On June 20, 2024 ImmunityBio, Inc. (NASDAQ: IBRX) reported the initial treatment of multiple patients in the United States to receive therapy with ANKTIVA (nogapendekin alfa inbakicept-pmln), ImmunityBio’s recently approved immunotherapy for Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) carcinoma in situ (Press release, ImmunityBio, JUN 20, 2024, https://immunitybio.com/immunitybio-announces-insurance-coverage-of-anktiva-across-multiple-states-with-first-commercial-doses-administered-just-weeks-after-fda-approval-opening-new-era-for-immunotherapy-beyond/ [SID1234644450]). ANKTIVA was approved by the U.S. Food and Drug Administration (FDA) on April 22, 2024 for the treatment of patients with BCG-unresponsive NMIBC CIS with or without papillary tumors.

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The intravesical therapy employs a combination of ANKTIVA, an IL-15 agonist in combination with BCG. The combination is the first FDA-approved immunotherapy in NMIBC that functions by activating the body’s NK and killer T-cell immune system to attack tumor cells, while simultaneously activating memory T cells, leading to a prolonged duration of complete response exceeding 47 months for some patients.

"We are grateful to be able to offer this first-in-class immunotherapy to qualified bladder cancer patients less than two months after the therapeutic was approved by the FDA," said Patrick Soon-Shiong, M.D., Executive Chairman and Global Chief Scientific and Medical Officer at ImmunityBio. "The interest in this next era of immunotherapy beyond checkpoint inhibitors—the era of cytokines—from urologists treating NMIBC patients has been strong and we look forward to offering more patients an alternative to bladder removal."

The first patients to receive commercial doses are located throughout the U.S. and several are being treated by community urologists, as the therapy does not require any special handling or equipment that would limit its use to specialty medical centers.

"In addition to its unique mechanism of action, ANKTIVA can be readily administered by urologists in their own offices and clinics enabling more patients to receive it in familiar settings from their own providers," said Richard Adcock, President and CEO of ImmunityBio. "We look forward to ANKTIVA reaching more and more eligible NMIBC patients and for our science to deliver even more therapies from our pipeline."

ANKTIVA received Breakthrough Therapy Designation and approval from the FDA based on the safety and efficacy outcome of complete responses (CR) and duration of complete response (DOR) in BCG-unresponsive NMIBC CIS. The 77 evaluable patients in this single-arm, multicenter trial received ANKTIVA with BCG maintenance therapy for up to 37 months. The tumor status was assessed with cystoscopy and urine cytology and will continue for up to five years after each patient began their participation in the trial.

The CR rate for the 77 evaluable patients was 62% with the upper end of the confidence interval being 73%. The duration of complete response as of the November 2023 cut-off was more than 47 months and is ongoing to date. These prolonged duration of complete response results beyond 24 months with ANKTIVA and BCG exceed the benchmark for the magnitude of meaningful clinical results suggested by a panel of experts at the International Bladder Cancer Group.

In May, ImmunityBio announced it had drug substance sufficient for 170,000 doses of ANKTIVA for commercial and clinical trial use.

ImmunityBio CARE

The ImmunityBio CARE program is designed to help patients access ImmunityBio’s innovative treatment for NMIBC CIS. The program offers services and resources for benefits investigation, prior authorization support and tracking, coding and billing assistance, claim denial guidance and payer specific appeal assistance. More information for patients and healthcare professionals is available on Anktiva.com.

How ANKTIVA Works
The cytokine interleukin-15 (IL-15) plays a crucial role in the immune system by affecting the development, maintenance, and function of key immune cells—NK and CD8+ killer T cells—that are involved in killing cancer cells. By activating NK cells, ANKTIVA overcomes the tumor escape phase of clones resistant to T cells and restores memory T cell activity with resultant prolonged duration of complete response.

ANKTIVA is a first-in-class IL-15 agonist IgG1 fusion complex, consisting of an IL-15 mutant (IL-15N72D) fused with an IL-15 receptor alpha, which binds with high affinity to IL-15 receptors on NK, CD4+, and CD8+ T cells. This fusion complex of ANKTIVA mimics the natural biological properties of the membrane-bound IL-15 receptor alpha, delivering IL-15 by dendritic cells and drives the activation and proliferation of NK cells with the generation of memory killer T cells that have retained immune memory against these tumor clones. The proliferation of the trifecta of these immune killing cells and the activation of trained immune memory results in immunogenic cell death, inducing a state of equilibrium with durable complete responses. ANKTIVA has improved pharmacokinetic properties, longer persistence in lymphoid tissues, and enhanced anti-tumor activity compared to native, non-complexed IL-15 in-vivo.

Selected Safety Information for ANKTIVA

The most common (≥15%) adverse reactions, including laboratory test abnormalities, are increased creatinine, dysuria, hematuria, urinary frequency, micturition urgency, urinary tract infection, increased potassium, musculoskeletal pain, chills, and pyrexia.

On June 20, 2024 Astellas Pharma US, Inc. ("Astellas") reported the company has entered into a sponsored research agreement with the UMass Chan Medical School to proceed with research for an adeno-associated virus (AAV) vector mediated gene therapy for the treatment of Alexander disease, a fatal, ultra-rare disease for which the only current treatment option is supportive care (Press release, Astellas, JUN 20, 2024, View Source [SID1234644449]). This collaboration is part of a focused initiative to deliver value to patients with rare disease through innovative R&D models including investigator-led research.

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Under the terms of the agreement, UMass Chan will lead research activities to accelerate the program toward clinical study while Astellas will support UMass Chan activities by providing drug discovery research expertise. The current agreement lasts for one year with an opportunity for Astellas to extend to two years.

Alexander disease is an ultra-rare and progressive central nervous system (CNS) disorder caused by mutations in the glial fibrillary acidic protein (GFAP) gene that usually has a fatal outcome. Most affected patients do not live beyond their first few years. Alexander disease affects astrocytes, a type of cell that makes up the majority of cells in the CNS and leads to the destruction of white matter in the brain, causing progressively worsening severe intellectual and physical disabilities; and eventually affected individuals will lose life-sustaining abilities.1

Yoshitsugu Shitaka, Ph.D., Chief Scientific Officer at Astellas

"We are pleased to partner with UMass Chan, a leading medical academic center in Massachusetts, and help foster innovation in this important ecosystem. At Astellas, we strive to find innovative ways to treat patients with the highest unmet medical needs, who have traditionally been left behind, including rare and ultra-rare diseases.

Gene therapy is a complex breakthrough area where traditional approaches might not be sufficient or optimal, and ultra-rare diseases like Alexander disease cannot be appropriately addressed with the usual pharma models. Only by working alongside all the key players such as patients, physicians, academic centers, can we advance pioneering work to challenge the status quo, by turning innovative science into meaningful treatments for those patients who are waiting."

The sponsored research agreement supports investigations being done by Jun Xie, PhD, associate professor of microbiology & physiological systems, and Guangping Gao, PhD, the Penelope Booth Rockwell Professor in Biomedical Research, professor of microbiology & physiological systems, director of the Horae Gene Therapy Center and co-director of the Li Weibo Institute for Rare Diseases Research at UMass Chan, who have developed an adeno-associated virus vector that can express a small RNA silencer that suppresses the mutant proteins that cause AxD in mice.

Guangping Gao, PhD, the Penelope Booth Rockwell Professor in Biomedical Research, professor of microbiology & physiological systems, director of the Horae Gene Therapy Center and co-director of the Li Weibo Institute for Rare Diseases Research, UMass Chan

"We are enthused to be working with Astellas. Their drug discovery research expertise is a critical component in translating this work from bench to bedside, and bringing gene therapy to patients in the clinic who are struggling with this deadly disease."

Jun Xie, Ph.D., associate professor of microbiology & physiological system, UMass Chan

"Silencing GFAP, the mutant protein that causes AxD, with our artificial miRNA could be a promising therapeutic approach to treatment. Collaborating with Astellas will bring us one step closer to our goal of helping patients with this disease."

On June 20, 2024 Allogene Therapeutics Inc. (Nasdaq: ALLO), a clinical-stage biotechnology company pioneering the development of allogeneic CAR T (AlloCAR T) products, and Foresight Diagnostics (Foresight), a leader in ultra-sensitive liquid biopsy-based minimal residual disease (MRD) detection, reported the initiation of the pivotal Phase 2 ALPHA3 trial evaluating the use of cemacabtagene ansegedleucel (cema-cel) as part of the first line (1L) treatment regimen for newly diagnosed LBCL patients who are likely to relapse after standard 1L treatment and need further therapy (Press release, Allogene, JUN 20, 2024, View Source [SID1234644448]).

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"The transformative impact that the ALPHA3 trial could have on the treatment of first line LBCL is hard to overstate," said David Chang, M.D., Ph.D., President, Chief Executive Officer and Co-Founder of Allogene. "Our investigational allogeneic CAR T product is designed to eliminate the complex logistics that have hindered autologous CAR T adoption to date and open the door for access by doctors in the community setting. ALPHA3 will proactively offer this potentially curative modality only to those patients who are likely to relapse."

The ALPHA3 trial will screen patients who are likely to relapse after 1L treatment for enrollment in the trial by using the Foresight CLARITY Investigational Use Only (IUO) MRD test, powered by PhasED-Seq, which recently received Investigational Device Exemption (IDE) approval from the U.S. Food and Drug Administration (FDA). Leveraging CLARITY’s ultra-sensitive MRD technology, cema-cel will be administered as a one-time infusion immediately upon detection of MRD at the completion of six cycles of R-CHOP or other standard 1L chemoimmunotherapy regimen. When given as a "7th cycle" of frontline treatment to eligible patients with MRD, consolidation treatment with cema-cel has the potential to meaningfully improve 1L cure rates in LBCL.

"Following the FDA Advisory Committee’s recent recommendation to include MRD as an endpoint to accelerate clinical trials in multiple myeloma, the ALPHA3 trial is yet another step forward towards broader implementation of MRD detection in drug development and clinical decision making," said Dr. Sandra Close, Chief Operating and Compliance Officer at Foresight Diagnostics. "We believe the Foresight CLARITY MRD platform has the performance to enable actionable treatment decisions at end of therapy when residual disease levels are challenging to detect using conventional methods."

The ALPHA3 trial will be conducted in a wide array of cancer treatment centers, including community cancer centers where most earlier line patients seek care. This randomized study will enroll approximately 240 patients and is designed to demonstrate a meaningful improvement in event free survival (EFS) in patients treated with cema-cel relative to patients who receive the current standard of care (observation). Efficacy analyses are expected to occur in 2026 and will include an interim EFS analysis monitored by the independent Data Safety Monitoring Board (DSMB) in 1H 2026 and the data readout of the primary EFS analysis in 2H 2026 with a potential biologics license application (BLA) submission targeted for 2027.

About Foresight Diagnostics
Foresight Diagnostics is a privately-held cancer diagnostics company and CLIA-registered laboratory. Its liquid biopsy platform, Foresight CLARITY, is a novel assay that measures minimal residual disease (MRD) with reported detection limits in parts per million1. The improved sensitivity of Foresight CLARITY has the potential to provide actionable information to physicians and biopharmaceutical companies to enable more personalized treatment approaches for patients with solid tumor and hematologic malignancies. For more information, please visit foresight-dx.com and follow us on Twitter and LinkedIn. Foresight CLARITY IUO is an investigational device. Limited by United States Law to investigational use.

About Cemacabtagene Ansegedleucel (cema-cel)
Cemacabtagene ansegedleucel, or cema-cel is a next generation anti-CD19 AlloCAR T investigational product for the treatment of large B cell lymphoma (LBCL). In June 2022, the U.S. Food and Drug Administration granted Regenerative Medicine Advanced Therapy (RMAT) designation to cema-cel in third line (3L) r/r LBCL. The ALPHA3 pivotal Phase 2 trial in first line (1L) consolidation for the treatment of LBCL launched in June 2024. Allogene has oncology rights to cema-cel in the US, EU and UK with options for rights in China and Japan.

About the ALPHA3 Trial
Over 60,000 patients are expected to be treated for LBCL annually in the US, the EU and the UK. While first line (1L) R-CHOP or other chemoimmunotherapy is effective for most patients, approximately 30% will relapse and require subsequent treatment. The current standard of care (SOC) after 1L treatment has been simply to "watch and wait" to see if the disease relapses. The pivotal Phase 2 ALPHA3 study takes advantage of cema-cel as a one-time, off-the-shelf treatment that can be administered immediately upon discovery of MRD following six cycles of R-CHOP or other chemoimmunotherapy, positioning it to become the standard "7th cycle" of frontline treatment available to all eligible patients with MRD.

On June 20, 2024 Alligator Bioscience (Nasdaq Stockholm: ATORX) reported it will present positive Phase 2 data on its lead drug candidate mitazalimab in first line metastatic pancreatic cancer at the European Society for Medical Oncology Gastrointestinal Cancers Congress 2024 (ESMO GI 2024), taking place in Munich, Germany from June 26-29 (Press release, Alligator Bioscience, JUN 20, 2024, View Source [SID1234644447]).

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The oral presentation outlines OPTIMIZE-1, an open-label, multicenter, Phase 1b/2 study, assessing the safety and efficacy of mitazalimab (CD40 mAb agonist) in combination with standard of care chemotherapy mFOLFIRINOX. The trial study met its primary endpoint, with mitazalimab showing a manageable safety profile and promising DoR associated with a clinically meaningful survival benefit.

Furthermore, there was a significant correlation between treatment-induced increases in natural killer T (NKT) cells and T cells expressing CD38 and depth of response, strongly suggestive of a mitazalimab-dependent contribution to deep anti-tumor responses.

The 5-year overall survival rate for metastatic pancreatic ductal adenocarcinoma (mPDAC) is less than 5%, and current systemic therapies are associated with poor outcomes. The OPTIMIZE-1 data have also recently been published in the peer-reviewed The Lancet Oncology and presented in two posters at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

Alligator expects to report 18-month survival follow-up data from OPTIMIZE-1 at the end of June 2024, and that these will provide further insights into the potential of mitazalimab.

"We are pleased to present these exciting results with mitazalimab to the scientific community at ESMO (Free ESMO Whitepaper) GI. It is an important validation of the potential of our product candidate to make a meaningful difference to pancreatic cancer patients, who currently have a very poor prognosis and limited treatment options," said Dr. Sumeet Ambarkhane, CMO of Alligator Bioscience. "In particular, the long-lasting responses and related biomarker associations reported in OPTIMIZE-1 demonstrate a critical immunomodulatory contribution of mitazalimab. The increase in ORR and PFS, compared to FOLFIRINOX alone, are superior outcomes and mitazalimab also showed a favorable safety profile. Taken as a whole, these are very encouraging data which form the basis of planning mitazalimab’s development in a randomized Phase 3 study."
About the OPTIMIZE-1 data
Results from the OPTIMIZE-1 trial showed mitazalimab in combination with mFOLFIRINOX had a confirmed ORR of 40.4% in 57 evaluable patients (unconfirmed ORR was 50.9%). Median DoR was 12.5 months and the median OS was 14.3 months. Median Progression Free Survival (PFS) was 7.7 months. These data compare favorably to the historically reported outcomes with FOLFIRINOX (ORR 31.6%, mDoR 5.9 months, mOS 11.1 months and mPFS 6.4 months)[1]. The recently approved new treatment regimen of NALIRIFOX was associated with an ORR of 42%, mDoR of 7.3 months, mPFS 7.4 months and a mOS of 11.1 months[2].

Details of the presentation:
Title: CD40 agonist mitazalimab combined with mFOLFIRINOX (mFFX) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): Primary analysis of the OPTIMIZE-1 phase 1b/2 study

Type: Oral presentation

Time: Saturday, June 29, 8:45am CET

Location: Room 13a

Presenter: Prof. Teresa Macarulla Mercade, MD, PhD, Vall d’Hebron, Barcelona

About pancreatic cancer
Pancreatic cancer is the 12th largest cancer by number of patients. It is expected to become the second leading cause of cancer death in the western world by 2030. There are about 200,000 annual cases in the U.S. and the EU, with very poor prognosis: five-year survival is about 10% and median survival about 6 months. For 80% of patients, the only option is chemotherapy that offers only marginal benefit. FOLFIRINOX is expected to be the preferred first line regimen in the U.S. and the EU for patients with good performance status.
Sources: POLARIS Market Research, KOL event.

On June 19, 2024 Researchers at the National Institutes of Health (NIH) reported a non-chemotherapy treatment regimen that is achieving full remissions for some people with aggressive B-cell lymphoma that has come back or is no longer responding to standard treatments (Press release, US NCI, JUN 19, 2024, View Source [SID1234644445]). The five-drug combination targets multiple molecular pathways that diffuse large B-cell lymphoma (DLBCL) tumors use to survive.

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In a clinical trial at NIH’s National Cancer Institute, researchers tested the combination of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (called ViPOR) in 50 patients with DLBCL, the most common type of lymphoma. The treatment shrank tumors substantially in 26 of 48 (54%) evaluable patients, with 18 (38%) of those patients’ tumors disappearing entirely, known as a complete response. At two years, 36% of all patients were alive and 34% were free of disease. These benefits were seen mainly in people with two specific subtypes of DLBCL.

The findings were published June 20, 2024, in the New England Journal of Medicine.

"Many of these patients who stopped responding to standard treatments would have otherwise died within a year, and now we have a good proportion who are still alive past two years, and some past four years," said Christopher J. Melani, M.D., of NCI’s Center for Cancer Research, who co-led the study. "It’s gratifying to see these long-term remissions and potential cures in patients."

Previous studies have identified various genetic pathways involved in the development and survival of the different molecular subtypes of DLBCL, such as activated B cell–like (ABC) DLBCL and germinal center B cell–like (GCB) DLBCL. Targeted drugs have shown effectiveness in blocking some of these pathways, but individual drugs rarely produced lasting responses in patients because the tumors may be resistant due to alternative survival pathways. Dr. Melani and his colleagues hypothesized that combining targeted drugs that block multiple survival pathways would lead to more durable responses.

Based on laboratory studies in which they analyzed which targeted drugs could best be combined to kill DLBCL cells in a synergistic manner, the researchers designed the five-drug regimen to test in human trials. To allow for the targeted drugs to work synergistically in patients, the researchers gave the drugs simultaneously in two-week cycles. To limit the accumulation of side effects, they scheduled a weeklong break between each cycle.

"DLBCL is one of the most genetically heterogeneous forms of cancer, and as a result we don’t yet have the ability to identify exactly which combination of drugs would be most effective for any given patient," Dr. Melani said. "By putting five drugs together, we believe that there will be some drug combination—either two, three, or more drugs—that will be particularly effective against that patient’s tumor."

In the phase 1b/2 trial, 50 people with DLBCL that had relapsed or stopped responding to treatment were given six cycles of the ViPOR regimen. Responses to ViPOR varied by DLBCL subtype, with complete responses concentrated in two subtypes, including in 8 of 13 (62%) people with non-GCB DLBCL and 8 of 15 (53%) people with a form of GCB DLBCL known as high-grade B-cell lymphoma "double hit."

At two years, people with non-GCB DLBCL and double-hit GCB DLBCL had higher rates of both progression-free and overall survival than other people in the study. Non-GCB DLBCL and double-hit GCB DLBCL are highly reliant on the survival mechanisms targeted by ViPOR, so it makes sense that they responded particularly well to the combination therapy. ViPOR also helped 6 of 20 (30%) patients whose lymphomas had not responded to or had come back after CAR T-cell therapy—the current standard of care for people with relapsed DLBCL—achieve lasting remissions.

Side effects of the five-drug regimen were generally mild to moderate when compared with those of standard treatments and improved during the treatment breaks. Only five patients had to stop treatment early for various reasons, including side effects. Given these relatively mild to moderate side effects, additional drugs could potentially be added to ViPOR to improve its efficacy, the researchers said. The team is also studying the ViPOR regimen in people with other types of lymphoma that are resistant to previous therapies.

The researchers have developed a larger phase 2 study, which will be conducted at multiple centers, to confirm the activity of ViPOR in people with non-GCB DLBCL and double-hit GCB DLBCL. More work is needed to develop therapies for GCB DLBCL subtypes that aren’t as responsive to ViPOR.

NCI’s Center for Cancer Research investigators Wyndham H. Wilson, M.D., Ph.D., Mark Roschewski, M.D., and Louis M. Staudt, M.D., Ph.D., co-led the study with Dr. Melani. Investigators from NIH’s National Center for Advancing Translational Sciences and other institutions contributed to the study.