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The head of research at Mass General Brigham’s Cell and Gene Therapy Institute discussed work the center is engaged in with cell and gene therapy. 

Nathan Yozwiak, PhD, on Collaboration for Cell and Gene Therapy Development 

The head of research at Mass General Brigham’s Cell and Gene Therapy Institute discussed research from the center presented at ASGCT 2024. 

Nathan Yozwiak, PhD, on Researching AAV Gene Therapy Delivery to the Brain

enGene's EG-70 (detalimogene voraplasmid), an investigational nonviral immuno-oncology gene therapy intended to treat bacillus Calmette-Guérin (BCG)-unresponsive nonmuscle-invasive bladder cancer (NMIBC), is currently being evaluated in the phase 1/2 LEGEND clinical trial (NCT04752722).

 With the company having recently announced that it intends to expand the trial with a new cohort, 

 has decided to take a closer look at this ongoing study.

LEGEND began on April 22,2021. Led by study director Christine Tosone, MS, RAC, enGene, the vice president, head of clinical development operations at enGene, the multicenter clinical trial consists of a dose-escalation portion (phase 1) focused on safety and an efficacy-focused portion (phase 2). The phase 1 portion, which has now finished treating patients, took the form of a 3+3 dose-escalation, with patients receiving 0.25 mg/mL (dose level 1, DL1), 0.8 mg/mL (DL2), or 2.5 mg/mL (DL3) on a schedule of either 2 doses per 12-week cycle (at Day 1 and Day 8) or 4 doses per 12-week cycle (Day 1, Day 8, Day 29, and Day 36).

 The portion, which was open to patients with high-risk NMIBC with carcinoma in situ (CIS) for whom previous BCG was unsuccessful, treated 24 patients in total. The schedule selected for the phase 2 portion was 4 doses at DL2 delivered at Week 1, Week 2, Week 5, and Week 6 of 12-week cycles. The phase 2 portion is treating a cohort of patients with BCG-unresponsive NMIBC with CIS (cohort 1); a second cohort of patients with NMIBC with CIS who are BCG-naive or who have received inadequate BCG (see recently announced update below); and includes a planned third cohort for patients with high-risk BCG-unresponsive papillary-only NMIBC. In a June 2024 announcement, enGene stated that the third cohort in the phase 2 portion is expected to begin enrolling patients in Q4 of this year.

 The company also plans to modify the second cohort to separately enroll patients with NMIBC with CIS who are BCG-naïve and BCG-exposed in cohorts 2a and 2b, respectively. This expansion of the second cohort is also expected to begin enrolling patients in Q4 2024, and the company has paused enrollment in the second cohort until then.

“Our $200 million private placement in February positioned us well to execute our primary strategy of broadly developing EG-70 to be a patient- and practice-friendly option across a multitude of potential bladder cancer indications,” Jason Hanson, JD, the chief executive officer of enGene, said in a June 2024 statement.

 “Correspondingly, our planned initial expansion of the LEGEND study will include a cohort focused on enrollment of patients with high-risk, BCG-unresponsive papillary-only NMIBC, a disease with persistent unmet need for which EG-70 may be well-suited. Furthermore, we plan to provide the interim data for the LEGEND BCG-unresponsive cohort by the end of September 2024. We believe the design of EG-70, with its ease-of-use and nonviral profile, positions it well to seamlessly slot into the standard of care, with the goal of becoming a practice-changing product that does not require a change in practice for urologists.”

According to its clinicaltrials.gov page, which was most recently updated on June 20, 2024, LEGEND is expected to enroll up to 222 participants in total and has an estimated completion date of May 2027, with an estimated primary completion date of June 2025. The study is recruiting in US states including Arizona, California, Washington DC, Florida, Georgia, Kansas, Maryland, Michigan, Michigan, Minnesota, New Jersey, New York, North Carolina, Ohio, Oregon, South Carolina, Texas, and Wisconsin.

The primary end point for the phase 1 portion of LEGEND consists of the nature, incidence, relatedness to treatment, and severity of all treatment-emergent adverse events (TEAEs) and serious TEAEs that occur during a 2-year timeframe. The phase 2 portion’s primary end points include the percentage of patients with a cystoscopic complete response (CR) at 48 weeks posttreatment, as assessed by the cystoscopy exam, urine cytology, bladder biopsies, and the nature, incidence, relatedness to treatment, and severity of TEAEs that occur during a 3-year timeframe. The phase 1 portion’s secondary end points include the number of patients who experienced a dose-limiting toxicity through the end of the first 12-week cycle and the CR rate as evaluated by cystoscopy at approximately 12 weeks posttreatment. The phase 2 portion’s secondary end points include the progression-free survival rate in a timeframe of approximately 3 years; the duration of response for patients who respond during a timeframe of approximately 3 years; a quality of life assessment carried out at 24 weeks posttreatment; and the CR rate at 12, 24, 36, and 96 weeks posttreatment.

LEGEND is open to patients aged 18 years and older. BCG-unresponsive patients with CIS must have experienced persistent disease within 12 months or a recurrence within 6 months of completing adequate BCG therapy—definitions consistent with the FDA’s definitions of BCG-unresponsive disease (2018). Patients who are BCG-naive or did not receive adequate BCG must have NMIMBC with current CIS of the bladder must have received either incomplete BCG consisting of at least 1 dose or have previously been treated with at least 1 dose of intravesical chemotherapy following transurethral resection of bladder tumor. All patients must have not undergone cystectomy and must have CIS documented or indicated by pathology.

Patients who have previously been treated unsuccessfully with an investigational or approved checkpoint inhibitor are eligible for inclusion in phase 1 at 30 days after treatment or in phase 2 at 3 months after treatment. Patients with T1 lesions enrolling in the phase 2 portion must have a screening biopsy that contains the muscularis layer. All patients in LEGEND must additionally have an Eastern Cooperative Oncology Group performance status of 0, 1, or 2; an absolute neutrophil count of more than 1,500/mm3; a hemoglobin level greater than 9.0 g/dL; a platelet count greater than 100,000/mm3; total bilirubin less than or equal to 1.5 times the upper limit of normal (ULN); aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels less than or equal to 2.5 times the ULN; adequate renal function with creatinine clearance greater than 30 mL/min; prothrombin time and partial thromboplastin time of less than or equal to 1.25 times the ULN or within the therapeutic range if the patient is on anticoagulation therapy; and satisfactory bladder function with the ability to retain EG-70 for a minimum of 60 minutes.

Patients with any malignancy besides NMIBC, basal/squamous cell skin cancers, or noninvasive cancer of the cervix that was diagnosed within 1 year of study entry or that has required therapy for active disease within the last 12 months and patients on concurrent treatment with any chemotherapeutic agent will be excluded from participation in LEGEND. Additional criteria for exclusion are treatment with any previous therapeutic agent within the 30 days before screening; evidence of metastatic disease or persistent or ongoing renal failure; participation in any other study for an investigational agent within 30 days prior to screening; any prior treatment of NMIBC with any investigational gene or immunotherapy agent; treatment with prostate brachytherapy within the last 12 months; active interstitial cystitis as observed by cystoscopy or biopsy; any active and uncontrolled infection requiring systemic therapy; any HIV, Hepatitis B, or Hepatitis C infection; significant cardiovascular risks such as coronary stenting within the past 8 weeks or myocardial infarction within the past 6 months; or hypersensitivity to any of the excipients of the study treatment. Patients with a history of partial cystectomy; unresolved vesicoureteral reflux or an indwelling urinary stent; unresolved hydronephrosis due to ureteral obstruction; external beam radiation to the pelvis; interstitial lung disease or pneumonitis in patients who have previously received a PD-1 or PD-L1 inhibitor therapy; or difficult catheterization that in the opinion of the investigator will prevent administration of EG-70 will also be ineligible to participate.

“enGene’s Phase 1/2 LEGEND study is designed to demonstrate the potential of EG-70 across a broad group of high-risk NMIBC patients, encompassing patients who are unresponsive to BCG as well as those who are naïve to BCG or were unable to receive a full course of treatment due to the ongoing global BCG shortage," Hanson said in a statement issued to 

 in June 2024. "In light of our recently announced decision to expand the study with a third cohort of patients who are BCG-unresponsive with high-risk papillary-only NMIBC, we believe LEGEND is well-positioned to generate a comprehensive dataset in support of EG-70’s use across a spectrum of high-risk NMIBC patients. Furthermore, EG-70 is a nonviral gene therapy candidate designed for straightforward intravesical administration at the point of care and to be well-suited for use in community- and high-volume urology clinics where the majority of NMIBC patients are treated. EG-70 has no thaw process, BSL2-like handling requirements, or pre- or post-treatment requirements for patients.”

EG-70 consists of a plasmid which encodes for IL-12, for the purpose of stimulating the adaptive immune system, and 2 RIG-I agonists, which are intended to stimulate the innate immune system.

 It is intravesically administered as a bladder instillation via catheter with a targeted retention time of 60 minutes. enGene recently presented data from the phase 1 portion of LEGEND at the American Urology Association 2024 Annual Meeting, held May 3-6, 2024 in San Antonio, TX.

“EG-70 was rationally designed to be easy to use and meet the needs of patients and urologists alike," Hanson said in a May 2024 statement.

 "As a nonviral, noninfectious, locally delivered genetic medicine, EG-70 is designed to synergistically activate both the innate and adaptive immune responses, be easily reconstituted in water, and require only a short procedural time. Within the subgroup of patients in LEGEND’s phase 1 who received our optimized phase 2 dose, we saw complete response rates of 70% and 60% at 3 months and 6 months, respectively, which speak to EG-70’s potential to drive durable remissions. The encouraging safety data from the phase 1 study also suggest that this efficacy was achieved without significant impairment to the patients’ quality of life. We look forward to providing additional updates on the broader EG-70 program as we look to expand its potential use across bladder cancer.”

REFERENCES
1. enGene Reports Second Quarter 2024 Financial Results and Provides a Business Update. News release. enGene Holdings Inc. June 14, 2024. Accessed June 24, 2024. https://engene.com/engene-reports-second-quarter-2024-financial-results-and-provides-a-business-update/
2. Kalota S, Joshi S, Bui M, et al. LEGEND: a Phase 1/2 study of EG-70 (detalimogene voraplasmid), a novel, non-viral intravesical gene therapy for patients with BCG-unresponsive nonmuscle invasive bladder cancer with carcinoma in situ (CIS). Presented at: the American Urology Association 2024 Annual Meeting, held May 3-6, 2024 in San Antonio, TX.
3. Steinberg GD, Kalota SJ, Lotan Y, Warner L, Dauphinee, Mazanet R. Clinical results of a phase 1 study of intravesical EG-70 in patients with BCG-unresponsive NMIBC. Presented at: American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, held in San Francisco, California, February 16-18, 2023. Abstract #512
4. enGene announces poster presentation containing interim Phase 1 clinical trial data at the 2023 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium. News release. enGene Inc. February 14, 2023. Accessed June 24, 2024. https://www.newswire.ca/news-releases/engene-announces-positive-preliminary-phase-1-2-data-with-eg-70-in-bcg-unresponsive-non-muscle-invasive-bladder-cancer-848397743.html
5. enGene to present details of its pivotal phase 1/2 LEGEND study of EG-70 in bcg-unresponsive non-muscle invasive bladder cancer with carcinoma in situ at the american urology association 2024 annual meeting. News release. enGene Holdings Inc. May 2, 2024. Accessed June 24, 2024. https://engene.com/engene-to-present-details-of-its-pivotal-phase-1-2-legend-study-of-eg-70-in-bcg-unresponsive-non-muscle-invasive-bladder-cancer-with-carcinoma-in-situ-at-the-american-urology-association-2024-annual-m/

With the company having recently announced that it intends to expand the clinical trial with a new cohort, CGTLive® has decided to take a closer look at this ongoing study. 

Topic

enGene Tackles Nonmuscle-Invasive Bladder Cancer With Expansive Phase 1/2 LEGEND Trial for Gene Therapy EG-70

SNK01 is an autologous, not genetically engineered, natural killer cell therapy with enhanced cytotoxicity and activating receptor expression that is being developed by NKGen Biotech for the potential treatment of 

The company is assessing SNK01 in a phase 1/2a trial (NCT06189963) at a dose of 6 billion SNK01 cells administered every 3 years for 1 year. The phase 1 portion enrolled 3 patients in which the therapy was seen to be well-tolerated. A safety review committee evaluated data from the first portion of the trial and an internal review board subsequently 

 The randomized, double-blind phase 2 trial will further assess efficacy and safety in a planned 30 participants with moderate Alzheimer disease.

“I am encouraged by the continued promise of NKGen’s SNK01 NK cell therapy in a difficult to treat disease such as Alzheimer,” Jesse Carr, MD, Medical Director, Behavioral Research Specialists, Glendale, California, who is independently overseeing the trial site, said in a statement.

“We are seeing remarkable preliminary clinical benefit in all patients without treatment-related adverse events (AEs), including apparent improvements in cognitive function, increases in daily living activities and overall quality of life. I look forward to the potential that this novel drug candidate holds as we continue to progress the trial.”

Altogether, the phase 1/2 trial has a planned enrollment of 36 participants. The study is enrolling individuals that can provide written informed consent and comply with study requirements. A reliable caregiver, in close contact with the participant and able to communicate in the assessment language, must also be available to assist with functional endpoint evaluations and sign a separate consent form. Participants should be aged 40 to 85, have a diagnosis of Alzheimer dementia based on 2011 National Institute on Aging-Alzheimer Association guidelines, possess at least 6 years of formal education, and be fluent in the test language. Female participants of childbearing potential must have a negative pregnancy test at screening and the first visit, and both male and female participants of reproductive potential must agree to abstinence or effective contraception during the study and for 30 days after the final dose. Participants must also have positive amyloid PET evidence of Alzheimer disease within the past 6 months and a CDR-SB score between 9.5 and 16.0.

ALS REGALS Trial Continues to Evaluate Cellenkos’ CK0803 Treg Therapy

Participants will be excluded from the study if they have significant cerebrovascular disease (Fazekas Grade 3), a history of stroke or intracranial hemorrhage related to cognitive impairment, or any substance use disorder not in remission for at least 12 months. Exclusion also applies to those with a history of cancer (excluding basal cell carcinoma) within the last 5 years, uncontrolled cardiovascular conditions, recent cerebrovascular incidents or unexplained loss of consciousness, significant pulmonary or ischemic heart diseases, liver disease or elevated liver enzymes, and gastrointestinal disorders. Immunological disorders, unstable hematological conditions, neurological or psychiatric disorders impacting cognitive function, recent history of major depression or anxiety, seizures in the past 3 years, and uncontrolled endocrine diseases also disqualify participants. Additionally, severe renal impairment, infections like HIV or hepatitis, current anticoagulant treatment (except low-dose aspirin), unstable doses of Alzheimer's medications, contraindications for MRI or PET scans, any medically unstable conditions, recent suicidal behavior or ideation, and any other condition deemed a risk by the investigator are exclusion criteria.

The study’s primary outcome measures include assessing the number of participants experiencing dose-limiting toxicity (DLT) within 3 weeks by reviewing labs, physical exams, and AEs to determine the maximum tolerated dose and the recommended phase 2 dose (RP2D). The number of participants with treatment-related AEs will be evaluated over 1 year using the CTCAE v5.0 criteria to assess the safety and tolerability of SNK01. Additionally, preliminary efficacy will be measured through changes in cognitive assessment scores from baseline over 1 year using various scales, including the Clinical Dementia Rating-Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), Alzheimer's Disease Cooperative Study-Activities of Daily Living-Severe (ADCS-ADL-Severe), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog).

The study’s secondary outcome measures assess changes in cerebrospinal fluid (CSF) and plasma biomarkers, including phosphorylated tau 181 (pTau 181), amyloid-beta 42/40 (Aβ42/40), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL), over the course of one year, comparing these levels to baseline to evaluate the impact of the treatment.

“We are excited to announce another important clinical milestone in our mission to advance SNK01 as the first potential disease modifying treatment of its kind for patients with more advanced Alzheimer’s disease,” Paul Y. Song, MD, Chairman and CEO, NKGen, added.

 “The Phase 2 trial will utilize our cryopreserved SNK01 product given at the highest dose we have ever delivered, and for a full year duration. To date, SNK01 has been found to be well-tolerated with no reported drug-related adverse events (AEs). We are also very encouraged with the clinical progress we have made to date in moderate Alzheimer’s disease research and look forward to generating additional significant clinical and biomarker data from our randomized placebo-controlled Phase 2 trial.”

SNK01 as manufactured by an older manufacturing process was assessed in the proof-of-concept phase 1 ASK-AD trial (NCT04678453). The study was an open label, 3+3 dose escalation study which demonstrated that 4 doses of 1, 2, or 4 billion SNK01 cells administered intravenously were safe and crossed the blood brain barrier to reduce amyloid, tau, and alpha-synuclein proteins. Investigators also observed a dose-dependent decrease in neuroinflammation and 90% of patients had improvements or maintenance in cognitive function as assessed by Alzheimer's disease composite score (ADCOMS).

The FDA also recently cleared NKGen Biotech’s investigational new drug application (IND) for SNK01 to be evaluated in people with Parkinson disease. NKGen expects to dose the first of 30 planned patients in a phase 1/2a clinical trial in the second half of 2024.

1. NKGen Biotech’s SNK01 NK Cell Therapy Cleared to Start Phase 2 Clinical Trial in Alzheimer’s Disease. News release. NKGen Biotech. May 20, 2024. https://www.globenewswire.com/news-release/2024/05/20/2884834/0/en/NKGen-Biotech-s-SNK01-NK-Cell-Therapy-Cleared-to-Start-Phase-2-Clinical-Trial-in-Alzheimer-s-Disease.html
2. NKGen Biotech Presents Updated NK Cell Therapy Data for Neurodegenerative Disease at the 12th Annual Alzheimer’s & Parkinson’s Drug Development Summit. News release. NKGen Biotech, Inc. April 25, 2024. https://nkgenbiotech.com/nkgen-biotech-presents-updated-nk-cell-therapy-data-for-neurodegenerative-disease-at-the-12th-annual-alzheimers-parkinsons-drug-development-summit/
3. NKGen Biotech announces FDA clearance of investigational new drug (IND) application for SNK01 NK cell therapy in Parkinson’s disease. News release. NKGen Biotech, Inc. April 30, 2024. Accessed April 30, 2024. https://nkgenbiotech.com/nkgen-biotech-announces-fda-clearance-of-investigational-new-drug-ind-application-for-snk01-nk-cell-therapy-in-parkinsons-disease/

The phase 1/2 trial is proceeding to its phase 2 trial after safety was demonstrated in its first phase. 

NKGen Continues Progress Evaluating SNK01 NK Cell Therapy for Alzheimer Disease 

Pfizer’s phase 3 CIFFREO study (NCT04281485) evaluating fordadistrogene movaparvovec (PF-06939926), an investigational adeno-associated virus (AAV) vector-based gene therapy expressing what Pfizer calls “minidystrophin”, failed to achieve its primary end point, according to an announcement from the company.

CIFFREO did not demonstrate improvement in gross motor function on the North Star Ambulatory Assessment for patients treated with the gene therapy in comparison to patients treated with placebo at 1 year posttreatment, the measurement that constituted the trial’s primary end point. Pfizer additionally noted that the trial missed the mark on key secondary end points, with patients treated with fordadistrogene movaparvovec showing no significant difference in the change from baseline on 10-meter run/walk test velocity and time to rise from floor velocity compared to patients who received the placebo.

The company characterized the safety profile of the gene therapy as “manageable” in the phase 3 trial. It noted that adverse events (AEs) were mostly mild to moderate in severity, and treatment-related serious AEs that did occur generally responded to clinical management. Pfizer stated that it is currently assessing its next steps for fordadistrogene movaparvovec, and that it will keep monitoring all of the participants in CIFFREO closely.

“We are extremely disappointed that these results did not demonstrate the relative improvement in motor function that we had hoped,” Dan Levy, MD, PhD, the development head for DMD at Pfizer, said in a statement.

 “We plan to share more detailed results from the study at upcoming medical and patient advocacy meetings, with the goal of ensuring that learnings from this trial can help improve future clinical research and development of treatment options that can improve care for boys living with Duchenne muscular dystrophy. We are grateful for the boys, their families, advocates, and the investigators who have participated in this research and the continuing effort to advance treatment options for this debilitating disease.”

According to its clinicaltrials.gov page, which was most recently updated on April 4, 2024, CIFFREO is active but no longer recruiting new patients. The global, multicenter, randomized, double-blind trial had been enrolling boys aged from 4 to 7 years who have a genetic diagnosis of DMD and are taking prednisone, prednisolone, or deflazacort on a stable daily dosing regimen.

 after being treated with fordadistrogene movaparvovec in the separate phase 2 DAYLIGHT study (NCT05429372) evaluating the gene therapy.

 CIFFREO was put on a dosing pause following the fatal AE (DAYLIGHT had already completed dosing prior to the death). Notably, DAYLIGHT’s participants are aged 2 to less than 4 years.

“We do not yet have complete information and are actively working with the trial site investigator to understand what happened,” Pfizer wrote in its letter to Parent Project Muscular Dystrophy.

 “The patient received the investigational gene therapy, fordadistrogene movaparvovec, in early 2023.” The letter noted that the participant had “passed away suddenly”.

Pfizer’s portfolio of gene therapy products also includes fidanacogene elaparvovec-dzkt (Beqvez), an AAV vector-based therapy developed for the treatment of hemophilia B.

 for use by in the United States by the FDA on April 26, 2024. The therapy also received 

 The US indication specifically covers the treatment of adults with moderate to severe hemophilia B who currently use factor IX prophylaxis therapy; or who have a history of, or current, life-threatening hemorrhage; or have repeated, serious spontaneous bleeding episodes, and do not have neutralizing antibodies to the AAVRh74var capsid as determined by 

REFERENCES
1. Pfizer provides update on phase 3 study of investigational gene therapy for ambulatory boys with Duchenne muscular dystrophy. News release. June 12, 2024. Accessed June 13, 2024. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-provides-update-phase-3-study-investigational-gene
2. Letter. Pfizer. https://www.parentprojectmd.org/wp-content/uploads/2024/05/Pfizer-DMD-PAG-Letter_Final.pdf
3. U.S. FDA Approves Pfizer’s BEQVEZ™ (fidanacogene elaparvovec-dzkt), a One-Time Gene Therapy for Adults with Hemophilia B. News release. Pfizer. April 26, 2024. Accessed June 13, 2024. https://www.businesswire.com/news/home/20240425269649/en/U.S.-FDA-Approves-Pfizer%E2%80%99s-BEQVEZ%E2%84%A2-fidanacogene-elaparvovec-dzkt-a-One-Time-Gene-Therapy-for-Adults-with-Hemophilia-B
4. Health Canada approves Pfizer Canada's gene therapy in hemophilia B. News release. Pfizer Canada. January 3, 2024. Accessed June 13, 2024. https://www.newswire.ca/news-releases/health-canada-approves-pfizer-canada-s-gene-therapy-in-hemophilia-b-841249479.html

Pfizer additionally noted that the trial missed the mark on key secondary end points.

Pfizer’s Phase 3 Trial for DMD Gene Therapy Fordadistrogene Movaparvovec Misses the Mark on Primary End Point

Patients with hematologic malignancies treated with IN8bio’s INB-100, an allogeneic gamma-delta T-cell therapy, after receiving haploidentical stem cell transplant (HSCT) have maintained complete remissions (CRs) for over a year.

 The data, which comes from a phase 1 clinical trial (NCT03533816), were presented in a poster at 

the European Hematology Association (EHA) 2024 Congress

, held June 13 to 16, both virtually and in Madrid, Spain.

Among 10 patients who were treated with INB-100 in the trial, all 10 (100%) maintained their state of CR at 12 months or more posttreatment, with a median follow-up time of 17.4 months. It was additionally noted that 3 patients who have high-risk disease have remained free of relapse for more than 35 months. First author Joseph P. McGuirk, MD, the Schutte-Speas professor of hematology-oncology, division director, hematologic malignancies and cellular therapeutics medical director, blood and marrow transplant, at the University of Kansas Cancer Center, and colleagues also pointed out that the study is the first to have shown in vivo expansion and persistence of gamma-delta T-cells for up to a year after HSCT.

“This data demonstrates the potential of allogeneic INB-100 gamma-delta T-cells to provide durable relapse-free periods for high-risk or relapsed acute myeloid leukemia (AML) and other hematologic malignancies undergoing HSCT,” Trishna Goswami, MD, the chief medical officer of IN8bio, said in a statement.

 “100% of evaluable patients remain in complete remission at one year of follow-up. In this trial, the first three patients were high-risk or relapsed AML patients with complex cytogenetics, including trisomy of chromosome 8 and deletion of chromosome 7. All 3 patients remain alive and progression free with one lost-to-follow-up at 42.4 months after they relocated away from the study site. Achieving these outcomes despite giving patients a reduced intensity conditioning regimen, which carries a higher risk of relapse, in an older population with a median age of 68 is very encouraging. We look forward to advancing our novel gamma-delta T cell therapy for patients who need additional options.”

In terms of safety, there were no dose-limiting toxicities and no cases of cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome (ICANS) reported.

 Although, 2 patients did experience cases of cytomegalovirus (CMV) reactivation. Furthermore, one patient experienced a chronic extensive case of graft versus host disease (GvHD) and 2 patients experienced cases of chronic limited GvHD. All cases of acute GvHD (aGvHD) were grade 2 or lower.

Serious adverse events (SAEs) deemed related to treatment included a grade 2 case of rash maculopapular and a grade 3 case of nausea (aGvHD 2B GI). SAEs deemed unrelated to treatment included grade 3 cases of acute kidney injury, anemia, CMV reactivation, fall, and decreased appetite. McGuirk and colleagues noted that infection rates were low, there were no unexpected safety results, and that the AE profile did not differ between dose-level 1 (DL1) and dose-level 2 (DL2).

One patient in the study passed away after treatment with INB-100, but the death was not deemed related to INB-100.The patient’s death was attributed to idiopathic pulmonary fibrosis, which IN8bio noted is a known toxicity caused by transplants.

 The patient did not show evidence of disease progression. Two other patients treated with INB-100 experienced disease relapse, one after 12.5 months in CR and the other after 14.7 months in CR.

 These 2 patients, who the company noted both have 

“The emerging safety, efficacy and durability profile of this novel gamma-delta T cell therapy supports its potential to improve relapse-free survival for patients with blood cancers following allogeneic stem cell transplantation,” McGuirk added to the statement.

 “Approximately 25% of patients relapse within the first 100 days, and nearly half by 1 year post stem cell transplant, which remains the primary cause of treatment failure and mortality. The results of this clinical trial are very encouraging and hold promise that a novel cellular therapy using donor-derived gamma-delta T cells may prevent relapse, resulting in improved relapse-free survival for patients with hematologic malignancies.”

The trial enrolled 14 patients in total, but 1 patient died before receiving INB-100, another patient was treated with an out of specification dose of INB-100, a third patient’s dose was not successfully manufactured, and a fourth patient did not pass screening because their disease relapsed before treatment.

 Four of the 10 succesfully treated patients received INB-100 at DL1 (1x10

 cells/kg) and the other 6 patients received INB-100 at DL2 (3x10

 cells/kg). Eight of the treated patients had AML, 1 had acute lymphoblastic leukemia, and 1 had myelodysplastic/myeloproliferative neoplasms. The treatment group included 6 men and 4 women; ages ranged from 44 to 71 years.

In light of the promising results, IN8bio is working on expanding the DL2 cohort to include 10 additional patients. The company is also planning a confirmatory study.

REFERENCES
1. McGuirk J, Abhyankar S, Goswami T, et al. INB-100: Pilot study of donor derived, ex-vivo expanded/activated gamma-delta t cell infusion following haploidentical hematopoietic stem-cell transplantation and post-transplant cyclophosphamide. Presented at: the European Hematology Association (EHA) 2024Hybrid Congress, June 13-16, held both virtually and in Madrid, Spain. Abstract #P1460
2. IN8bio presents durable complete remission in 100% of evaluable patients in phase 1 inb-100 trial in leukemia at European Hematology Association 2024. News release. June 13, 2024. Accessed June 13, 2024. https://investors.in8bio.com/news-releases/news-release-details/in8bio-presents-positive-data-demonstrating-durable-1-year

Among 10 patients who were treated with INB-100 in the trial, all 10 (100%) maintained their state of CR at 12 months or more posttreatment.

IN8bio’s Gamma-Delta T-cell Therapy INB-100 Helps Maintain Complete Remissions After HSCT in Patients With Hematologic Malignancies

IGNYTE-ESO (NCT03967223) sub study 2 evaluating letetresgene autoleucel (lete-cel; 

) in patients with synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCLS) met its primary endpoint of safety and efficacy at a planned interim analysis, with a 40% overall response rate in evaluable participants.

Data from the substudy were presented at the 

2024 American Society of Clinical Oncology (ASCO) Annual Meeting

, held May 31 - June 4, in Chicago, Illinois, by Sandra P. D’Angelo, MD, sarcoma oncologist, cellular therapist, and associate attending physician, Memorial Sloan Kettering Cancer Center.

“[These data] support the potential of lete-cel as a novel therapy for patients with advanced or metastatic SS and MRCLS. The primary analyses will be presented late 2024 (sic). Further analyses of translational correlates are pending,” D’Angelo said during her presentation.

Lete-cel is comprised of autologous CD4+ and CD8+ T-cells genetically engineered to express a T-cell receptor recognizing NY-ESO-1 peptide presented by HLA-A*2:01, A*2:05, or A*2:06.

The study dosed 73 participants with human leukocyte antigen (HLA)-A*02:01, A*02:05, or A*02:06 and NY-ESO-1–expressing, unresectable or metastatic SS (n = 23; 51%) or MRCLS (n = 22; 49%). Participants received a median of 6.4 billion cells and 51% of patients received bridging therapy between leukapheresis and lymphodepletion.

Eighteen of all 45 patients with at least 6 months of follow-up responded (40% [95% CI, 25.7-55.7]), with similar rates across patients with SS (39% [95% CI, 19.7-61.5) and MRCLS (41% 95% CI, 20.7-63.6]) and an 89% concordance between investigator- and independent-assessed response rates. One patient in each arm (SS and MRCLS) had a complete response. At the time of data cutoff, 9 responses were ongoing and median duration of response was 10.6 months (95% CI, 3.3-not estimable).

"As the current treatment options in these 2 indications are significantly limited, both represent a greatly unmet medical need for novel, innovative therapies,” D’Angelo said in a statement.

In the safety set of 73 participants, the findings were consistent with previous observations with lete-cel,. Most patients (93%) had a serious adverse event (AE); 83% had serious cytokine release syndrome (CRS). Grade 1 immune-effector cell associated neurotoxicity occurred in 3 (4%) patients and grade 3 rash occurred in 23 (32%) patients. Two patients (5%) experienced grade 5 AEs associated with lymphodepletion; these were neutropenia in the setting of pancytopenia that led to a fatal pulmonary infection, and pulmonary alveolar hemorrhage in the setting of pancytopenia and a platelet count of 0.

"We're encouraged by the findings from the IGNYTE-ESO trial and the potential of our sarcoma franchise. Our lead cell therapy product, afami-cel, targets MAGE-A4 in synovial sarcoma and the ability to now also target the NY-ESO-1 cancer antigen with lete-cel will enable us to reach a greater number of people impacted by advanced sarcomas. We are eager to continue advancing lete-cel to further realize the promise of engineered TCR T-cell therapies for patients and healthcare providers... We continue to work toward commercializing afami-cel later this year and lete-cel in 2026,” Dennis Williams, PharmD, Senior Vice President, Late-Stage Development, Adaptimmune, added.

1. D’Angelo SP, Furness AJS, Thistlethwaite D, et al. Lete-cel in patients with synovial sarcoma or myxoid/round cell liposarcoma: Planned interim analysis of the pivotal IGNYTE-ESO trial. Presented at: 2024 (ASCO) Annual Meeting; May 31 - June 4; Chicago, Illinois. Abstract #2500
2. Adaptimmune to Present Data from Planned Interim Analysis of Pivotal IGNYTE-ESO Trial with Lete-cel at ASCO; Data Continue to Support further Development of Sarcoma Franchise. News release. Adaptimmune. June 3, 2024. https://www.adaptimmune.com/investors-and-media/news-center/press-releases/detail/270/adaptimmune-to-present-data-from-planned-interim-analysis

Nine responses were ongoing as of the March 2023 cutoff date. 

Lete-cel Study in Synovial Sarcoma, MRCLS Meets Primary Endpoint With 40% ORR 

MELPIDA (AAV9/AP4M1; Elpida Therapeutics)

has been well-tolerated in patients with hereditary spastic paraplegia, type 50 (SPG50).

Initial data from a phase 1 study (NCT05518188) were presented at the 

American Society of Gene & Cell Therapy (ASGCT) Annual Meeting 2024

, held May 7-10 in Baltimore, Maryland, by Souad Messahel, BS, MS, PhD, head, clinical operations, Elpida Therapeutics.

“Our approach utilizes early intervention and higher intrathecal AAV doses than are used in most other intrathecal AAV clinical trials. We speculate that the self-complimentary design of the vector contributes to its potential efficacy, and the relatively modest strength UsP promoter contributes to its safety,” Messahel and colleagues wrote in their poster.

SPG50 is a rare, autosomal recessive disorder caused by biallelic variants in the AP4M1 gene which impact the function of adaptor complex 4 proteins (AP4). Children with SPG50 have a progressive spastic paraplegia that starts in infancy or early childhood, which may evolve into progressive lower-extremity spasticity. Most children become non-ambulatory and wheelchair dependent. There are no current disease-modifying therapies available for SPG50 and standard of care treatment is palliative and aims to prevent secondary complications.

Carlos A. Ramos, MD, on Alternatives to T-Cell Therapy

MELPIDA delivers a functional AP4M1 transgene via an adeno-associated virus (AAV9) vector and has demonstrated safety and meaningful benefits in murine studies. The phase 1 study is recruiting participants with SPG50 between the ages of 4 months and 10 years at UT Southwestern Medical Center in Dallas, Texas. Data have been reported from 4 participants up to 24 months post treatment with MELPIDA, 3 in the United States and 1 treated separately in Canada. Three participants aged 3 to 5 years received 1x10

 vg MELPIDA and the fourth, 5-month-old participant with presymptomatic SPG50 received 4x10

 vg. The authors noted that that patient may be the youngest patient dosed intrathecally with AAV9.

MELPIDA has had a positive safety profile so far, with no negative immune responses and a manageable safety profile, as measured by MRI brain and spine scans, cerebral spinal fluid analysis, complete blood profiles, EKGs, and nerve conduction studies. There has been no evidence of dorsal root ganglion toxicity and nerve conduction was stable or improved after treatment.

Future data will report on efficacy measures being assessed in the study, including Clinical Global Impression of Overall Change, Vineland Adaptive Behavior Scales, Bayley Scales of Infant and Toddler Development, Caregiver Priorities and Child Health Index of Life with Disabilities, Spastic Paraplegia Rating Scale, Gross Motor Function Measure, 3-minute walk test, and SPATAX-EUROSPA Disability Score. After the initial 24 month period of follow-up there will be annual visits for 3 more years.

“Since SPG50 is caused by a monogenic mutation, gene replacement therapy may be a good choice to treat the disease. As AAV9/AP4M1 is expected to provide a fully functional human AP4M1 cDNA copy to participant’s neuronal cells, there is a potential for reducing the neurodegeneration in patients,” Messahel and colleagues concluded their poster. “These preliminary data in humans that demonstrate its safety and tolerability, in addition to proven observations of safety and efficacy of the preclinical in vitro and in vivo studies, justify the clinical development of MELPIDA for the SPG50 population, for which there is a significant unmet medical need.”

Click here to read more coverage of the 2024 ASGCT Annual Meeting.

Messahel S, Chen X, Pirovolakis T, et al. Preliminary Safety Data of a Phase 1/2 Clinical Trial to Support the Use of High Dose Intrathecal AAV9/AP4M1 for the Treatment of Patients with SPG50 Disease. Presented at: ASGCT Annual Meeting 2024, May 7-10; Baltimore, Maryland.

MELPIDA was well-tolerated in patients and nerve conduction was stable or improved after treatment.

Nathan Yozwiak, PhD

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