On December 19, 2022 XtalPi, a pioneering pharmaceutical technology company powered by artificial intelligence (AI) and automation, reported a strategic collaboration with the Experimental Drug Development Centre (EDDC), Singapore’s national platform for drug discovery and development hosted by the Agency for Science, Technology and Research of Singapore (A*STAR), to discover novel treatment candidates for non-small cell lung cancer (NSCLC) (Press release, XtalPi, DEC 19, 2022, View Source [SID1234625532]).

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Lung cancer is the second most common cancer and the leading cause of cancer death worldwide. NSCLC accounts for over 80% of all lung cancer cases and its incidence continues to increase globally. The estimated global market size for NSCLC therapeutics will exceed USD20 billion by 2027, according to Research and Markets. Despite increasing interest and investment in drug research, there remains significant unmet needs for effective targeted therapy options for NSCLC patients to achieve better outcomes.

In this collaboration, XtalPi joins forces with EDDC to apply its AI technology, automation platform, and expert domain knowledge to discover promising candidates against a NSCLC target chosen by EDDC. XtalPi will leverage its quantum physics and AI-driven platform to generate and screen through millions of molecules in de novo drug design. The predicted top-performing molecules with desirable drug properties will be validated and optimized in its robotics-powered synthesis and testing lab through iterations. EDDC will offer valuable insight and data on the novel NSCLC target, further accelerating the drug discovery process and propelling the program towards development.

Dr. Shuhao Wen, co-founder and chairman of XtalPi, comments: "We are delighted to establish this strategic collaboration with EDDC. XtalPi is committed to serving patients globally by advancing the speed, scale, novelty, and success rate of drug R&D with AI and automation. Through this partnership, we hope to continue expanding our collaborations with top-tier research institutes in the booming Pan-Asia biotech community, drive the quick translation of new discoveries into much-needed therapeutics, and contribute to the improved health and longevity of patients in Asia and around the world."

Professor Damian O’Connell, Chief Executive Officer of EDDC, comments: "We are excited to partner XtalPi in the translation of science and research into effective and targeted therapies that enable the treatment of cancer. With XtalPi’s expertise in AI and automation technologies, we are confident that this collaboration will accelerate the development of potential targeted therapy options for NSCLC patients, which are very much needed."

On December 19, 2022, Sutro Biopharma, Inc. (the "Company") reported that it has entered into a letter agreement (the "Agreement") with Vaxcyte, Inc. ("Vaxcyte") under which the Company granted to Vaxcyte (i) authorization to enter into an agreement with an independent alternate contract manufacturing organization ("CMO") to source cell-free extract solely for the products it licensed from the Company, allowing Vaxcyte to have direct oversight over financial and operational aspects of the relationship with the CMO, and (ii) a right, but not an obligation, to obtain certain exclusive rights to internally manufacture and/or source extract from certain CMOs and the right to independently develop and make improvements to extract for use in connection with the exploitation of certain vaccine compositions (the "Option") (Filing, 8-K, Sutro Biopharma, DEC 19, 2022, View Source [SID1234625452]). The Option is exercisable for five years following the effective date of the Agreement (the "Option Period"), subject to potential acceleration in the event of a change of control of Vaxcyte.

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Pursuant to the Agreement, Vaxcyte will make an upfront payment of $22.5 million to the Company, of which $7.5 million will be paid in shares of Vaxcyte’s common stock and the remaining $15.0 million will be paid in cash. In the event that Vaxcyte elects to exercise the Option, Vaxcyte would pay the Company $75.0 million in cash in two installments, and upon the occurrence of certain regulatory milestones, certain additional milestone payments totaling up to $60.0 million in cash. In the event that Vaxcyte undergoes a change of control, and subsequently exercises the option, a substantial majority of the milestone payments are accelerated.

The Agreement contains customary provisions for termination, including by either party upon mutual written agreement, upon written notice by Vaxcyte that it has elected not to exercise the Option, upon expiration of the Option Period if the Option has not been exercised by then, upon execution by both parties or release from escrow of a definitive agreement following option exercise, and by the Company upon 15 business days’ written notice to Vaxcyte for cause.

The economic terms of the existing agreements between the Company and Vaxcyte will not change upon the effectiveness of the Agreement.

The foregoing description of the terms of the Agreement and the transactions contemplated thereby does not purport to be complete and is subject to, and qualified in its entirety by reference to, the full text of the Agreement, a copy of which will be filed with the Securities and Exchange Commission as an exhibit to the Company’s Annual Report on Form 10-K for the year ending December 31, 2022.

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.