On January 13, 2025 Rakovina Therapeutics Inc. (TSX-V: RKV), a biopharmaceutical company dedicated to advancing new cancer therapies based on novel DNA-damage response technologies, reported the successful achievement of a shortlist of AI-generated molecules targeting ATR (Ataxia Telangiectasia and Rad3-related protein) with specific designs for central nervous system (CNS) penetration (Press release, Rakovina Therapeutics, JAN 13, 2025, View Source;utm_medium=rss&utm_campaign=rakovina-therapeutics-announces-key-milestone-in-cancer-drug-innovation-in-collaboration-with-variational-ai [SID1234649672]).

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This milestone represents the first significant deliverable in Rakovina’s partnership with Variational AI, which leverages their state-of-the-art Enki platform to fast-track the discovery of innovative inhibitors for specific DNA damage response (DDR) kinase targets. ATR is an important drug target due its critical involvement in the DNA damage response (DDR). Its inhibition can lead to selective cancer cell death and improved therapeutic outcomes when combined with other treatments.

These new ATR-targeted inhibitors will now advance to chemical synthesis followed by preclinical validation, a critical step in Rakovina’s mission to address unmet medical needs in oncology.

Innovative Approach to Drug Discovery

The shortlisted molecules were developed using Variational AI’s proprietary Enki foundation model platform to generate novel chemical compounds from the estimated 1060 molecules in chemical space, far greater than any screening library. The platform identifies promising drug candidates while reducing timelines from years to just months. With CNS penetration capabilities, these molecules are poised to address cancers that metastasize to the brain or originate within the CNS, areas with historically limited treatment options.

This achievement is just the beginning of a dynamic journey. Rakovina is broadening its research scope with Variational AI to target additional DDR kinase pathways, with the vision of building a comprehensive pipeline of next-generation small-molecule therapies. By leveraging generative AI, the Company can eliminate traditional barriers, promising a new era of faster, more precise cancer treatment development.

"We are pleased to announce the achievement of this first milestone in our collaboration with Variational AI," said Jeffrey Bacha, Executive Chairman of Rakovina Therapeutics. "The identification of ATR-targeted drug candidates with CNS penetration exemplifies the transformative potential of AI in cancer therapy. This progress represents a meaningful step forward in our research and demonstrates the growing impact of AI in accelerating drug development and innovation in oncology."

On January 13, 2025 Protara Therapeutics, Inc. (Nasdaq: TARA), a clinical-stage company developing transformative therapies for the treatment of cancer and rare diseases, reported recent updates and anticipated 2025 milestones (Press release, Protara Therapeutics, JAN 13, 2025, View Source [SID1234649671]).

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"Following a highly productive 2024 marked by positive data in our non-muscle invasive bladder cancer (NMIBC) program and with the funds from a successful financing, we are well positioned to accelerate our development programs and deliver on our mission to provide novel therapies to patients impacted by cancer and rare diseases," said Jesse Shefferman, Chief Executive Officer of Protara Therapeutics. "Looking ahead, we expect several key milestones in 2025, including reporting data on 12-month evaluable patients in our ADVANCED-2 trial of TARA-002 in NMIBC mid-year. On the heels of our recently reported positive interim data from six-month evaluable patients, we continue to believe that TARA-002 could represent a meaningful and differentiated addition to the NMIBC treatment paradigm with an attractive product profile for both physicians and patients."

"In addition, we expect to begin the pivotal THRIVE-3 study of intravenous (IV) Choline Chloride in the first half of 2025. We also expect data from our ongoing Phase 2 STARBORN-1 trial of TARA-002 in lymphatic malformations (LMs) by the end of the first half of 2025."

Recent Company Updates and Planned 2025 Milestones

TARA-002 in NMIBC

In December 2024, the Company reported positive interim results from its ongoing Phase 2 open-label ADVANCED-2 trial in in NMIBC patients with carcinoma in situ or CIS (± Ta/T1) who are Bacillus Calmette-Guérin (BCG)-Unresponsive and BCG-Naïve at the 25th Annual Meeting of the Society of Urologic Oncology (SUO) in Dallas, Texas. The complete response (CR) rate across BCG exposures was 72% (13/18) at six months and 70% (14/20) at any time, with 100% (9/9) of patients maintaining a CR from three months to six months. In addition, two of three patients maintained a CR at nine months. TARA-002 showed a favorable safety profile, with no Grade 2 or greater treatment-related adverse events and no treatment discontinuations due to adverse events.
The Company expects to report data on 12-month evaluable patients in the ADVANCED-2 trial in mid-2025 and results from a futility analysis of approximately 25 six-month evaluable BCG-Unresponsive patients are expected by the end of 2025. As previously announced, the BCG-Unresponsive cohort is designed to be registrational in alignment with the 2024 BCG-Unresponsive Non-muscle Invasive Bladder Cancer: Developing Drugs and Biological Products for Treatment Draft Guidance for Industry issued by the U.S. Food and Drug Administration (FDA).
The Company expects to provide an update on the design of its planned BCG-Naïve registrational trial by the end of the first half of 2025 following regulatory alignment.
The Company continues to explore the administration of systemic priming dosing prior to initiation of intravesical administration, as well as combination therapy with TARA-002 in NMIBC patients with CIS. Given TARA-002’s mechanism of action and safety profile, the Company believes it has strong potential for use in combination therapy and is working to finalize various opportunities for the clinical program.
IV Choline Chloride for Patients on Parenteral Support (PS)

The Company expects to commence the THRIVE-3 registrational trial of IV Choline Chloride, an investigational phospholipid substrate replacement, in adolescents and adults on long-term PS when oral or enteral nutrition is not possible, insufficient, or contraindicated, in the first half of 2025. IV Choline Chloride was previously granted Fast Track designation by the FDA as a source of choline for this patient population.
In September 2024, the Company announced results from THRIVE-1, a prospective, observational study, which found that 78% of PS-dependent patients were choline deficient, and 63% of these patients demonstrated liver dysfunction, including steatosis, cholestasis, and hepatobiliary injury.
TARA-002 in LMs

Protara remains on track to report initial results from additional cohorts in the Phase 2 STARBORN-1 trial of TARA-002 in pediatric patients with macrocystic and mixed cystic LMs by the end of the first half of 2025. The Company previously announced completion of the study’s first safety cohort, in which TARA-002 demonstrated encouraging efficacy and was generally well-tolerated.
Financial Guidance

The Company today provided updated financial guidance. Protara believes its approximately $81.5 million of cash, cash equivalents, and investments in marketable debt securities as of September 30, 2024, together with approximately $100 million gross proceeds from its December 2024 public offering, will be sufficient to fund its planned operations into 2027.

On January 13, 2025 Phio Pharmaceuticals Corp. (Nasdaq: PHIO) is a clinical-stage biotechnology company developing therapeutics that use its INTASYL siRNA gene silencing technology designed to make the body’s immune cells more effective in killing cancer cells (Press release, Phio Pharmaceuticals, JAN 13, 2025, View Source [SID1234649670]). Phio reported pathologic responses for patients enrolled in the 2nd cohort, which includes 2 patients with a complete response or 100% tumor clearance.

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Phio’s ongoing Phase 1b clinical study (NCT 06014086) is designed to evaluate the safety and tolerability of neoadjuvant use of intratumoral PH-762 in Stages 1, 2 and 4 cutaneous squamous cell carcinoma, Stage 4 melanoma and Stage 4 Merkel cell carcinoma.

Of the patients enrolled to date, 6 patients were diagnosed with cutaneous squamous cell carcinoma and 1 patient was diagnosed with metastatic melanoma. At Day 36 (tumor excision), while patients in the first cohort had stable disease, results are now available for the 4 patients who completed treatment in the 2nd cohort:

· Complete response (100% tumor clearance) is reported for 2 patients with cutaneous squamous cell carcinoma. Partial response (90% tumor clearance) is reported for 1 patient with cutaneous squamous cell carcinoma and 1 patient had stable disease, having not progressed.

There have been no dose-limiting toxicities, or clinically relevant treatment-emergent adverse events in the patients receiving intratumoral PH-762. The intratumoral injections have been well tolerated.

"We are pleased and encouraged by the profound tumor response in the second dose cohort, coupled with reassuring safety data," said Mary Spellman MD, Phio’s acting Chief Medical Officer. "We look forward to continued enrollment which will permit assessment of higher dose concentrations of PH-762."

"These positive results in the early stages of dose escalation offer promise for our vision, ‘striving for a cancer free future’ using INTASYL technology" said Robert Bitterman, CEO of Phio Pharmaceuticals.

On January 13, 2025 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, reported early Phase 1b combination data for ORIC-944, operational highlights for 2024, and anticipated upcoming milestones (Press release, ORIC Pharmaceuticals, JAN 13, 2025, View Source [SID1234649669]).

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"We made strong progress on multiple fronts in 2024, most notably with the initiation of multiple cohorts for ORIC-114 in NSCLC and ORIC-944 in mCRPC. We also forged three strategic collaborations with leading pharma partners, strengthened our leadership team to expand functional capabilities, and completed a $125 million PIPE financing, extending our cash runway into late 2026," said Jacob M. Chacko, M.D., president and chief executive officer. "These accomplishments position us well for 2025 and beyond, with seven anticipated data readouts over the next 18 months as we advance toward potentially initiating registrational studies for ORIC-114 in the second half of 2025 and for ORIC-944 in early 2026."

Updated Phase 1b Combination Data for ORIC-944

ORIC-944 is a potent and selective allosteric inhibitor of the polycomb repressive complex 2 (PRC2) via allosteric targeting of the embryonic ectoderm development (EED) subunit. ORIC-944 was initially evaluated as a single agent in a Phase 1b trial in patients with advanced prostate cancer and demonstrated potential best-in-class drug properties, including a clinical half-life of approximately 20 hours, robust target engagement, and a favorable safety profile.

In mid-2024, the Company initiated once daily dosing of ORIC-944 in combination with 240 mg QD apalutamide or with 600 mg BID darolutamide, as part of the ongoing Phase 1b trial in patients with metastatic castration resistant prostate cancer (mCRPC). As of the December 10, 2024 data cut-off, the Company completed the first two ORIC-944 dose escalation cohorts (n=6 patients) for the apalutamide combination. This initial experience demonstrated:

Deep prostate-specific antigen (PSA) decreases across both the 600 mg and 800 mg dose cohorts; 3 of 6 patients achieved confirmed PSA50 responses, of which 2 achieved confirmed PSA90 responses. All the PSA responses were maintained at ≥12 weeks, including a durable confirmed PSA90 response ongoing at 38 weeks.
Well-tolerated safety, with primarily Grade 1 and Grade 2 treatment related adverse events (TRAE), consistent with PRC2 and androgen receptor (AR) inhibition, and one Grade 3 TRAE of fatigue (patient remains on treatment without dose modification). The first two dose levels cleared without dose limiting toxicities or treatment discontinuations related to safety. Dose escalation is ongoing.
Dose escalation for the combination of ORIC-944 with darolutamide is also ongoing with the first dose cohort completed and the second enrolling. Preliminary clinical activity seen to date is consistent with the apalutamide combination cohort.

2024 Key Accomplishments

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

Entered into a clinical trial collaboration and supply agreement with Johnson & Johnson to evaluate ORIC-114 in combination with subcutaneous (SC) amivantamab for the 1L treatment of NSCLC patients with EGFR exon 20 insertion mutations.
Initiated a cohort to evaluate ORIC-114 monotherapy for the treatment of patients with 1L treatment-naïve EGFR exon 20 insertion NSCLC.
Announced the completion of the dose escalation portion of the Phase 1b trial of ORIC-114 and the selection of two provisional recommended phase 2 doses; after which, first patients were dosed across three expansion cohorts in the Phase 1b trial of ORIC-114 in patients with mutated non-small cell lung cancer (NSCLC), including 2L EGFR exon 20 insertion (EGFR exon 20 inhibitor naïve), 2L+ HER2 exon 20 insertion, and 2L+ EGFR atypical mutations.
Presented preclinical data demonstrating potential best-in-class properties, including potency and selectivity, of ORIC-114 to treat NSCLC harboring EGFR exon 20 insertions and other atypical EGFR mutations at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics.
ORIC-944: a potent and selective allosteric inhibitor of PRC2

Initiated dosing of ORIC-944 in combination with ERLEADA (apalutamide) and in combination with NUBEQA (darolutamide) in mid-2024 in the ongoing Phase 1b trial for prostate cancer.
Entered into clinical trial collaboration and supply agreements with Johnson & Johnson and Bayer to support the ongoing Phase 1b trial of ORIC-944 in combination with AR inhibitors for the treatment of prostate cancer.
Reported initial Phase 1b single agent data for ORIC-944 in metastatic prostate cancer supporting advancement into combination development and demonstrating the potential as a best-in-class PRC2 inhibitor, including a clinical half-life of ~20 hours, robust target engagement, no signs of CYP autoinduction that was observed with first-generation PRC2 inhibitors, and a generally well-tolerated safety profile.
Presented preclinical data at the 2024 AACR (Free AACR Whitepaper) Annual Meeting demonstrating superior drug properties and synergy data in prostate cancer models, reinforcing the promise of ORIC-944 as a potential best-in-class treatment for combination with AR inhibitors.
Corporate Highlights:

Strengthened cash position and runway with a $125 million private placement financing from new and existing healthcare specialist funds.
Expanded the leadership team with the appointment of industry veteran Keith Lui as Senior Vice President of Commercial and Medical Affairs.
Anticipated Program Milestones

ORIC anticipates the following upcoming data milestones:

ORIC-114 (NSCLC):
1H 2025: 2L EGFR exon 20 and 2L+ HER2 exon 20
2H 2025: 2L+ EGFR atypical
1H 2026: 1L EGFR exon 20
Mid-2026: 1L EGFR exon 20 combination with SC amivantamab and 1L EGFR atypical
ORIC-944 (mCRPC):
4Q 2025 / 1H 2026: Combination with AR inhibitors
Financial Guidance
As of September 30, 2024, cash, cash equivalents and investments totaled $282.4 million, which the company expects will be sufficient to fund its operating plan into late 2026.

Presentation and Webcast

Jacob M. Chacko, M.D., president and chief executive officer, will present a company overview at the 43rd Annual J.P. Morgan Healthcare Conference on Tuesday, January 14, 2025, 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 13, 2025 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, reported that the company has entered into a supply agreement with Janssen Research & Development, LLC, a Johnson & Johnson company, to evaluate ORIC-114, a brain penetrant, orally bioavailable, irreversible EGFR/HER2 inhibitor, in combination with subcutaneous (SC) amivantamab, Johnson & Johnson’s fully-human EGFR-MET bispecific antibody, for the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations (Press release, ORIC Pharmaceuticals, JAN 13, 2025, View Source [SID1234649668]).

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Under the terms of the agreement, ORIC will conduct and sponsor the trial and Johnson & Johnson will provide SC amivantamab. ORIC maintains development and commercial rights to ORIC-114 and is free to expand the program in combination with other agents.

"ORIC-114 has already demonstrated encouraging systemic and intracranial activity in heavily pre-treated patients with EGFR/HER2 mutated NSCLC," said Jacob M. Chacko, MD, chief executive officer. "Given the prevalence of brain metastases across all lines of EGFR exon 20 NSCLC, we aim to further explore ORIC-114’s emerging profile in the first-line setting both as a monotherapy and in combination with SC amivantamab."

ORIC expects to initiate the combination Phase 1b trial to evaluate the safety and tolerability of ORIC-114 in combination with SC amivantamab for the first-line treatment of patients with advanced NSCLC with EGFR exon 20 insertion mutations in the first quarter of 2025. The primary objectives are to determine the provisional recommended Phase 2 dose (RP2D) for the combination, and additional objectives include assessment of efficacy and further characterization of the safety profile of ORIC-114 in combination with SC amivantamab. The company expects to report initial data from the trial in mid-2026.

In 2024, the company announced the completion of the monotherapy dose escalation portion of the Phase 1b trial of ORIC-114 in patients with advanced solid tumors with EGFR and HER2 exon 20 alterations or HER2 amplifications. Based upon these data, ORIC selected the two provisional RP2D levels of ORIC-114 at 80 mg and 120 mg QD, which are being further evaluated in three dose expansion cohorts for dose optimization and final RP2D selection in patients with NSCLC with EGFR exon 20 (EGFR exon 20 inhibitor naïve), HER2 exon 20, or EGFR atypical mutations as well as an extension cohort for the treatment of patients with first-line, treatment-naïve EGFR exon 20 mutated NSCLC.

About ORIC-114

ORIC-114 is a highly selective, brain penetrant, orally bioavailable, irreversible inhibitor that selectively targets EGFR exon 20, HER2 exon 20 and EGFR atypical mutations, making it a promising therapeutic candidate to address the unmet medical need of having both meaningful systemic as well as CNS antitumor activity.