Noah Stansfield

The Israeli Ministry of Health (IMOH) has cleared a phase 1/2 clinical trial (NCT05581719) investigating Enlivex’s Allocetra cell therapy for the treatment of solid tumors for continuation, following a positive review from an independent data and safety monitoring board (DSMB) of data from the first cohort.

Allocetra is an investigational allogeneic cell therapy intended to reprogram macrophages that have become "pro-tumor" tumor associated macrophages (TAMs) back into a homeostatic state.

 It is comprised of non-HLA matched peripheral blood mononuclear cells derived from a healthy human donor that have been induced into an apoptotic stable state. The clinical trial’s first cohort treated 3 patients with Allocetra as monotherapy.

 Allocetra was administered either intravenously (IV) or intraperitoneally (IP), depending on tumor location, in 3 once-weekly doses. At 21 days of follow-up from the first dose, there were no deaths or safety signals identified by the DSMB for the 3 treated patients. The DSMB recommended that the trial continue without modifications to its design. In light of the data, the IMOH provided regulatory clearance for Enlivex to begin recruiting patients for the trial’s next 2 cohorts, which will treat patients with higher doses of Allocetra. In 1 of these cohorts, patients will receive Allocetra as a monotherapy, while in the other cohort, patients will receive Allocetra in combination with the anti-PD1 immune checkpoint inhibitor nivolumab.

"We are pleased with the safety profile of Allocetra as demonstrated in the first 3 patients in this trial,” Oren Hershkovitz, PhD, chief executive officer, Enlivex, said in a statement regarding the news.

 “We look forward to initiating the next 2 cohorts in which higher doses of Allocetra will be administered in patients, allowing Enlivex to obtain additional safety data as well as a potential indication of effect."

In total, the multicenter, open-label, dose escalation trial is anticipated to enroll approximately 48 patients aged 18 years and older who have advanced, unresectable or metastatic solid tumors. Patients are required to have relapsed or been refractory to available approved therapies, or to be ineligible for or declined treatment with additional standard of care systemic therapy. Patients with peritoneal carcinomatosis may be included if an appropriate IP catheter or port is placeable. Patients are additionally required to have measurable disease, an Eastern Cooperative Oncology Group score of 1 or lower, and adequate renal, hepatic, and bone marrow function. Patients with clinically unstable primary central nervous system (CNS) malignancy or CNS involvement; clinically significant uncontrolled infection; autoimmune or inflammatory diseases requiring systemic immunosuppression; clinically significant cardiovascular disease; severe pulmonary diseases; or additional malignancies will be excluded from participation. Participants in the trial’s second stage, which will treat patients with the combination therapy approach, must additionally not have previously had an immune checkpoint inhibitor (ICI)-related adverse reaction that resulted in discontinuation of the ICI.

The study’s primary end point is safety based on dose-limiting toxicities. Secondary end points include the overall response rate (ORR) and best ORR, clinical benefit rate, duration of response, time to response, progression-free survival, and overall survival. Changes in immune cell and cytokine profiling in the peritoneal fluid will also be evaluated. The trial is recruiting at several centers in Israel and is estimated to be completed in June 2024.

originally cleared the trial for initiation

 Allocetra had previously demonstrated potential in preclinical research. In an ovarian cancer mouse model, mice treated with Allocetra in combination with an anti-PD1 checkpoint inhibitor showed an 83% increase in survival duration compared to an untreated group.

 Additionally, the combination therapy group had a survival probability up to 50%, compared to 0% in the untreated group. In addition to solid tumors, Allocetra is also being evaluated for the treatment of patients with peritoneal metastasis (NCT05431907), patients with COVID-19 (NCT04659304, NCT04922957), 

1. Enlivex announces positive DSMB recommendation and IMOH clearance to continue phase I/II trial of Allocetra in patients with advanced solid tumors. News release. Enlivex Therapeutics Ltd. Janaury 25, 2023. Accessed Janaury 25, 2023. 

https://finance.yahoo.com/news/enlivex-announces-positive-dsmb-recommendation-133700145.html

2. Enlivex receives Israeli Ministry of Health approval for the initiation of a phase I/II trial evaluating Allocetra alone and in combination with a PD1 checkpoint inhibitor in patients with advanced solid tumors. News release. Enlivex Therapeutics Ltd. August 17, 2022. 

https://www.globenewswire.com/news-release/2022/08/17/2499939/0/en/Enlivex-Receives-Israeli-Ministry-of-Health-Approval-for-the-Initiation-of-a-Phase-I-II-Trial-Evaluating-Allocetra-Alone-and-in-Combination-with-a-PD1-Checkpoint-Inhibitor-in-Patie.html

3. Enlivex announces new preclinical data in ovarian cancer showing a substantial survival benefit when Allocetra is combined with PD-1 checkpoint inhibition at the American Society of Clinical Oncology (ASCO) annual meeting. News release. Enlivex Therapeutics Ltd. May 31, 2022. 

https://www.globenewswire.com/en/news-release/2022/05/31/2453221/0/en/Enlivex-Announces-New-Preclinical-Data-in-Ovarian-Cancer-Showing-a-Substantial-Survival-Benefit-when-Allocetra-is-Combined-with-PD-1-Checkpoint-Inhibition-at-the-American-Society-o.html

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There were no deaths or safety signals identified by the DSMB for the 3 treated patients in cohort 1.

Solid Tumor Cell Therapy Combination Trial Cleared to Continue

Orbsen Therapeutics’ ORBCEL, an investigational allogeneic bone marrow-derived mesenchymal stromal cell (MSC) therapy being evaluated in the phase 1/2a NEPHSTROM clinical trial (NCT02585622) for the treatment of progressive diabetic kidney disease (DKD) in adults with type 2 

 (T2D), has generated promising safety and efficacy data in interim results from the study’s first cohort.

ORBCEL consists of highly purified immunomodulatory stromal cells and is administered intravenously. The first cohort treated 12 participants with ORBCEL at a dose of 80x10

 cells and 4 participants with a placebo (Cryostor CS10). It was noted that the safety and tolerability profile was similar for both the ORBCEL and placebo cohorts, with no adverse events (AEs) related to the infusions of stromal cells reported. In terms of efficacy, serum creatinine-based estimated glomerular filtration rate (CKD-EPI, 

 = 0.034) measurements indicated a statistically significant association between ORBCEL treatment and preservation of kidney function over baseline during the study's 18 month duration, in comparison to the treatment with the placebo. Furthermore, it was noted that, based on monitored blood markers, evidence of stabilization in the proportion of regulatory T-cells in the blood was associated with treatment with ORBCEL, while a tendency for a decrease in the proportion of regulatory T-cells in the blood was observed in patients who received the placebo.

"The current standard of care for DKD patients includes multiple types of drug therapy, such as renin-angiotensin-aldosterone system inhibitors and the more recently approved drug class known as sodium-glucose transporter 2 (SGLT2) inhibitors, which have a proven ability to slow the decline of kidney function,” Guiseppe Remuzzi, director, Mario Negri Institute for Pharmacological Research IRCCS, Bergamo, Italy, said in a statement regarding the news. “However, these medication classes are not tolerated by all patients and are not always effective to fully halt or reverse the progression of kidney injury in DKD. ORBCEL cell therapy might be particularly useful as an additional treatment in patients with rapidly progressive kidney disease caused by diabetes."

The multicenter, double-blind NEPHSTROM study is enrolling patients aged at least 40 years and less than 85 years who have had T2D for at least 3 years. Participants are additionally required to have a urinary albumin excretion of at least 60 µg/min, a urine albumin-to-creatinine ratio of at least 88 mg/g, an estimated GFR (eGFR) of 30 to 50 ml/min/1.73 m

 by the CKD-EPI equation on 2 or more consecutive measurements at least 30 days apart within the previous 6 months, and a documented decline of eGFR of at least -10ml/min/1.73 m

 over the past 3 years or a documented rate of eGFR decline of at least -5 ml/min/1.73 m

per year based on 3 or more consecutive readings at least 90 days apart in the previous 18 months. Participants must also not have a suspected 

 diagnosis other than DKD. Patients with a current resting systolic blood pressure (BP) of 150 mmHg or greater and a current resting diastolic BP greater than or equal to 90 mmHg in a clinical setting, even with treatment with 3 hypertensive agents of different classes; patients who began treatment with a new anti-hypertensive agent, a new lipid lowering agent, or a new hypoglycemic agent within the past 6 months; patients who increased their dose of an anti-hypertensive agent by 100% or more of the previous dose within the previous 3 months; patients with a current HbA1c greater than 75 mmol/mol, a current fasting total cholesterol more than 7 mmol/l, or current fasting total triglycerides more than 3.5 mmol/l will be excluded from participation. Patients who screen positive for clinically significant anti-HLA antibodies will also be excluded. Additional exclusion criteria relate to patient health status, health history, and treatment history.

The study’s primary end point is the number and severity of all pre-specified infusion-associated events and the overall number and frequency of adverse events. Among the study’s numerous secondary end points are measures of GFR, Urinary Albumin/Creatinine Ratio, Urinary albumin excretion, and fasting blood glucose. The study is taking place at locations in Ireland, Italy, and the United Kingdom.

Orbsen Therapeutics has announced its intention to submit the results from the first cohort to a peer-reviewed journal for publication. The company also noted that the trial’s second cohort, which will treat 13 patients, either at a dose of 160x10

 cells or with the placebo, completed enrollment in late 2022, and interim data from this cohort is anticipated in the second half of 2023. A phase 2b study for ORBCEL is also in the planning stage, with the company seeking communication with regulatory agencies regarding trial design.

"We're very encouraged by the safety profile and the preliminary efficacy signal that we have seen with our allogeneic cell therapy in patients with diabetes and chronic kidney disease,” Stephen Elliman, chief scientific officer, Orbsen Therapeutics, added to the statement. “Our goal with ORBCEL is to resolve systemic inflammation and improve kidney function, so that these patients will not require dialysis or a kidney transplant. The growing burden of DKD and its impact on healthcare make this an important disease target for Orbsen and our technology."

Orbsen Therapeutics announces encouraging interim results from the NEPHSTROM proof of concept clinical study evaluating ORBCEL cell therapy in patients with diabetes and advanced chronic kidney disease. News release. Orbsen Therapeutics Limited. January 26, 2023. Accessed January 27, 2023. 

https://finance.yahoo.com/news/orbsen-therapeutics-announces-encouraging-interim-090000140.html

No adverse events related to the infusions of stromal cells were reported.

MSC Therapy Shows Promise in Diabetic Kidney Disease

The phase 3 CARTITUDE-4 clinical trial (NCT04181827), which is evaluating Janssen’s and Legend Biotech's ciltacabtagene autoleucel (cilta-cel; CARVYKTI) against standards of care (SOC) in the treatment of relapsed/refractory multiple myeloma (MM), will be unblinded according to an independent data monitoring committee recommendation following the study meeting its primary end point in a pre-specified interim analysis.

CARTITUDE-4 is evaluating cilta-cel for the treatment of relapsed and lenalidomide-refractory MM against SOC pomalidomide, bortezomib, and dexamethasone (PVd) and daratumumab, pomalidomide, and dexamethasone (DPd). The chimeric antigen receptor (CAR) T-cell therapy demonstrated a significant improvement in progression-free survival (PFS), the study's primary end point, over PVd and DPd. 

“The CARTITUDE-4 study represents the first phase 3 program in our comprehensive clinical development strategy for CARVYKTI, and further demonstrates our commitment to advance the treatment of patients with relapsed/refractory MM,” Jordan Schecter, MD, vice president, Clinical Development Cellular Therapy Program, Janssen Research & Development, LLC, said in a statement regarding the news.

 “We look forward to the presentation of the data from the CARTITUDE-4 study at a future medical meeting.”

CARTITUDE-4 enrolled 419 patients aged 18 years and older who had received between 1 and 3 prior lines of therapy for MM, including a proteasome inhibitor and an immunomodulatory drug. Participants were required to have measurable disease at screening; to have documented evidence of progressive disease according to International Myeloma Working Group criteria based on investigator determination within 6 months of their last regimen; to be refractory to lenalidomide according to study-specific criteria; and to meet a set of study-specific clinical laboratory value requirements. Patients who had previously been treated with any CAR T-cell therapy; those who had previously been treated with B-cell maturation antigen (BCMA)-targeting therapy; and those experiencing ongoing toxicity from previous anticancer therapy that had not resolved to baseline levels or to grade 1 or less, excepting alopecia, were excluded from participation. Additional exclusion criteria related to other treatment history. Patients who had grade 1 peripheral neuropathy with pain or grade 2 or higher peripheral neuropathy were not eligible to receive PVd in the trial but could receive DPd. 

Among the trial’s numerous secondary end points are complete response rate, overall minimal residual disease negative rate, overall survival, overall response rate, time to worsening of symptoms, and incidence and severity of adverse events. The trial has an estimated completion date of April 10, 2026. 

Cilta-cel previously demonstrated positive results in the phase 2 

 clinical trial (NCT04133636), including a 100% overall response rate in patients who had experienced early relapse after initial treatment for MM.

, MD, PhD, professor, cancer immunology and hematology, Amsterdam University Medical Centers, about data from CARTITUDE-2.

"Cilta-cel has now shown efficacy in early relapse and end stage patients...,” van de Donk said in the interview. “Because of the high efficacy of cilta-cel in high-risk populations and end stage myeloma, cilta-cel is not only moving to 1 to 3 prior lines, but there are also now several studies that will soon start enrolling patients in the first line. We hope to see that cilta-cel is really superior to autologous stem cell transplant and will improve the clinical outcomes of newly diagnosed myeloma patients.”

1. Janssen announces unblinding of phase 3 CARTITUDE-4 study of CARVYKTI (cilta-cel) as primary endpoint met in treatment of patients with relapsed and refractory multiple myeloma. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. January 27, 2023. Accessed January 27, 2023. 

https://www.jnj.com/janssen-announces-unblinding-of-phase-3-cartitude-4-study-of-carvykti-cilta-cel-as-primary-endpoint-met-in-treatment-of-patients-with-relapsed-and-refractory-multiple-myeloma

2. van de Donk NWCJ, Agha ME, Cohen AD, et al. Biological correlative analyses and updated clinical data of ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR-T cell therapy, in patients with multiple myeloma (MM) and early relapse after initial therapy: CARTITUDE-2, cohort B. Presented at: 2022 ASCO Annual Meeting, June 3-7, 2022. Poster #453.

Cilta-cel demonstrated a significant improvement in progression-free survival over standards of care.

Cilta-cel CARTITUDE-4 Trial to be Unblinded After Meeting Primary End Point

A phase 1a clinical trial for Chimeric Therapeutics’ CHM 1101 (CLTX CAR T), an autologous investigational chimeric antigen receptor T-cell (CAR-T) therapy being evaluated for the treatment of 

-positive recurrent/progressive glioblastoma, has reached 28 days of follow-up for all patients dosed in its third cohort, with no dose-limiting toxicities (DLTs) reported.

CHM 1101 utilizes a chlorotoxin (CLTX) tumor-targeting domain, which is derived from deathstalker scorpion venom.

 The therapy was licensed by Chimeric Therapeutics from City of Hope National Medical Center, which developed it.

 The 3 patients in the trial’s third cohort received CHM 1101 at a total dose of 240x10

, with half of the dose delivered by intratumoral (ICT) administration and half of the dose delivered by intracerebroventricular (ICV) administration.

 Chimeric Therapeutics announced that the trial will advance to the dosing of patients in its fourth and last cohort. Patients in the fourth cohort will be treated with a total dose of 440x10

 cells, split across the same routes of ICT and intraventricular ICV administration.

Data from patients in the trial’s second dose cohort, who received a total dose of 88x10

 Chimeric Therapeutics noted that the administration of the therapy was generally well tolerated in this cohort, and that 2 of the 3 treated patients achieved local disease stability.

“This preliminary data is encouraging as it demonstrates safety with dual routes of administration,” Behnam Badie, MD, professor and chief, Division of Neurosurgery; director, Brain Tumor Program, Department of Surgery, City of Hope, said in a February 2022 statement.

 “We now look forward to advancing the trial to higher dose levels which may provide more therapeutic benefit to patients."

Earlier, in November 2021, the company presented data from the trial’s first cohort.

 The first cohort included 4 patients who received 44x10

 cells via the ICT route of administration only. Among these patients, 3 achieved stable disease. It was additionally reported that the CHM 1101 cells persisted in the tumor cavity throughout treatment, indicating non-immunogenicity, and that the therapy was generally well tolerated in this cohort. A case of grade 3 edema occurred, which was deemed “possibly” related to CHM 1101; however, it was noted that cerebral edema is a common adverse event in patients with 

. Furthermore, a correlation between expression of 

 on tumor cells and binding with CLTX was observed, indicating that 

 positivity may be able to function as an indicator of response for the therapy. 

The phase 1a study is expected to enroll 18 to 36 patients in total across the 4 dose cohorts.

 A phase 1b clinical trial (NCT05627323), which has an estimated enrollment of 42 patients, is planned, but the initiation of recruitment has not yet been announced. Chimeric Therapeutics noted that it may explore CLTX CAR-T therapy for additional solid tumor indications, beginning with metastatic 

1. Successful completion of 28-day follow up period for 3rd patient cohort in brain cancer phase 1 trial. News release. Chimeric Therapeutics. January 23, 2023. Accessed January 23, 2023. 

https://chimerictherapeutics.com/wp-content/uploads/2023/01/Follow-up-Period-completed-for-3rd-Cohort-in-CHM1101-Trial-23-Jan-2023.pdf

2. CHM 1101(CLTX CAR T) phase 1 initial data release. Webinar. Chimeric Therapeutics. November 2021. Accessed January 23, 2023. 

https://chimerictherapeutics.com/wp-content/uploads/2021/11/CHM-1101-CLTX-CAR-T-Phase-1-Initial-Data-Release-Presentation.pdf

3. Encouraging data reported for 2nd dose cohort in CLTX CAR T trial. News release. Chimeric Therapeutics. February 8, 2022. Accessed January 23, 2023. 

https://chimerictherapeutics.com/wp-content/uploads/2022/02/2nd-CLTX-Cohort-COH-FINAL.pdf

4. Completion of dosing in 3rd dose cohort in CHM 1101 (CLTX CAR T) clinical trial. News release. Chimeric Therapeutics. December 22, 2022. Accessed January 23, 2023. 

https://chimerictherapeutics.com/wp-content/uploads/2022/12/Completion-of-Dosing-in-3rd-Dose-Cohort-in-CHM-1101-CLTX-CAR-T-Clinical-Trial-22-Dec-2022.pdf

No dose-limiting toxicities were observed at 28 days of follow-up.

Glioblastoma CAR-T Trial Completes Initial Follow-up of Third Dose Cohort

XyloCor Therapeutics’ XC001 (AdVEGFXC1), an investigational 

 intended to treat refractory angina, has demonstrated promising safety and efficacy in newly announced data from the phase 2 portion of the phase 1/2 EXACT clinical trial (NCT04125732).

 muscle via a transthoracic epicardial procedure as a 1-time treatment. It is intended to increase the expression of vascular endothelial growth factor (VEGF) in order to induce the creation of new blood vessels, which is expected to reduce ischemic burden. The phase 2 portion of EXACT treated 28 patients. At 6 months of follow-up, decreases in ischemic burden on cardiac positron emission tomography (PET) imaging were observed in the patients. It was additionally noted that prior to administration of the therapy, almost all of the participants' physical activity was substantially limited, while nearly half of the participants were able to engage in normal physical activity without angina at 6 months post-treatment. In terms of safety, there were no unexpected serious adverse events (AEs) observed in relation to the therapy’s administration, and no safety issues related to the therapy were reported.

"We are excited to see EXACT completing its 6-month endpoint,” Thomas Povsic, MD, PhD, professor of Medicine, Duke University School of Medicine, and national principal investigator for the EXACT study, said in a statement regarding the news.

 “The trial met all of its safety and exploratory objectives, showing intriguing benefits in these needy patients across a variety of objective and subjective measures. The strong range of mechanistic evidence demonstrate that administration of XC001 is a scientifically-sound approach for achieving a biological effect that has the potential to improve patients’ quality of life."

The phase 2 data builds on the results of the trial’s phase 1 portion, data from which were announced in May 2022.

 Among 7 of the 12 patients treated in the first phase, there were 17 serious AEs reported by 6 months of follow-up, but none were deemed related to the gene therapy. These AEs included 6 events deemed related to the administration procedure for XC001 and 11 events deemed related to the underlying disease or other causes. The 6 administration-related AEs occurred in 4 patients and were not considered to be unexpected.

The multicenter, open-label EXACT study enrolled 41 participants in total, with an age eligibility of 18 years to 80 years. The phase 1, dose-escalation portion treated participants at 4 ascending dose levels, with 3 participants in each dose cohort: 1x10

 vp. A dose-dependent correlation was inferred based on a preliminary efficacy data analysis, and as such, the highest of the dose levels was selected for the study’s phase 2 expansion portion. The trial’s primary end point is safety as assessed by AEs and serious AEs. Secondary end points include an exercise tolerance test, the Seattle Angina Questionnaire, Canadian Cardiovascular Society angina class, and angina episodes.

"We are excited to share this positive topline data from the phase 2 portion of the EXACT trial, reinforcing our confidence in XC001 as a novel therapeutic approach with the potential to address the significant unmet medical needs of people with refractory angina," Al Gianchetti, president and chief executive officer, XyloCor Therapeutics, added to the statement.

 "We now look forward to pursuing key upcoming milestones in XC001’s continued development, including finalizing our pivotal trial design through our ongoing discussions with the FDA and other regulatory authorities."

1. Xylocor Therapeutics reports positive topline safety and efficacy results from phase 2 EXACT clinical trial of XC001 novel gene therapy for refractory angina. News release. XyloCor Therapeutics. January 26, 2023. Accessed January 26, 2023. 

http://www.xylocor.com/news.html#:~:text=XyloCor%20Therapeutics%20Reports%20Positive%20Topline%20Safety%20and%20Efficacy%20Results%20from%20Phase%C2%A02%20EXACT%20Clinical%20Trial%20of%20XC001%20Novel%20Gene%20Therapy%20for%20Refractory%C2%A0Angina

2. Xylocor Therapeutics announces presentation of preliminary clinical data from phase 1 portion of the EXACT phase 1/2 study of XC001 novel gene therapy for refractory angina at AATS and ASGCT. News release. XyloCor Therapeutics. May 18, 2022. Accessed January 26, 2023. 

http://www.xylocor.com/news.html#:~:text=XyloCor%20Therapeutics%20Announces%20Presentation%20of%20Preliminary%20Clinical%20Data%20from%20Phase%C2%A01%20Portion%20of%20the%20EXACT%20Phase%C2%A01/2%20Study%20of%20XC001%20Novel%20Gene%20Therapy%20for%20Refractory%20Angina%20at%20AATS%20and%C2%A0ASGCT

Nearly half of participants were able to engage in normal physical activity without angina at 6 months post-treatment.

Refractory Angina Gene Therapy Demonstrates Safety and Efficacy in Phase 2 Trial 

Capricor Therapeutics’ CAP-1002, an investigational allogeneic cardiosphere-derived cell therapy intended to treat 

, has demonstrated efficacy in updated 18-month data from the HOPE-2 clinical trial (NCT03406780)’s open-label extension (OLE) study (HOPE-2-OLE; NCT04428476).

HOPE-2-OLE enrolled 13 of the 20 patients who had previously participated in HOPE-2, 6 of whom had received CAP-1002 in HOPE-2 and 7 of whom had received a placebo. Twelve of these 13 patients completed 18 months of follow-up after treatment with CAP-1002 in HOPE-2-OLE. Capricor Therapeutics reported that at the 18-month follow-up, the patients demonstrated statistically significant (

 = 0.02) improvements on the Performance of the Upper Limb (PUL version 2.0) scale compared to the placebo group from HOPE-2. Patients who received CAP-1002 in HOPE-2-OLE also demonstrated attenuation of disease progression, regardless of whether they had participated in the treatment group or the placebo group in HOPE-2. During the OLE, CAP-1002 was well-tolerated with a consistent safety profile.

The new data from HOPE-2-OLE builds on the positive data from HOPE-2, including PUL, cardiac MRI assessments, and left ventricular ejection fraction (LVEF) findings. Patients who received CAP-1002 had a favorable mean 2.6-point improvement difference from baseline on the PUL 1.2 mid-level dimension compared to the patients who received placebo (

 = 0.014), improvements in heart structure and function on cardiac MRI assessments, and an increase in LVEF indicating slowing of cardiac disease progression by 107% (

 = 0.002). HOPE-2 included pediatric and young adult male patients with DMD who are non-ambulant. The patients received infusions of either CAP-1002 or the placebo every 3 months, with the data analyzed at 12 months after the first infusion. In terms of safety, it was noted that 3 patients in HOPE-2 experienced infusion-related hypersensitivity reactions without long-term sequelae and 1 patient discontinued participation in relation to a severe allergic rection

“DMD is a progressive disease associated with loss of function over time and there is a critical need for treatment options to slow the rate of decline and preserve upper limb function to enable key everyday activities,” Craig McDonald, national principal investigator and University of California, Davis, professor and Department of Physical Medicine and Rehabilitation chair, said in a statement regarding the news.

 “We are encouraged by the improvements in upper limb function in the treatment group at 18-months and will continue to treat and follow these patients to further evaluate the disease modifying potential of CAP-1002. Taken together, these data build on the impressive results from HOPE-2 and suggest that patients accumulate benefit over time with steady preservation of skeletal muscle functions, which underscore the potential long-term benefit of CAP-1002.”

The participants in HOPE-2-OLE began treatment between 239 and 567 days (mean, 392) after ending treatment with CAP-1002 or the placebo in HOPE-2. In HOPE-2-OLE, the participants received infusions of 150 million CAP-1002 cells every 3 months for 18 months. The trial’s primary end points are the incidence and severity of all treatment-emergent adverse events (TEAEs) at 12 months and the mean change from baseline in upper limb function according to PUL 2.0 at 12 months. Secondary end points include the incidence and severity of all TEAEs at 24 and 36 months; the change from baseline in PUL at 24 and 36 months; the change from baseline in distal-level PUL at 12, 24, and 36 months; the change from baseline in mid-level PUL at 12, 24, and 36 months; and the mean change from baseline in LVEF at 24 and 36 months.

CAP-1002 is now also being evaluated in the phase 3 HOPE-3 clinical trial (NCT05126758). The randomized, double-blind, placebo-controlled study is currently enrolling, with an expected total enrollment of approximately 70 patients. In July 2022, 

“In the OLE phase of the HOPE-2 study, we observed statistically significant slowing of the progression of disease across patients treated with CAP-1002,” Linda Marbán, PhD, chief executive officer, Capricor, added to the statement.

 “We are extremely pleased by the robust and consistent results observed to date, which, together with the favorable safety/tolerability profile, suggest that CAP-1002 holds promise as a potential anchor therapy for DMD patients. Further, the long-term efficacy and potential disease modification effect will augment our clinical package as we continue on our regulatory pathway towards potential approval of CAP-1002 for treatment of patients with DMD. We thank the patients, their families, caregivers, and the broader Duchenne community for working with us on this promising therapy.”

1. Capricor Therapeutics announces positive 18-month results from ongoing HOPE-2 open label extension study of CAP-1002 in Duchenne muscular dystrophy patients. News release. Capricor Therapeutics. January 25, 2023. Accessed January 25, 2023. 

https://feeds.issuerdirect.com/news-release.html?newsid=7181150467767720

2. McDonald CM, Marbán E, Hendrix S, et al. Repeated intravenous cardiosphere-derived cell therapy in late-stage Duchenne muscular dystrophy (HOPE-2): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet. 2022;399(10329):1049-1058. Doi: 10.1016/S0140-6736(22)00012-5

3. Capricor Therapeutics announces first patient dosed in pivotal phase 3 study of CAP-1002 for the treatment of Duchenne muscular dystrophy. News release. Capricor Therapeutics. July 19, 2022. Accessed January 25, 2023. 

https://feeds.issuerdirect.com/news-release.html?newsid=7011515935297837

Patients continued to show statistically significant upper limb performance improvements. 

DMD Cell Therapy Continues to Demonstrate Efficacy After 18-month Follow-up 

The cell and gene therapy sectors are growing exponentially, with new players emerging daily and much progress being made both in and out of the lab. 

Around the Helix is your chance to catch up with the latest news in cell and gene therapies, including partnerships, pipeline updates, and more.

1. 10 Cell and Gene Therapies to Watch in 2023

With several Prescription Drug User Fee Act dates already on the calendar and a host of biologics license applications on the horizon, there are 10 therapies we’ll have our eyes on in 2023.

2. Editas Sells off iNK Preclinical Cell Therapy Program, Gene-Editing Technologies to Shoreline

Shoreline Biosciences’ is acquiring Editas Medicines’ cell therapy programs, including its induced pluripotent stem cell derived natural killer cell (iNK) preclinical programs, and licensing its SLEEK (SeLection by Essential-gene Exon Knock-in) and AsCas12a gene editing technologies for oncologic and other indications.

3. Late-Onset Pompe Disease Gene Therapy Cleared to Continue Trial

The FDA has lifted the clinical hold on Astellas Pharma’s phase 1/2 FORTIS trial (NCT04174105) of AT845 in patients with late-onset Pompe disease (LOPD). Astellas is working to resume dosing in the trial.

4. Rett Syndrome Gene Therapy Cleared for Clinical Trial

The FDA has cleared Neurogene’s investigational new drug application of NGN-401 and the company is planning to initiate a phase 1/2 clinical trial to evaluate intracerebroventricular (ICV) injection of the gene therapy in girls with Rett syndrome in 2023.

5. Catalent Announces New Case Management Service for Cell and Gene Therapy Supply Chains

The service will assign customers a case manager who serves as a point of contact for the entire process of supply, manufacture, and delivery.

6. Regen BioPharma Files Patent Application for Method of Stimulating Immune Response to Cancer

The use of survivin-engineered dendritic cells and exosomes to stimulate anti-cancer immunity is the focus of the provisional patent application.

7. Cellectis Makes Changes to Terms of $20 Million Convertible Note Issued by Cytovia Therapeutics

The note was originally issued in relation to the research collaboration and non-exclusive license agreement between the 2 companies.

8. University of Virginia Announces Plans to Launch Paul and Dian Manning Institute of Biotechnology

The institute, which will be launched with the assistance of a $100 million gift, will conduct research and provide care related to advanced medicines, including cell and gene therapies.

9. Medigene Gets $20 Million Milestone Payment from 2seventy bio 

The payment relates to a MAGE-A4 cell therapy 2seventy bio is developing  in a collaboration with JW Therapeutics that uses a T-cell receptor discovered with Medigene's technology platform.

10. bluebird bio to Put Proceeds from Public Stock Offering Towards ZYNTEGLO and SKYSONA

The net proceeds from the $120 million public offering of common stock will be used in part to fund commercialization and manufacturing activities related to the 2 approved gene therapies.

11. 4D Molecular Therapeutics Pauses Enrollment in Fabry Disease Clinical Trials

Cases of atypical hemolytic uremic syndrome occurred in some patients treated with 4D-310. The company announced intention to use a different immune inhibition regimen in any potential future studies of the gene therapy.

Catch up on the latest news, breakthroughs, and announcements from biotechnology companies making advancements in cell and gene therapies. 

Around the Helix: Cell and Gene Therapy Company Updates – January 25, 2023

The first patient has been dosed in a phase 1/2 clinical trial (NCT04959903) evaluating Smart Immune’s SMART101, an investigational allogeneic human T lymphoid progenitor (HTLP) cell therapy intended to assist in the restoration of the immune system of patients who have received T-cell-depleted allogeneic hematopoietic stem cell transplantation (HSCT).

SMART101 consists of T-cell progenitors which are derived from donor blood stem cells via the company’s ProTcell T-cell therapy platform in a 7-day process. The cells are intended to develop into functional and self-tolerant T-cells in the thymus of the patient after injection. Based on findings from preclinical research, Smart Immune expects that this process could allow for recovery of the patient’s immune system within 100 days, a substantial decrease from the typical 1 year to 18 months observed following allogeneic HSCT. The dosing of the first patient took place at Memorial Sloan Kettering Cancer Center (MSK) in December 2022. To date, no adverse events (AEs) related to the therapy have been reported.

“The infusion of the first patient is a significant milestone in our journey to address the challenge of slow immune reconstitution after allogeneic HSCT, using the power of the thymus,” Frédéric Lehmann, chief medical officer, Smart Immune, said in a statement regarding the news of the first patient’s dosing. “We are grateful to the dedicated investigators at MSK and look forward to continuing enrollment in this important trial.”

The multicenter, open-label clinical trial is expected to enroll approximately 36 patients adult or pediatric patients who have been affected by 

 according to study-specific criteria. The adult patient group will include patients aged 21 years or older who are eligible for allogeneic HSCT, have a Karnofsky Performance Status of at least 70%, and have normal organ function. The pediatric patient group will include patients under the age of 21 who are eligible for allogeneic HSCT, do not have a matched sibling donor, have a Karnofsky/Lansky Performance Status of at least 70%, and have normal organ function. Patients who have undergone prior therapy with allogeneic stem cell transplantation, those who are planning to receive an HLA matched cord blood transplantation (8/8 allele matched), and those who have been treated with another cell therapy within 1 month will be excluded.

The study’s primary end points include the cumulative incidence of grade 3 to 4 graft versus host disease, the occurrence of AEs related to SMART101, and CD4+ T-cell count, all of which will be assessed for the 100 day timeframe after patients receive HSCT. Secondary end points include the time for T-cell immune reconstitution, the cumulative incidence of infections, and non-relapse mortality. Overall survival and disease-free survival will also be assessed. The company has noted that SMART101 will be manufactured for the trial by the MEARY Center for Cell and Gene Therapy at Paris St Louis Hospital.

“We are excited to sponsor this pioneering trial,” Karine Rossignol, chief executive officer and co-founder, Smart Immune, added to the statement. “Accelerated reconstitution of a full polyclonal T-cell repertoire after stem cell transplantation could improve both quality of life and clinical outcomes for patients with acute leukemia, and we look forward to releasing more data as the trial progresses.”

First US leukemia patient dosed with Smart Immune’s investigational SMART101 cell therapy. News release. Smart Immune SAS. January 23, 2023. Accessed January 23, 2023. 

https://www.globenewswire.com/news-release/2023/01/23/2593079/0/en/First-US-leukemia-patient-dosed-with-Smart-Immune-s-investigational-SMART101-cell-therapy.html

The dosing of the first patient took place in December 2022 and no adverse events related to the therapy have been reported.

Allogeneic T-cell Progenitor Therapy Trial Doses First Patient With Leukemia 

Tevogen Bio’s TVGN 489, an investigational allogeneic CD8+ T-cell therapy intended to treat patients with 

 with acute high-risk disease, has demonstrated safety and met efficacy end points in a phase 1, proof-of-concept (POC) clinical trial (NCT04765449).

TVGN 489 consists of cytotoxic T lymphocytes derived from healthy volunteers who have recovered from COVD-19. The cells are manufactured to target multiple proteins across the SARS-CoV-2 genome that are preserved regardless of variant; the cell therapy is not limited to targeting the spike protein, which is the target of current vaccines and monoclonal antibodies.

 A recent review carried out by the company suggested that the therapy “is expected to retain activity against recent variants, including XBB and BQ and its subtypes, which appear to have the ability to evade some existing prophylactic options and immunity.”

 last summer, compared results from 12 patients who received TVGN 489 to 18 patients enrolled in the study’s observational arm, who received standard of care treatment for COVID-19.

 It was noted that no patients who received TVGN 489 showed progression of their COVID-19 infections and that none of these patients experienced reinfection with COVID-19 or long COVID during 6 months of follow-up. All patients treated with TVGN 489 returned to their baseline level of health by 14 days post-treatment. Furthermore, patients treated with TVGN 489 showed disease symptom relief in a rapid, consistent time frame, while patients treated with the standard of care demonstrated improvement in a less consistent and sometimes longer time frame. The study additionally met its secondary end points for reductions in viral load and post-treatment presence of cellular and humoral anti-COVID-19 responses.

In terms of safety, no dose-limiting toxicities occurred in the 12 patients treated with TVGN 489 and these patients experienced no cases of grade 3 or higher infusion reactions, grade 2 or higher cytokine release syndrome (CRS), grade 2 or higher neurotoxicity, or graft versus host disease. There were no grade 4 or higher adverse events (AEs) determined to be related to the cell therapy and outside the scope of identified COVID-19-related AEs.

“I’m greatly encouraged by the POC trial experience of TVGN 489 and hopeful that our investigational COVID-19 therapy will eventually offer hope to a substantial segment of patients,” Neal Flomenberg, MD, chief scientific officer, Tevogen Bio, said in a statement regarding the news.

Patients in both the treatment arm and the observational arm were ambulatory, had a newly diagnosed COVID-19 infection, and were higher risk for COVID-19-related complications from advanced age, heart disease, lung disease, liver disease, kidney disease, hypertension, diabetes, cancer, or obesity. In order to receive treatment with TVGN 489, patients were required to have a matching human leukocyte antigen (HLA) with the cells. Patients that did not have the matching HLA were able to participate in the observational arm. It was noted that 50% of the patients in the treatment arm were immunocompromised, while only 6% of those in the observational arm were immunocompromised. The immunocompromised status of the treated patients was related to prior treatment for cancer or autoimmune disease. It was additionally noted that the treatment arm included patients infected with “a variety of COVID variants ranging from Delta through Omicron BA.5.2.” The number of comorbidities in the treated patients ranged from 2 to 5.

The trial was open to patients aged 18 years and older. Patients requiring supplemental oxygen, those showing evidence of active COVID-19-related CRS according to study-specific criteria, those with a corrected QT interval greater than 450 milliseconds, and those receiving concomitant treatment with another experimental intervention for COVID-19 other than Remdesivir were excluded from the study. Additional exclusion criteria related to patient health status, current treatments, and treatment history. The study was carried out at Thomas Jefferson University. 

Tevogen Bio expects that the data from the trial will be submitted for publication in a peer-reviewed journal in the coming weeks. In December 2022, the company announced that it will pursue a new clinical trial for TVGN 489 specifically focused on evaluating the therapy’s efficacy in patients who are immunocompromised.

“The highly encouraging data of TVGN 489 allows us to turn our attention to the critical unmet need in the COVID-19 landscape,” Dolores Grosso, DNP, principal investigator of the trial, added to the statement.

 “Immunocompromised and the elderly and infirm usually do not benefit from currently available prevention or treatment strategies for COVID-19 and remain highly vulnerable to poor outcomes with a COVID-19 infection. These patients, as well as those individuals with long COVID, urgently require new treatment options.”

1. Tevogen Bio announces positive proof-of-concept clinical trial results of its off-the-shelf, allogeneic cytotoxic CD8+ T-cell therapy for treatment of acute high-risk COVID patients, first clinical product of company’s precision cell therapy platform. News release. Tevogen Bio. January 23, 2023. Accessed January 23, 2023. 

https://tevogen.com/press_release/tevogen-bio-announces-positive-proof-of-concept-clinical-trial-results/

2. Tevogen Bio Announces Positive Safety Results Upon Completion of Patient Enrollment in Proof-of-Concept Clinical Trial of T cell Therapy for Elderly or High-Risk COVID-19 Patients. News release. Tevogen Bio. August 1, 2022. Accessed January 23, 2023. 

https://tevogen.com/press_release/tevogen-bio-announces-positive-safety-results-upon-completion-of-patient-enrollment/

3. TevogenBio to study its investigational COVID-19 T cell therapy in immunocompromised patients who are unable to benefit from currently available prevention or treatment options. News release. Tevogen Bio. December 7, 2022. Accessed January 23, 2023. 

https://tevogen.com/press_release/tevogen-bio-to-study-its-investigational-covid-19-t-cell-therapy-in-immunocompromised-patients-who-are-unable-to-benefit-from-currently-available-prevention-or-treatment-options/

No patients treated with Tevogen Bio’s TVGN 489 showed progression of their COVID-19 infections. 

COVID-19 Cell Therapy Shows Promise in Proof-of-Concept Clinical Trial 

The phase 1/2 AFFINITY DUCHENNE clinical trial (NCT05693142) for REGENXBIO’s RGX-202, an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat 

The initiation of the AFFINITY DUCHENNE trial was originally expected to being in the first half of 2022, following the FDA’s clearance of RGX-202's investigational new drug application in January of that year.

 due to an “unexpected and isolated observation” that occurred during the vial-filling stage of the manufacturing process at a third-party manufacturing facility.

 Alongside AFFINITY DUCHENNE, REGENXBIO has also initiated recruitment for AFFINITY BEYOND, an observational study assessing the prevalence of AAV8 antibodies in male patients under the age of 12 years with DMD.

 The trial may help to identify patients for enrollment in AFFINITY DUCHENNE.

"I am pleased that we are now able to initiate the trial for RGX-202 and also begin enrollment activities in our AAV8 antibody screening study," Kenneth T. Mills, president and chief executive officer, REGENXBIO, said in a statement.

 "The RGX-202 program is a key piece of our '5x'25' strategy to have 5 AAV therapeutics either on the market or in late-stage development by 2025. We look forward to continuing to work closely with the Duchenne community as we advance a highly differentiated product candidate developed with the potential to improve muscle strength and motor function in boys with Duchenne."

RGX-202 uses REGENXBIO’s proprietary NAV AAV8 vector and is intended to deliver a novel transgene which contains the functional elements of the C-Terminal (CT) domain seen in natural dystrophin.

 The company has noted that the CT domain's presence “has been shown in preclinical studies to recruit several key proteins to the muscle cell membrane, leading to improved muscle resistance to contraction-induced muscle damage in dystrophic mice.”

The multicenter, open-label AFFINITY DUCHENNE trial will initially seek to recruit 6 patients with DMD who are ambulatory and aged 4 to 11 years. The patients will be divided into 2 cohorts including 3 patients each, with the lower-dose cohort receiving 1x10

 genome copies (GC)/kg body weight and the higher-dose cohort receiving 2x10

 GC/kg body weight. The study may later recruit an additional 9 patients based on the results of an independent safety data review.

Participants in the trial will be required to have a DMD gene mutation in exons 18 and above, must be able to walk 100 meters independently without assistive devices, must be able to complete the Time to Stand Test per protocol-specific criteria, and must be on a stable dose of systemic glucocorticoids according to the standard of care for at least 12 weeks prior to screening. Patients with detectable AAV8 total binding antibodies in serum, those with a left ventricular ejection fraction on screening of less than 55%, those who have received ataluren or an exon-skipping therapy for the treatment of DMD within 6 months of entry into the study, and those who are unable to cease taking ataluren or exon-skipping therapy for 5 years from the time of RGX-202's administration will be excluded from the study. Additional exclusion criteria relate to patient health status, treatment-history, and investigator discretion. 

The study’s primary end point is the incidence of adverse events (AE) and serious AEs. Secondary end points include changes in North Star Ambulatory Assessment raw and total score, microdystrophin protein expression, and measures of pharmacokinetics and vector shedding. Participants in the trial will receive a prophylactic immunosuppression regimen intended to mitigate potential complement-mediated immune responses. The trial will begin at sites in the United States, with sites in Canada and Europe expected to open later on.

"DMD is a devastating disease and there are still unmet therapeutic needs," Aravindhan Veerapandiyan, MD, a principal investigator in the study and director of the Comprehensive Neuromuscular Program, PPMD Certified Duchenne Care Center, and co-director of the Muscular Dystrophy Association Care Center at Arkansas Children's Hospital, added to the statement.

 "Gene therapies, like RGX-202, have the potential to impact the progressive nature of Duchenne."

1. REGENXBIO announces phase I/II trial of RGX-202, a novel gene therapy candidate for Duchenne muscular dystrophy, is active and recruiting patients. News release. REGENXBIO Inc. January 23, 2023. 

https://regenxbio.gcs-web.com/news-releases/news-release-details/regenxbio-announces-phase-iii-trial-rgx-202-novel-gene-therapy

2. REGENXBIO announces FDA clearance of IND for clinical trial of RGX-202, a novel gene therapy candidate for Duchenne muscular dystrophy. News release. REGENXBIO. January 6, 2022. 

https://regenxbio.gcs-web.com/news-releases/news-release-details/regenxbio-announces-fda-clearance-ind-clinical-trial-rgx-202

3. REGENXBIO reports first quarter 2022 financial results and recent operational highlights. News release. REGENXBIO. May 4, 2022. 

REGENXBIO has also initiated recruitment for AFFINITY BEYOND, an observational study assessing the prevalence of AAV8 antibodies in male patients with DMD.