On January 8, 2024 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, reported initial data for its PRC2 inhibitor ORIC-944, operational highlights for 2023, and anticipated upcoming milestones (Press release, ORIC Pharmaceuticals, JAN 8, 2024, View Source [SID1234639099]).

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"2023 was a landmark year for ORIC with both ORIC-114 and ORIC-944 generating clinical proof of concept data that position them as potential best-in-class therapies for NSCLC and prostate cancer, respectively. Additionally, with the completion of an $85 million PIPE financing from top tier new and existing funds, we extended our cash runway into 2026," said Jacob M. Chacko, M.D., president and chief executive officer. "In 2024, we are focused on initiating multiple dose expansion cohorts for ORIC-114 in NSCLC as well as combination studies with one or more AR inhibitors in prostate cancer for ORIC-944, all in anticipation of both programs potentially entering pivotal studies in 2025."

Initial Phase 1b Data for ORIC-944

As of December 10, 2023, the initial Phase 1b monotherapy data for ORIC-944, a potent and selective allosteric inhibitor of PRC2, in patients with metastatic prostate cancer demonstrated:
Potential best-in-class drug properties, including clinical half-life consistent with preclinical prediction of >10 hours, which is superior to other PRC2 inhibitors and supports QD dosing;
No signs of CYP autoinduction that is seen with first-generation PRC2 inhibitors;
Robust target engagement with maximal decrease (≥75%) in H3K27me3 in monocytes from peripheral blood samples at doses as low as 200 mg QD, with low inter-patient variability; and
Favorable safety with only grade 1 and 2 treatment-related adverse events at dose levels corresponding with strong target engagement.
Emerging profile with superior drug properties support advancement into combination development in prostate cancer with AR inhibitor(s).
2023 Key Accomplishments

ORIC-114: a brain penetrant, orally bioavailable, irreversible EGFR/HER2 inhibitor

Presented initial data from the ongoing Phase 1b dose escalation trial for patients with EGFR or HER2 exon 20 mutated non-small cell lung cancer (NSCLC) at the ESMO (Free ESMO Whitepaper) Congress 2023. Initial data demonstrated potential best-in-class profile, with favorable safety and both systemic and CNS activity in heavily pretreated patients, with 81% of patients having received prior EGFR exon 20 targeted agents and 86% having CNS metastases at baseline.
Presented preclinical data for ORIC-114 at ESMO (Free ESMO Whitepaper) Congress 2023, demonstrating potent activity across atypical mutations in EGFR, thus expanding the potential patient population.
ORIC-944: a potent and selective allosteric inhibitor of PRC2

Presented preclinical data highlighting a comprehensive biomarker strategy for the ongoing Phase 1b trial in metastatic prostate cancer at the 2023 AACR (Free AACR Whitepaper) Annual Meeting.
Demonstrated via preclinical studies the potential for ORIC-944 to synergize with enzalutamide and other AR inhibitors in prostate cancer.
ORIC-533: a highly potent, orally bioavailable small molecule inhibitor of CD73

Presented initial data from Phase 1b trial of ORIC-533 in patients with relapsed/refractory multiple myeloma at the 2023 ASH (Free ASH Whitepaper) Annual Meeting. Initial data demonstrated preliminary evidence of clinical antimyeloma activity and immune effects, as well as a clean safety profile, with only grade 1 and 2 treatment-related events in heavily pre-treated patients.
Expect to complete dose escalation for the Phase 1b trial of ORIC-533 in the first quarter of 2024, and company plans to pursue strategic partnership for combination studies.
Discovery Pipeline:

Presented preclinical data confirming the therapeutic potential of highly selective PLK4 inhibitors as a synthetic lethal therapy for TRIM37 amplified breast cancers at the 2023 AACR (Free AACR Whitepaper) Annual Meeting.
Advanced ORIC-613, a novel, highly selective PLK4 inhibitor, through IND enabling studies.
Corporate Highlights:

Strengthened cash position with $85 million private placement financing from new and existing healthcare specialist funds in the second quarter of 2023.
Anticipated Program Milestones

ORIC-944 initiation of combination study with AR inhibitor(s): 1H 2024
ORIC-944 program update: mid-2024
ORIC-114 initiation of dose expansion in multiple cohorts: 1H 2024
ORIC-114 updated Phase 1b data: 1H 2025
Financial Guidance

As of September 30, 2023, cash, cash equivalents and investments totaled $256.2 million, which the company expects will be sufficient to fund its operating plan into 2026.

Presentation and Webcast
Jacob M. Chacko, M.D., president and chief executive officer, will present a company overview at the 42nd Annual J.P. Morgan Healthcare Conference on Tuesday, January 9, 2024, at 11:15 a.m. PT. A live webcast will be available through the investor section of the company’s website at www.oricpharma.com. A replay of the webcast will be available for 90 days following the event.

On January 8, 2024 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported that the fourth patient has now been enrolled into its Phase 1/2 study of ONCT-534, its dual-action androgen receptor inhibitor, for the treatment of patients with advanced prostate cancer who are relapsed or refractory to approved androgen receptor pathway inhibitors (ARPI) (Press release, Oncternal Therapeutics, JAN 8, 2024, View Source [SID1234639098]). The last two patients were enrolled into the third dosing cohort, to receive ONCT-534 at a dose of 160 mg taken orally each day. The study utilizes an adaptive Bayesian Optimal Interval (BOIN) design, under which the first two dosing cohorts treated one patient each at 40 mg ONCT-534 per day and 80 mg ONCT-534 per day, respectively. The decision to proceed to dose level 3 was confirmed by the study’s Safety Review Committee (SRC).

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"The ONCT-534-101 investigators are enthusiastic about this study, and we are excited about the enrollment and progress through the initial dosing levels. Reaching the third cohort represents an important milestone for the program, as we believe we are nearing potentially therapeutic doses that may benefit prostate cancer patients who have progressed after treatment with approved ARPI such as enzalutamide, abiraterone, apalutamide and darolutamide," said Salim Yazji M.D., Chief Medical Officer at Oncternal Therapeutics. "We believe ONCT-534, with its novel mechanism of action involving both the ligand-binding domain and the N-terminal domain of the androgen receptor (AR), may address a significant unmet medical need for patients with advanced metastatic prostate cancer, especially those with splice variants of the AR, mutations in the ligand-binding domain of the AR, or AR amplification, common mechanisms of resistance that may develop to treatment with currently approved AR pathway inhibitors."

About Study ONCT-534-101
Study ONCT-534-101 is a Phase 1/2, single-arm, open-label, multi-center study to evaluate the safety and tolerability, pharmacokinetics, and preliminary anti-tumor activity of ONCT-534 in patients with mCRPC who have relapsed or are refractory to approved ARPIs including enzalutamide, abiraterone, apalutamide and darolutamide. After the safety and tolerability and preliminary antitumor activity of ONCT-534 have been assessed in the Phase 1 portion of this study, Phase 2 will commence to further evaluate the safety and preliminary antitumor activity of ONCT-534 to support selecting an optimal dose.

On January 8, 2024 Olema oncology presented its corporate presentation (Presentation, Olema Oncology, JAN 8, 2024, View Source [SID1234639097]).

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On January 8, 2024 Nurix presented its corporate presentation (Presentation, Nurix Therapeutics, JAN 8, 2024, View Source [SID1234639096]).

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On January 8, 2024 Novartis reported positive results from the primary analysis of ASC4FIRST, a pivotal Phase III trial comparing Scemblix (asciminib) with investigators’ choice of tyrosine kinase inhibitor (TKI) treatment in newly diagnosed patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP)1. ASC4FIRST is the first and only randomized head-to-head Phase III trial comparing a CML treatment vs. approved standard-of-care first- and second-generation TKIs1 (Press release, Novartis, JAN 8, 2024, View Source [SID1234639095]).

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The trial met both primary endpoints of major molecular response (MMR) rate for Scemblix compared to investigator-selected TKIs (imatinib, nilotinib, dasatinib, and bosutinib) and compared to imatinib, demonstrating clinically meaningful and statistically significant results for both endpoints1. Scemblix showed a favorable safety and tolerability profile with fewer adverse events (AEs) and treatment discontinuations vs. investigator selected standard-of-care TKIs1. The ASC4FIRST data showed no new safety signals compared to the established safety profile of Scemblix1,14.

"We are very encouraged by these results given that a significant proportion of patients with newly diagnosed chronic myeloid leukemia, or CML, do not achieve their treatment goals," said Prof. Tim Hughes, MD, South Australian Health & Medical Research Institute (SAHMRI). "There remains a significant need in first-line therapy of CML for tolerable treatment options, allowing people with CML to balance their treatment alongside their quality of life."

Improvements in treatment have transformed CML into a chronic disease, with a life expectancy similar to that of the general population, making tolerability an important treatment goal9. While many patients with CML may benefit from available TKI therapy, intolerance and AEs remain a primary reason for TKI therapy discontinuation, with discontinuation rates due to AEs of up to 25% by five years2-6. Additionally, over 60% of newly diagnosed CML patients fail to meet 12-month molecular response goals 5-13.

"We are excited that Scemblix may help people newly diagnosed with CML achieve their treatment goals while continuing to live their lives," said Shreeram Aradhye, M.D., President, Development and Chief Medical Officer, Novartis. "Given the chronic nature of their condition, patients often need to be on TKI therapy for many years, so treatment options that are well tolerated and highly efficacious are crucial to support adherence. This study outcome builds on our 20-year legacy in CML innovation as we strive to continue to address the remaining unmet needs for people living with this blood cancer."

The trial remains ongoing, with the next scheduled data readout planned for week 96, which will evaluate the key secondary endpoint (MMR at week 96) as well as additional secondary endpoints.

Details will be presented at an upcoming medical conference and included as part of regulatory submissions in 2024.

About ASC4FIRST Phase III Clinical Trial
ASC4FIRST (NCT04971226) is a Phase III, head-to-head, multi-center, open-label, randomized study of oral Scemblix 80 mg QD versus investigator-selected first- or second-generation TKI (imatinib, nilotinib, dasatinib, or bosutinib) in 405 adult patients with newly diagnosed Ph+ CML-CP1. The two primary endpoints of the study are to compare efficacy of asciminib vs. investigator-selected TKI and to compare efficacy vs that of TKI within the stratum of participants with imatinib as pre-randomization selected TKI, based on proportion of patients that achieve MMR at week 481. The study remains ongoing with a key secondary endpoint of proportion of patients that achieve MMR at week 96 and a safety endpoint of discontinuation of study treatment due to an AE (TTDAE) by week 96. The study also assesses additional secondary safety and efficacy endpoints, including MMR, MR4, MR4.5, complete hematological response (CHR) and BCR::ABL1 ≤1% at and by all scheduled data collection time points; duration of and time to first MMR, MR4 and MR4.5; time to treatment failure; event-free survival, failure-free survival, progression-free survival, and overall survival1.

About Scemblix (asciminib)
Scemblix is the first CML treatment that works by specifically targeting the ABL myristoyl pocket15,16 and was intentionally designed to be highly specific and minimize off-target kinase mediated effects, which translates into an improved safety and tolerability profile compared to current standard of care.

Scemblix is approved in more than 60 countries, including the US and the EU, to treat adults with Ph+ CML-CP who have previously been treated with two or more TKIs14,19. In some countries including the US, Scemblix is also approved in patients with Ph+ CML-CP with the T315I mutation2-14,18,19.

Scemblix represents an important potential treatment option for patients who experience resistance and/or intolerance to currently available TKI therapies, and it is being studied across multiple treatment lines for Ph+ CML-CP, both as monotherapy and in combination.