On December 8, 2023 Onconova Therapeutics, Inc. (NASDAQ: ONTX), ("Onconova" or "the Company"), a clinical-stage biopharmaceutical company focused on discovering and developing novel products for patients with cancer, reported preclinical data highlighting narazaciclib’s multi-kinase profile, broad anti-tumor activity and increased anti-tumor immunity, compared to palbociclib and other CDK4/6 inhibitors, in a poster presented at the San Antonio Breast Cancer Symposium (SABCS) on December 8, 2023 (Press release, Onconova, DEC 8, 2023, View Source [SID1234638337]).

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"We are very pleased to share new data characterizing narazaciclib’s differentiated activity, compared to palbociclib and other CDK4/6 inhibitors, especially in breast and ovarian cell lines, in a poster presentation at this year’s San Antonio Breast Cancer Symposium (SABCS 2023)," said Steve Fruchtman, M.D., President and Chief Executive Officer.

Dr. Fruchtman continued, "Narazaciclib impacts a wider array of kinase targets and produced a more substantial reduction in cell viability across several large panels of breast and ovarian cell lines carrying a range of mutations, compared to palbociclib. In addition, narazaciclib treatment induced higher levels of T-cell recruiting chemokines, supporting greater anti-tumor immune activity."

"We believe that the totality of the data presented at SABCS supports narazaciclib’s multi-kinase activity, its ability to target resistance pathways missed by other CDK4/6 inhibitors, and its differentiated anti-tumor and immunomodulatory activity. We hope to further demonstrate the promise of narazaciclib’s differentiated profile in patients as we progress the clinical program in 2024 towards the definition of a recommended Phase 2 dose (RP2D). We are also preparing to initiate pivotal studies in the lead indication of low grade endometrioid endometrial cancer (LGEEC), and to expand into investigator-sponsored studies in breast and ovarian cancers," concluded Dr. Fruchtman.

Poster Overview

Title: Narazaciclib’s differential targets and kinase inhibitory activity compared to the approved CDK4/6 inhibitors (CDK4/6is) contribute to the enhanced inhibition of tumor growth in preclinical models

Objectives: To explore the activity of narazaciclib and its metabolite, ON1232580, in comparison to the FDA-approved CDK4/6 inhibitor (CDK4/6i) palbociclib, and identify additional targets engaged by narazaciclib. Activity was measured by exposing narazaciclib and other CDK4/6 inhibitors (CDK4/6i’s) to panels of resistant, mutated, or modified tumor cell lines to evaluate each agent’s activity and potency to inhibit growth and reduce cell line viability.

Results:

Comprehensive analysis of cellular targets: "Thermal Shift" assays affirmed that while narazaciclib and palbociclib impact a handful of similar, expected cell pathway targets, including Rb, Akt, and mTOR, narazaciclib and its main metabolite impact more kinases than palbociclib. We believe this observation could contribute to improved efficacy for narazaciclib by overcoming cancer resistance pathways not targeted by other CDK4/6i’s.
Deeper analysis in human breast and ovarian cells/cell lines: Using bioinformatics data from human cancer databases showed that high BUB1 kinase expression is associated with low survival in patients with breast and uterine corpus endometrial carcinomas (UCEC) and was degraded by low doses of narazaciclib. Western blot analysis of data from several breast cancer cell line panels (including those with known mutations or the overexpression of the membrane receptor, FGFr, an independent prognostic factor in some solid tumor cancers and a driver of resistance to CDK4/6 inhibitors), showed that narazaciclib and its metabolite resulted in a more substantial reduction in cell viability compared to other CDK4/6i’s dosed as monotherapy or in combination with autophagy inhibitors. These data support the potential use of narazaciclib in breast cancer and UCEC, either as monotherapy or in combination with other agents.
Ability to induce senescence and T-cell recruiting chemokines: Treatment with narazaciclib/metabolite produced more profound reductions in cell viability in PYMT murine breast cancer cells, compared to palbociclib and other CDK4/6i’s (combined with autophagy inhibitors). In addition, narazaciclib treatment produced significantly higher increases in T-cell recruiting chemokines, including CXCL10, than palbociclib. These results suggest that narazaciclib has the differentiated potential to promote greater levels of anti-tumor immunity, which could enhance its efficacy.
Conclusions: Expansive analysis of narazaciclib and its metabolite, compared to palbociclib and other CDK4/6i’s, shows that narazaciclib has the potential to be differentiated by its:

Multi-kinase profile, including its impact on BUB1 which is associated with poor prognosis in breast and uterine cancers;
Potent ability to inhibit cell viability in a wide range of breast and ovarian cancer cell panels, including those with common mutations and over-expression of the FGFr, with or without autophagy inhibitors;
Ability to produce significantly higher increases in T-cell recruiting chemokines and promote greater anti-tumor immunity.
These data support the potential use of narazaciclib in patients with breast and ovarian cancer, as well as its potential in LGEEC, based on broad, differentiated multi-kinase activity, supported by potential anti-tumor activity and anti-tumor immunity, compared to palbociclib and other CDK4/6i’s. Evaluation across a range of cell lines, mutations, and prognostic factors, with or without autophagy inhibitors, underscores the strength and consistency of these data.

On December 8, 2023 SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a commercial-stage biopharmaceutical company focused on severe rare diseases and cancer, reported the closing of its previously announced underwritten public offering of 10,905,171 shares of its common stock at a public offering price of $29.00 per share, which includes the exercise in full by the underwriters of their option to purchase up to an additional 1,422,413 shares of common stock in this offering (Press release, SpringWorks Therapeutics, DEC 8, 2023, View Source [SID1234638336]). The gross proceeds from the offering, before deducting underwriting discounts and commissions and estimated offering expenses, were approximately $316.25 million.

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Goldman Sachs & Co. LLC, J.P. Morgan Securities LLC, Cowen and Company, LLC and Guggenheim Securities, LLC acted as joint book-running managers for the offering.

An automatic shelf registration statement on Form S-3ASR (including a prospectus) relating to these securities has been filed with the Securities and Exchange Commission (SEC) and has become effective.

The offering was made only by means of a prospectus and prospectus supplement that form part of the automatic shelf registration statement. A copy of the final prospectus supplement and accompanying prospectus relating to the offering has been filed with the SEC and may be obtained from: Goldman Sachs & Co. LLC, Attention: Prospectus Department, 200 West Street, New York, NY 10282, or by telephone at (866) 471-2526 or by email at [email protected]; J.P. Morgan Securities LLC, Attention: Broadridge Financial Solutions, 1115 Long Island Avenue, Edgewood, NY 11717, or by telephone at (866) 803-9204, or by email at [email protected]; Cowen and Company, LLC, 599 Lexington Avenue, New York, NY 10022, by email at [email protected] or by telephone at (833) 297-2926; or Guggenheim Securities, LLC, Attention: Equity Syndicate Department, 330 Madison Avenue, 8th Floor, New York, NY 10017, or by telephone at (212) 518-9544, or by email at [email protected].

This press release shall not constitute an offer to sell or the solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

On December 8, 2023 Rigel Pharmaceuticals, Inc. (Nasdaq: RIGL) and The University of Texas MD Anderson Cancer Center (MD Anderson) reported a multi-year strategic development collaboration to expand the evaluation of REZLIDHIA (olutasidenib) in acute myeloid leukemia (AML) and other hematologic cancers (Press release, Rigel, DEC 8, 2023, View Source [SID1234638334]).

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The alliance brings together MD Anderson’s clinical research expertise with Rigel’s differentiated targeted molecule. Under the strategic collaboration, Rigel and MD Anderson will evaluate the potential of olutasidenib to treat newly diagnosed and relapsed or refractory (R/R) patients with AML, higher-risk myelodysplastic syndromes (MDS), and advanced myeloproliferative neoplasms (MPN), in combination with other agents. The collaboration will also support the evaluation of olutasidenib as monotherapy in lower-risk MDS and as maintenance therapy in post-hematopoietic stem cell transplant patients.

"We are excited to enter into this strategic alliance with the exceptional team at MD Anderson to evaluate REZLIDHIA as a potential therapy for a broad range of IDH1-mutant cancers," said Raul Rodriguez, Rigel’s president and CEO. "We believe REZLIDHIA has the potential to become a standard of care for patients in urgent need of new hematology-oncology therapies. We look forward to a close collaboration with MD Anderson to advance this as a new therapeutic option for more patients."

REZLIDHIA is a potent, selective, oral, small-molecule inhibitor of mutated IDH1 (mIDH1)1 designed to bind to and inhibit mIDH1 to reduce 2-hydroxyglutarate levels and restore normal cellular differentiation of myeloid cells. REZLIDHIA is approved by the Food and Drug Administration (FDA) for the treatment of adult patients with R/R AML with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.

"Based on its differentiated profile and compelling clinical data to date, REZLIDHIA has the potential, beyond its currently approved indication, to benefit patients with various cancers where mutant IDH1 is thought to play a role," said Courtney DiNardo, M.D., professor of Leukemia. "We look forward to collaborating with Rigel to conduct in-depth studies that will determine the broader potential of REZLIDHIA in these patient populations."

Rigel and MD Anderson will jointly lead all clinical development efforts, which will be overseen by a joint steering committee. Rigel will provide $15 million in time-based milestone payments and study material over the five-year collaboration. Rigel will retain all rights to its programs under the collaboration.

About AML
Acute myeloid leukemia (AML) is a rapidly progressing cancer of the blood and bone marrow that affects myeloid cells, which normally develop into various types of mature blood cells. AML occurs primarily in adults and accounts for about 1 percent of all adult cancers. The American Cancer Society estimates that in the United States alone, there will be about 20,380 new cases, most in adults, in 2023.2

Relapsed AML affects about half of all patients who, following treatment and remission, experience a return of leukemia cells in the bone marrow.3 Refractory AML, which affects between 10 and 40 percent of newly diagnosed patients, occurs when a patient fails to achieve remission even after intensive treatment.4 Quality of life declines for patients with each successive line of treatment for AML, and well-tolerated treatments in relapsed or refractory disease remain an unmet need.

About REZLIDHIA
INDICATION
REZLIDHIA is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME

Differentiation syndrome, which can be fatal, can occur with REZLIDHIA treatment. Symptoms may include dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, hypotension, fever, and weight gain. If differentiation syndrome is suspected, withhold REZLIDHIA and initiate treatment with corticosteroids and hemodynamic monitoring until symptom resolution.

WARNINGS AND PRECAUTIONS
Differentiation Syndrome
REZLIDHIA can cause differentiation syndrome. In the clinical trial of REZLIDHIA in patients with relapsed or refractory AML, differentiation syndrome occurred in 16% of patients, with grade 3 or 4 differentiation syndrome occurring in 8% of patients treated, and fatalities in 1% of patients. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal. Symptoms of differentiation syndrome in patients treated with REZLIDHIA included leukocytosis, dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, fever, edema, pyrexia, and weight gain. Of the 25 patients who experienced differentiation syndrome, 19 (76%) recovered after treatment or after dose interruption of REZLIDHIA. Differentiation syndrome occurred as early as 1 day and up to 18 months after REZLIDHIA initiation and has been observed with or without concomitant leukocytosis.

If differentiation syndrome is suspected, temporarily withhold REZLIDHIA and initiate systemic corticosteroids (e.g., dexamethasone 10 mg IV every 12 hours) for a minimum of 3 days and until resolution of signs and symptoms. If concomitant leukocytosis is observed, initiate treatment with hydroxyurea, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms. Differentiation syndrome may recur with premature discontinuation of corticosteroids and/or hydroxyurea treatment. Institute supportive measures and hemodynamic monitoring until improvement; withhold dose of REZLIDHIA and consider dose reduction based on recurrence.

Hepatotoxicity
REZLIDHIA can cause hepatotoxicity, presenting as increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased blood alkaline phosphatase, and/or elevated bilirubin. Of 153 patients with relapsed or refractory AML who received REZLIDHIA, hepatotoxicity occurred in 23% of patients; 13% experienced grade 3 or 4 hepatotoxicity. One patient treated with REZLIDHIA in combination with azacitidine in the clinical trial, a combination for which REZLIDHIA is not indicated, died from complications of drug-induced liver injury. The median time to onset of hepatotoxicity in patients with relapsed or refractory AML treated with REZLIDHIA was 1.2 months (range: 1 day to 17.5 months) after REZLIDHIA initiation, and the median time to resolution was 12 days (range: 1 day to 17 months). The most common hepatotoxicities were elevations of ALT, AST, blood alkaline phosphatase, and blood bilirubin.

Monitor patients frequently for clinical symptoms of hepatic dysfunction such as fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. Obtain baseline liver function tests prior to initiation of REZLIDHIA, at least once weekly for the first two months, once every other week for the third month, once in the fourth month, and once every other month for the duration of therapy. If hepatic dysfunction occurs, withhold, reduce, or permanently discontinue REZLIDHIA based on recurrence/severity.

ADVERSE REACTIONS
The most common (≥20%) adverse reactions, including laboratory abnormalities, were aspartate aminotransferase increased, alanine aminotransferase increased, potassium decreased, sodium decreased, alkaline phosphatase increased, nausea, creatinine increased, fatigue/malaise, arthralgia, constipation, lymphocytes increased, bilirubin increased, leukocytosis, uric acid increased, dyspnea, pyrexia, rash, lipase increased, mucositis, diarrhea and transaminitis.

DRUG INTERACTIONS

Avoid concomitant use of REZLIDHIA with strong or moderate CYP3A inducers.
Avoid concomitant use of REZLIDHIA with sensitive CYP3A substrates unless otherwise instructed in the substrates prescribing information. If concomitant use is unavoidable, monitor patients for loss of therapeutic effect of these drugs.
LACTATION
Advise women not to breastfeed during treatment with REZLIDHIA and for 2 weeks after the last dose.

GERIATRIC USE
No overall differences in effectiveness were observed between patients 65 years and older and younger patients. Compared to patients younger than 65 years of age, an increase in incidence of hepatotoxicity and hypertension was observed in patients ≥65 years of age.

HEPATIC IMPAIRMENT
In patients with mild or moderate hepatic impairment, closely monitor for increased probability of differentiation syndrome.

Click here for Full Prescribing Information, including Boxed WARNING.

To report side effects of prescription drugs to the FDA, visit www.fda.gov/medwatch or call 1-800-FDA-1088 (800-332-1088).

REZLIDHIA is a registered trademark of Rigel Pharmaceuticals, Inc.

On December 8, 2023 Ribometrix, a biotechnology company developing small molecule therapeutics that modulate RNA biology, reported preclinical data supporting the potential of its eIF4E inhibitors in Estrogen Receptor-positive (ER+) breast cancer at the annual San Antonio Breast Cancer Symposium (SABCS), held December 5-9, 2023, in San Antonio, TX. This builds on analogous data announced last month in melanoma, providing further depth to the data supporting this target and Ribometrix’s portfolio of eIF4E-targeted small molecule inhibitors (Press release, Ribometrix, DEC 8, 2023, View Source [SID1234638333]).

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Ribometrix’s preclinical studies in ER+ breast cancer include evaluation of eIF4E inhibition via both monotherapy and in combination with standard-of-care (SoC) CDK4/6 inhibitors, which target key pro-oncogenic signaling pathways shared with eIF4E. Furthermore, eIF4E controls parts of the pathway that complement those targeted by CDK4/6 inhibition, suggesting additive benefit from combined therapy. All patients eventually develop resistance to CDK4/6 inhibitors, leaving a large unmet need and opportunity to restore tumor sensitivity to treatment and improve outcomes. Ribometrix expects to present additional data and select a development candidate in 2024.

"The data presented at SABCS reflect Ribometrix’s ability to efficiently translate the well-supported eIF4E target hypothesis into an RNA-modulating small molecule drug that has now achieved preclinical in vivo proof-of-concept in an additional tumor indication," said Michael Solomon, Ph.D., Chief Executive Officer of Ribometrix. "We are encouraged to see the added validation of eIF4E as an important mediator of pro-oncogenic signaling, this time in ER+ breast cancer, and the excellent emerging profiles of our eIF4E inhibitors. These data provide a strong foundation on which to build and refine the clinical development strategy for which eIF4E inhibition can ultimately have the greatest impact for patients."

Key takeaways from the presentation at SABCS include:

• Daily oral dosing of single agent Ribometrix eIF4E inhibitors shows anti-tumor efficacy in vivo with no signs of overt toxicity in an ER+ breast cancer tumor model

• Targeting ER+ breast cancer resistant to CDK4/6 inhibitors with a Ribometrix eIF4E inhibitor has the potential to mitigate drug resistance and restore sensitivity to standard of care (SoC) in a second line setting

• eIF4E inhibition with Ribometrix compounds potentiates cancer cell sensitivity to CDK4/6 inhibition, supporting a combination approach to improve SoC response durability in ER+ breast cancer

The data will be presented as a poster by Matthew Friedersdorf, Ph.D. and on display beginning today, December 8, 2023, at 12pm CT, at which time it will become available on the Ribometrix website.

About eIF4E
Eukaryotic translation initiation factor 4E (eIF4E), the main regulatory component of cap-dependent mRNA translation, selectively promotes pro-oncogenic protein synthesis in response to activation of multiple tumor signaling pathways. Interestingly, many pro-oncogenic signaling pathways require eIF4E activity to promote tumor growth. Clinically, eIF4E activity is elevated in many tumor indications and is typically associated with poor prognosis. Thus, targeting eIF4E has the potential to enhance anti-cancer activity when given in combination with standard-of-care (SoC). Additionally, eIF4E is also central to many resistance mechanisms, therefore eIF4E inhibition has the potential to overcome drug resistance and re-sensitize tumors to anti-cancer therapies. Ribometrix is developing eIF4E inhibitors as a promising therapeutic strategy to inhibit oncogene expression to enhance efficacy in combination with SoC and overcome resistance to targeted anti-cancer therapies.

On December 8, 2023 Phio Pharmaceuticals Corp. (Nasdaq: PHIO), a clinical stage biotechnology company whose proprietary INTASYL RNAi platform technology is designed to make immune cells more effective in killing tumor cells, reported the agreement by several accredited investors to exercise certain outstanding warrants to purchase up to an aggregate of 2,130,252 shares of common stock of the Company originally issued in October 2018 through June 2023, having exercise prices between $5.40 and $4.03 per share, at a reduced exercise price of $1.33 per share (Press release, Phio Pharmaceuticals, DEC 8, 2023, View Source [SID1234638332]). The shares of common stock issuable upon exercise of the warrants are registered pursuant to effective registration statements on Form S-1 (Nos. 333-227173, 333-227617, 333-234032, 333-238204, 333-239779, 333-271521 and 333-272526) and Form S-3 (No. 333-256100). The gross proceeds to the Company from the exercise of the warrants are expected to be approximately $2.8 million, prior to deducting placement agent fees and estimated offering expenses.

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H.C. Wainwright & Co. is acting as the exclusive placement agent for the offering.

In consideration for the immediate exercise of the warrants for cash, the exercising holders will receive new unregistered warrants to purchase shares of common stock in a private placement pursuant to Section 4(a)(2) of the Securities Act of 1933, as amended (the "1933 Act"). The new warrants will be exercisable for an aggregate of up to 4,260,504 shares of common stock, at an exercise price of $1.08 per share and will be immediately exercisable upon issuance. 2,270,320 of the new warrants will have a term of five and one-half years from the issuance date and 1,990,184 of the new warrants will have a term of eighteen months from the issuance date.

The offering is expected to close on or about December 8, 2023, subject to satisfaction of customary closing conditions. The Company intends to use the net proceeds from the offering for working capital and other general corporate purposes.

The new warrants described above were offered in a private placement pursuant to an applicable exemption from the registration requirements of the 1933 Act and, along with the shares of common stock issuable upon their exercise, have not been registered under the 1933 Act, and may not be offered or sold in the United States absent registration with the SEC or an applicable exemption from such registration requirements. The securities were offered only to accredited investors. The Company has agreed to file a registration statement with the SEC covering the resale of the shares of common stock issuable upon exercise of the new warrants.

This press release shall not constitute an offer to sell or a solicitation of an offer to buy nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of any such state or jurisdiction.