On November 2, 2023 BridgeBio Pharma, Inc. (Nasdaq: BBIO) (BridgeBio or the Company), a commercial-stage biopharmaceutical company focused on genetic diseases and cancers, reported its financial results for the third quarter ended September 30, 2023, and provided an update on the Company’s operations (Press release, BridgeBio, NOV 2, 2023, View Source [SID1234636740]).

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"We continue to be extremely grateful to the patient and physician communities with whom we collaborate; their partnership has helped us to realize tremendous advancement recently across the programs that make up our portfolio," said Neil Kumar, Ph.D., founder and CEO of BridgeBio. "We are excited about the progress from our late-stage pipeline, and have begun to highlight areas of differentiation for the upcoming, potentially blockbuster launch of our ATTR-CM asset. In particular, recent real-world evidence on ATTR-CM therapies presented at the HFSA scientific sessions suggests that the survival levels observed on acoramidis treatment in our Phase 3 study are indeed differentiated even in the context of the contemporary care setting as compared to other agents in the field. This continues to reinforce our hypothesis that better stabilization leads to better outcomes for patients with ATTR-CM."

BridgeBio’s key programs:

Acoramidis (AG10) – Transthyretin (TTR) stabilizer for transthyretin amyloid cardiomyopathy (ATTR-CM):
In August 2023, the Company presented detailed positive results from its Phase 3 ATTRibute-CM study of acoramidis for patients with ATTR-CM; a highly statistically significant result was observed on the primary endpoint with a Win Ratio of 1.8 (p<0.0001). This primary endpoint result consistently favored acoramidis treatment across key subgroups, including National Amyloidosis Center (NAC) ATTR stage I, II, and III patients.
Absolute values observed across all-cause mortality (ACM), cardiovascular mortality (CVM) and CVH showed that over 30 months, patients survived more and were hospitalized less than has been seen in prior interventional studies of ATTR-CM to the Company’s knowledge, including real-world evidence presented at recent cardiology medical meetings.
The 81% survival rate on acoramidis approaches the survival rate in the age-matched U.S. database (~85%); the 0.29 mean annual CVH rate on acoramidis approaches the annual hospitalization rate observed in the broader U.S. Medicare population (~0.26).
Assessment of measures of disease progression in the trial suggest that on acoramidis, 45% of subjects experienced an improvement from baseline in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) versus 9% on placebo, and 40% of subjects experienced an improvement from baseline on 6-minute walk distance (6MWD) versus 24% on placebo. To the Company’s knowledge, the proportions of treated patients improving on these measures over 30 months are higher than have been observed in prior controlled studies in ATTR-CM.
We believe these points of differentiation observed in the ATTRibute-CM results are made possible by acoramidis achieving near-complete stabilization of transthyretin (TTR) in both wild-type and variant ATTR patients; serum TTR was promptly and consistently elevated throughout the study.
In an exploratory post-hoc analysis of the relationship between on-treatment serum TTR levels and on-treatment measures of CVH, NT-proBNP, and Kansas City Cardiomyopathy Questionnaire (KCCQ), there was an association between the mean on-treatment TTR level and each of these three variables, consistent with the premise that higher degrees of stabilization lead to better outcomes for patients.
Acoramidis was well-tolerated with no safety signals of potential clinical concern identified.
The Company intends to file an NDA for acoramidis with the FDA by the end of 2023 and marketing authorization applications with additional regulatory authorities globally in 2024.
Additional detailed results of ATTRibute-CM are planned for presentation at the American Heart Association Scientific Sessions and the American College of Cardiology Scientific Sessions.
Low-dose infigratinib – FGFR1-3 inhibitor for achondroplasia and hypochondroplasia:
In September 2023, the Company completed positive regulatory meetings with the FDA and the EMA. Alignment from the FDA and EMA was reached on the adequacy of a one-year, 2:1 randomized, placebo-controlled Phase 3 pivotal trial for infigratinib to support a marketing application for the treatment of children with achondroplasia.
Based on the positive results to date, the Company has been enrolling children in the run-in for PROPEL3, the Phase 3 registrational study, and expects to initiate PROPEL3 by the end of 2023.
If approved, the Company believes that infigratinib has the potential to capture a significant share of the market based on blinded market research.
The Company is committed to exploring the potential of infigratinib on the wider medical and functional impacts of achondroplasia, hypochondroplasia and other skeletal dysplasias, which hold significant unmet needs for families.
BBP-418 – Glycosylation substrate for limb-girdle muscular dystrophy type 2I/R9 (LGMD2I/R9):
In October 2023, the Company shared new long-term data from its Phase 2 trial in patients with LGMD2I/R9 at the Annual Congress of World Muscle Society. The new long-term data remains consistent with earlier data from the Phase 2 study showing a well-tolerated safety profile and encouraging preliminary efficacy. Additionally, early changes in glycosylated αDG levels at 3 months predicted ambulatory improvements at 9 months, providing support for the possible use of glycosylated αDG levels as a surrogate endpoint in the ongoing Phase 3 study for Accelerated Approval by the FDA.
FORTIFY, the global Phase 3 registrational trial of BBP-418, continues to enroll in the U.S. with clinical trial sites planned for Europe and Australia. The Company believes there is potential to pursue Accelerated Approval for BBP-418 based on recent interactions with the FDA on the use of glycosylated αDG levels as a surrogate endpoint.
The Company believes BBP-418 has the potential to address a population of 7,000 patients in the U.S. and Europe.
There are currently no disease-modifying treatments available for LGMD2I/R9.
Encaleret – Calcium-sensing receptor (CaSR) inhibitor for autosomal dominant hypocalcemia type 1 (ADH1):
In September 2023, the Company announced proof-of-concept Phase 2b data evaluating the effects of encaleret on mineral homeostasis in patients with ADH1 were published in the New England Journal of Medicine in partnership with the NIH. The results highlighted that encaleret restored physiologic mineral homeostasis in 13 participants with ADH1, specifically correcting hypocalcemia and reducing hypercalciuria.
Population genetics analyses estimate approximately 25,000 carriers of gain-of-function variants of the CaSR, the underlying cause of ADH1, in the U.S. and European Union.
The Company has received approval to begin enrollment for CALIBRATE, its Phase 3 clinical trial of encaleret, in European Union and Japan, and anticipates sharing topline data from CALIBRATE in 2024.
If approved, encaleret could be the first therapy specifically indicated for the treatment of ADH1.
BBP-631 – AAV5 gene therapy candidate for congenital adrenal hyperplasia (CAH):
The Phase 1/2 gene therapy trial of BBP-631 for CAH continues to progress, with the dose-escalation portion of the study (N=6) fully enrolled; the Company plans to share data from the program in early 2024.
CAH is one of the most prevalent genetic diseases potentially addressable with adeno-associated virus (AAV) gene therapy, with more than 75,000 cases estimated in the U.S. and European Union.
RAS cancer portfolio:
BBO-8520, an investigational, next-generation small molecule direct KRASG12C(ON) inhibitor candidate that is designed to directly bind and inhibit KRASG12C in both its ON (GTP-bound) and OFF (GDP-bound) conformations, remains on track to file an IND in 2023.
The novel, direct KRAS (ON) targeting mechanism of BBO-8520 was observed to be potentially superior to KRAS (OFF) by data presented at the recent Triple Meeting, suggesting scope for a potent, next-generation agent to have an effect.
The Company’s PI3Kα:RAS breaker candidate BBO-10203 and pan-KRAS program remain on track for an IND and a development candidate selection, respectively, in 2024.
Recent Corporate Updates:

Multi-year partnership with Resilience to advance BBP-631, BBP-812 and future gene therapy treatments: The Company and Resilience signed an agreement to transfer the manufacturing process for the Company’s lead AAV-based gene therapy candidates, BBP-631 and BBP-812, to Resilience’s network of gene therapy manufacturing sites. Resilience will also be the primary manufacturer for future clinical projects across the Company’s gene therapy portfolio. The deal is intended to reduce manufacturing costs, which have historically accounted for approximately 50%-60% of the Company’s gene therapy budget.
$316 million gross proceeds raised between ATM and PIPE financing: The PIPE financing (as detailed in the forthcoming S-3 filing) included significant participation from four of the largest investment management firms in the U.S., as well as a number of large institutional investors and existing investors.
Third Quarter 2023 Financial Results:

Cash, Cash Equivalents, Marketable Securities and Short-Term Restricted Cash

Cash, cash equivalents and short-term restricted cash, totaled $521.9 million as of September 30, 2023, compared to cash, cash equivalents, marketable securities and short-term restricted cash of $466.2 million as of December 31, 2022. The net increase of $55.7 million in cash, cash equivalents, marketable securities and short-term restricted cash was primarily attributable to net proceeds received of $450.3 million from various equity financing offerings, and $5.2 million from stock option exercises, primarily offset by net cash used in operating activities of $402.9 million during the nine months ended September 30, 2023.

Revenue

Revenue for the three and nine months ended September 30, 2023 was $4.1 million and $7.6 million, respectively, as compared to $0.3 million and $75.8 million for the same periods in the prior year, respectively. The net decrease of $68.2 million for the nine months ended September 30, 2023, compared to the same period in the prior year, was primarily attributable to the timing of revenue recognized from the Navire-BMS License Agreement which was entered into in May 2022.

Operating Costs and Expenses

Operating costs and expenses for the three and nine months ended September 30, 2023 were $161.8 million and $437.5 million, respectively, compared to $129.5 million and $458.7 million, for the same periods in the prior year, respectively.

The overall increase of $32.3 million in operating costs and expenses for the three months ended September 30, 2023, compared to the same period in the prior year, was primarily due to an increase of $32.6 million in research and development and other expenses (R&D) to advance the Company’s pipeline of development programs, an increase of $4.6 million in selling, general and administrative (SG&A) expenses to support commercialization readiness efforts, offset by a decrease of $4.7 million in restructuring, impairment and related charges.

The overall decrease of $21.2 million in operating costs and expenses for the nine months ended September 30, 2023, compared to the same period in the prior year, was primarily due to a decrease of $28.9 million in restructuring, impairment and related charges given that the majority of the restructuring initiatives occurred in the prior year, a decrease of $8.3 million in SG&A expenses as a result of restructuring initiatives, offset by an increase of $16.0 million in R&D expenses to advance the Company’s pipeline of development programs.

Restructuring, impairment and related charges for the three and nine months ended September 30, 2023, amounted to $0.3 million and $7.2 million, respectively. These charges primarily consisted of winding down, exit costs, and severance and employee-related costs. Restructuring, impairment and related charges for the same periods in the prior year were $5.0 million and $36.1 million, respectively. These charges primarily consisted of impairments and write-offs of long-lived assets, severance and employee-related costs, and exit and other related costs. The Company expects that the remaining restructuring, impairment and related charges will be immaterial through the end of 2023.

Stock-based compensation expenses included in operating costs and expenses for the three months ended September 30, 2023 were $27.2 million, of which $14.1 million is included in R&D expenses, and $13.1 million is included in SG&A expenses. Stock-based compensation expenses included in operating costs and expenses for the three months ended September 30, 2022 were $18.7 million, of which $6.2 million is included in R&D expenses, and $12.5 million is included in SG&A expenses.

Stock-based compensation expenses included in operating costs and expenses for the nine months ended September 30, 2023 were $77.9 million, of which $39.2 million is included in R&D expenses, and $38.7 million is included in SG&A expenses. Stock-based compensation expenses included in operating costs and expenses for the nine months ended September 30, 2022 were $71.2 million, of which $29.0 million is included in R&D expenses, $41.0 million is included in SG&A expenses, and $1.2 million is included in restructuring, impairment and related charges.

"We were pleased to partner with leading institutional investors on our PIPE financing last quarter," said Brian Stephenson, Ph.D., CFA, Chief Financial Officer of BridgeBio. "We continue to take advantage of our optionality in exploring less-dilutive forms of financing and anticipate that these, in conjunction with the PIPE financing, could capitalize us to profitability."

On November 2, 2023 bluebird bio, Inc. (Nasdaq: BLUE) reported that new long-term efficacy, safety and health-related quality of life (HRQoL) follow-up data from its lentiviral vector (LVV) gene therapy programs in patients with sickle cell disease who have a history of vaso-occlusive events and patients with beta-thalassemia who require regular red blood cell transfusions will be presented at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, bluebird bio, NOV 2, 2023, View Source [SID1234636739]). The meeting will take place December 9-12, 2023 at the San Diego Convention Center and online.

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"The bluebird bio data to be presented at ASH (Free ASH Whitepaper) 2023 underscore the maturity of LVV gene therapies for hemoglobinopathies, with up to 9 years of follow-up data in transfusion-dependent beta-thalassemia and 5 years of follow-up in sickle cell disease," said Richard Colvin, M.D., Ph.D., chief medical officer, bluebird bio. "The robustness of this dataset is unparalleled, giving us continued confidence that the transformational impact these therapies may have for patients is sustained over time. We especially look forward to the first ever presentation of data from our long-term follow-up study of lovo-cel, the most deeply studied gene therapy in development for sickle cell disease."

bluebird bio will present updated follow-up data for lovotibeglogene autotemcel (lovo-cel) in patients from the HBG-206 Group C and HGB-210 studies with sickle cell disease followed for up to 60 months (median of 35.5 months), demonstrating sustained hemoglobin AT87Q production and near-complete resolution of vaso-occlusive events (VOEs) and severe VOEs, as well as sustained improvements in HRQoL. lovo-cel treatment regimen largely reflects known side effects of hematopoietic stem cell collection and busulfan conditioning regimen and underlying sickle cell disease.

Updated analyses of efficacy, safety, and HRQoL data from Phase 1/2 and Phase 3 studies of betibeglogene autotemcel (beti-cel) in patients with transfusion-dependent beta-thalassemia will also be presented, demonstrating sustained transfusion independence with up to nine years of follow-up and improvements in quality of life reported at Month 36. Updated iron management outcomes demonstrating sustained improvements in iron burden, with the majority of patients able to stop iron chelation therapy, will also be presented. Safety of beti-cel treatment largely reflects the known side effects of hematopoietic stem cell collection and busulfan conditioning regimen.

Sickle Cell Disease Data
Oral Presentation [#1051]: Efficacy, Safety, and Health-Related Quality of Life (HRQOL) in Patients with Sickle Cell Disease (SCD) Who Have Received lovotibeglogene autotemcel (lovo-cel) Gene Therapy: Up to 60 Months of Follow-up
Presenting Author: Julie Kanter, M.D., director of the UAB Adult Sickle Cell clinic, associate professor in the Division of Hematology and Oncology, and co-director of the UAB Comprehensive Sickle Cell Disease Center at the University of Alabama in Birmingham
Date/Time: Monday, December 11, 2023, 4:30 p.m. PT

Beta-Thalassemia Data
Poster Presentation [#1102]: Sustained, Efficacy, Safety, and Improved Quality of Life in Adult and Pediatric Patients with Transfusion-Dependent β-Thalassemia up to 9 Years Post Treatment with betibeglogene autotemcel (beti-cel)
Presenting Author: Alexis A. Thompson, M.D., M.P.H., professor of pediatrics (hematology), Perelman School of Medicine, University of Pennsylvania, Philadelphia, and chief, Division of Hematology, Children’s Hospital of Philadelphia
Date/Time: Saturday, December 9, 2023, 5:30 p.m. PT

Poster Presentation [#2480]: Improvement in Iron Burden in Patients with Transfusion-Dependent β-Thalassemia (TDT) Treated with betibeglogene autotemcel (beti-cel) Gene Therapy: Up to 9 Years of Follow-up
Presenting Author: Janet L. Kwiatkowski, M.D., MSCE, professor of pediatrics (hematology), Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, and director, Thalassemia Center, Children’s Hospital of Philadelphia
Date/Time: Sunday, December 10, 2023, 6:00 p.m. PT

Abstracts outlining bluebird bio’s accepted data at ASH (Free ASH Whitepaper) 2023 are available on the ASH (Free ASH Whitepaper) conference website.

The U.S. Food and Drug Administration previously accepted the lovo-cel Biologics Licensing Application (BLA) for Priority Review and set a Prescription Drug User Fee Act (PDUFA) goal date of December 20, 2023. beti-cel was approved by the FDA in August 2022 and is commercially available in the United States as ZYNTEGLO.

About sickle cell disease (SCD)
Sickle cell disease (SCD) is a complex and progressive genetic disease associated with debilitating and unpredictable pain crises, anemia, irreversible damage to vital organs, and early death. In SCD, high concentrations of sickle hemoglobin (HbS) in red blood cells (RBCs) cause RBCs to become sickled, sticky, and rigid with a shorter life span, which manifests acutely as hemolytic anemia, vasculopathy, and vaso-occlusion. Pain onset can be sudden and unpredictable, often requiring hospitalization. Fifty to sixty percent of adults with SCD have end organ damage, with 24 percent experiencing damage in multiple organs, and one in four patients have a stroke by the age of 45. The impact of SCD is pervasive and affects every aspect of life for patients and their families and caregivers – from missed work and school, decreased quality of life and mental health, and ability to complete daily tasks. In the U.S., there are approximately 100,000 people living with SCD, and the median age of death is 45 years of age.

While SCD was the first disease to have a genetic cause identified, treatment advances have lagged – since that discovery in 1949,i only four therapies have been approved,ii none of which address the underlying genetic cause of disease.

About lovotibeglogene autotemcel (lovo-cel)
lovotibeglogene autotemcel (lovo-cel) gene therapy is an investigational one-time treatment being studied for sickle cell disease (SCD), that is designed to add functional copies of a modified form of the β-globin gene (βA-T87Q-globin gene) into a patient’s own hematopoietic (blood) stem cells (HSCs). Once patients have the βA-T87Q-globin gene, their red blood cells (RBCs) can produce anti-sickling hemoglobin (HbAT87Q) that decreases the proportion of HbS, with the goal of reducing sickled RBCs, hemolysis, and other complications. bluebird bio’s clinical development program for lovo-cel includes the completed Phase 1/2 HGB-205 and ongoing Phase 1/2 HGB-206 and Phase 3 HGB-210 studies. bluebird bio is also conducting a long-term safety and efficacy follow-up study (LTF-307) for people who have been treated with lovo-cel in bluebird bio-sponsored clinical studies.

In the BLA submission, as of August 2022, the majority of adverse events in treated patients were attributed to underlying sickle cell disease or conditioning with busulfan. Nonserious adverse events related to lovo-cel included infusion reactions (hot flush and decreased blood pressure) in two patients (2% each). Serious adverse events related to lovo-cel included anemia in two patients (4%) with concurrent alpha-thalassemia trait. Three cases of hematologic malignancy have been reported, including one case of myelodysplastic syndrome that remains under investigation. No cases have been associated with insertional oncogenesis. Three of 50 patients (6%) died, one due to sudden cardiac death and two due to aforementioned hematologic malignancy.

The U.S. Food and Drug Administration accepted the lovo-cel Biologics Licensing Application (BLA) for Priority Review and set a Prescription Drug User Fee Act (PDUFA) goal date of December 20, 2023. The FDA previously granted lovo-cel orphan drug designation, fast track designation, regenerative medicine advanced therapy (RMAT) designation, and rare pediatric disease designation.

About ZYNTEGLO (betibeglogene autotemcel) or beti-cel
ZYNTEGLO is a first-in-class, one-time ex-vivo LVV gene therapy approved for the treatment of beta-thalassemia in adult and pediatric patients who require regular red blood cell transfusions. ZYNTEGLO works by adding functional copies of a modified form of the beta-globin gene (βA-T87Q-globin gene) into a patient’s own hematopoietic (blood) stem cells to enable the production of a modified functional adult hemoglobin (HbAT87Q). Once a patient has the βA-T87Q-globin gene, they have the potential to increase ZYNTEGLO-derived adult hemoglobin (HbAT87Q) and total hemoglobin to normal or near normal levels that can eliminate the need for regular red blood cell (RBC) transfusions.

Indication
ZYNTEGLO is indicated for the treatment of adult and pediatric patients with beta-thalassemia who require regular red blood cell (RBC) transfusions.

Important Safety Information

Delayed Platelet Engraftment

Delayed platelet engraftment has been observed with ZYNTEGLO treatment. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia; 15% of patients had ≥ Grade 3 decreased platelets on or after Day 100.

Patients should be made aware of the risk of bleeding until platelet recovery has been achieved. Monitor patients for thrombocytopenia and bleeding according to standard guidelines. Conduct frequent platelet counts until platelet engraftment and platelet recovery are achieved. Perform blood cell count determination and other appropriate testing whenever clinical symptoms suggestive of bleeding arise.

Risk of Neutrophil Engraftment Failure

There is a potential risk of neutrophil engraftment failure after treatment with ZYNTEGLO. Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥ 500 cells/microliter obtained on different days by Day 43 after infusion of ZYNTEGLO. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with ZYNTEGLO, provide rescue treatment with the back-up collection of CD34+ cells.

Risk of Insertional Oncogenesis

There is a potential risk of LVV mediated insertional oncogenesis after treatment with ZYNTEGLO.

Patients treated with ZYNTEGLO may develop hematologic malignancies and should be monitored lifelong. Monitor for hematologic malignancies with a complete blood count (with differential) at Month 6 and Month 12 and then at least annually for at least 15 years after treatment with ZYNTEGLO, and integration site analysis at Months 6, 12, and as warranted.

In the event that a malignancy occurs, contact bluebird bio at 1 833-999-6378 for reporting and to obtain instructions on collection of samples for testing.

Hypersensitivity Reactions

Allergic reactions may occur with the infusion of ZYNTEGLO. The dimethyl sulfoxide (DMSO) in ZYNTEGLO may cause hypersensitivity reactions, including anaphylaxis.

Anti-retroviral and Hydroxyurea Use

Patients should not take prophylactic HIV anti-retroviral medications or hydroxyurea for at least one month prior to mobilization, or for the expected duration for elimination of the medications, and until all cycles of apheresis are completed. If a patient requires anti-retrovirals for HIV prophylaxis, then confirm a negative test for HIV before beginning mobilization and apheresis of CD34+ cells.

Interference with Serology Testing

Patients who have received ZYNTEGLO are likely to test positive by polymerase chain reaction (PCR) assays for HIV due to integrated BB305 LVV proviral DNA, resulting in a false-positive test for HIV. Therefore, patients who have received ZYNTEGLO should not be screened for HIV infection using a PCR‑based assay.

Adverse Reactions

The most common non-laboratory adverse reactions (≥20%) were mucositis, febrile neutropenia, vomiting, pyrexia, alopecia, epistaxis, abdominal pain, musculoskeletal pain, cough, headache, diarrhea, rash, constipation, nausea, decreased appetite, pigmentation disorder, and pruritus. The most common Grade 3 or 4 laboratory abnormalities (>50%) include neutropenia, thrombocytopenia, leukopenia, anemia, and lymphopenia.

Drug Interactions

Drug-drug interactions between iron chelators and the myeloablative conditioning agent must be considered. Iron chelators should be discontinued at least 7 days prior to initiation of conditioning. The prescribing information for the iron chelator(s) and the myeloablative conditioning agent should be consulted for the recommendations regarding co-administration with CYP3A substrates.

Some iron chelators are myelosuppressive. After ZYNTEGLO infusion, avoid use of these iron chelators for 6 months. If iron chelation is needed, consider administration of non-myelosuppressive iron chelators. Phlebotomy can be used in lieu of iron chelation, when appropriate.

Pregnancy/Lactation

Advise patients of the risks associated with conditioning agents, including on pregnancy and fertility. ZYNTEGLO should not be administered to women who are pregnant, and pregnancy after ZYNTEGLO infusion should be discussed with the treating physician.

ZYNTEGLO is not recommended for women who are breastfeeding, and breastfeeding after ZYNTEGLO infusion should be discussed with the treating physician.

Females and Males of Reproductive Potential

A negative serum pregnancy test must be confirmed prior to the start of mobilization and re-confirmed prior to conditioning procedures and before ZYNTEGLO administration.

Women of childbearing potential and men capable of fathering a child should use an effective method of contraception (intra uterine device or combination of hormonal and barrier contraception) from start of mobilization through at least 6 months after administration of ZYNTEGLO.

Advise patients of the option to cryopreserve semen or ova before treatment if appropriate.
Please see full Prescribing Information for ZYNTEGLO.

On November 2, 2023 Biomea Fusion, Inc. ("Biomea" or "the company") (Nasdaq: BMEA), a clinical-stage biopharmaceutical company dedicated to discovering and developing novel covalent small molecules to treat and improve the lives of patients with genetically defined cancers and metabolic diseases, reported that abstracts related to BMF-219, a novel, investigational covalent menin inhibitor, currently in Phase 1 clinical study across multiple liquid and KRAS-mutated solid tumors, and BMF-500, a novel, investigational covalent FMS-like tyrosine kinase 3 (FLT3) inhibitor currently in Phase 1 clinical study in FLT3-mutated acute leukemias, have been accepted for presentation at the upcoming American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, to be held in San Diego from December 9-12, 2023 (Press release, Biomea Fusion, NOV 2, 2023, View Source [SID1234636738]). Both BMF-219 and BMF-500 were originated in-house with Biomea’s proprietary FUSION system platform, which discovers and designs next-generation covalent-binding small molecule product candidates.

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"We look forward to our first presentation of clinical data of BMF-219 from our ongoing, extensive study of this novel covalent menin inhibitor across a broad spectrum of mutation-specific liquid and solid tumors in patients with significant unmet needs," said Steve Morris, M.D., Chief Development Officer at Biomea. "The upcoming presentation at ASH (Free ASH Whitepaper) follows our initial reporting earlier this year of topline data from our ongoing COVALENT-101 trial, which demonstrated two complete responses out of five relapsed/refractory acute myeloid leukemia patients with menin-dependent mutations."

Details for the abstracts are listed below and can be viewed online at the ASH (Free ASH Whitepaper) conference website.

Publication Number: 2916
Title: Covalent Menin Inhibitor BMF-219 in Patients with Relapsed or Refractory (R/R) Acute Leukemia (AL): Preliminary Phase 1 Data from the COVALENT-101 Study
Session Name: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II
Session Date: Sunday, December 10, 2023
Presentation Time: 6:00 PM – 8:00 PM
Location: San Diego Convention Center, Halls G-H

Full Text of Abstract

Background: Menin, a protein involved in transcriptional regulation, plays a role in the genesis of multiple cancers. Preclinical data from BMF-219, an investigational, highly selective, oral small-molecule inhibitor of menin, show sustained potent abrogation of menin-dependent oncogenic signaling.

BMF-219 is the first and only covalent menin inhibitor in clinical development and is being evaluated in multiple hematologic malignancies, solid tumors, and diabetes mellitus. COVALENT-101 (NCT05153330) is a Phase I dose-escalation and -expansion study of BMF-219 in R/R AL (Cohort 1), DLBCL (Cohort 2), MM (Cohort 3), and CLL (Cohort 4). Here we report preliminary safety, PK and anticancer activity data from Cohort 1 (AL).

Methods: Doses of BMF-219 are escalated independently for each indication, initially in single-subject cohorts followed by a "3 + 3" design.

Eligible patients (pts) include adults with R/R AL ineligible for standard therapy. Initially pts were enrolled agnostic to molecular status. A subsequent amendment introduced quotas for KMT2Ar (MLL1r), NPM1 and other known menin-dependent mutations: CEBP/A, MLL1-PTD, MN1, NUP98, NUP214, PICALM-AF10, SETBP1. Prior exposure to reversible menin inhibitor therapy is permitted.

Subjects receive BMF-219 daily for continuous 28-day cycles until progression/intolerability. There are 2 parallel dose-escalation arms: pts not taking (Arm A) or taking (Arm B) moderate or strong CYP3A4 inhibitors. The study is ongoing and accruing in the escalation. Expansion cohorts will enroll pts to obtain further safety and efficacy data at the OBD/RP2D.

Results: As of data cutoff of 7/24/2023, 26 pts with R/R AL (24 AML; 2 ALL) are enrolled; 7 remain on study treatment. Baseline characteristics include 17(65%) males and 9(35%) females with a median age of 57.5 years (range 33-84). There is a median of 4 (range 1-8) prior lines of therapy and 11 (42%) with prior HSCT(s). Six pts (23%) had KMT2Ar, 3 (12%) KMT2A-PTD, 4 (15%) NPM1, and 13 (50%) WT for KMT2A and NPM1.

Dosing began with single-patient cohorts at 100 mg QD (Arm A) and 25 mg QD (Arm B) and has been escalated through 4 dose levels. Thus far, pts have been dosed up to 500 mg QD (Arm A) and 125 mg QD (Arm B).

BMF-219 exposures were comparable between arms, with ~2-4-fold higher exposures observed with co-administration of a moderate or strong CYP3A4 inhibitor. At the highest dose (DL4) in which PK was evaluated, Arm A (500 mg QD) and Arm B (125 mg QD), pts on average achieved ~50% of target exposure (2000 ng*hr/mL) with some pts surpassing it. Higher QD dosing or corresponding BID dosing is expected to achieve desired exposure.

BMF-219 has generally been well tolerated with no DLTs observed and no discontinuations due to treatment-related toxicities. No related QTc prolongation was observed. At the time of data cutoff, 23 of 26 pts were included in the safety population. Common TRAEs (≥10%) include vomiting 13% (3) and Differentiation Syndrome (DS) 13% (3). No Grade 5 TRAEs were reported. The only common Grade ≥3 TRAE (≥5%) was DS 13% (3).

The efficacy evaluable population includes AML pts who meet the following criteria: dosed at or near predicted efficacious dose (500 mg or above [Arm A]; 125 mg or above [Arm B]), had known menin-dependent mutations, and completed at least one scheduled response assessment (or had a minimum of 7 doses if discontinued prematurely). Thus far, 2 of 5 efficacy evaluable patients achieved a complete remission (1 CR; 1 CRi) and both continue BMF-219 treatment.

Patient A: 39/M, NUP98-NSD1, ECOG=0, 500 mg QD, Arm A, 4 prior lines of treatment including intensive chemotherapy and allo-HSCT. At C1D27, marrow blasts were reduced to 6% from 13% at study entry. The patient achieved CR at C2D28 with 0% blasts.
Patient B: 70/F, NPM1m, ECOG=1, 125 mg QD, Arm B, 1 prior line of treatment with decitabine and an investigational agent. At C1D28, marrow blasts were reduced to 34% from 52% at study entry. The patient achieved CRi with 3% blasts at C2D28.
Conclusion: BMF-219 is generally well tolerated with no DLT observed (and able to be taken with and without CYP3A4 inhibitors) with no pts discontinuing therapy due to toxicity. BMF-219 dose escalation is ongoing and approaching target exposure. BMF-219 demonstrates early signs of clinical activity in different genomic subgroups. The trial is ongoing and includes enrollment for pts diagnosed with AL, DLBCL, MM and CLL.

Publication Number: 1546
Title: COVALENT-103: A Phase 1, Open-Label, Dose-Escalation, and Dose-Expansion Study of BMF-500, an Oral Covalent FLT3 Inhibitor, in Adults with Acute Leukemia (AL)
Session Name: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster I
Session Date: Saturday, December 9, 2023
Presentation Time: 5:30 PM – 7:30 PM
Location: San Diego Convention Center, Halls G-H

Full Text of Abstract

Background: FLT3 mutations occur in 25-35% of patients with AML and are associated with poor prognosis. FLT3 mutations are most frequently the result of an internal tandem duplication (ITD) of amino acids in the juxtamembrane region of FLT3 or point mutations in the tyrosine kinase domain (TKD). FLT3-ITD mutations are associated with increased incidence of relapse, shorter duration of remission, and decreased disease-free and overall survival.

BMF-500 is a novel orally bioavailable, highly potent and selective covalent inhibitor of FLT3 including wildtype (WT), ITD, TKD, as well as a variety of additional resistance-conferring mutations such as the gatekeeper F691. BMF-500 has demonstrated high affinity for FLT3, lack of cKIT inhibition, and sustained cell-killing capacity despite drug washout (Law et al., ASH (Free ASH Whitepaper) 2022 Abstract 2756). BMF-500 has shown sustained tumor regression and improved survival in both subcutaneous and disseminated xenograft models of mutant FLT3-driven AML.

Study Design: COVALENT-103 (NCT05918692) is an open-label, non-randomized, multicenter, first-in-human Phase I study evaluating the safety, tolerability, and clinical activity of escalating doses of twice daily oral BMF-500 in patients with relapsed or refractory (R/R) AL, including AML, ALL, or MPAL, with or without FLT3 mutations.

The trial has 2 arms that will undergo dose escalation in parallel: Arm A (without) and Arm B (with) concomitant use of a moderate or strong CYP3A4 inhibitor. Utilizing an accelerated titration design (ATD), doses of BMF-500 will be escalated in single-subject cohorts until 1 subject experience either a Grade 2 or higher related-adverse event or dose-limiting toxicity (DLT). At that point, the cohort will switch to a classical "3 +3" design. Patients with WT FLT3 AL may be enrolled, up to a limit of 33% per arm. Treatment will continue in 28-day cycles until progression or intolerability. Expansion cohorts will enroll additional patients to obtain further safety and efficacy data.

Patients must be refractory, relapsed or must have progressed on or following discontinuation of the most recent anti-cancer therapy or be ineligible for any approved standard of care therapies, including HSCT. Participants with FLT3-mutant AML must have received treatment with a FLT3 inhibitor approved for treatment of relapsed or refractory FLT3-mutant AML.

Key inclusion criteria include ECOG PS ≤ 2, adequate organ function, and documented FLT3 mutation status. Key exclusion criteria include known CNS disease involvement, clinically significant cardiovascular disease, and WBC count >50,000/µL (uncontrollable with cytoreductive therapy).

Objectives: The primary objective of the study is to evaluate safety and tolerability and to determine the optimal biological dose (OBD)/ recommended Phase 2 dose (RP2D) of BMF-500 oral monotherapy based on evaluation of available PK/ PD, safety and efficacy data. Secondary objectives include characterization of the pharmacodynamics and pharmacokinetics of BMF-500, and assessment of its antitumor activity per modified Cheson (2003) criteria or the NCCN Clinical Practice Guidelines (ALL Version 1.2022) as determined by the investigator. Endpoints include best overall response rate (ORR), complete remission (CRc), duration of response (DOR), relapse-free survival (RFS) and overall survival (OS).

The study was initiated in July 2023 and will enroll ~110 participants at approximately 30 sites.

About COVALENT-101

COVALENT-101 is a Phase I, open-label, multi-center, dose-escalation and dose-expansion study designed to assess the safety, tolerability, and pharmacokinetics/pharmacodynamics of oral dosing of BMF-219 in patients with relapsed/refractory (R/R) acute leukemias —including subpopulations where menin inhibition is expected to provide therapeutic benefit (e.g., patients with MLL1/KMT2A gene rearrangements or NPM1 mutations). The study is designed to enroll subsets of acute leukemia patients who are receiving a CYP3A4 inhibitor and also those not receiving a CYP3A4 inhibitor. COVALENT-101 is also investigating the dosing of BMF-219 in other patient populations where preclinical studies have shown high menin dependence, such as multiple myeloma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia. Additional information about this Phase I clinical trial of BMF-219 can be found at ClinicalTrials.gov using the identifier NCT05153330.

About COVALENT-103

COVALENT-103 is a multicenter, open-label, non-randomized trial seeking to evaluate the safety and efficacy of BMF-500, a twice daily oral treatment, in adult patients with relapsed or refractory acute leukemia with FMS-like tyrosine kinase 3 (FLT3) wild-type and FLT3 mutations. Additional information about the Phase I clinical trial of BMF-500 can be found at ClinicalTrials.gov using the identifier NCT05918692.

On November 2, 2023 BioCryst Pharmaceuticals, Inc. (Nasdaq:BCRX) reported its financial results for the third quarter ended September 30, 2023, and provided a corporate update (Press release, BioCryst Pharmaceuticals, NOV 2, 2023, View Source [SID1234636737]).

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"With nearly three years of launch data, we have excellent visibility into the pattern of growth for ORLADEYO and we remain on track to achieve the no less than $320 million in ORLADEYO revenues we have expected for 2023. Our solid base and the consistent addition of new patients each quarter, combined with the ongoing improvement in our percentage of paid patients and launches in new global markets, are all driving peak revenues to $1 billion," said Jon Stonehouse, president and chief executive officer of BioCryst.

Program Updates

ORLADEYO (berotralstat): Oral, Once-daily Treatment for Prevention of Hereditary Angioedema (HAE) Attacks

"Strong, steady new patient switches continue to fuel the growth in ORLADEYO as more and more patients want to experience the benefits of the only oral, once-daily therapy to prevent HAE attacks," said Charlie Gayer, chief commercial officer of BioCryst.

ORLADEYO net revenue in the third quarter of 2023 was $85.7 million (+29.8 percent year-over-year (y-o-y)).

Total growth in patients taking ORLADEYO continued on a strong, linear trajectory.

The ongoing APeX-P trial in pediatric HAE patients who are 2 to <12 years of age continues to enroll as expected.

Sales from outside the U.S. contributed 12.2 percent of global ORLADEYO net revenues in the third quarter.

Austria has approved the reimbursement of ORLADEYO for the targeted prophylaxis of hereditary angioedema (HAE) in patients 12 years of age or older.
Upcoming R&D Day—November 3, 2023

BioCryst will host a Research and Development (R&D) Day at 1:00p ET on Friday, November 3 at its Discovery Center of Excellence in Birmingham, AL. At the R&D Day, the company plans to describe its drug discovery process and introduce additional therapies from its pipeline. The live webcast and replay of the R&D Day will be available online in the investors section of the company website at www.biocryst.com.

Third Quarter 2023 Financial Results

For the three months ended September 30, 2023, total revenues were $86.7 million, compared to $75.8 million in the third quarter of 2022 (+14.4 percent y-o-y). The increase was primarily due to an increase in ORLADEYO net revenue of $19.7 million, partially offset by a reduction in RAPIVAB (peramivir injection) revenue of $8.8 million, compared to the third quarter of 2022.

Research and development expenses for the third quarter of 2023 decreased to $46.9 million from $52.7 million in the third quarter of 2022 (-11.0 percent y-o-y), primarily due to the discontinuations of the BCX9930 and BCX9250 programs, partially offset by additional investment in BCX10013 and pipeline programs.

Selling, general and administrative expenses for the third quarter of 2023 increased to $50.7 million, compared to $36.9 million in the third quarter of 2022 (+37.1 percent y-o-y). The increase was primarily due to increased investment to support the commercial launch of ORLADEYO.

Interest expense was $27.3 million in the third quarter of 2023, compared to $24.8 million in the third quarter of 2022 (+10.1 percent y-o-y). The increase was due to additional interest to service the Pharmakon debt secured in April 2023.

Net loss for the third quarter of 2023 was $36.1 million, or $0.19 per share, compared to a net loss of $42.5 million, or $0.23 per share, for the third quarter of 2022.

Cash, cash equivalents, restricted cash and investments totaled $399.2 million at September 30, 2023, compared to $462.6 million at September 30, 2022. Operating cash use for the third quarter of 2023 was $16.5 million (-43.9 percent y-o-y).

Financial Outlook for 2023

The company expects full year 2023 global net ORLADEYO revenue to be no less than $320 million. The company continues to be disciplined in its approach to capital allocation and is reducing its outlook for operating expenses for full year 2023, not including non-cash stock compensation, to between $365 million and $375 million, reflecting an expected decline from 2022 operating expenses.

Conference Call and Webcast

BioCryst management will host a conference call and webcast at 8:30 a.m. ET today to discuss the financial results and provide a corporate update. The live call may be accessed by dialing 1-866-777-2509 for domestic callers and 1-412-317-5413 for international callers. A live webcast and replay of the call will be available online in the investors section of the company website at www.biocryst.com.

On November 2, 2023 Bicycle Therapeutics plc (NASDAQ: BCYC), a biotechnology company pioneering a new and differentiated class of therapeutics based on its proprietary bicyclic peptide (Bicycle) technology, reported financial results for the third quarter ended September 30, 2023, and provided recent corporate updates (Press release, Bicycle Therapeutics, NOV 2, 2023, View Source [SID1234636736]).

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"In the third quarter, we took important steps toward achieving our goal of quickly getting our novel therapies to those who need them. We are extremely pleased to have aligned with the FDA on an expedited clinical development plan and regulatory pathway for BT8009, our lead investigational therapy for metastatic bladder cancer, and that the agency selected BT8009 to be part of a new program that will help facilitate its expedited CMC development. Through close collaboration with the FDA, we will work to ensure BT8009’s commercial manufacturing readiness keeps pace with its expedited clinical development timeframe," said Kevin Lee, Ph.D., CEO of Bicycle Therapeutics. "With a strengthened balance sheet through the proceeds of an upsized equity offering completed in July, we believe we are well-positioned to conduct our Phase 2/3 registrational trial, scheduled to begin in the first quarter of 2024, to support the potential accelerated approval of BT8009 in a broad metastatic bladder cancer population. Additionally, we continue to advance our research and development efforts across our pipeline, and we look forward to providing clinical updates on BT8009, BT5528 and BT7480 at our R&D Day next month."

Third Quarter 2023 and Recent Highlights

BT8009 Selected to Participate in U.S. Food and Drug Administration (FDA) Program to Expedite Commercial Manufacturing Readiness. In October, Bicycle Therapeutics announced the FDA selected BT8009 to participate in the new Chemistry, Manufacturing and Controls (CMC) Development and Readiness Pilot (CDRP) Program, which was created to facilitate CMC development for therapies with expedited clinical development timeframes, based on the anticipated clinical benefits of earlier patient access to the therapy. BT8009 is one of up to nine products selected for the inaugural cohort of the CDRP Program.
Announced Expedited Clinical Development Plan and Regulatory Pathway for BT8009 in Metastatic (Urothelial) Bladder Cancer. In September, Bicycle Therapeutics announced the company will proceed with its plan to expedite development of BT8009 for metastatic bladder cancer following recent discussions with the FDA. The company aligned with the FDA on a Phase 2/3 registrational trial, called Duravelo-2, that has an innovative design allowing for potential accelerated approval in untreated (first-line) and previously treated (second-line plus) metastatic bladder cancer. The company plans to initiate the Duravelo-2 trial in the first quarter of 2024.
In Cohort 1, two doses of BT8009 plus standard pembrolizumab regimen will be initially assessed. Following selection of the optimal dose, BT8009 plus pembrolizumab will be evaluated against chemotherapy. Potential accelerated approval will be determined by objective response rate (ORR), and progression-free survival (PFS) will be used to confirm clinical benefit.
In Cohort 2, two doses of BT8009 as monotherapy will be initially studied. Following selection of the optimal dose, an additional arm of BT8009 plus standard pembrolizumab regimen will be added. Potential accelerated approval for BT8009 monotherapy and in combination with pembrolizumab will be determined by ORR compared to historical control data. Discussions with the FDA about the design of the confirmatory trial for previously treated metastatic bladder cancer are ongoing.
Raised Net Proceeds of $215.1 Million in Public Offering. In July, Bicycle Therapeutics announced the closing of an underwritten public offering resulting in gross proceeds of approximately $230.0 million, including the full exercise of the underwriters’ option to purchase additional shares. Net proceeds were approximately $215.1 million. In addition, the company also received net proceeds from Bicycle’s at-the-market (ATM) offering program during the third quarter of 2023 totaling $19.4 million.
Pipeline updates planned at upcoming Research & Development (R&D) Day on December 14, 2023, in New York

Bicycle Therapeutics will provide updates from the company’s Phase 1/2 clinical trials for BT8009, a Bicycle Toxin Conjugate (BTC) targeting Nectin-4, a well-validated tumor antigen; BT5528, a BTC targeting EphA2; and BT7480, a Bicycle TICA targeting Nectin-4 and agonizing CD137. The company will also provide an overview of its novel Bicycle technology, the broad capabilities of its drug discovery platform and potential future pipeline programs.

The R&D Day will begin at 8 a.m. ET on Thursday, December 14, 2023, and will conclude at approximately 12 p.m. ET. Analysts and investors who are interested in attending in person can RSVP to [email protected]. A webcast of the event will be accessible from the Investor section of the company’s website, www.bicycletherapeutics.com. A replay of the webcast will be archived and available following the event.

Financial Results

Cash and cash equivalents were $572.1 million as of September 30, 2023, compared to $339.2 million as of December 31, 2022. The increase in cash and cash equivalents is primarily due to $215.1 million in net proceeds from the underwritten public offering in July 2023, $34.2 million of year-to-date net proceeds from our ATM offering program and $95.0 million received from our collaboration agreements with Novartis and Bayer, offset by cash used in operating activities.
R&D expenses were $39.9 million for the three months ended September 30, 2023, compared to $22.8 million for the three months ended September 30, 2022. The increase in expense of $17.1 million was primarily due to increased clinical program expenses for BT8009 development and other discovery and platform-related activities, as well as increased personnel-related expenses, including incremental non-cash share-based compensation expense of $0.7 million.
General and administrative expenses were $16.3 million for the three months ended September 30, 2023, compared to $10.0 million for the three months ended September 30, 2022. The increase of $6.3 million for the three months ended September 30, 2023, as compared to the same period in the prior year was primarily due to an increase in professional and consulting fees as well as an increase in personnel-related expenses, including incremental non-cash share-based compensation expense of $1.3 million.
Net loss was $49.9 million, or $(1.26) basic and diluted net loss per share, for the three months ended September 30, 2023, compared to net loss of $28.3 million, or $(0.96) basic and diluted net loss per share, for three months ended September 30, 2022.