AbbVie Presents Results from Phase III CANOVA Study of Venetoclax in Patients with Relapsed or Refractory Multiple Myeloma

AbbVie has released findings from its Phase III CANOVA trial, which assessed the safety and effectiveness of venetoclax (marketed as VENCLEXTA®/VENCLYXTO®) in combination with dexamethasone (known as VenDex) for patients with relapsed or refractory (R/R) multiple myeloma featuring the t(11;14) genetic abnormality. The study did not demonstrate a significant improvement in progression-free survival (PFS), the primary endpoint of the trial. Patients treated with VenDex experienced a median PFS of 9.9 months, compared to 5.8 months for those on the study comparator pomalidomide and dexamethasone (PomDex) combination. However, these results did not reach statistical significance [Hazard Ratio (HR) = 0.823, 95% Confidence Interval (CI): (0.596, 1.136); p-value = 0.237].

In the trial, the safety profile of the combination of venetoclax and dexamethasone remained consistent with their individual safety profiles, with no new safety concerns arising. The most frequently reported adverse events (>20%) among patients treated with VenDex included infections (61%), diarrhea (41%), lymphopenia (24%), and nausea (22%). For those treated with PomDex, the most common adverse events were neutropenia (63%), infections (57%), thrombocytopenia (39%), and anemia (35%). 

Multiple myeloma ranks as the second most prevalent blood cancer worldwide. As per the assessment done by DelveInsight, the total incident cases of multiple myeloma in the 7MM comprised more than 70,000 cases in 2022 and are projected to increase during the forecast period. DelveInsight estimates that the total incident multiple myeloma cases were the highest in the United States. Data suggests that roughly half of newly diagnosed multiple myeloma patients are ineligible for transplant, and around a third of eligible patients do not receive the transplant. Despite recent advancements in treatment, a significant number of patients still face relapse, particularly those with the t(11;14) biomarker, the most prevalent chromosomal translocation in multiple myeloma, which can lead to overexpression of the BCL-2 protein. 

Although the CANOVA trial did not achieve its primary endpoint, we are encouraged by the positive trends observed in the study. We intend to engage in discussions with healthcare authorities in the near future regarding these findings. Our commitment to improving the standard of care for blood cancer patients globally, including those with multiple myeloma, remains unwavering.

Mariana Cota Stirner, M.D., Ph.D., Head of Oncology Hematology at AbbVie.

Venetoclax has received regulatory approval for patients with both untreated and treated chronic lymphocytic leukemia (CLL) as well as newly diagnosed acute myeloid leukemia (AML). However, it should be noted that as of now, there is no regulatory approval for the use of Venetoclax in the treatment of multiple myeloma. In the United States, it is jointly marketed by AbbVie and Genentech, which is part of the Roche Group. Outside of the United States, AbbVie holds the commercialization rights.

Novartis’ Iptacopan Shows Promise in Phase III Study for IgA Nephropathy

Novartis has released encouraging preliminary findings from the Phase III APPLAUSE-IgAN study after a 9-month interim analysis. The investigational factor B inhibitor, iptacopan, designed to target the alternative complement pathway, has exhibited remarkable efficacy compared to a placebo in reducing proteinuria. This reduction is both clinically significant and statistically robust, especially when administered in conjunction with standard supportive care for patients suffering from IgA nephropathy (IgAN), a complement-mediated disease. The safety profile of iptacopan (200 mg twice daily) aligns with previously reported data. The study is set to continue in a double-blind format, with the primary endpoint being the assessment of iptacopan’s ability to slow IgAN progression, as measured by the estimated glomerular filtration rate (eGFR) slope over 24 months. We anticipate the release of final results in 2025.

These positive data from the Phase III APPLAUSE study reinforce the potential of iptacopan to provide clinically meaningful benefit to patients with IgAN, a debilitating disease that affects mostly young adults,” said Shreeram Aradhye, M.D., President, Development and Chief Medical Officer, Novartis. “We are excited about this milestone in the development of our factor B inhibitor of the alternative complement pathway and remain focused on further advancing our portfolio of renal programs through pivotal trials.

Novartis has pioneered iptacopan, a drug aimed at treating IgAN and other complement-mediated diseases by inhibiting factor B, a crucial enzyme in the alternative complement pathway. Iptacopan is currently undergoing regulatory review after yielding positive Phase III results in paroxysmal nocturnal hemoglobinuria (PNH) trials (APPLY-PNH [NCT04558918] and APPOINT-PNH [NCT04558918]). In addition to PNH, Iptacopan is the subject of ongoing Phase III studies for C3 glomerulopathy (APPEAR-C3G [NCT04817618]), atypical hemolytic uremic syndrome (APPELHUS [NCT04889430]), and immune complex membranoproliferative glomerulonephritis (APPARENT [NCT05755386]). Novartis recently expanded its renal portfolio through the acquisition of Chinook Therapeutics, adding two more late-stage medicines in development for IgAN, thereby complementing their existing pipeline. Novartis aims to submit Iptacopan for possible accelerated approval with the FDA in 2024.

Bolt Biotherapeutics Receives Orphan Drug Designation for BDC-1001 for Treatment of Gastric Cancers

On September 28, 2023, Bolt Biotherapeutics (Nasdaq: BOLT) announced that the U.S. Food and Drug Administration (FDA) had awarded Orphan Drug Designation to BDC-1001 for the management of gastric cancer, which encompasses gastroesophageal junction cancer as well.

BDC-1001 is an innovative therapeutic agent that combines a HER2-targeting biosimilar of trastuzumab with a non-cleavable linker and a proprietary TLR7/8 agonist. After successfully completing the dose-escalation trial for BDC-1001 in patients with HER2-expressing solid tumors, Bolt Biotherapeutics is presently engaged in two Phase 2 clinical trials across multiple regions, including the United States, Europe, and South Korea. The first trial, with the identifier NCT04278144, is focused on patients with colorectal, endometrial, and gastroesophageal cancers. The second trial, identified as NCT05954143, is specifically designed for patients with breast cancer.

Receiving Orphan Drug Designation from the FDA is an important step forward in the development of BDC-1001 and reinforces the potential of BDC-1001 to address the unmet needs of patients with gastric cancers. Our Boltbody™ ISAC platform is the only one with emerging clinical validation, and we are working diligently to advance our ongoing Phase 2 program. In addition to gastric cancer, we are also evaluating BDC-1001 in three other tumor types with significant unmet medical needs: HER2-positive breast, colorectal, and endometrial cancers. We look forward to advancing BDC-1001 in clinical development and bringing this novel immunotherapy to patients in need of further treatment options.

Edith A. Perez, M.D., Chief Medical Officer of Bolt Biotherapeutics

As per DelveInsight, GLOBOCAN data, in 2020 the estimated number of cases of Gastric cancer in the US, EU4, the UK, and Japan, was 26,000+; 50,000+; 138,000+; and 478,000+ cases, respectively. It is observed that, in developed countries, gastric cancer is 2.2 times more likely to be diagnosed in males than females. In developing countries, this ratio is 1.83. While the occurrence of gastric cancer is on the decline in Western nations, including the United States, there is a rising trend in the incidence of gastroesophageal junction (GEJ) cancer. This increase can be largely attributed to a variety of potential risk factors, including dietary choices (such as consumption of salty and smoked foods), gastroesophageal reflux disease, body weight and obesity, H. pylori infection, smoking, and more. In order to offer more effective therapeutic options on a global scale, numerous pharmaceutical industry leaders are actively assessing their leading candidate drugs at different stages of clinical development. This proactive approach reflects a commitment to advancing medical research and addressing unmet medical needs across the world. These efforts encompass rigorous evaluation and testing to ensure that promising treatments can ultimately reach patients and make a meaningful impact on healthcare outcomes.

FDA Approves Rivfloza™ For Children ≥9 years Old and Adults With Primary Hyperoxaluria Type 1 (PH1)

On October 2, 2023, Novo Nordisk announced the approval by the U.S. Food and Drug Administration (FDA) of its RivflozaTM (nedosiran) injection in dosages of 80 mg, 128 mg, or 160 mg. This approval pertains to a monthly subcutaneous ribonucleic acid interference (RNAi) therapy, which is intended to reduce urinary oxalate levels. The therapy is indicated for individuals aged 9 years and older, including both children and adults, who have Primary Hyperoxaluria type 1 (PH1) and still maintain a relatively functional kidney. RivflozaTM was developed by Dicerna Pharmaceuticals. Novo Nordisk acquired Dicerna Pharmaceuticals in 2021. Novo Nordisk has a strategic plan to offer RivflozaTM to eligible patients starting in early 2024.

This approval is grounded in the findings of the pivotal phase 2 clinical trial known as PHYOXTM2 and interim data obtained from the ongoing phase 3 extension study known as PHYOXTM3. PHYOXTM2 successfully met its primary objective, demonstrating that patients who were treated with RivflozaTM achieved a significant reduction in 24-hour urinary oxalate (Uox) excretion compared to their baseline levels, specifically from Day 90 to Day 180. This reduction in 24-hour Uox was quantified using an area under the curve (AUC) analysis. The least-squares (LS) mean difference in AUC24-hour Uox between the RivflozaTM and placebo groups was 4976 (95% CI: 2803, 7149; p<0.0001) over the 90-day period, signifying a statistically significant difference.

The most frequently reported adverse reaction, occurring in more than 20% of patients, is related to injection site reactions. Furthermore, interim findings from the PHYOXTM3 extension study indicated that the reductions in 24-hour Uox excretion were maintained among the 13 patients with Primary Hyperoxaluria type 1 (PH1) who received an additional six months of treatment with RivflozaTM.

The FDA approval of RivflozaTM builds on Novo Nordisk’s legacy of advancing research, fostering innovation, and creating strategic partnerships to expand treatment options in rare diseases. We are committed to driving change on behalf of people living with rare diseases and helping address the significant unmet needs of the PH1 community. We look forward to making our first RNAi treatment available to people living with PH1 and the healthcare professionals partnering on their care.

Blandine Lacroix, Senior Vice President, Strategy and Rare Disease at Novo Nordisk Inc.

RNA interference is a proven treatment approach for individuals with PH1. With the approval of RivflozaTM, we now have a novel treatment that lowers oxalate production safely and effectively. Using the GalXC™ RNAi platform, RivflozaTM targets the liver-specific lactate dehydrogenase enzyme, which is the final step of oxalate production in PH1.

Dr. David S. Goldfarb, MD Clinical Chief, Nephrology Division, NYU Langone Medical Center and Professor of Medicine and Physiology, NYU Grossman School of Medicine.

RivflozaTM, the first RNAi therapeutic from Novo Nordisk, was created utilizing the exclusive GalXCTM RNAi technology platform. This innovative medication has been engineered with the aim of suppressing the production of the liver enzyme lactate dehydrogenase. Lactate dehydrogenase is a pivotal liver enzyme responsible for catalyzing the ultimate step in the glyoxylate metabolism pathway, a process linked to the excessive production of oxalate in individuals with Primary Hyperoxaluria type 1 (PH1).

Primary Hyperoxaluria is a rare genetic disorder characterized by the excessive production of oxalate by the liver, and it is estimated to impact approximately 1 in 38,600 individuals globally. As per DelveInsight’s latest Primary Hyperoxaluria epidemiology assessment report, the total prevalent population of PH in 7MM was 11,900+ in 2021, The US accounted for the highest prevalent population of PH among 7MM with 8,700+ cases in 2021. Moreover, among the European countries (EU5), the UK had the highest diagnosed prevalent cases of PH with 200+ cases, followed by Germany which had a diagnosed prevalent population of 180, in 2021. On the other hand, Spain had the lowest diagnosed prevalent population (90 cases). Along with Novo Nordisk, globally, several other major pharmaceutical and biotech companies are actively working in the Primary Hyperoxaluria therapeutics market to improve the treatment outlook.

FDA Grants Fast Track Designation to AVB-001 for R/R Platinum-Resistant Ovarian Cancer

The FDA has approved AVB-001 for Fast Track Designation (FTD) to be utilized as a treatment option for adult patients dealing with relapsed/refractory ovarian cancer.

AVB-001 is a specialized cell product designed to generate human interleukin-2 (hIL-2). This treatment is administered to patients via an intraperitoneal injection. AVB-001 is a fundamental aspect of Avenge Bio’s LOCOcyte™ immunotherapy platform, which ensures precise delivery of potent immune effector molecules by synthetically modifying allogeneic cells. This platform is engineered to localize therapy to the primary tumor site and is intended to treat previously untreatable forms of cancer.

The regulatory decision for AVB-001 encompasses cases of platinum-resistant, high-grade serous adenocarcinoma affecting the ovary, primary peritoneum, or fallopian tube.

Currently, AVB-001 is undergoing investigation in an open-label, first-in-human, multicenter, phase 1/2 study. The trial aims to assess the safety and effectiveness of this agent in patients aged 18 and above, confirmed histologically with metastatic or unresectable, platinum-resistant, high-grade serous adenocarcinoma of the ovary, primary peritoneum, or fallopian tube, who have not undergone more than 5 prior lines of therapy.

To qualify for the study, patients must have received prior treatment with a PARP inhibitor, bevacizumab (Avastin), or any other antiangiogenic agent, immunotherapy, or cell therapies. Disease progression or intolerance to a PARP inhibitor is required for patients with germline or somatic BRCA mutations. Patients must also possess an ECOG performance status of 0 or 1, measurable disease as per RECIST v1.1 criteria, specific blood count levels, and satisfactory kidney function.

The phase 1/2 study consists of 2 parts. Part 1, the dose-escalation phase, involves administering a single intraperitoneal dose of AVB-001 to up to 24 patients at different hIL-2/kg/day dosages. In Part 2, the dose-expansion phase, up to 20 additional patients will be enrolled and treated with a single dose of AVB-001 at the determined recommended phase 2 dose (RP2D).

Part 2 may involve further expansion cohorts to assess AVB-001 either as monotherapy or in combination as part of an exploratory approach. 

Primary endpoints for Part 1 of the trial include assessing dose-limiting toxicities (DLTs), determining the maximum tolerated dose and RP2D, and evaluating treatment-emergent adverse events (AEs) or serious AEs. Secondary endpoints consist of measuring overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). For Part 2, the primary endpoint is ORR as per RECIST v1.1 criteria, while secondary endpoints encompass safety, DOR, PFS, and OS.

In a significant development in April 2023, the initial dose level cohort of the phase 1/2 trial was completed successfully, demonstrating AVB-001’s good tolerance among patients with refractory ovarian cancer. No dose-limiting toxicities (DLTs) or unexpected events were observed. Subsequently, dosing for the phase 2 dose-expansion portion of the trial has been initiated by the investigators.

FDA Issues Complete Response Letter for Lebrikizumab Based on Inspection Findings at Third-Party Manufacturer

Eli Lilly made an announcement today regarding the FDA’s issuance of a complete response letter (CRL) for the biologic license application (BLA) of lebrikizumab (Ebglyss) aimed at treating moderate to severe atopic dermatitis. The FDA’s letter specifically referenced findings from an inspection carried out by multiple sponsors at a third-party contract manufacturing organization, which included the monoclonal antibody drug substance for lebrikizumab. Notably, there were no concerns raised regarding the clinical data package, safety, or label associated with lebrikizumab.

The BLA submitted by Eli Lilly for lebrikizumab drew upon data from the ADvocate 1, ADvocate 2, and ADhere studies. These studies encompassed a diverse group of over 1000 adult and adolescent patients (ages 12 and above) grappling with moderate to severe atopic dermatitis, where conventional topical medicines or other systemic treatments were insufficient in managing their symptoms.

Karl Ziegelbauer, Chief Scientific Officer at Almirall, Eli Lilly’s partnering company for lebrikizumab, lauded this CHMP endorsement, underlining the potential of Ebglyss as a next-generation biologic therapy for individuals contending with atopic dermatitis. He highlighted the medication’s selective mechanism of action, demonstrated long-term efficacy, and convenient monthly maintenance dosing, expressing confidence in its potential to emerge as a primary treatment option for moderate-to-severe atopic dermatitis.

In the previous month, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency voiced a positive opinion, recommending marketing authorization for lebrikizumab in Europe