IN8bio, Inc (NASDAQ:INAB) reported second quarter 2024 financial results and achievements on August 8th followed a few days later by an update on the INB-100 and INB-200 programs and the anticipated path forward. In addition to showing continued impressive survival duration, IN8bio also shared the anticipated registrational trial design for INB-100 in acute myeloid leukemia (AML). In June, the company presented INB-100 and INB-200 data at the European Hematology Association (EHA) Congress and the American Society of Clinical Oncology (ASCO) Annual Meeting. Other recent highlights include presentation of γδ T cell manufacturing processes at the International Society for Cell & Gene Therapy meeting and participation in investor conferences.
IN8bio released second quarter 2024 earnings along with the filing of its Form 10-Q on August 8th. IN8bio generated no revenues in 2Q:24 and incurred operating expense of $8.7 million, producing a net loss of ($8.6) million or ($0.19) per share.
For the quarter ending June 30th, 2024 and versus the same comparable prior year period:
? Research & development expenses totaled $5.2 million, rising 25% from $4.1 million due to higher personnel related costs and direct clinical costs. By program, more spending on the INB-100 and INB-400 program were partially offset by lower INB-200 spending. Preclinical expenses were also down;
? General & administrative expenses were $3.5 million, falling 1% from $3.6 million;
? Interest income was $60,000 versus $0 with the contribution arising interest income;
? Net loss was ($8.6) million, or ($0.19) per share, compared to ($7.7) million, or ($0.27) per share.
At the end of 2Q:24, cash and marketable securities totaled $10.2 million, compared to year end 2023 cash balance of $21.3 million. Cash burn for the second quarter was ($6.2) million versus ($5.4) million in the comparable prior year period. For the first half, cash burn was ($14.2) vs. ($13.2) in 1H:23. Cash from financing was $3.1 million in 1H:24 which was mostly related to proceeds from stock issuance. This compares to $12.0 million of cash from financing in 1H:23.
EHA INB-100
IN8bio presented updated results from its Phase I INB-100 trial at the European Hematology Association (EHA) Congress on June 13th in Madrid, Spain. Details of the presentation were provided in a press release and conference call after the close on June 13th, 2024 along with a slide deck to guide the discussion. Stakeholders had been eagerly awaiting the update on this trial since impressive data was presented back in December 2023 at the American Society of Hematology (ASH) Annual Meeting. Six months later, all (N=10) of the treated leukemia patients achieved complete remission at the one-year mark. Of the 10 patients evaluated, 30% have achieved overall survival in excess of three years and one beyond four years. Only one patient has died, and this was attributed to idiopathic pulmonary fibrosis and not the experimental medication nor leukemia. Multiple resources suggest that about 50% of patients relapse 12 months after hematopoietic stem cell transplant for hematological malignancies, highlighting the remarkable results that were achieved with no patients relapsing during the year long period.
The achievement is even more impressive when subject risk profiles are considered. The average age of the 10-patient group was approximately 68 years1 and over half had mutations or unfavorable cytogenetics associated with worse performance. Complete remission at one year is an excellent result that provides more confidence of success in a registrational trial which will be the topic of IN8bio’s next interaction with the FDA.
IN8bio will expand the trial to enroll another 10 patients at the recommended Phase II dose which is a single dose of 3 x 106 γδ T cells/kg. Further updates from the trial are expected over the remainder of 2024 and in 2025. The company plans to discuss the details of a registrational trial with the FDA in a Type B meeting this summer.
In a follow up presentation on August 12th, IN8bio provided INB-100 patient status as of August 1st. Survival for all of the AML patients had continued from the prior update on May 31st, extending overall survival for each patient by two months. Three patients have now remained relapse-free for over three years compared to two in May.
IN8bio has met with the FDA for guidance on pivotal study design that can support the filing of a biologic license application (BLA). The trial will enroll just under 300 AML patients in a 2:1 randomization. The primary endpoint for the trial will be relapse free survival with secondary endpoints revolving around safety, time to relapse, overall survival and quality of life metrics.
Persistence
In the December 2023 update, IN8bio presented data showing a year of persistence for γδ T cells in the two trial cohorts. The persistence was especially strong in the second dosing level, which also demonstrated in vivo expansion. The data six months later reinforced this finding and closely matched December’s data as shown in the following exhibit.
Safety
Safety was another strong point reinforced in the updated information for INB-100. No dose limiting toxicities, cytokine release syndrome (CRS), neurotoxicity or immune effector cell-associated neurotoxicity syndrome (ICANS) were observed. There have been few serious infections which can arise during immune system reconstitution. One patient died due to idiopathic pulmonary fibrosis, which is an associated adverse response to transplants. The patient population presented several high-risk features including trisomy of chromosome 8 and deletion of chromosome 7 as well as other difficult mutations that appeared in six of the ten evaluable subjects. Below we summarize the treatment-emergent adverse events (TEAEs) that occurred in 2 or more subjects.
The INB-100 trial will continue with 10 more subjects planned and IN8bio. 100% remission for over one year for all 10 patients and persistence and durability of γδ T cells are strong indicators of the success of this program. Safety has been a strong attribute of INB-100, with most of the adverse events related to transplantation and not the γδ intervention. Graft vs. host disease (GvHD) has been limited with no greater than Grade 2 GvHD and 30% incidence of chronic GvHD.
IN8bio updated INB-200 patient status in its August 12th update call using an August 1st cutoff. This is three months after the May 1st data which was presented at ASCO. No patients died over the three-month period increasing the average time that evaluable patients have exceeded the Stupp Regimen median progression free survival of seven months to 92%. This compares to the 83% that were reported at ASCO and associated with the May 1st cutoff.
One patient remains progression free at 38 months. Overall survival (OS) was not calculated as five of thirteen remain alive and measurements are ongoing. Safety appears to be good with no cell therapy related toxicities such as immune effector cell-associated neurotoxicity syndrome or cytokine release syndrome reported in patients receiving up to the maximum dose of six infusions.
Standard of care (SoC) for newly diagnosed GBM requires primary resection, six weeks of daily chemoradiation therapy followed by six cycles of monthly maintenance temozolomide therapy (Stupp regimen). SoC produces a median PFS of 7 months and an overall survival (OS) of approximately 14 to 16 months as reported by IN8bio.
Our own review finds a range of reported survival of nine months to the upper twenty-month range depending upon specific characteristics. Most of the more recent resources we reviewed were 15 months or less. Factors associated with differing survival rates include age, further tumor treatment after surgery and MGMT promoter methylation among other contributors.2,3,4,5,6,7
Key Findings
All patients who completed the protocol mandated doses surpassed the median PFS of seven months with a majority also exceeding expected PFS based on age and O?-methylguanine-DNA methyltransferase (MGMT) status. 92% exceeded mPFS of seven months as of May 30, 2024. The most common treatment-emergent adverse events were Grade 1 or 2 toxicities consisting of white blood cell and platelet count decreases related to temozolomide.
? Radiographic evaluation pre- and post-treatment included resolution of midline shift in one patient with evidence of changes in enhancement attributed to treatment effect in multiple patients;
? One subject was found to have a 36% decrease in a lesion attributed to positive treatment effect;
? Preserved γδ T cells were found in relapsed tumors 148 days after initial drug-resistant immunotherapy (DRI) infusion in one patient with paired biopsies, pointing to durability of DRI γδ T cells.
In this first study evaluating the use of γδ T cells in GBM, there has been promising data so far that exceeds SoC thresholds for PFS. γδ T cells have shown that they are safe with limited negative side effects and strong synergies with temozolomide which functions as an effective lymphodepleting regimen for use with cellular therapy. The DRI feature of IN8bio’s modified γδ T cells allows the therapy to thrive in the tumor environment, immune from the effects of temozolomide and alerted to the cancer cells which are more visible to γδ T cell therapy when exposed to temozolomide. Early data from the INB-200 study shows that repeat doses result in longer time to progression. Positive results from the trial so far support further study. A follow-on trial for candidate INB-400 will take the baton from INB-200 and evaluate a larger group of patients.
INB-400 (Autologous and Allogeneic)
INB-400 is carrying on the effort initiated with INB-200 in the DeltEx DRI γδ T cell therapy for GBM. It is a Phase Ib/II study that will deploy activated, modified (DRI) γδ T cells along with TMZ for recurrent or newly diagnosed GBM. The trial’s title is A Phase 1b / 2 Drug Resistant Immunotherapy with Activated, Gene Modified Allogeneic or Autologous γδ T Cells (DeltEx) in Combination with Maintenance Temozolomide in Subjects With Recurrent or Newly Diagnosed Glioblastoma. Trial details are provided on clinicaltrials.gov under the identifier NCT05664243.
The study has three arms. Arm A that will incorporate autologous cells, while Arms B and C will incorporate allogeneic cells. Arms A and C will enroll patients with newly diagnosed disease while Arm B will enroll individuals with relapsed disease. Subjects will receive SoC. During surgical resection of the tumor, a Rickham catheter will be placed so that INB-400 therapy can be delivered directly. Following resection, Arm A patients will undergo apheresis to extract γδ T cells that will be modified to be TMZ resistant. Allogeneic donors will provide cell product for Arms B and C. Subjects in all arms will then receive six weeks of chemotherapy with TMZ and radiation. The patients will take a break as they recover from the initial round of SoC then maintenance therapy will begin.
The Phase Ib portion of the trial will further develop the safety and efficacy profile for allogeneic cells (INB-400 DeltEx DRI allogeneic cells) administered to relapsed GBM patients. If determined safe, two cohorts of patients with either relapsed disease (Arm B) or newly diagnosed disease (Arm C) will receive allogeneic γδ T cells. Trial objectives seek to:
? establish the safety of allogeneic, genetically modified γδ T cells;
? assess the efficacy of these cells in treating patients with relapsed GBM; and
? assess the relative benefit and risk of treating newly diagnosed GBM patients with either allogeneic or autologous genetically modified γδ T cells.
Primary outcome measures are overall survival (OS) and maximum tolerated dose. Secondary measures include further safety assessments, overall response rate (ORR), time to progression, and progression free survival (PFS) among others.
Twelve sites in the United States have been identified to enroll patients and three are open and enrolling. An April 30th press release announced that IN8bio had dosed its first patient in the Phase II trial. An expansion cohort will enroll 10 additional patients and data from the trial will be gathered to support an investigational new drug (IND) submission to allow for a Phase II study. INB-400 is actively enrolling and dosing subjects in the Phase II trial and should report initial data from the study in 2025.
Previous work has been conducted evaluating allogeneic products showing that they may benefit from a younger and healthier donor These have demonstrated direct anti-tumor cytotoxicity. However, further elaboration and validation of the autologous product is necessary. The allogeneic version is considered a separate product from the autologous cell therapy and requires a separate investigational new drug (IND) application.
IN8bio’s longer term goal with this program is to move towards an allogeneic therapy that would allow for an off-the-shelf alternative. This approach would provide a number of benefits relative to an autologous version. Some of these advantages include lower manufacturing costs, immediate availability of drug product and sourcing of γδ T cells from subjects with younger, healthier and better-balanced immune systems.
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1. In the Luznik 2008 paper, median age was 46 years. Luznik, L. et al. HLA-Haploidentical Bone Marrow Transplantation for Hematologic Malignancies Using Nonmyeloablative Conditioning and High-Dose, Post-transplantation Cyclophosphamide. Biology of Blood and Marrow Transplantation 14:641-650 (2008)
2. Brown, N.F. et al. Survival Outcomes and Prognostic Factors in Glioblastoma. Cancers. July 2022. (9.2 months)
3. Hertler, C. et al. Long-term survival with IDH wildtype glioblastoma: first results from the ETERNITY Brain Tumor Funders’ Collaborative Consortium. European Journal of Cancer, 2023 (9.9 months)
4. Bjorland, L.S. et al. Treatment approach and survival from glioblastoma: results from a population-based retrospective cohort study from Western Norway. Oncology, 2021. (10.2 months)
5. Stupp R. et al. Radiotherapy plus concomitant and adjuvant Temozolomide for glioblastoma. N Engl J Med. 2005. (14.6 months)
6. Chang, K. et al. Multimodal imaging patterns predict survival in recurrent glioblastoma patients treated with bevacizumab. Neuro-Oncology. 2016. (15 months)
7. Alafandi, A. et al. Association of pre-radiotherapy tumour burden and overall survival in newly diagnosed glioblastoma adjusted for MGMT promoter methylation status. European Journal of Cancer. 2023. (27 methylated & 14 unmethylated).
