On December 19, 2022 Sermonix Pharmaceuticals Inc., a privately held biopharmaceutical company developing innovative targeted therapeutics to specifically treat ESR1-mutated metastatic breast and gynecological cancers, reported two poster presentations initially released at the 2022 San Antonio Breast Cancer Symposium (SABCS) (Press release, Sermonix Pharmaceuticals, DEC 19, 2022, View Source [SID1234625451]). The presentations discussed exploratory analyses evaluating mutant allele frequencies (MAF) of ESR1 (mutESR1) in circulating tumor DNA (ctDNA) from patients who participated in each of Sermonix’s Evaluation of Lasofoxifene in ESR1 Mutations (ELAINE) Phase 2 studies.

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Using the Sysmex Inostics OncoBeam or SafeSeq assays, ELAINE 1 assessed the efficacy and safety of Sermonix’s lead development candidate, oral lasofoxifene, versus the current standard of care, intramuscular fulvestrant, in postmenopausal women with locally advanced or metastatic ER+/HER2- breast cancer (mBC) and an ESR1 mutation. ELAINE 2, which used the SafeSeq assay, evaluated lasofoxifene in combination with the CDK 4 and 6 inhibitor abemaciclib in a heavily pre-treated ESR1 mutation positive patient population.

"The ELAINE studies are biomarker driven, with patients selected for treatment utilizing liquid biopsy detection of ESR1 mutations," said Dr. David Portman, Sermonix chief executive officer. "The results confirm robust target engagement with decrease and clearance of ctDNA seen with lasofoxifene as both monotherapy and when combined with abemaciclib, and associated with improved progression-free survival (PFS) and clinical benefit. Future studies may help clarify the role of molecular response in optimizing clinical outcomes and we look forward to exploring this further in our upcoming Phase 3 program."

ELAINE 1 data demonstrated that targeted lasofoxifene more effectively decreased or cleared mutESR1 than fulvestrant. Further, mutESR1 MAF decreases on lasofoxifene were associated with prolonged progression-free survival of 8 months, whereas fulvestrant patients with a decrease in MAF achieved a median PFS of 4.5 months. These data indicate lasofoxifene results in robust mutESR1 target engagement. Taken together, the data suggest mutESR1 as a potential biomarker for predicting response to lasofoxifene in mutESR1, endocrine-resistant mBC patients.

In ELAINE 2, 81% of patients had decreased/cleared mutESR1 after 4 weeks of lasofoxifene plus abemaciclib, which correlated with clinical benefit. All mutESR1 variants detected appear targeted with this therapy. High sensitivity and favorable positive predictive value were observed in patients with undetectable MAF at 4 weeks, indicating that ESR1 liquid biopsy evaluation may be a potential molecular biomarker for monitoring patients on this treatment if confirmed in a larger randomized study.

ELAINE 1 RESULTS:

Among 103 patients, with 52 receiving lasofoxifene and 51 fulvestrant, median PFS was 6.04 mos. (95% CI, 2.82–8.04) for lasofoxifene vs. 4.04 mos. (95% CI, 2.93–6.04) for fulvestrant, P=0.138 (HR, 0.699 [95% CI, 0.445–1.125]).
The most common baseline ESR1 variants detected were D538G (56%), Y537S (39%), Y537N (29%), E380Q (22%); 56 (54%) pts were polyclonal.
Of the 61 participants with evaluable baseline and Week 8 ctDNA, lasofoxifene decreased ESR1 mutant allele fraction (MAF) in 29 of 35 pts (83%) while fulvestrant decreased ESR1 MAF in 16/26 pts (61.5%).
Median change from baseline in MAF across all mESR1 variants was −87.1% for lasofoxifene compared with −14.7% for fulvestrant.
Decreases in most commonly observed mESR1 variants (D538G, Y537S, Y537N, E380Q, Y537C) occurred more frequently for lasofoxifene than fulvestrant.
Among patients with the ESR1 Y537S variant, Y537S MAF decreased in most patients receiving lasofoxifene (87% [13/15]; in marked contrast, Y537S MAF increased in most patients receiving fulvestrant (61% [11/18]).
Median change from baseline to week 8 in Y537S MAF was −89.1% with lasofoxifene vs. +82.3% with fulvestrant.
Complete clearance of Y537S was observed in 5/15 (33%) and 1/18 (6%) patients receiving lasofoxifene and fulvestrant, respectively.
"The use of ctDNA is dramatically improving our understanding about the molecular evolution of breast cancer, particularly with regards to endocrine resistance," said Dr. Massimo Cristofanilli, a chief of breast oncology in New York and past president of the International Society of Liquid Biopsy. "The information allows us to evaluate the targeted endocrine agents and monitor not only the clinical response, but also the impact of such therapies on the molecular patient journey, especially in light of variants of the ESR1 mutation that are known to confer the worst outcomes."

ELAINE 2 RESULTS:

In an open-label, single-arm study of lasofoxifene in combination with abemaciclib in 29 heavily pre-treated post-CDK4/6i patients, the median PFS was 55.7 weeks (over 13 months), (95% CI, 32.0-NE).
Among patients with measurable target lesions (n=18), 10 had a confirmed partial response (PR), resulting in an ORR of 56% (95% CI, 29.0 – 71.0).

There was baseline mutESR1 of Y537S (66%), D538G (45%), Y537N (28%), and other less frequently detected mutations; 14 (48.3%) patients were polyclonal.
In 26 of 29 patients with evaluable baseline and Week 4 ctDNA: 21 patients had decreasing mutant ESR1 MAF (81%), 14 had undetectable MAF (54%), 3 (12%) had increased, and 2 (8%) had equivocal MAF changes.
Clinical benefit at 24 weeks was seen in 17 patients with a decrease, 2 with an increase, and 1 with equivocal MAF change.

A sensitivity of 89.5% and specificity of 20% were calculated for predicting clinical benefit based on direction of ESR1 MAF change. The positive predictive value (PPV) for clinical benefit with decreased MAF was 81% and the negative predictive value (NPV) for an increased MAF was 33%.
Of the 14 (54%) patients with total clearance of ESR1 MAF, 13 had clinical benefit resulting in 87% sensitivity, 50% specificity, 93% PPV, and 33% NPV.

About Lasofoxifene

Lasofoxifene is an investigational targeted endocrine treatment and next-generation nonsteroidal selective estrogen receptor modulator (SERM), which Sermonix licensed globally from Ligand Pharmaceuticals Inc. (NASDAQ: LGND) and has been studied in previous comprehensive Phase 1-3 non-oncology clinical trials in more than 15,000 postmenopausal women worldwide. Lasofoxifene’s bioavailability and activity in mutations of the estrogen receptor could potentially hold promise for patients who have acquired endocrine resistance due to ESR1 mutations, a common finding in the metastatic setting and an area of high unmet medical need. Lasofoxifene’s novel activity in ESR1 mutations was discovered at Duke University and Sermonix has exclusive rights to develop and commercialize the product in this area. Lasofoxifene, a potent, oral SERM could, if approved, play a critical role in the targeted precision medicine treatment of advanced ER+ breast cancer.

On December 19, 2022 (the "Closing Date"), Regeneron Pharmaceuticals, Inc. ("Regeneron" or the "Company") entered into a credit agreement (the "Credit Agreement") by and among the Company, as a borrower and guarantor; certain direct subsidiaries of the Company, as the initial subsidiary borrowers; the lenders and issuing banks from time to time party thereto; and JPMorgan Chase Bank, N.A., as administrative agent, swingline lender, and an issuing bank (Filing, 8-K, Regeneron, DEC 19, 2022, View Source [SID1234625449]).

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The Credit Agreement provides for a $750 million senior unsecured five-year revolving credit facility (with a $25 million sublimit for swingline borrowings and a $50 million sublimit for letters of credit) (the "Credit Facility") and replaces the Company’s previously existing $750 million revolving credit facility, which was contemporaneously terminated as described in Item 1.02 below. The loans under the Credit Facility have a variable interest rate based on either the Secured Overnight Financing Rate-based rate or the alternate base rate (or other applicable rate with respect to non-dollar borrowings), plus an applicable margin that varies with the Company’s debt rating and total leverage ratio. The Credit Agreement includes an option for the Company to elect to increase the commitments under the Credit Facility and/or to enter into one or more tranches of term loans in the aggregate principal amount of up to $500 million, subject to the consent of the lenders providing the additional commitments or term loans, as applicable, and certain other conditions.

As set forth in the Credit Agreement, the Company has the option to amend the Credit Agreement to establish environmental, social, and governance targets which will be used to adjust pricing under the Credit Facility, subject to parameters to be provided in the amended Credit Agreement.

The proceeds of the loans under the Credit Facility may be used to finance the working capital needs, and for general corporate or other lawful purposes, of Regeneron and its subsidiaries. The Company has guaranteed all obligations under the Credit Facility.

The Credit Agreement contains operating covenants and a maximum total leverage ratio financial covenant. Operating covenants include, among other things, limitations on (i) the incurrence of indebtedness by the Company’s subsidiaries, (ii) liens on assets of the Company and its subsidiaries, and (iii) certain fundamental changes and the disposition of assets by the Company and its subsidiaries. The Credit Agreement contains other customary covenants, representations and warranties, and events of default.

The Credit Facility matures, and all amounts outstanding thereunder will become due and payable in full, on December 19, 2027. The Credit Agreement includes an option for the Company to elect to extend the maturity date of the Credit Facility, subject to the consent of the extending lenders and certain other conditions. Amounts borrowed under the Credit Facility may be prepaid, and the commitments under the Credit Facility may be terminated, at any time without premium or penalty. As of the date of this report, no borrowings were outstanding under the Credit Facility.

The foregoing summary of the Credit Agreement is qualified in its entirety by the full text of the Credit Agreement, which is attached as Exhibit 10.1 hereto and is incorporated herein by reference.

On December 19, 2022 Nuvation Bio Inc. (NYSE: NUVB), a biopharmaceutical company tackling some of the greatest unmet needs in oncology by developing differentiated and novel therapeutic candidates, reported that it has dosed the first patient in a Phase 1b study of its BD2-selective BET inhibitor, NUV-868, in combination with olaparib (Press release, Nuvation Bio, DEC 19, 2022, View Source [SID1234625428]).

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The Phase 1b study will be conducted under two separate dosing regimens. Patients in the first regimen will be dosed with NUV-868 in combination with olaparib for the treatment of ovarian cancer, pancreatic cancer, metastatic castration-resistant prostate cancer (mCRPC), triple negative breast cancer and other solid tumors. Patients in the second regimen will be dosed with NUV-868 in combination with enzalutamide for the treatment of mCRPC.

"We are excited to build upon the progress of our Phase 1 monotherapy study of NUV-868 with the initiation of dosing in this Phase 1b combination study. We expect this study to provide a deeper understanding of the potential benefit that NUV-868 can offer a wide range of patients with advanced solid tumors," said David Hung, M.D., Founder, President and Chief Executive Officer of Nuvation Bio. "This milestone underscores the continued clinical momentum of our pipeline as we work to tackle some of the greatest unmet needs in oncology."

As part of the Phase 1b study, NUV-868 will be administered at escalating dose levels in combination with olaparib until the recommended Phase 2 combination dose is determined.

On December 19, 2022 Oxford BioDynamics Plc (AIM: OBD, the Company), a biotechnology company developing precision medicine tests for immune health based on the EpiSwitch 3D genomics platform, reported that its senior leadership will be in San Francisco during the 41st Annual J.P. Morgan Healthcare Conference, Jan 9-12 2023 (Press release, Oxford Biodynamics, DEC 19, 2022, View Source [SID1234625427]).

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OBD concluded a successful year in 2022, with its flagship EpiSwitch Checkpoint Inhibitor Response Test (CiRT) made available and in commercial use both in the UK and the US, where it also received a unique reimbursement code by the American Medical Association’s CPT (Current Procedural Terminology) Editorial Board. The year has also seen compelling data and clinical utility described by renowned oncologists with pharma collaborators at leading global conferences, such as ASCO (Free ASCO Whitepaper) 2022 and ESMO (Free ESMO Whitepaper) 2022.

OBD’s EpiSwitch platform was developed to diagnose patients and determine how individuals might respond to disease or treatment, leveraging the Company’s deep understanding of how the 3D configuration of the genome plays a crucial role in gene regulation. The Company’s flagship product, the EpiSwitch CiRT, is a first-of-its-kind precision medicine blood test that predicts a cancer patient’s likely response to Immune Checkpoint Inhibitors (ICIs), including widely used anti-PD-L1 and anti-PD-1 therapies. Despite their potential benefit, it is estimated that 70%+ of patients treated with an ICI will not have a clinical response.

OBD’s CEO Dr Jon Burrows and CSO Dr Alexandre Akoulitchev will be attending meetings to discuss details of the unique EpiSwitch platform, as well as future plans for its use. If you would like to meet the team, please contact [email protected]

On December 19, 2022 Zymeworks Inc. (NASDAQ: ZYME), a clinical-stage biotechnology company developing multifunctional biotherapeutics, reported positive topline results from the pivotal Phase 2b HERIZON-BTC-01 open-label, single-arm clinical trial investigating zanidatamab, a HER2-targeted bispecific antibody, as monotherapy in patients with previously treated HER2-amplified and expressing BTC (Press release, Zymeworks, DEC 19, 2022, View Source [SID1234625426]).

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The positive topline results showed that 41.3% (95% CI: 30.4, 52.8) of enrolled patients with HER2-amplified and expressing (IHC2+ and 3+) disease achieved an objective response as assessed by independent central review. The median duration of response was 12.9 months (95% CI: 5.95 to not reached). The safety profile of zanidatamab in this trial was consistent with that observed in previously reported monotherapy studies, with no new safety signals identified. Full results from the pivotal trial are expected to be presented at a medical meeting in 2023.

Biliary tract cancers, including gallbladder cancer and cholangiocarcinoma, are diagnosed in more than 210,000 people every year1, with most patients presenting with inoperable disease2. Disease control with front-line therapy is modest and patients need treatment options after progression3,4. The human epidermal growth factor receptor 2 (HER2) is a promising target in approximately 5%-10% of cholangiocarcinomas and up to 20% of gallbladder cancers5. Currently no HER2-targeted therapy has been approved for the treatment of BTC.

"Through our work with the BTC patient community, we see first-hand the challenge these patients face in not only getting a diagnosis, but in the limited treatment options available," said Stacie Lindsey, Founder & CEO of the Cholangiocarcinoma Foundation. "Each investigative trial begins to close the gap on this high unmet medical need by helping to bring more treatment options to BTC patients and we’re looking forward to watching zanidatamab’s progression through the global regulatory review process."

"We are thrilled to report these positive topline data from the HERIZON-BTC-01 clinical trial, which further support the potential of zanidatamab as a new chemotherapy-free therapeutic option for HER2-amplified and expressing BTC. These data demonstrate that zanidatamab, as a single agent, improves on the current standard of care for patients in a difficult-to-treat disease who currently have a poor prognosis based on the limited treatment options currently available," said Neil Josephson, M.D., Chief Medical Officer at Zymeworks. "I want to thank all of the patients, their families and the investigators who participated in this important study."

Conference Call for Investors and Analysts

Zymeworks management will host a conference call and webcast for investors and analysts on December 19, 2022 at 8:00 am ET. The event will be webcast live with dial-in details and webcast replays available on Zymeworks’ website at View Source

About HERIZON-BTC-01

HERIZON-BTC-01 is a global, multicenter, open-label, single-arm study (NCT04466891) with a primary endpoint of confirmed objective response rate (cORR) by independent central review (ICR) per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Secondary endpoints include duration of response (DOR), proportion of subjects with a DOR ≥16 weeks, disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. HER2 amplification, as determined centrally by in situ hybridization (ISH) in tumor tissue, was an inclusion criterion for all subjects enrolled into the two study cohorts: Cohort 1, the primary efficacy cohort, with tumor tissue showing HER2 immunohistochemistry (IHC) 2+ or 3+ staining, and Cohort 2 with tumor tissue showing HER2 IHC 0 or 1+ staining. The study was initiated in July 2020 and has active sites in North America, Asia Pacific, Europe, and South America, and shares sites with the pivotal Phase 3 trial, HERIZON-GEA-01 (NCT05152147), in first-line gastroesophageal adenocarcinoma (GEA) patients.

About Zanidatamab

Zanidatamab is an investigational, bispecific antibody, based on Zymeworks’ Azymetric platform, that can simultaneously bind two non-overlapping epitopes of HER2, known as biparatopic binding. This unique design results in multiple mechanisms of action including dual HER2 signal blockade, increased binding and removal of HER2 protein from the cell surface, and potent effector function leading to encouraging antitumor activity in patients. Zymeworks is developing zanidatamab in multiple Phase 1, Phase 2, and pivotal clinical trials globally as a targeted treatment option for patients with solid tumors that express HER2. Zymeworks continues to enroll subjects in the Phase 3 randomized clinical trial, HERIZON-GEA-01, evaluating zanidatamab in combination with chemotherapy plus or minus tislelizumab for HER2-expressing GEA. Zymeworks has entered into separate agreements with each of BeiGene, Ltd. (BeiGene) and Jazz Pharmaceuticals Ireland Limited (Jazz), granting each of BeiGene and Jazz with exclusive rights to develop and commercialize zanidatamab throughout various countries around the world.

Zymeworks has an ongoing Expanded Access Program (EAP) for use of zanidatamab in patients with HER2-positive advanced solid tumors who are not eligible for zanidatamab clinical trials, meet the criteria for EAP, and who in the opinion of the treating oncologist, would potentially benefit from treatment with zanidatamab. Additional information is available on our website at View Source