FDA Granted Fast Track Designation to Oncternal Therapeutics’s ONCT-534 for the Treatment of Metastatic Castration-Resistant Prostate Cancer

On Oct. 26, 2023, Oncternal Therapeutics, Inc. (Nasdaq: ONCT) announced that the U.S. Food and Drug Administration (FDA) has designated ONCT-534, its novel dual-acting androgen receptor inhibitor (DAARI), as a Fast Track development program for the investigation of the treatment of patients with relapsed or refractory metastatic castration-resistant prostate cancer (mCRPC) resistant to approved androgen receptor pathway inhibitors (ARPIs).

“The receipt of Fast Track designation for ONCT-534 supports our belief that patients with mCRPC who relapse after treatment with ARPIs such as enzalutamide or abiraterone, represent an important unmet medical need,” said James Breitmeyer, M.D., Ph.D., Oncternal’s President, and CEO. “We believe that due to ONCT-534’s novel mechanism of action, it may address important androgen receptor (AR) escape mechanisms that result in resistance to currently approved ARPIs. We look forward to working with FDA, investigators, and industry collaborators to bring ONCT-534 to patients as quickly as possible.”

The ONCT-534-101 study is a Phase 1/2 trial that is single-armed, open-label, and conducted at multiple centers. Its primary objectives are to investigate the safety and tolerability, pharmacokinetics, and initial antitumor effects of ONCT-534 in metastatic castration-resistant prostate cancer (mCRPC) patients who have either relapsed or shown resistance to approved androgen receptor pathway inhibitors (ARPIs) such as enzalutamide, abiraterone, apalutamide, and daralutamide. Following the assessment of safety, tolerability, and initial antitumor activity in Phase 1, Phase 2 will be initiated to further explore the safety and early antitumor responses of ONCT-534 with the goal of determining the optimal dosage.

Prostate cancer imposes a substantial healthcare burden. It ranks as the third most frequent cancer in the United States and the fourth most common globally. Notably, about 1 in 9 men in the U.S. will receive a prostate cancer diagnosis during their lifetime. According to data from the American Cancer Society in 2019, prostate cancer is the second most common cause of cancer-related deaths in American men, following closely behind lung cancer. This prevalence underscores the significant impact prostate cancer has on both individuals and the healthcare system, highlighting the need for continued research, innovative treatments, and early detection methods to address this pressing health concern. To overcome the treatment challenges, several major pharma and biotech companies are actively working in the prostate cancer therapeutics market. 

The FDA’s Fast Track Designation for ONCT-534 from Oncternal Therapeutics in the treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC) signifies a crucial development in the field of mCRPC therapy. It expedites the drug’s regulatory review process, potentially leading to quicker access for patients to this innovative treatment. This designation underscores the urgency in addressing mCRPC, offering hope for improved treatment outcomes and a more promising outlook for those affected by this challenging disease.

Phase III RUBY Trial of Jemperli Plus Chemotherapy Meets Endpoint of Overall Survival In Patients With Primary Advanced or Recurrent Endometrial Cancer

GSK plc reported favorable initial findings from the first segment of the RUBY/ENGOT-EN6/GOG3031/NSGO phase III trial, evaluating Jemperli (dostarlimab) in conjunction with standard chemotherapy (carboplatin and paclitaxel), followed by dostarlimab as a standalone treatment. This combination showcased a marked improvement in overall survival (OS) for adult patients with primary advanced or recurrent endometrial cancer, achieving statistical significance and clinical significance across the patient cohort.

Significant benefits in overall survival (OS) were evident across distinct patient groups in the trial: those with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) and those with mismatch repair proficient (MMRp)/microsatellite stable (MSS). OS, a primary endpoint in RUBY Part 1, showed a clinically relevant advantage. Notably, the trial had already successfully met the primary endpoint of progression-free survival (PFS), demonstrating a remarkable 72% and 36% reduction in the risk of disease progression or mortality within the dMMR/MSI-H population (HR: 0.28 [95% CI: 0.16-0.50]) and the overall patient cohort (HR: 0.64 [95% CI: 0.51–0.80]), respectively.

Hesham Abdullah, Senior Vice President, Global Head of Oncology Research and Development at GSK, commented on the latest findings: “The recent headline outcomes from Part 1 of the phase III RUBY trial underline the efficacy of dostarlimab combined with chemotherapy, marking it as the sole immunotherapy combination demonstrating a survival advantage within this expanded patient cohort for this specific treatment context. We eagerly anticipate presenting the comprehensive analysis to regulatory bodies and the wider scientific community.

Jemperli has secured regulatory approval for a specific segment of endometrial cancer patients, based on the previously reported positive outcomes in the RUBY trial’s primary endpoint of progression-free survival. In July 2023, the FDA granted approval for Jemperli in combination with carboplatin and paclitaxel, followed by solo Jemperli use, for treating adult patients with primary advanced or recurrent endometrial cancer displaying mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H), as determined by an FDA-approved test. Similarly, Jemperli received approval in the United Kingdom in October 2023 for its use alongside platinum-based chemotherapy in adults with dMMR/MSI-H primary advanced or recurrent endometrial cancer eligible for systemic therapy. Applications are pending review in the European Union (EU), Australia, Canada, Switzerland, and Singapore.

FDA Approves Roche’s Vabysmo for the Treatment of Retinal Vein Occlusion

Roche’s Vabysmo® (faricimab) has received FDA approval for treating macular edema resulting from retinal vein occlusion (RVO), marking its third approved indication. Vabysmo® is already established for neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). These three retinal conditions collectively impact approximately 70 million individuals globally and stand among the primary causes of vision impairment.

Vabysmo represents a promising new approach for managing RVO, offering potential vision preservation and enhancement alongside the advantage of addressing retinal drying, remarked Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development. The extensive global clinical trials have firmly established the efficacy and safety of Vabysmo, further supported by an expanding body of real-world evidence derived from hundreds of thousands of treated individuals.

Vabysmo, the pioneering bispecific antibody authorized for ocular use, has been approved for treating retinal vein occlusion. This approval is based on the affirmative outcomes from the extensive phase III BALATON and COMINO trials on a global scale. These trials showcased that regular administration of Vabysmo resulted in early and sustained enhancements in vision for individuals with branch and central RVO, meeting the primary objective of achieving comparable visual acuity improvements at the 24-week mark when compared to aflibercept. The studies also highlighted Vabysmo’s ability to promptly and effectively reduce retinal fluid accumulation. Throughout BALATON and COMINO, Vabysmo exhibited a generally favorable tolerance level, with its safety profile aligning with previous trial outcomes. The most frequently reported adverse effect was conjunctival hemorrhage (3%). The safety observations remained consistent across all arms of the studies. 

Vabysmo has received approval in over 80 countries worldwide for individuals affected by nAMD and DME, with an estimated global distribution of around 2 million doses.

Coherus and Junshi Biosciences Announce FDA Approval of LOQTORZI™ (toripalimab-tpzi) for the Treatment of Recurrent or Metastatic Nasopharyngeal Carcinoma (NPC)

On October 27, 2023, Coherus BioSciences, Inc. and Shanghai Junshi Biosciences jointly announced that the U.S. Food and Drug Administration (FDA) had granted approval to LOQTORZI™ (toripalimab-tpzi). LOQTORZI is approved in combination with cisplatin and gemcitabine as a first-line treatment for adults with metastatic or recurrent locally advanced Nasopharyngeal Carcinoma (NPC). 

Additionally, LOQTORZI has been approved as a monotherapy for adults with recurrent, unresectable, or metastatic NPC whose disease has progressed after receiving platinum-containing chemotherapy. This approval is based on the results from both the JUPITER-02 Phase 3 study and the POLARIS-02 Phase 2 study and is independent of a patient’s PD-L1 status. LOQTORZI is an advanced programmed death receptor-1 (PD-1) monoclonal antibody, which effectively inhibits PD-1 ligands PD-L1 and PD-L2 at a unique PD-1 receptor site with high potency. This action enables the immune system to become activated and target and destroy the tumor.

“LOQTORZI’s first approval is a pivotal event for Coherus as an innovative oncology company. As a next generation PD-1 inhibitor it is the keystone of our I-O strategy to extend cancer patient survival as shown with the impressive results in NPC,” said Denny Lanfear, Chairman and Chief Executive Officer of Coherus. “We are particularly excited to now turn our attention to developing LOQTORZI across multiple tumor types in combination with I-O agents that target the tumor microenvironment, such as our IL27-targeted antibody, casdozokitug, and our CCR8 inhibitor CHS-114, potentially greatly expanding the number of cancer patients achieving improved survival benefit.”

“We’re excited to reach another significant company milestone of ‘going overseas’,” said Dr. Ning LI, Chief Executive Officer of Junshi Biosciences. “Following etesevimab, toripalimab has become Junshi Biosciences’ second product to receive FDA approval for commercialization—an achievement that will further enhance the company’s international presence. Currently, the establishment of toripalimab’s global commercialization network is in progress, and the network aims to span over 50 countries. In accordance with the company’s ‘In China, For Global’ strategy, we will continue working with our collaborators to promote the commercialization of toripalimab in other regions, in order to provide innovative and high-quality drugs from China to more patients overseas.”

In the Phase 3 JUPITER-02 study, the combination of LOQTORZI with chemotherapy exhibited a substantial enhancement in progression-free survival (PFS). It effectively reduced the risk of disease progression or mortality by 48% when compared to the use of chemotherapy by itself. Moreover, LOQTORZI exhibited a noteworthy and statistically significant improvement in overall survival (OS), displaying a 37% reduction in the risk of death in comparison to chemotherapy as a standalone treatment. The safety profile of LOQTORZI was in line with the characteristics typical of PD-1 inhibitors. The occurrence of severe adverse events (AEs) of Grade ≥3 was similar in both groups (89.7% vs. 90.2%), as was the incidence of fatal AEs (3.4% vs. 2.8%). However, more individuals in the LOQTORZI group experienced AEs that led to discontinuation compared to the placebo group (11.6% vs. 4.9%). Additionally, immune-related adverse events (irAEs) were more frequent in the LOQTORZI group (54.1% vs. 21.7%), as were severe irAEs of Grade ≥3 (9.6% vs. 1.4%).

In the clinical trial POLARIS-02, LOQTORZI showed persistent effectiveness against tumors in patients who had experienced relapse or metastasis in the case of NPC and had not responded to prior chemotherapy. This was evidenced by an objective response rate (ORR) of 20.5%, a disease control rate (DCR) of 40.0%, and a median overall survival (OS) of 17.4 months. These results were achieved while maintaining a favorable safety profile.

Nasopharyngeal carcinoma (NPC) is an aggressive cancer originating in the nasopharynx, which is the upper part of the throat situated behind the nose and near the base of the skull. NPC is a rare occurrence in the United States, with an annual incidence of less than one case per 100,000 individuals. While the five-year survival rate for all NPC patients hovers around 60%, individuals diagnosed with advanced-stage disease have a somewhat lower five-year survival rate of approximately 49%. 

Companies are actively researching innovative treatments and therapies to address the challenges in the Nasopharyngeal carcinoma (NPC) market, aiming to improve patient outcomes and quality of life. They are also exploring advanced diagnostic tools for earlier detection and more effective management of the disease. The FDA’s approval of LOQTORZI™ for all lines of treatment in recurrent or metastatic Nasopharyngeal Carcinoma (NPC) offers patients more comprehensive and potentially more effective treatment options, potentially improving outcomes and the quality of NPC care. This decision represents a significant step forward in addressing this challenging cancer.

FDA Grants Priority Review to Tovorafenib in Pediatric Relapsed/Progressive Low-Grade Glioma

The FDA has given priority review status to a new drug application aiming for the approval of tovorafenib (DAY101) as a standalone treatment for pediatric patients with relapsed or progressive low-grade glioma.

The application is backed by data from the phase 2 FIREFLY-1 trial (NCT04775485). This trial involved evaluating patients aged 6 months to 25 years who had relapsed or progressive low-grade glioma with a known activating BRAF alteration. Among the 69 patients who received tovorafenib monotherapy, there was an overall response rate of 67% based on the Response Assessment in Neuro-Oncology–high grade glioma criteria. The clinical benefit rate was 93%, with a complete response rate of 17%, a partial response rate of 49%, and a stable disease rate of 26%. The median duration of response was 16.6 months.

The FIREFLY-1 trial, an open-label pivotal study, is enrolling patients aged 6 months to 25 years with relapsed or progressive low-grade glioma featuring an activating BRAF alteration (arms 1 and 2). The trial also includes an arm for pediatric patients with locally advanced or metastatic solid tumors harboring an activating RAF fusion (arm 3). In arms 1 and 2, patients must have received at least one prior line of systemic therapy and show evidence of radiographic disease progression. They also need to have at least one measurable lesion per RANO criteria.

Key exclusion criteria involve previously known activating molecular alterations, clinical progression symptoms without radiographic progression, or a known or suspected diagnosis of neurofibromatosis type 1.

Patients enrolled in the trial received tovorafenib once a week. The trial’s primary endpoint is the overall response rate according to RANO-HGG criteria. Secondary endpoints include overall response rate per Response Assessment in Pediatric Neuro-Oncology low-grade glioma (RAPNO-LGG) criteria, progression-free survival, duration of response, time to response, clinical benefit rate, and safety.

Additional data from FIREFLY-1 demonstrated that among the evaluable patients (n = 76), there was an overall response rate of 51% per RAPNO-LGG criteria and a clinical benefit rate of 82%. Patients experienced a partial response rate of 37%, a minor response rate of 14%, and a stable disease rate of 30%. The median duration of response was 13.8 months.

FDA Approves Lilly’s Omvoh, A First-in-Class Treatment for Adults with Moderately to Severely Active Ulcerative Colitis

Eli Lilly and Company has announced that the U.S. Food and Drug Administration (FDA) has given the green light to Omvoh™ (mirikizumab-mrkz) infusion (300 mg/15 mL)/injection (100 mg/mL). This marks a significant milestone as Omvoh is the first and only interleukin-23p19 (IL-23p19) antagonist approved for treating moderately to severely active ulcerative colitis in adults.

Omvoh is unique in that it specifically targets the p19 subunit of IL-23, which is involved in the inflammation associated with ulcerative colitis.

The FDA’s approval was based on results from the LUCENT program, which included two randomized, double-blind, placebo-controlled Phase 3 clinical trials. These trials consisted of a 12-week induction study (UC-1) and a 40-week maintenance study (UC-2) for continuous 52-week treatment. All patients in the LUCENT program had prior treatments, including biologic treatments, that were ineffective or intolerable.

After 12 weeks of Omvoh treatment, nearly two-thirds (65%) of patients achieved a clinical response, and almost one-fourth (24%) achieved clinical remission, compared to the placebo (43% and 15%, respectively). Among those who responded to treatment at 12 weeks, Omvoh consistently demonstrated effectiveness across different subgroups, with 51% of all patients and 45% of patients who had previously failed biologic treatment or Janus kinase inhibitors achieving clinical remission at one year, in contrast to the placebo (27% and 15%, respectively). Among those who responded at 12 weeks, half (50%) achieved a steroid-free clinical remission at one year, compared to the placebo (27%). According to a post-hoc analysis, nearly all patients (99%) who achieved clinical remission at one year were also steroid-free. Patients who achieved steroid-free clinical remission had been free from steroids for at least three months leading up to the end of the 52-week assessment. Among those who responded at 12 weeks, approximately two-thirds (66%) of patients maintained clinical remission throughout one year of continuous treatment compared to the placebo (40%).

Symptom improvement, such as reduced rectal bleeding and stool frequency, was observed as early as three weeks in patients treated with Omvoh. Notably, the LUCENT trials were the first to use the Urgency Numeric Rating Scale, a patient-centric scale ranging from 0-10, with zero indicating no bowel urgency and 10 indicating the most severe bowel urgency. At the start, patients had a median Urgency NRS weekly average score of 7. Among patients with an Urgency NRS weekly average score of 3 or higher at the beginning, and who responded to Omvoh induction therapy, a significantly greater percentage of patients (39%) treated with Omvoh achieved a weekly average score of 0 to 1 at one year, compared to those who received a placebo (23%).

Patients taking Omvoh were less likely to discontinue treatment due to adverse events (1.6% in UC-1 and 1.5% in UC-2) compared to those on a placebo (7.2% in UC-1 and 8.3% in UC-2). The most common adverse reactions (reported in at least 2% of subjects at a higher frequency than the placebo) associated with Omvoh treatment included upper respiratory infections, injection site reactions, arthralgia, rash, headache, and herpes viral infection. The labeling for Omvoh contains warnings and precautions regarding hypersensitivity reactions, the risk of infection, tuberculosis, hepatotoxicity, and immunizations.