacy and safety results confirm the potential therapeutic value of ZFN-mediated modification of the BCL11A ESE region and SAR445136 infusion to address current unmet needs of patients with SCD. All 4 infused patients had no SCD related events including VOCs following SAR445136 infusion, as well as increases in total Hb, HbF, and %F cells, and clinical improvements in PROMIS-57 domains. SAR445136 is generally well tolerated in the 4 subjects infused to date, with no related AEs or SAEs reported. Figure 1 Figure 1. Disclosures Abedi: BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Speakers Bureau; Abbvie: Speakers Bureau. Galeon: Sanofi: Current Employment. Reiner: Sanofi: Current Employment. Smith: Sanofi: Current Employment. Wang: Sanofi: Current Employment. Ramezi: Sanofi: Current Employment. Rendo: Sanofi: Current Employment, Other: May hold shares and/or stock options . Walters: AllCells, Inc: Consultancy; Vertex pharmaceuticals: Consultancy; Ensoma, Inc.: Consultancy; BioLabs, Inc: Consultancy.

OP0079 LIMB GIRDLE MUSCULAR DYSTROPHY TYPE 2B - A RARE MYOSITIS MIMIC

Background:Proximal muscle weakness with associated raised creatine kinase (CK) commonly leads to referral to Rheumatology for the investigation of Idiopathic Inflammatory Myopathy (IIM). Some genetic myopathies can have a similar presentation with investigations that suggest inflammatory disease, leading to difficulty with accurate diagnosis (Amato & Brown, 2011; Harlan & Mammen, 2019).Objectives:To describe the case of a patient with Limb Girdle Muscular Dystrophy Type 2B (LGMD2B), whose initial presentation mimicked an inflammatory myopathy.Methods:Case report.Results:A 43-year-old patient was reviewed by Rheumatology due to proximal muscle weakness with a raised CK. Muscle biopsy was suggestive of inflammatory myopathy. Therefore, he was started on treatment with corticosteroids. Corticosteroid treatment resulted in no improvement in his weakness or CK. His diagnosis was reviewed, and he was referred to the Neurology and Genetics services. Following molecular genetic analysis, a diagnosis of Limb Girdle Muscular Dystrophy Type 2B was made.Conclusion:Muscle biopsies can suggest an inflammatory aetiology in some genetic myopathies (Amato & Brown, 2011; Harlan & Mammen, 2019). If a patient with suspected IIM presents with atypical features, or they do not respond as expected to treatment, then consider a genetic myopathy such as LGMD2B as a cause and involve the Neurology and Genetics services in the case.References:[1]Amato, A. A., & Brown, R. H., Jr. (2011). Dysferlinopathies. Handb Clin Neurol, 101, 111-118. https://doi.org/10.1016/b978-0-08-045031-5.00007-4[2]Harlan, M & Mammen A. L (2019). Myositis Mimics: The Differential Diagnosis of Myositis. In: R. Aggarwal and C. V. Oddis (Eds.) Managing Myositis (pp. 209-223). Springer, Cham.Disclosure of Interests:None declared

Giant Prolactinoma Causing Proptosis and Stroke

Background: Although suprasellar and cavernous sinus invasion are common in giant prolactinomas, intra-orbital extension is extremely uncommon [1]. Even less reported are cases of giant prolactinomas causing cerebral ischemia or death. Clinical Case: A 51-year old woman presented to the ED with confusion, right-sided weakness and severe left eye proptosis with loss of vision. Five years prior, she underwent a partial transphenoidal resection for a macroprolactinoma due to acute vision changes with compression of the optic chiasm. Prior to surgery, prolactin level was elevated to 2,106 ng/mL (n 2.4-24.0 ng/mL). Post-operative MRI showed residual 2.7 x 3.1 x 2.6 cm mass. Thereafter she was prescribed cabergoline which she self-discontinued three years later. MRI of the brain at time of presentation demonstrated a 10.1 x 6.4 x 4.3 cm sellar/suprasellar mass extending into the left orbit causing severe proptosis and mass effect on the left frontal lobe, temporal lobe, midbrain, and basilar artery with encasement of the left cavernous internal carotid artery. A recent left striatocapsular infarct due to compression of the left middle cerebral artery was present. Prolactin level was elevated to 16,487 ng/mL. Neurosurgery was consulted and recommended medical management. Free thyroxine level was low and thyroid hormone replacement was started. Although the cosyntropin stimulation test showed an appropriate cortisol level peak of 21.5 mcg/dL, she was given stress dose glucocorticoids. Bromocriptine was initially started and titrated and later changed to cabergoline. Six weeks after discharge, she was readmitted with worsening confusion and seizure activity. On day 2 of admission, she decompensated. New hemorrhage inside the mass with increased vasogenic edema and a midline shift was discovered on a head CT. She underwent emergent craniotomy with surgical debulking of the tumor. Unfortunately, her mental status did not improve post-operatively. She was transitioned to hospice care and died 7 days after surgery. Surgical pathology showed a lactotroph adenoma with markedly elevated Ki67 proliferation index of 20-30%. Conclusion: This case demonstrates an unusually aggressive macroprolactinoma causing severe proptosis, ischemic stroke and death and adds to the very few cases previously reported [2]. References: 1. Karcioglu ZA, Aden LB, Cruz AA, Zaslow L, Saloom RJ. Orbital invasion with prolactinoma: a clinical review of four patients. Ophthalmic Plast Reconstr Surg. 2002 Jan;18(1):64-71. 2. Navarro-Bonnet J, Martínez-Anda JJ, Balderrama-Soto A, Pérez-Reyes SP, Pérez-Neri I, Portocarrero-Ortiz L. Stroke associated with pituitary apoplexy in a giant prolactinoma: a case report. Clin Neurol Neurosurg. 2014 Jan;116:101-3.

SAT-257 Coexisting Craniopharyngioma and Acromegaly

Background: Craniopharyngioma has a bimodal age distribution with adults having more pronounced hormone deficiencies.1 Studies indicate hormone deficiencies in >80% of cases, most commonly growth hormone (GH) deficiency.2 Comparatively, acromegaly is due to excess GH primarily from a pituitary adenoma.3 Coexistence of a craniopharyngioma and a secretory pituitary adenoma is extremely rare,4 and here we present a case with both. Clinical Case: A 59-year-old woman presented with a two-month history of acutely worsening headache and a week of vision change. A computerized tomography (CT) head scan revealed a 2.2 cm partially solid and cystic sellar mass compressing the optic chiasm. The patient underwent emergent resection. Pre-operational biochemical studies demonstrated normal hypothalamus-pituitary axes except a mildly elevated insulin-like growth factor 1 (IGF-1). Pathology revealed an adamantinomatous craniopharyngioma. Although decreased, IGF-1 remained elevated post-operatively and magnetic resonance imaging (MRI) showed a small non-enhancing area within the pituitary. The patient recalled a gradual increase in shoe and glove size, coarser facial features, weight gain, bilateral carpal tunnel, and mild fluid retention in ankles over the past few years. The GH remained unsuppressed in a glucose suppression test. Conclusion: We present a case of pathology proven craniopharyngioma and concurrent GH excess. The patient presented with a sellar mass with mass effect prompting emergent pituitary resection. Although findings of combined solid and cystic with calcification on MRI point to craniopharyngioma diagnosis,1 it is difficult to discern a concurrent GH-secreting tumor as it tends to be smaller and hypointense on T2-weighted MRI.5 While most craniopharyngioma patients demonstrate hormone deficiency, comprehensive hormonal evaluation and close follow-up are warranted, as in rare cases, patients can have co-existing secretory pituitary adenoma and craniopharyngioma. Early diagnosis and intervention can help prevent detrimental complications related to excess growth hormone. References: 1. Müller HL. Craniopharyngioma. Handb Clin Neurol. 2014;124:235-53. 2. Zoicas F, Schöfl C. Craniopharyngioma in adults. Front Endocrinol. 2012;3:46. 3. Gadelha, M. et al. Complications of Acromegaly and the Impact of the Current Treatment Landscape: An Update. Endocrine Reviews. 2019;40(1):268-332. 4. Fountas A, Chai ST, Ayuk J, Gittoes N, Chavda S, Karavitaki N. A rare challenging case of co-existent craniopharyngioma, acromegaly and squamous cell lung cancer. Endocrinol Diabetes Metab Case Rep. 2018;2018:18-0018. 5. Potorac I, et al. Pituitary MRI characteristics in 297 acromegaly patients based on T2-weighted sequences. Endocrine Related Cancer. 2015;22:169-77.