On January 5, 2023 iOnctura, a clinical-stage biotech developing selective cancer therapies against targets that play critical roles in multiple tumor survival pathways, reported an update on IOA-244, its lead cancer drug, which is in development for solid and hematologic malignancies including uveal melanoma, a rare cancer arising within the uveal tract of the eye (Press release, iOnctura, JAN 5, 2023, View Source [SID1234625936]).

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After assessing the novel chemical and biological properties of IOA-244, and the promising signals of clinical activity seen to date in patients with uveal melanoma, the US FDA granted Orphan Drug Status for IOA-244. This grants certain benefits during development and commercialization. Uveal melanoma is a disease in which cancer originates in the tissues of the eye, causing symptoms such as blurred vision or a dark spot on the iris. When the cancer metastases, which it does in approximately 50% of patients, there are limited treatment options and projected overall survival is only a year.

A PI3Kδ inhibitor, IOA-244 recently received the proposed name roginolisib and is being investigated in the DIONE-01 trial, a two-part, first-in-human Phase I study (ClinicalTrials.gov, identifier NCT04328844). Part A of the study investigated the safety and pharmacokinetics of continuous daily dosing of IOA-244 at 10, 20, 40 and 80mg. Part B is an ongoing cohort-expansion of the biologically-effective dose (BED) of 80mg in solid and hematologic malignancies including a recently opened non-Hodgkin´s lymphoma cohort.

As of December 2022, 38 patients (including 23 with metastatic uveal melanoma and eight patients with follicular lymphoma) have been treated with IOA-244. Across all patients treated to date, roginolisib given at the BED showed less than 5% Grade 3 or Grade 4 toxicities, with these toxicities being transient in nature. There have been no dose-limiting drug reductions or interruptions and long-term (over six months) administration of IOA-244 is well tolerated.

Clinical activity, including partial and complete responses, are being seen in patients with both solid and hematologic malignancies. Further details on clinical responses will be released at a future international clinical conference in 2023. Fourteen of 38 patients (including 11 of 23 uveal melanoma patients) are still on treatment, with two patients having been on treatment for more than two years. The one-year OS rate is currently 70%; median OS has not been reached.

Catherine Pickering, Chief Executive Officer of iOnctura, said: "We are delighted to provide these positive updates on IOA-244, our lead clinical program. These important new data, taken together with previous findings, show a drug with a game-changing clinical safety and activity profile. These data demonstrate for the first time that a semi-allosteric inhibitor of PI3Kδ can be given to patients safely for long durations with no serious adverse events. We are excited to take IOA-244 forwards into a monotherapy registration study in uveal melanoma and to further explore its potential both in lymphoma and solid tumors such as NSCLC."

On January 5, 2023 Esperovax, an innovative developer of oral mRNA biologics, and Ginkgo Bioworks (NYSE: DNA), which is building the leading platform for cell programming and biosecurity, reported a partnership to develop circular RNAs (circRNAs) for a variety of therapeutic applications (Press release, Esperovax, JAN 5, 2023, View Source [SID1234625934]). Initially, Ginkgo and Esperovax will work to develop circRNAs harboring payloads to specifically target colorectal cancer by inducing cell death only in cancerous cells.

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CircRNAs represent an emerging, powerful mechanism for delivering therapeutics and vaccines due to their protein-coding potential and improved stability in comparison to their linear mRNA counterparts. This partnership aims to further exploit circRNAs by developing a novel mechanism to facilitate RNA circularization specifically in colorectal cancer cells. This would result in extended expression of the toxic payload solely in cancer cells, reducing toxicity and resulting side effects from the death of normal cells. By combining omics datasets, computational approaches, and high-throughput screening capabilities, Ginkgo will design, build and screen large numbers of RNA designs that leverage and optimize Esperovax’s novel mechanism of cell-type specific circularization. Through its growing portfolio of programs in cell and gene therapy and RNA therapeutics, and recent acquisition of Circularis, Ginkgo is uniquely positioned to enable new solutions in these areas with circRNA.

"One of the most exciting things about being at Ginkgo is the opportunity to work together with startups like Esperovax in the early stages of development and collaborate on such incredible innovations as circular RNA technology," said Narendra Maheshri, Head of Mammalian Foundry at Ginkgo Bioworks. "Building off of Esperovax’s novel mechanism for circularization, we’re thrilled to use our platform to further develop and optimize it to enable advancements in the therapeutics space – a core area of our work."

"Given therapeutic developments in recent years, the idea of inducing a suicide gene therapy system in a tissue-specific manner has gained traction," said Randy Wayne Schekman, a Nobel Prize recipient in Physiology or Medicine and Advisor at Esperovax. "As we aim to build off that traction with the ultimate goal of improving cancer patient outcomes, Ginkgo’s momentum and achievements in the therapeutics space made the company an essential and trusted team to partner with, giving us the confidence that we can eventually make this goal a reality."

On January 5, 2023 Jnana Therapeutics, a biotechnology company leveraging its next-generation chemoproteomics platform to discover medicines for challenging-to-drug targets, reported that Joanne Kotz, Ph.D., Co-founder and Chief Executive Officer, will present a corporate overview at the 41st Annual J.P. Morgan Healthcare Conference on Tuesday, January 10, 2023, at 3:30 p.m. PT (6:30 p.m. ET) (Press release, Jnana Therapeutics, JAN 5, 2023, View Source [SID1234625933]).

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On January 5, 2023 A trial led by City of Hope, one of the largest cancer research and treatment organizations in the nation, contributed to the U.S. Food and Drug Administration’s reported approval of mosunetuzumab (commercial name: Lunsumio), the first bispecific antibody to treat people with relapsed or difficult to treat follicular lymphoma (FL), a type of non-Hodgkin lymphoma, after they have received two or more standard therapies (Press release, City of Hope, JAN 5, 2023, View Source [SID1234625931]).

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Mosunetuzumab is a CD20xCD3 T cell engaging bispecific antibody and represents a new class of fixed-duration cancer immunotherapy, which is off-the-shelf and readily available for infusion, allowing patients to start treatment soon after diagnosis in an outpatient setting.

Instead of concentrating on a singular target, bispecific antibodies are therapeutics that act on two cellular targets simultaneously. In the case of mosunetuzumab, one "arm" targets the CD3 protein on T cells, an immune cell that fights against cancer once engaged; a second "arm" binds to CD20, a protein commonly found on lymphoma cells.

"This approval is a significant milestone for people with relapsed or refractory follicular lymphoma and signifies the beginning of a new treatment modality for lymphoma since mosunetuzumab is the first bispecific antibody approved for lymphoma," said Elizabeth Budde, M.D., Ph.D., hematologic oncologist and associate professor, City of Hope Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation, and the mosunetuzumab pivotal trial principal investigator. "At City of Hope, the integration of scientific research and clinical trials allows us to deliver groundbreaking science and treatments from laboratory to patient. Mosunetuzumab is a first in class T cell engaging bispecific antibody and could change the way advanced follicular lymphoma is treated."

Budde led a multicenter Phase 2 study in people with heavily pretreated FL, including those who were at high risk of disease progression or whose disease didn’t respond to prior therapies. Results from the study showed high and durable response rates and an impressive benefit-risk profile.

An overall response rate, which is the combination of a complete response rate, or the disappearance of all signs and symptoms of cancer, and a partial response rate was seen in 80% of patients treated with mosunetuzumab, with a majority maintaining responses after 24 months. The median duration of response among those who responded was not reached. A complete response rate was achieved in 60% of patients.

The most common side effects were cytokine release syndrome, which occurred in 44% of patients. Other common side effects included fatigue, rash, pyrexia and headache.

"The two cell groups are pulled together, with mosunetuzumab serving as a kind of bridge," Budde said. "Being in such close proximity allows the now activated T cells to better recognize and attack the lymphoma cells."

Ninety patients with follicular lymphoma, who ranged in age from 29 to 90 years old, were enrolled in the multicenter international trial. The patients received mosunetuzumab, a Genentech medicine, intravenously every 21 days for a minimum of eight cycles and up to 17 cycles.

Juan Yee, 49, of San Diego was one of the patients in the City of Hope trial whose lymphoma had relapsed for a second time.

"I couldn’t go through chemo again," said Yee. He was first diagnosed in 2012 with FL and relapsed in 2016. He experienced weight loss, easy fatigue and persistent night sweats. "It was painful, and I was tired. I was done."

But thanks to one last try with mosunetuzumab, Yee has been in complete remission for nearly five years now.

"When I was going through treatments, I would ask God why this was happening to me," Yee said. "And now I think it’s so that I could do this (mosunetuzumab) trial and help other people. I can share my positive experience and let people know they shouldn’t give up. Have faith."

Follicular lymphoma is the most common slow-growing form of non-Hodgkin’s lymphoma, accounting for about 1 in 5 cases. It typically responds well to treatment, but is often characterized by periods of remission and relapse. The disease typically becomes harder to treat each time a patient relapses, and early progression can be associated with poor long-term prognosis. It is estimated that, in the United States, approximately 13,000 new cases of FL will be diagnosed in 2022, and more than 100,000 people are diagnosed with FL each year worldwide.

City of Hope is a leader in blood cancer immunotherapies. The National Cancer Institute-designated comprehensive cancer center has performed more than 18,000 bone marrow/stem cell transplants and is a leader in chimeric antigen receptor (CAR) T therapy, with more than 1,000 patients treated with immune effector cells, including CAR T therapy, and more than 70 open trials.

On January 5, 2023 Triumvira Immunologics, a clinical-stage company developing novel, targeted autologous and allogeneic T cell therapeutics that co-opt the natural biology of T cells to treat patients with solid tumors, reported a clinical trial collaboration and supply agreement with Merck (known as MSD outside the U.S. and Canada) (Press release, Triumvira Immunologics, JAN 5, 2023, View Source [SID1234625930]). Triumvira’s ongoing TACTIC-2 trial will evaluate the use of its novel autologous cell therapy TAC01-HER2 as a monotherapy but also in combination with Merck’s anti-PD-1 therapy KEYTRUDA (pembrolizumab) for the treatment of HER2-positive solid tumors.

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"We believe the addition of an immune checkpoint inhibitor, such as KEYTRUDA, to TAC01-HER2 will effectively release inhibitory PD-L1/PD1 signaling in T cells, potentially leading to improved and durable therapeutic responses, said Paul Lammers, M.D., M.Sc., Chief Executive Officer of Triumvira. We are pleased to work collaboratively with Merck to explore the potential of this approach to treat relapsed or refractory solid tumors and bring new drug therapies to patients who do not respond to existing treatments."

At the European Society for Medical Oncology 2022 Congress, Triumvira presented interim data from the ongoing TACTIC-2 Phase 1/2 trial that demonstrated the safety and preliminary efficacy of TAC01-HER2 in patients with HER2-positive solid tumors regardless of level of expression. TACTIC-2 is actively enrolling participants at five clinical trial sites across the U.S. and Canada. The expansion phase of the trial is expected to launch in 2023. The trial will enroll a monotherapy arm with TAC01-HER2 and a combination therapy arm with TAC01-HER2 and KEYTRUDA, in patients with HER2-positive solid tumors.

"We are encouraged by the interim preliminary safety and efficacy data to date from our TACTIC-2 trial, and this has the potential to drive a real breakthrough in the treatment of solid tumors that express HER2," said Deyaa Adib, M.D., Chief Medical Officer of Triumvira. "Beyond TAC01-HER2 monotherapy, we hope to demonstrate the benefits of using TAC01-HER2 in combination with KEYTRUDA, and we look forward to collaborating with Merck on this trial."

Merck will supply Triumvira with KEYTRUDA for the trial and the two companies will form a Joint Development Committee to review the clinical trial results. More details on the Phase 1/2 TACTIC-2 trial can be found at clinicaltrials.gov using ClinicalTrials.gov Identifier NCT04727151.