On December 11, 2022 Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, reported positive updated clinical data from its ongoing Phase 2 APEX clinical trial evaluating the selective KIT D816V inhibitor bezuclastinib in patients with advanced systemic mastocytosis (AdvSM) (Press release, Cogent Biosciences, DEC 11, 2022, View Source [SID1234625014]). The data are being presented in an oral presentation at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in New Orleans, LA.

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"Advanced systemic mastocytosis is a rare and life-threatening disease," said Daniel J. DeAngelo, M.D., Ph.D., Chief of the Division of Leukemia at the Dana-Farber Cancer Institute and APEX clinical trial investigator. "Updated results from the APEX trial demonstrate rapid and deep responses with bezuclastinib while maintaining an impressive safety and tolerability profile."

"We are very encouraged by the clinical profile that bezuclastinib has shown to date," said Andrew Robbins, President and Chief Executive Officer at Cogent Biosciences. "We are especially excited that a growing body of data supports bezuclastinib’s differentiated safety and tolerability profile enabling therapeutic exposures that could support key differentiation for both AdvSM patients and non-advanced systemic mastocytosis patients."

Updated Data from Ongoing Phase 2 APEX Clinical Trial
APEX is a global, open-label, multi-center, two-part Phase 2 clinical trial in patients with AdvSM evaluating the safety, efficacy, pharmacokinetic, and pharmacodynamic profiles of bezuclastinib. As of the data cutoff date of October 26, 2022, 16 patients had been treated in Part 1 at one of four dose levels (50 mg BID, 100 mg BID, 200 mg BID or 400 mg QD). The median age of patients at study entry was 69 years (ranging from 33-87 years). Patients were enrolled with the following sub-types: three patients with aggressive systemic mastocytosis (ASM), 12 patients with systemic mastocytosis with associated hematologic neo-plasm (SM-AHN), and one patient with mast cell leukemia (MCL). Three patients had received prior avapritinib and midostaurin treatment.

Updated Safety Data
As of the cutoff date October 26, 2022, bezuclastinib was generally well-tolerated at all doses. The majority of adverse events were Grade 1/2 and occurred in no more than one patient. Grade 3 events reported as at least possibly related to bezuclastinib were neutropenia (2 patients), thrombocytopenia (1 patient), anemia (1 patient) and hypersensitivity/mediator flare (1 patient). Importantly, there were no related cases of cognitive impairment and no reported intracranial bleeding events, which have been associated with other KIT inhibitors. Limited low-grade edema was observed, and analysis of platelet counts in bezuclastinib-treated patients showed no trend in platelet reduction at any dose.

Updated Clinical Activity Data
As of the cutoff date of October 26, 2022, 11 patients were evaluable for response per the modified IWG-MRT-ECNM criteria, and 12 patients were evaluable for response using pure pathological response (PPR) criteria. Reported ORR per mIWG-MRT-ECNM criteria includes centrally adjudicated confirmed and unconfirmed CR, CRh, PR, and CI.

89% ORR in TKI therapy naïve patients, including 67% of patients achieving CR, CRh or PR, and 22% of patients achieving CR or CRh
73% ORR in all patients, regardless of prior treatment
75% ORR in all patients by PPR criteria, regardless of prior treatment
Additionally, results of key markers of clinical activity were reported from 16 patients.

14/16 patients achieved ≥ 50% reduction in serum tryptase levels by central assessment
85% median reduction in serum tryptase
Eight of these patients achieved reduction to <20 ng/mL
13/13 patients with ≥2 cycles of treatment achieved ≥50% reduction in bone marrow mast cells by central review
10 of these patients achieved complete clearance of bone marrow mast cell aggregates
11/12 patients with baseline D816V mutation and ≥2 cycles of treatment achieved ≥50% reduction in KIT D816V variant allele fraction (VAF) by droplet digital polymerase chain reaction (ddPCR)
Bezuclastinib Clinical Development
Based on the continued favorable safety and tolerability profile and clinical activity observed to date in the Phase 2 APEX clinical trial with bezuclastinib for patients with AdvSM, Cogent will continue enrolling patients in Part 1 of APEX to determine a recommended dose for use in Part 2 of the trial.

In addition, Cogent continues to actively enroll patients in SUMMIT, a Phase 2 clinical trial with bezuclastinib for patients with non-advanced systemic mastocytosis (NonAdvSM), and PEAK, a registrational randomized, open-label, global, Phase 3 clinical trial in patients with imatinib-resistant Gastrointestinal Stromal Tumors (GIST). Cogent plans to present initial clinical efficacy results from the PEAK lead-in study during the first half of 2023 and present initial clinical data from SUMMIT in the second half of 2023.

Webcast Information & ASH (Free ASH Whitepaper) Poster
Cogent will host a webcast on December 12, 2022 at 8:00 a.m. ET (7:00 a.m. CT) to discuss today’s updated clinical data from the ongoing APEX trial. The live event can be accessed on the Investor page of Cogent’s website at investors.cogentbio.com. A replay of the webcast will be available approximately two hours after the completion of the event and will be archived for up to 30 days.

The ASH (Free ASH Whitepaper) poster is available to registered conference attendees as well as on the Posters and Publications section of Cogent’s website at www.cogentbio.com/research.

On December 11, 2022 Boston Scientific Corporation (NYSE: BSX) and Acotec Scientific Holdings Limited ("Acotec" and 6669.HK) reported that Boston Scientific will make a partial offer to acquire a majority stake, up to a maximum of 65%, of shares of Acotec, a Chinese medical technology company that offers solutions designed for a variety of interventional procedures (Press release, Boston Scientific, DEC 11, 2022, View Source [SID1234625013]). The proposed price is HK$20 per share, which represents a total upfront cash payment consideration of approximately US$523 million for the 65% stake at current exchange rates.i

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Acotec is a leader in innovative medical solutions, including drug-coated balloons (DCBs), which are used in the treatment of vascular and other diseases. In 2016, the company launched the first peripheral DCB in China after receiving approval from the National Medical Products Administration. The Acotec portfolio also includes radiofrequency ablation technologies and thrombus aspiration catheters, as well as more than 20 other products in various stages of development across a range of specialties. In the 12-month period ending June 30, 2022, Actotec generated sales of RMB 339 million (approximately US$53 million), growing 25% year-over-year in the first six months of 2022 with strong double-digit growth in each of the two years prior.ii

"Acotec is a profitable, fast-growing company with a strong portfolio and innovative pipeline of medical technologies, and we believe this investment will generate growth opportunities for both companies," said Art Butcher, executive vice president and group president, MedSurg and Asia Pacific, Boston Scientific. "We expect completion of the partial offer to further strengthen our presence in China and create the potential for commercialization of Acotec products globally, providing an increased number of physicians and patients access to our robust and complementary product portfolios."

Boston Scientific expects the impact to adjusted earnings per share to be immaterial in 2023 and the impact to GAAP earnings per share to be less accretive, or dilutive, as the case may be, due to amortization expense and acquisition-related net charges.

The completion of the transaction, which is anticipated in the first half of 2023, is subject to acceptance and approval by Acotec shareholders and other conditions set forth in related filings.

Additional information about this investment is available on the Events and Presentations section of the Boston Scientific investor relations website.

On December 11, 2022 Bellicum Pharmaceuticals, Inc. (Nasdaq: BLCM), a leader in developing novel, controllable cellular immunotherapies for cancers, reported a poster presentation by the University of North Carolina Lineberger Comprehensive Cancer Center (UNC Lineberger) team at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition being held in New Orleans December 10-13, 2022 (Press release, Bellicum Pharmaceuticals, DEC 11, 2022, View Source [SID1234625011]). The presentation, scheduled for today at 6 p.m. CT, will provide data on four patients who received rimiducid to activate the CaspaCIDe safety switch in an investigator sponsored trial.

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The poster titled "Abrogation of Immune Effector Cell Neurotoxicity Syndrome (ICANS) By Rimiducid (RIM) in Patients Treated with CD19-Specific Chimeric Antigen Receptor Modified T-Cells (CAR-T) Engineered with an Inducible Caspase 9 (iC9 CAR.19)" will also be available on Bellicum’s website.

The UNC Lineberger research team reported the clinical and pharmacodynamic courses of ICANS for four patients treated with rimiducid in an ongoing cell dose expansion cohort of a Phase I/II trial of iC9 CAR.19 cells to treat B-lymphoblastic leukemia (B-ALL). According to the poster, rimiducid administration to these patients experiencing corticosteroid-unresponsive grade 3-4 ICANS was associated with abrupt reduction of circulating iC9 CAR.19 cells and lower ICANS grade within 24 hours. The UNC Lineberger research team concluded that iC9 holds promise as a tool to potentially abrogate the most severe CAR T-cell toxicities.

"There is an unmet need in the management of severe ICANS, and these results suggest that the iC9 switch may mitigate such life-threatening toxicities," commented Natalie Grover, M.D., clinical director of UNC Lineberger’s cellular therapy program. "We look forward to further studies to explore ways to manage adverse reactions and improve patient outcomes for cellular immunotherapy regimens."

"These encouraging findings from UNC reinforce the potential benefit of the CaspaCIDe safety switch and rimiducid in resolving CAR T-cell related adverse events," said Rick Fair, President & CEO of Bellicum Pharmaceuticals. "We continue to support further clinical evaluation of the technology and remain committed to incorporating this important safety feature more broadly in additional cell therapies."

The UNC Lineberger team is exploring lower doses of rimiducid to determine if—by preserving a higher percentage of CAR-T cells—toxicity may be mitigated without diminishing the therapeutic benefit.

On December 11, 2022 AbbVie (NYSE: ABBV) reported data from multiple clinical trials evaluating epcoritamab (DuoBody-CD3xCD20), an investigational subcutaneous bispecific antibody, alone or in combination for the treatment of patients with relapsed/refractory (R/R) follicular lymphoma (FL), previously untreated FL, R/R diffuse large B-cell lymphoma (DLBCL), as well as Richter’s syndrome at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, AbbVie, DEC 11, 2022, View Source [SID1234625009]).

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Notably, initial results of investigational epcoritamab in patients with R/R FL and previously untreated FL are featured during session 623 on Sunday, December 11 starting at 4:30 p.m. CST. The results are part of the EPCORE NHL-2 study, a Phase 1b/2, open-label trial to assess the safety and preliminary efficacy of epcoritamab in combination with other agents in patients with B-cell non-Hodgkin’s lymphoma, including FL. Approximately 2.7 per 100,000 people in the U.S. are newly diagnosed with FL every year and the median age of patients at diagnoses with FL is 63.1,2,3 FL is typically a slow-growing or indolent form of non-Hodgkin’s lymphoma (NHL) that arises from B-lymphocytes.4 Although FL is a slow-growing lymphoma, it is considered incurable with conventional therapy.5,6

"These data at this year’s ASH (Free ASH Whitepaper) meeting are promising as they support continued investigation of epcoritamab for patients in need of new treatment options for follicular lymphoma and other B-cell lymphomas," said Mohamed Zaki, M.D., Ph.D., vice president and head, global oncology development, AbbVie. "Along with Genmab, we look forward to continuing to build on our promise of exploring a potential core therapy for patients with B-cell malignancies in a variety of treatment settings."

Additional results from the EPCORE NHL-2 study as well as the EPCORE CLL-1 study were presented for investigational epcoritamab in R/R DLBCL and Richter’s syndrome respectively. The EPCORE CLL-1 study is an open-label, multi-center, safety and efficacy trial of epcoritamab in R/R chronic lymphocytic leukemia (CLL) and Richter’s syndrome. The trial consists of two parts, a dose escalation Phase (Phase Ib) and an expansion Phase (Phase II).7

Abstract #609: Subcutaneous Epcoritamab with Rituximab + Lenalidomide in Patients with Relapsed or Refractory Follicular Lymphoma: Phase 1/2 Trial Update

Oral Presentation: Sunday, December 11, 2022 at 5:00 p.m. CST

In the R/R FL arm of the EPCORE NHL-2 trial, 95 percent (63/66) of efficacy-evaluable patients treated with subcutaneous epcoritamab in combination with rituximab and lenalidomide achieved an overall response rate (ORR) and 80 percent (53/66) achieved complete metabolic response (CMR). The majority of patients achieved a response at first tumor response assessment and most continued to respond through the latest assessment at the time of data collection.

A manageable cytokine release syndrome (CRS) occurrence was observed with only low-grade events, mainly following the first full dose, all of which resolved. The most common treatment-emergent adverse events (TEAEs) of any grade were neutropenia (47%), CRS (43%), injection-site reactions (32%), fatigue (31%), constipation (25%), COVID-19 (25%), pyrexia (25%) and infusion-related reaction (21%).

Abstract #611: Subcutaneous Epcoritamab in Combination with Rituximab + Lenalidomide for First-Line Treatment of Follicular Lymphoma: Initial Results from Phase 1/2 Trial

Oral Presentation: Sunday, December 11, 2022 at 5:30 p.m. CST

In the previously untreated FL patient arm of the EPCORE NHL-2 trial, 94 percent (34/36) of efficacy-evaluable patients who received subcutaneous epcoritamab in combination with rituximab and lenalidomide achieved an ORR, including 86 percent (31/36) achieving CMR as their best overall response. In the trial, the investigational combination therapy showed a manageable CRS occurrence with only low-grade events, all of which resolved.

The most common TEAEs of any grade were CRS (54%), neutropenia (47%), pyrexia (44%), fatigue (37%), injection-site reaction (37%), headache (34%), COVID-19 (33%), diarrhea (32%), constipation (29%), rash (27%), increased alanine aminotransferase (ALT) (22%), and vomiting (22%).

Abstract #443: Subcutaneous Epcoritamab + R-Dhax/C in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma Eligible for Autologous Stem Cell Transplant: Updated Phase 1/2 Results

Oral Presentation: Sunday, December 11, 2022 at 10:30 a.m. CST

Results from the EPCORE NHL-2 arm evaluating 27 patients with R/R DLBCL who were eligible for autologous stem cell transplant, showed an 85 percent (23/27) ORR and 67 percent (18/27) CMR following treatment with the combination of subcutaneous epcoritamab plus standard rituximab, dexamethasone, cytarabine, and oxaliplatin or carboplatin (R-DHAX/C) salvage therapy.

The most common TEAEs of any grade were thrombocytopenia (69%), anemia (51%), neutropenia (44%), CRS (41%), nausea (31%), fatigue (28%), constipation (24%), diarrhea (24%), headache (24%), pyrexia (24%) and increased aspartate aminotransferase (AST) (21%). All CRS events were low-grade and resolved.

Abstract #348: Subcutaneous Epcoritamab in Patients with Richter’s Syndrome: Early Results from Phase 1b/2 Trial (EPCORE CLL-1)

Oral Presentation: Saturday, December 10, 2022 at 5:15 p.m. CST

Preliminary results from the EPCORE CLL-1 trial showed that treatment with subcutaneous epcoritamab monotherapy had promising antitumor activity in 10 patients with Richter’s syndrome, with a 60 percent ORR and a 50 percent CMR rate. Most responses were observed by the first assessment at week six. In the trial, patients experienced only low-grade CRS events, mostly associated with the first full dose, all of which resolved.

The most common TEAEs of any grade were CRS (90%), anemia (50%), neutropenia (50%), injection-site reaction (40%), thrombocytopenia (40%), hypophosphatemia (30%), Hypokalemia (30%), hyperglycemia (30%), COVID-19 (30%), diarrhea (30%), fatigue (30%), and nausea (30%).

About Diffuse Large B-Cell Lymphoma (DLBCL)
DLBCL is a fast-growing type of NHL that affects B-cell lymphocytes, a type of white blood cell.8 It is the most common type of NHL worldwide and accounts for approximately 30 percent of all NHL cases.8 DLBCL can arise in lymph nodes, as well as in organs outside of the lymphatic system.8 The disease occurs more commonly in the elderly and is slightly more prevalent in men.8

About Richter’s Syndrome
Richter’s syndrome, also known as Richter’s transformation, is defined as the transformation of CLL into an aggressive lymphoma, most commonly DLBCL.9,10 Richter’s syndrome occurs in approximately 2 percent to 10 percent of CLL patients during the course of their disease.9

About the EPCORE NHL-2 Trial
EPCORE NHL-2 is a Phase 1b/2, open-label, multinational, interventional trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics/biomarkers, immunogenicity, and preliminary efficacy of epcoritamab in combination with other standard-of-care agents in subjects with B-cell non-Hodgkin’s lymphoma. The trial consists of two parts: Part 1 (Dose Escalation) and Part 2 (Dose Expansion).11

The primary objective of Part 1 is safety, and it includes Arm 1–5. Part 2 includes all 8 arms (Arm 1–8) and the primary goal of all arms, except Arm 7, is preliminary efficacy. For Arm 7, the primary goal is safety. Patients in Arm 1–5 can only participate in either Part 1 or Part 2. Dose Limiting Toxicities will be assessed in Part 1 and for a selected number of patients in Arm 8 during a 28-day period (safety-run Phase). The arms are conducted in parallel.11

About Epcoritamab
Epcoritamab is an investigational IgG1-bispecific antibody created using Genmab’s proprietary DuoBody technology. Genmab’s DuoBody-CD3 technology is designed to direct cytotoxic T-cells selectively to elicit an immune response toward target cell types. Epcoritamab is designed to simultaneously bind to CD3 on T-cells and CD20 on B-cells and induces T-cell mediated killing of CD20+ cells.12 CD20 is expressed on B-cells and a clinically validated therapeutic target in many B-cell malignancies, including DLBCL, FL, mantle cell lymphoma and CLL.13,14

AbbVie recently announced that the Biologics License Application (BLA) for epcoritamab for the treatment of adult patients with R/R large B-cell lymphoma after two or more lines of systemic therapy was accepted for priority review by the U.S. Food and Drug Administration. Additionally, the European Medicines Agency has validated a Marketing Authorization Application for epcoritamab for the treatment of adult patients with R/R DLBCL after two or more lines of systemic therapy.

Epcoritamab is being co-developed by AbbVie and Genmab as part of the companies’ oncology collaboration. The companies will share commercial responsibilities in the U.S. and Japan with AbbVie responsible for further global commercialization. The companies are committed to evaluating epcoritamab as a monotherapy, and in combination, across lines of therapy in a range of hematologic malignancies. This includes an ongoing Phase 3, open-label, randomized trial evaluating epcoritamab as a monotherapy in patients with R/R DLBCL (NCT: 04628494) and a Phase 3, open-label clinical trial evaluating epcoritamab in combination in patients with R/R FL (NCT: 05409066).

On December 10, 2022 On December 10, 2022, Sangamo Therapeutics, Inc., or Company, reported updated preliminary proof-of-concept clinical data from the Phase 1/2 PRECIZN-1 study of BIVV003, a zinc finger nuclease gene-edited autologous cell therapy product candidate for the treatment of sickle cell disease, or SCD, at the 64th American Society for Hematology Annual Meeting and Exposition, or ASH (Free ASH Whitepaper) (Press release, Sangamo Therapeutics, DEC 10, 2022, View Source [SID1234625142]). Also on December 11, 2022, the Company presented at ASH (Free ASH Whitepaper) updated follow-up data from the Phase 1/2 Alta study of giroctocogene fitelparvovec, an investigational gene therapy for patients with moderately severe to severe hemophilia A in development with Pfizer Inc. Summaries of the data presented are below.

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Summary of Updated Preliminary Safety, Tolerability and Efficacy Results from the Phase 1/2 PRECIZN-1 Study of BIVV003 Presented at ASH (Free ASH Whitepaper)

•PRECIZN-1 is an ongoing, first-in-human, open label, single arm, multi-site study evaluating the safety, tolerability and efficacy of BIVV003 in patients with severe SCD (n=8; aged 18-40 years).

•Eligible patients underwent mobilization and apheresis with plerixafor. Autologous hematopoietic stem and progenitor cells, or HSPCs, were transfected ex vivo with zinc finger nuclease messenger ribonucleic acid to manufacture BIVV003. A single intravenous infusion was administered at least 72 hours after pre-conditioning with busulfan.

•Patients were monitored for stem cell engraftment and hematopoietic recovery, adverse events, clinical and laboratory hemolysis markers, total hemoglobin, or Hb, and fetal hemoglobin, or HbF, percentage of F cells and SCD-related events post‑BIVV003 infusion.

•Six patients achieved successful target yields of HSPCs. Five of the six patients achieving successful target yields of HSPCs had been infused with BIVV003 as of the September 30, 2022 cutoff date. Baseline characteristics of these five patients are in Table 1 below. The first four patients dosed received BIVV003 produced using the initial manufacturing process and are referred to in Table 1 below as Group 1. Group 1 patients have been followed for up to 30 months post-infusion. The patient referred to in Table 1 below as Group 2 received BIVV003 manufactured using improved methods that have been shown in internal experiments to increase the number of long-term progenitor cells in the final product. As of the cutoff date, the first patient treated in Group 2, or Patient 5, had been followed for 5 months. A second patient in Group 2 was dosed after the cutoff date.

•Four of five patients in aggregate across both Groups 1 and 2 improved clinically since BIVV003 infusion through the September 30, 2022, cutoff date.

In Group 1:

•The effects of BIVV003 infusion on total Hb and HbF levels were maintained up to 30 months.

•Three of the four patients had stable engraftment of zinc finger nuclease-modified HSPCs, resulting in sustained elevated HbF levels greater than 30% and an absence of severe vaso-occlusive crisis, or VOCs, post-BIVV003 administration.
In Group 2:

•Patient 5 received BIVV003 manufactured using improved methods that have been shown in internal experiments to increase the number of long-term progenitor cells in the final product.

•The HbF level of 45% and total Hb of 12.4 g/dL at week 26 post-infusion for Patient 5 in the latest sample collected post data cutoff were greater than the levels observed in Group 1 at week 26.

•As of the September 30, 2022 cutoff date, BIVV003 was generally well tolerated, and most adverse events reported in the screening, mobilization, apheresis and conditioning periods were SCD-related events. The investigator reported two serious adverse events of sickle cell anemia with a VOC as related to plerixafor, and one serious adverse event of nausea as related to busulfan. Nearly half of the adverse events reported after infusion of BIVV003 were related to busulfan. The investigator reported two serious adverse events of sickle cell anemia with a VOC nine months and 16 months after infusion in the one patient in Group 1 who had low HbF levels (11-14%). No other SCD-related serious adverse events were reported after infusion. No adverse events related to BIVV003 were reported by the investigator or sponsor. See Figure 2 below for VOCs reported before and after infusion of BIVV003.

Number of severe vaso-occlusive crises (VOCs) reported in the 24 months before signing the study informed consent form (ICF) and in the post-BIVV003 infusion period.
Red lines represent severe VOCs; 2 severe VOCs occurring in the same month appear as one red line
Group 1 includes the first four patients dosed, who received BIVV003 produced using the initial manufacturing process.
Group 2 includes patient 5 who received BIVV003 manufactured using improved methods that have been shown in internal experiments to increase the number of long-term progenitor cells in the final product.
Summary of Updated Follow-up Data from the Phase 1/2 Alta Study of Giroctocogene Fitelparvovec Presented at ASH (Free ASH Whitepaper)
•Alta is a Phase 1/2 single-dose multicenter dose-ranging study to assess the safety and tolerability of giroctocogene fitelparvovec in adults with severe hemophilia A.
•Patients were monitored for adverse events, change in circulating Factor VIII, or FVIII, activity, change from baseline in use of FVIII replacement therapy, change in frequency and severity of bleeding episodes, measurement of FVIII inhibitor levels and vector shedding in bodily fluids.
•Maintenance of FVIII activity in the mild range (>5%) or greater improves outcomes for patients with severe hemophilia A.
•Eleven male patients participated in the study overall, with five patients in the 3e13-vg/kg highest dose cohort. See Table 1 below for baseline patient demographics. As of the September 6, 2022 cutoff date, all patients had been followed for 153 to 263 weeks and all participants have completed at least 35 months of follow-up.
•As of the September 6, 2022 cutoff date, six of the eleven patients had experienced treatment-related adverse events, including four of the five patients in the highest dose cohort. The most commonly reported treatment-related adverse events included elevated liver enzymes and infusion-related reactions: increased alanine aminotransferase, or ALT (5/11 (45.5%) overall; 3/5 (60.0%) in the highest dose cohort), increased aspartate aminotransferase, or AST (3/11 (27.3%) overall; 2/5 (40.0%) in the highest dose cohort), pyrexia (3/11 (27.3%) overall; 3/5 (60.0%) in the highest dose cohort), and tachycardia (2/11 (18.2%) overall; 2/5 (40.0%) in the highest dose cohort).
•Treatment-related serious adverse events were reported in one patient in the highest dose cohort who experienced grade 3 hypotension and fever with onset approximately six hours after giroctocogene fitelparvovec infusion; the events fully resolved with treatment and did not delay post-infusion discharge the next day. See Table 2 below for more details on treatment-related adverse events.
•As of the September 6, 2022 cutoff date, no confirmed FVIII inhibitor development occurred, and no thrombotic events, neoplastic events, abnormal alfa-fetoprotein and/or liver masses were reported.

•All five patients in the highest dose cohort demonstrated FVIII activity as shown in Table 3 below through week 156. Mean FVIII activity at week 156 was 25.5% of normal as measured by chromogenic clotting assay at the central laboratory. In this highest dose cohort, the annualized bleeding rate, meaning the number of all bleeding episodes starting three weeks after infusion divided by the observation period in years, was zero for the first year post-infusion and the mean overall annual bleeding rate throughout the total duration of follow-up was 1.2 as of the September 6, 2022 cutoff date.
•In this highest dose cohort, two patients experienced bleeding events necessitating treatment with exogenous FVIII: one patient experienced 17 bleeding events (8 traumatic, 5 spontaneous, 4 unknown), and one patient experienced one bleeding event in a target joint, circumstances unknown. No participants in this highest dose cohort have resumed prophylaxis as of the cutoff date.
•Additional follow-up is required to assess durability of therapeutic effect and other long-term effects of giroctocogene fitelparvovec, such as impact on overall patient liver health.