On May 11, 2023 UroGen Pharma Ltd. (Nasdaq: URGN), a biotech company dedicated to developing and commercializing innovative solutions that treat urothelial and specialty cancers, reported financial results for the first quarter ended March 31, 2023, and provided an overview of recent developments (Press release, UroGen Pharma, MAY 11, 2023, View Source [SID1234631540]).

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"2023 is off to a promising start as we reported double-digit year-over-year growth in worldwide JELMYTO net sales during the first quarter," said Liz Barrett, President, and Chief Executive Officer of UroGen. "JELMYTO adoption continues to grow, attributable to the growing body of evidence supporting its benefits in a real-world setting, combined with key initiatives that have expanded access and improved logistical efficiencies for physicians and patients. As we look ahead to summer 2023, we have several key events to prepare for, primarily topline results from both the ENVISION and ATLAS clinical trials investigating the potential of UGN-102 for the treatment of LG-IR-NMIBC. With prospective favorable results, we will look to submit a New Drug Application (NDA) for UGN-102 in 2024 to the U.S. Food & Drug Administration (FDA), for which we are already actively preparing."

Business Highlights:

UGN-102 (mitomycin) for intravesical solution:

A topline data readout of the primary endpoint from the ENVISION Phase 3 pivotal study of UGN-102 evaluating the complete response (CR) rate of ~240 patients at 3-months after first instillation is expected this summer.
Topline data from the ATLAS clinical trial, the predecessor to ENVISION, is expected summer 2023 and will evaluate complete response, duration of response and safety from ~280 patients that completed the trial.
Announced preliminary results of a study to assess the feasibility of home instillation of UGN-102. In this study, UGN-102 was suitable to administer at home by a visiting nurse under the supervision of a treating physician and resulted in 75% (n=8) of patients achieving a complete response, defined as no detectable disease 3 months after starting treatment.
JELMYTO (mitomycin) for pyelocalyceal solution in low-grade upper tract urothelial cancer (LG-UTUC):

Generated net product revenue of $17.2 million for the first quarter of 2023, representing ~27% growth over the first quarter of 2022.
Activated sites on May 1, 2023 were 1,009, compared to 983 on March 1, 2023, while repeat accounts on May 1, 2023 were 235, compared to 214 on March 1, 2023.
A positive American Urologic Association (AUA) meeting was headlined by the first ever AUA and Society of Urologic Oncology (SUO) treatment guideline for LG-UTUC, recommending use of JELMYTO in certain clinical scenarios. The guideline states that tumor ablation should be the initial management option for patients with low-risk favorable UTUC, for which JELMYTO can be a treatment option as part of a kidney sparing approach intended to prevent radical nephroureterectomies (RNU) in low-risk UTUC patients.
New retrospective study presented at AUA 2023 reported on the use of JELMYTO in treating patients with UTUC after complete endoscopic ablation. Patients in this retrospective study who underwent complete endoscopic ablation followed by JELMYTO were more likely to be disease-free at first endoscopic evaluation than those who underwent chemoablation alone (69% vs. 40%). In the Phase 3 OLYMPUS study of JELMYTO, LG-UTUC patients in the primary chemoablation setting achieved a 58% complete response rate at first endoscopic evaluation.
New retrospective study presented at AUA 2023 reported similar outcomes when utilizing Jelmyto in treating LG-UTUC of the ureter compared to renal pelvic cancers. In this analysis, 47 patients had UTUC tumors involving the ureter, with 12 cases of ureteral tumor only (8.8%) and 35 cases of ureteral plus renal pelvic tumors (25.7%). The investigators reported no difference in outcomes at first endoscopic evaluation based on tumor location (p=0.644). JELMYTO is approved for the chemoablation of low-grade upper tract urothelial cancer (LG-UTUC) involving the renal pelvis and calyces.
First Quarter 2022 Financial Results:

Jelmyto Revenue: UroGen reported net product revenue of Jelmyto for the first quarter 2023 of $17.2 million, compared to $13.6 million in the first quarter of 2022.

R&D Expense: Research and development expenses for the first quarter 2023 were $12.5 million, including non-cash share-based compensation expense of $0.5 million as compared to $12.7 million, including non-cash share-based compensation expense of $0.7 million, for the same period in 2022.

SG&A Expense: Selling, general and administrative expenses for the first quarter 2023 were $24.5 million, including non-cash share-based compensation expense of $1.8 million. This compares to $21.3 million, including non-cash share-based compensation expense of $2.2 million, for the same period in 2022.

Financing on Prepaid Forward Obligation: UroGen reported non-cash financing expense related to the prepaid forward obligation to RTW Investments of $5.2 million for the first quarter 2023. The rate applied to cash payments incurred in 2023 is 13% based on global net product sales of JELMTYO in 2022.

Interest Expense on Long-Term Debt: Interest expense related to the $100 million term loan facility with funds managed by Pharmakon Advisors was $3.6 million for the first quarter of 2023, compared to $0.3 million for the same period last year due to the transaction closing in March 2022 and the final $25 million draw down under the term loan facility in December 2022.

Net Loss: UroGen reported a net loss of $30.2 million, or basic and diluted net loss per ordinary share of $1.30, for the first quarter 2023 as compared to $28.4 million, or basic and diluted net loss per ordinary share of $1.25, for the same period in 2022.

Cash & Cash Equivalents: As of March 31, 2023, cash, cash equivalents and marketable securities totaled $75.2 million.

2023 Revenue, Operating Expense and RTW Expense Guidance: The Company reiterates anticipated full year 2023 net product revenues from JELMYTO to be in the range of $76 to $86 million. The Company reiterates anticipated full year 2023 operating expenses in the range of $135 to $145 million, including non-cash share-based compensation expense of $6.0 to $11.0 million, subject to market conditions. The Company reiterates anticipated full year 2023 non-cash financing expense related to the prepaid obligation to RTW Investments in the range of $21.0 to $26.0 million. Of this amount approximately $9.9 to $11.2 million is expected to be in cash.

Conference Call & Webcast Information: Members of UroGen’s management team will host a live conference call and webcast today at 10:00 AM Eastern Time to review UroGen’s financial results and provide a general business update.

The live webcast can be accessed by visiting the Investors section of the Company’s website at View Source Please connect at least 15 minutes prior to the live webcast to ensure adequate time for any software download that may be needed to access the webcast.

On May 11, 2023 Theseus Pharmaceuticals, Inc. (NASDAQ: THRX) (Theseus or the Company), a clinical-stage biopharmaceutical company focused on improving the lives of cancer patients through the discovery, development, and commercialization of transformative targeted therapies, reported business highlights and provided financial results for the first quarter ended March 31, 2023 (Press release, Theseus Pharmaceuticals, MAY 11, 2023, View Source [SID1234631539]).

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"We look forward to continued clinical execution and important pipeline advancements in the months ahead, most notably with two anticipated clinical readouts from our lead program, THE-630, in advanced GIST," said Tim Clackson, Ph.D., President and Chief Executive Officer of Theseus. "We maintain a strong financial position as we continue to progress our pipeline, with an anticipated IND submission for THE-349 in the fourth quarter of this year as well as advancement of our BCR-ABL and discovery programs."

Recent Pipeline Highlights and Upcoming Expected Milestones:

THE-630 is a pan-variant tyrosine kinase inhibitor (TKI) of the receptor tyrosine kinase KIT, designed for patients with gastrointestinal stromal tumors (GIST) that have developed resistance to earlier lines of therapy.
•As of March 31, 2023, Theseus is enrolling patients in cohort 7 of its ongoing phase 1/2 dose escalation and expansion clinical trial evaluating THE-630 in patients with advanced GIST.

•Theseus submitted its initial dose escalation results to the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, taking place June 2-6, in Chicago, Illinois, and the abstract was selected for online publication. Theseus plans to present data with an updated cutoff date during a virtual investor event on May 25, 2023, at 5:30pm ET, after the public release of the abstract. The initial dose escalation data will include preliminary safety, pharmacokinetic (PK), and clinical activity data through cohort 6, as well as an analysis of circulating tumor DNA (ctDNA) through cohort 5.

•Theseus plans to present follow-up data at a scientific conference in the fourth quarter of 2023, which is expected to include data from additional dose escalation cohorts, including cohort 8, where Theseus expects to have reached the target systemic exposure for pan-variant KIT activity.

THE-349 is a fourth-generation (4G) epidermal growth factor receptor (EGFR) TKI development candidate, which has demonstrated activity against single-, double-, and triple-mutant EGFR variants, including T790M and C797X, found in EGFR-mutant non-small cell lung cancer (NSCLC) that has developed resistance to first- or later-line osimertinib.
•Preclinical data demonstrate THE-349 can potently inhibit all major classes of EGFR activating and resistance mutations observed in a post-first- or later-line osimertinib setting, possesses kinome and wild-type EGFR selectivity, and has central nervous system (CNS) activity.

•Theseus expects to submit an Investigational New Drug Application (IND) for THE-349 to the U.S. Food and Drug Administration (FDA) in the fourth quarter of 2023 and to initiate the first-in-human trial as soon as possible thereafter, subject to clearance of the IND by the FDA.

BCR-ABL Program: Theseus aims to develop a potent and selective, next-generation, pan-variant BCR-ABL TKI candidate that optimizes the balance of safety and efficacy for patients with relapsed/refractory chronic

myelogenous leukemia (CML) and patients with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).

•Preclinically, Theseus lead molecules have been observed to show a high degree of potency against BCR-ABL and clinically relevant resistance mutations, such as the T315I gatekeeper mutation, and substantial kinome selectivity.
•Theseus expects to nominate a development candidate for this program by early 2024, with the goal of pursuing clinical development in patients with CML who have been previously treated with a second-generation TKI or have the T315I mutation, and in newly diagnosed patients with Ph+ ALL.

Business Highlights:

•In May 2023, Theseus announced the appointment of Franklin Vairinhos, Ph.D., as Vice President, Regulatory Affairs. Dr. Vairinhos has more than 30 years of experience in Regulatory Affairs, predominantly in developing regulatory strategies for oncology therapies.

First Quarter Financial Results:

Cash Position: As of March 31, 2023, Theseus had cash, cash equivalents, and marketable securities of $243.6 million, as compared to $211.8 million as of December 31, 2022. Theseus expects its current cash, cash equivalents, and marketable securities to fund operations and capital expenditures into the third quarter of 2025 based on its current operating plan.

R&D Expenses: Research and development expenses were $12.4 million for the first quarter of 2023, as compared to $6.5 million for the same period in 2022. This increase was primarily due to a $2.7 million increase in expense for preclinical studies and drug manufacturing to support THE-349 IND enabling studies, a $1.4 million increase in development expense related to discovery programs, as well as a $1.5 million increase in employee-related costs driven by an increase in headcount.

G&A Expenses: General and administrative expenses were $4.7 million for the first quarter of 2023, as compared to $4.0 million for the same period in 2022. This increase was primarily due to an increase in stock-based compensation expense and employee-related costs.

Net Loss: Net loss was $14.6 million for the first quarter of 2023, as compared to a net loss of $10.5 million for the same period in 2022.

On May 11, 2023 TCR2 Therapeutics Inc. (Nasdaq: TCRR) (TCR2 or the Company), a clinical-stage cell therapy company with a pipeline of novel next-generation T cell therapies for patients suffering from solid tumors, reported financial results for the first quarter ended March 31, 2023 and provided a corporate update (Press release, TCR2 Therapeutics, MAY 11, 2023, View Source [SID1234631538]).

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"We are pleased with our continued progress during the last quarter which included the announcement of the strategic combination of TCR2 with Adaptimmune. We believe that the integration of the two companies’ complimentary technology platforms and pipelines focused on treating solid tumors has the potential to fundamentally change the war on cancer," said Garry Menzel, Ph.D., President and Chief Executive Officer of TCR2 Therapeutics.

Recent Developments

•
TCR2 announced a strategic combination with Adaptimmune Therapeutics plc (Adaptimmune) to create a preeminent cell therapy company for solid tumors. The two companies entered into a definitive agreement under which Adaptimmune will combine with TCR² in an all-stock transaction. The transaction is expected to close in the second quarter of 2023, subject to approval by TCR2 stockholders and Adaptimmune shareholders and satisfaction or waiver of other closing conditions. Following the closing of the transaction, Adaptimmune shareholders will own approximately 75% and TCR² stockholders will own approximately 25% of the combined company. As a result, and following the closing of the transaction, it is anticipated that the combined company’s cash runway will extend into 2026. A special meeting of TCR2 stockholders to approve the merger with Adaptimmune will be held on May 30, 2023. Proxy materials and voting instructions have been made publicly available. Please call TCR2’s proxy solicitor, Innisfree M&A Incorporated, at (877) 750-8233, with any questions.
•
TCR2 presented Phase 1 gavo-cel data at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) meeting and published preclinical gavo-cel data in OncoImmunology.

Financial Highlights

•
Cash Position: TCR2 ended the first quarter of 2023 with $110.3 million in cash, cash equivalents, and investments compared to $149.2 million as of December 31, 2022. Net cash used in operations was $40.0 million for the first quarter of 2023 compared to $31.1 million for the first quarter of 2022.
•
R&D Expenses: Research and development (R&D) expenses were $29.2 million for the first quarter of 2023 compared to $22.3 million for the first quarter of 2022. The increase in R&D expenses was primarily due to an increase in clinical trial expenses associated with patient treatment and product manufacturing.
•
Impairment and Restructuring Expenses: Impairment expenses were $4.0 million for the first quarter of 2023 compared to $0.6 million for the first quarter of 2022. The increase in impairment expenses for the first quarter includes $2.1 million in severance and related costs and $1.9 million in charges related to construction in progress and certain laboratory equipment.
•
G&A Expenses: General and administrative expenses were $8.2 million for the first quarter of 2023 compared to $6.3 million for the first quarter of 2022. The increase in general and administrative expenses for the first quarter includes $3.6 million in transactions costs related to the proposed transaction with Adaptimmune.
•
Net Loss: Net loss was $40.4 million for the third quarter of 2023 compared to $29.1 million for the first quarter of 2022.

About gavo-cel, TC-510, and TC-520

Our most advanced program, gavo-cel, targets tumors that express the protein mesothelin.

TC-510 is an enhanced version of gavo-cel that co-expresses a PD-1:CD28 chimeric switch receptor that the Company believes may lead to deeper responses and more durable benefit.

TC-520 is the Company’s first TRuC-T cell targeting CD-70-expressing solid and liquid tumors which incorporates IL-15 pathway enhancements designed to improve T-cell persistence. TCR2 is currently advancing TC-520 to Investigational New Drug (IND) status.

On May 11, 2023 Synlogic, Inc. (Nasdaq: SYBX), the leading company advancing therapeutics based on synthetic biology, reported its financial results for the first quarter ended March 31, 2023, and provided an update on its pipeline programs (Press release, Synlogic, MAY 11, 2023, View Source [SID1234631537]).

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"We continue to advance the SYNB1934 program towards initiation of our pivotal study, Synpheny-3, in the first half of the year, focused on our opportunity to transform the medical management of PKU," said Aoife Brennan, M.B. Ch.B., Synlogic President and Chief Executive Officer. "The quarter also included recognition of Synthetic Biotics as novel biotherapeutics for rare metabolic diseases more broadly, as both our PKU and homocystinuria (HCU) programs were spotlighted at the leading medical congress for inborn errors of metabolism."

First Quarter 2023 and Recent Business Highlights

Received Orphan Drug Designation (ODD) and Rare Pediatric Disease Designation (RPDD) from the U.S. Food and Drug Administration (FDA) for SYNB1934 for PKU
Received positive opinion on orphan designation from the European Medicines Agency (EMA) for SYNB1934 for PKU
Announced full data from both the Phase 2 Synpheny-1 study in PKU and the Phase 1 study in HCU at the Society for Inherited Metabolic Disorders (SIMD) 44th Annual Meeting
Anticipated Upcoming Milestones

Initiation of Phase 3 clinical trial of SYNB1934 for PKU in the first half of 2023
Advancing SYNB1353 to Phase 2 study in patients with HCU
Progression of preclinical pipeline programs, including partnerships
First Quarter 2023 Financial Results

As of March 31, 2023, Synlogic had cash, cash equivalents and short-term investments of $57.4 million.

Revenue was $0.2 million for each of the three months ended March 31, 2023 and March 31, 2022. Revenue in both periods was primarily associated with the ongoing research collaboration with Roche for the discovery of a novel Synthetic Biotic for the treatment of inflammatory bowel disease.

For the three months ended March 31, 2023, Synlogic reported a consolidated net loss of $15.6 million, or $0.23 per share, compared to a consolidated net loss of $15.7 million, or $0.22 per share, for the corresponding period in 2022.

Research and development expenses were $12.5 million for the three months ended March 31, 2023, compared to $11.7 million for the corresponding period in 2022.

General and administrative expenses were $4.0 million for the three months ended March 31, 2023, compared to $4.3 million for the corresponding period in 2022.

Financial Outlook

Based upon its current operating plan and balance sheet as of March 31, 2023, Synlogic expects to have sufficient cash to be able to fund operations into the second half of 2024.

Upcoming Investor and Industry Conference Participation

Synlogic leadership will attend the Jefferies Global Healthcare Conference being held June 7-9, 2023, in New York City.

On May 11, 2023 SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a clinical-stage biopharmaceutical company focused on developing life-changing medicines for patients with severe rare diseases and cancer, reported that data from two collaborator-sponsored clinical studies evaluating nirogacestat, an investigational oral gamma secretase inhibitor, in combination with B-cell maturation agent (BCMA) therapies in patients with relapsed or refractory multiple myeloma (RRMM) will be presented at the European Hematology Association (EHA) (Free EHA Whitepaper) 2023 Congress, taking place in Frankfurt, Germany from June 8-11, 2023 (Press release, SpringWorks Therapeutics, MAY 11, 2023, View Source [SID1234631536]). Updated clinical data from the Phase 1/2 study sponsored by GSK plc (LSE/NYSE: GSK) evaluating nirogacestat in combination with low-dose belamaf (belantamab mafodotin-blmf), GSK’s antibody-drug conjugate targeting BCMA, in patients with RRMM will be presented in a poster presentation. In addition, new data from the Phase 1b clinical trial sponsored by Janssen Research & Development, LLC (Janssen) evaluating nirogacestat in combination with teclistamab, Janssen’s bispecific antibody targeting BCMA and CD3, will be presented in an oral presentation.

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"These data provide further validation of the mechanistic approach supporting nirogacestat’s ability to enhance the activity of BCMA-directed therapies across modalities. We are pleased that updated data from the GSK-sponsored trial continue to support our thesis that the combination with nirogacestat may further optimize the benefit-risk profile of belamaf monotherapy. We are also encouraged that the Janssen-sponsored trial establishes an initial tolerability, safety and efficacy profile for combining nirogacestat with a BCMA bispecific antibody," said Saqib Islam, Chief Executive Officer of SpringWorks. "Our goal is to improve the outcomes for patients with multiple myeloma and we believe that developing a robust clinical data set across BCMA modalities and treatment lines can help us demonstrate where within the multiple myeloma treatment landscape nirogacestat has the greatest opportunity to maximize clinical benefit."

Poster Presentation at the EHA (Free EHA Whitepaper) 2023 Congress

Low-dose belantamab mafodotin (belamaf) in combination with nirogacestat vs belamaf monotherapy in patients with relapsed/refractory multiple myeloma (RRMM): Phase 1/2 DREAMM-5 Platform Sub-study 3

Abstract #: P913

Session Date and Time: Friday, June 9, 18:00-19:00 CEST (12:00-1:00 p.m. ET)

This ongoing Phase 1/2 trial, which is sub-study 3 of GSK’s DREAMM-5 platform trial (NCT04126200), aims to determine if low-dose belamaf in combination with nirogacestat results in similar efficacy with an improved ocular toxicity profile compared to belamaf alone at a higher dose. Patients were randomized 1:1 to 0.95 mg/kg belamaf every three weeks (Q3W, low-dose) combined with 100 mg twice daily nirogacestat or belamaf 2.5 mg/kg Q3W monotherapy.

Initial results from the pre-planned interim analysis were presented at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. Updated data from a randomized cohort expansion in which 34 patients received low-dose belamaf plus nirogacestat and 37 patients received belamaf monotherapy will be presented at EHA (Free EHA Whitepaper). Patients had a median of 5 (range 3-14) prior lines of therapy. As of the December 9, 2022 data cut-off, patients received a median of 4 (range 1-20) cycles of the combination and a median of 3 (range 1-9) monotherapy cycles.

Overall response rate (ORR) in the low-dose belamaf (0.95 mg/kg Q3W) plus nirogacestat arm was 29%, with 1 patient (3%) achieving a complete response (CR), 5 patients (15%) achieving a very good partial response (VGPR), and 4 patients (12%) achieving a partial response (PR). ORR in the belamaf monotherapy arm (2.5 mg/kg Q3W) was 38%, with no patient achieving a CR, 5 patients (14%) achieving a VGPR, and 9 patients (24%) achieving a PR. Per the prespecified analysis plan, ORR was also calculated incorporating prior ORR for low-dose belamaf plus nirogacestat from the dose exploration cohort of this DREAMM-5 sub-study 3 and from the DREAMM-2 belamaf monotherapy study; ORR across these studies was 36% in the low-dose belamaf plus nirogacestat combination arm and 33% in the belamaf monotherapy arm.

Safety results showed a substantial reduction of high-grade ocular events in the low-dose belamaf plus nirogacestat arm compared to the monotherapy arm of belamaf at a higher dose. Specifically, Grade 3 ocular events were 29% for low-dose belamaf + nirogacestat versus 59% for belamaf monotherapy (per the KVA scale); no Grade 4 ocular events or new toxicities occurred in either arm.

"These clinical data suggest that combining nirogacestat with a low dose of belamaf may result in comparable efficacy to a higher monotherapy belamaf dose, while simultaneously substantially reducing the frequency high-grade ocular adverse events," said Jim Cassidy, M.D., Ph.D., Chief Medical Officer of SpringWorks. "We are encouraged by these results and we look forward to the further evaluation of this combination with standard of care agents in relapsed refractory multiple myeloma as well as its potential in earlier lines of therapy."

Oral Presentation at the EHA (Free EHA Whitepaper) 2023 Congress

Teclistamab (tec) + nirogacestat (niro) in relapsed/refractory multiple myeloma (RRMM): the Phase 1b MajesTEC-2 study

Session Title: MM Clinical: New combinations and novel targets

Abstract #: S194

Session Date and Time: Saturday, June 10, 12:30-12:45 CEST (6:30-6:45 a.m. ET)

This ongoing Phase 1b trial (NCT04722146), which is part of a multi-arm trial being conducted by Janssen, aims to evaluate the safety, tolerability and preliminary efficacy of nirogacestat in combination with teclistamab in patients with RRMM. Patients in the study had received ≥3 prior lines of therapy or were double refractory to a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) and triple exposed to a PI, an IMiD, and an anti-CD38 antibody, with progressive disease within 12 months of their last line of therapy. Three dose levels were evaluated: 1) teclistamab 720 μg/kg weekly plus concurrent nirogacestat 100 mg twice daily starting with the first dose of teclistamab (n=8); 2) teclistamab 720 μg/kg weekly plus once daily nirogacestat 100 mg starting after teclistamab step-up dosing (n=7); and 3) 1500 μg/kg (which is the FDA-approved dose) weekly plus once daily nirogacestat 100 mg starting after teclistamab step-up dosing (n=13).

As of the December 16, 2022 data cut-off, 28 patients received the combination of teclistamab and nirogacestat across three different dose levels. Median prior lines of therapy was 4 (range 2-12) and median duration of treatment was 9.4 months (range 0.13-19.7) for teclistamab and 4.7 months for nirogacestat (range 0.16-13.0).

The most frequent (>20%) treatment-emergent adverse events (TEAEs) for all doses were neutropenia (82%), cytokine release syndrome, or CRS (75%), diarrhea (64%), injection-site erythema (54%), decreased appetite (50%), fatigue (42.9%), and anemia (35%). Of eight patients who received teclistamab 720 μg/kg plus concurrent nirogacestat, two dose-limiting toxicities were reported (one Grade 3 GI bleed and Grade 3 diarrhea; one Grade 3 immune effector cell-associated neurotoxicity syndrome, or ICANS). In addition, one patient had Grade 3 CRS and one patient had Grade 3 confusional state. These events led to the decision to delay the starting dose of nirogacestat in subsequent cohorts. In the dose level 2 and dose level 3 cohorts, when nirogacestat was added after teclistamab step-up dosing and reduced to once daily, no dose-limiting toxicities or Grade 3 CRS or neurologic adverse events were reported.

The overall response rate was 71% for dose level 1, 57% for dose level 2, and 92% for dose level 3. The total ORR across the three dose levels was 78% and all responses were VGPR or better. The percentage of patients experiencing complete response (CR) or stringent CR (sCR) was 43%, 57% and 54%, respectively (total percentage of CR or sCR across the three cohorts was 52%).

"This is the first clinical data set of nirogacestat in combination with a BCMA bispecific agent. We believe these data provide important insights into a tolerable treatment schedule and early evidence of an encouraging ORR, including promising CR and sCR rates, when combining nirogacestat with this BCMA modality," commented Dr. Cassidy. "Nirogacestat is being evaluated in combination with three other bispecific agents and we look forward to generating more data with these combinations."

About Nirogacestat

Nirogacestat is an oral, selective, small molecule gamma secretase inhibitor in Phase 3 clinical development for desmoid tumors and in Phase 2 clinical development for ovarian granulosa cell tumors. Nirogacestat is an investigational drug for which safety and efficacy have not been established.

Gamma secretase cleaves multiple transmembrane protein complexes, including Notch, which is believed to play a role in activating pathways that contribute to growth of desmoid and ovarian granulosa cell tumors. Gamma secretase has also been shown to directly cleave membrane-bound B cell maturation antigen (BCMA), resulting in the release of the BCMA extracellular domain (ECD) from the cell surface. By inhibiting gamma secretase, membrane-bound BCMA can be preserved, increasing target density while reducing levels of soluble BCMA ECD, which may serve as decoy receptors for BCMA-directed therapies. Nirogacestat’s ability to enhance the activity of BCMA-directed therapies has been observed in preclinical models of multiple myeloma. SpringWorks is evaluating nirogacestat as a BCMA potentiator and has several collaborations with industry-leading BCMA developers to evaluate nirogacestat in combinations across modalities. SpringWorks has also formed research collaborations with Fred Hutchinson Cancer Research Center and Dana-Farber Cancer Institute to further characterize the ability of nirogacestat to modulate BCMA and potentiate BCMA-directed therapies using a variety of preclinical multiple myeloma models.

The U.S. Food and Drug Administration (FDA) has accepted a New Drug Application (NDA) for nirogacestat for the treatment of adults with desmoid tumors, which is being reviewed under the FDA’s Real-Time Oncology Review program. The NDA was granted Priority Review designation and has been given a Prescription Drug User Fee Act (PDUFA) action date of August 27, 2023. The FDA also granted Fast Track and Breakthrough Therapy Designations to nirogacestat for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis. In addition, nirogacestat has received Orphan Drug Designation from the FDA for the treatment of desmoid tumors and from the European Commission for the treatment of soft tissue sarcoma.