Victoria Johnson

A phase 1/2 clinical trial (NCT05360238) has dosed its first patient with MB-106 

, a chimeric antigen receptor (CAR) T-cell therapy for the treatment of relapsed or refractory B-cell non-Hodgkin lymphomas (B-NHL) and chronic lymphocytic leukemia (CLL).

The patient did not experience cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). The trial is a multicenter, open-label trial that builds on the ongoing trial at Fred Hutchinson Cancer Center under the same investigational new drug application (IND). It is evaluating the safety and efficacy of MB-106, a first-in-class CD20-targeted, autologous CAR T cell therapy.

“The first clinical trial under Mustang’s IND is an important milestone in the ongoing development and evaluation of MB-106. Data presented at several prestigious medical meetings earlier this year from the initial, ongoing Phase 1/2 clinical trial at Fred Hutch show that MB-106 continues to demonstrate high efficacy and a favorable safety profile across patients with a wide range of hematologic malignancies. We look forward to providing updates on our multicenter MB-106 clinical trial as it progresses and anticipate reporting efficacy data in the fourth quarter of this year,” Manuel Litchman, MD, president and chief executive officer, Mustang, said, in a statement.

Recent interim data, as of September 9, 2022, from 28 patients treated in the ongoing, investigator-sponsored study, have continued to support MB-106's benefit. No patients experienced CRS or ICANS greater than grade 3. Overall response rate is 96% and complete response (CR) rate is 75% in patients with follicular lymphoma, CLL, diffuse large B-cell lymphoma, and Waldenstrom macroglobulinemia.

Mazyar Shadman, MD, MPH, on MB-106's Potential in Follicular Lymphoma

Twelve patients had a CR for over 12 months with 10 CRs still ongoing. The longest CR is 33 months, and 4 patients had a CR for over 2 years. Six patients with a partial response (PR) improved to ongoing CRs. Three patients had been previously treated with CD19 CAR T-cell therapy and all responded. Investigators also found that CAR-T persistence resulted in deepening responses after the initial 28-day assessment.

“We are excited to broaden the evaluation of MB-106 with this multicenter clinical trial under Mustang’s IND. To date, the data from the initial, ongoing clinical trial at Fred Hutch continue to demonstrate a high rate of complete and durable responses,” Mazyar Shadman, MD, MPH, study chair, associate professor and physician, Fred Hutch and University of Washington, added to the statement. “In addition, MB-106 has shown potential to treat patients in an outpatient setting and provide another immunotherapy option for patients treated previously with CD19-directed CAR T cell therapy.”

The trial is aiming to enroll 287 patients with CLL and B-NHLs, including mantle cell lymphoma. Patients must have evidence of CD20 expression. Phase 1 of the trial will assess escalating dose levels of MB-106 in a 3+3 design in 3 arms. Each arm will have up to 18 patients, with 6 at the maximum tolerated dose. The Safety Review Committee will assess 28-day data and the recommended phase 2 dose will be established. In the phase 2 portion, a total of 71 patients will participate with up to 20 patients in each arm. Up to an additional 51 patients may be added to each arm after an interim analysis.

Mustang Bio announces first patient treated in its multicenter phase 1/2 clinical trial of MB-106, a first-in-class CD20-targeted, autologous CAR T cell therapy to treat B-cell non-hodgkin lymphoma and chronic lymphocytic leukemia. News release. Mustang Bio. October 6, 2022. https://www.globenewswire.com/news-release/2022/10/06/2529538/0/en/Mustang-Bio-Announces-First-Patient-Treated-in-Its-Multicenter-Phase-1-2-Clinical-Trial-of-MB-106-a-First-in-Class-CD20-targeted-Autologous-CAR-T-Cell-Therapy-to-Treat-B-cell-Non-H.html

Articles

Interim data from an ongoing study demonstrate continuing efficacy in B-NHL, CLL, and FL. 

New, Multicenter Trial of MB-106 Doses First Patient 

The CardiAMP cell therapy showed clinical improvements in patients with 

, according to 2-year data from a phase 3 trial (NCT02438306).

CardiAMP is an autologous cell therapy developed by BioCardia. It is intended to be a comprehensive therapeutic treatment that includes a proprietary molecular diagnostic to determine eligibility of patients’ bone marrow cells, a point of care processing platform that prepares the cells at the patient’s bedside, and the proprietary Helix biotherapeutic delivery system to administer the therapy.

“The 2-year outcomes for patients with heart failure receiving the investigational CardiAMP Cell Therapy in the roll-in cohort showed clinical improvement with 100% survival over two years. These outcomes surpassed our expectations in terms of patient benefit across prespecified primary and secondary endpoints,” Peter Altman, PhD, president and chief executive officer, BioCardia, said in a statement.

 “While this smaller cohort is not a head-to-head comparison, current state of the art therapies for these patients which have been successful in slowing disease, are assessed by us to have 79.9% survival after 2 years.”

These data were presented at Heart Failure Society of America meeting in Washington, D.C by Peter Johnston, MD, assistant professor of medicine and site principal investigator, Johns Hopkins University. The study has enrolled around 114 patients as of the conference call, however, data reported is from 10 patients in a roll-in cohort with 2 years of follow-up. The study’s total enrollment target is 260. Patient characteristics were typical of patients with New York Heart Association (NYHA) Class 2 and 3 and ischemic heart failure.

Daniel Judge, MD, on Translational Gene Therapy for Cardiac Disorders

“We have had our most recent safety data monitoring committee their recommendations were that the study 

 and that no change or actions were required. They did ask that we provide an updated statistical analysis plan that would include an adaptive design,” co-principal investigator Carl Pepine, MD, professor, cardiovascular medicine, University of Florida, said in a conference call.

Investigators observed no serious adverse events (AEs) related to treatment. All 10 patients completed 24 months of follow-up and 2-year survival was 100%. Patients had minimal changes in guideline-directed medical therapy over the study period. Clinical improvements were demonstrated by 6-minute walk distance test (6MWT) scores at 6 months (6% improvement; 28.5 m; 

 = .01) and 24 months (8% improvement; 31.0 m; 

“The remarkable thing is that in patients with very serious heart disease and very impaired cardiac function, there were no deaths in the first 1 years of follow up and there were only 2 hospitalizations out of the 10 patients in the 2 years... 1 was related to heart failure progression and the other patients had multiple return admissions and acute myocardial infarction,” Pepine added.

Quality of life scores were also positive, with 70% of patients reporting improved or stable scores over 24 months.

 Half of patients improved by at least 1 NYHA class, with 4 at class 1, 20% had an unchanged class and 30% deteriorated from class 2 to 3 at 24 months. Median left ventricular ejection fraction (LVEF) improved at months 6, 12, and 24, compared to baseline. Echocardiography also showed recruitment of previously akineticleft ventricular wall segments at month 24 compared to baseline.

“There’s still a great unmet need. Looking at the more recent studies of the various drugs being used, such as the PARADIGM-HF study, EMPEROR, and DAPA-HF studies... you can still see there is an unmet need with around a 13% death rate still exists...our study will follow patients after 24 months and how these numbers unfold in this patient population will still be determined,” co-principal investigator Amish Raval, MD, professor, cardiovascular medicine, University of Wisconsin, said during the call.

1. BioCardia presents positive CardiAMP cell therapy heart failure trial two-year data at HFSA Annual Meeting. News release. BioCardia. October 3, 2022. 

https://finance.yahoo.com/news/biocardia-presents-positive-cardiamp-cell-110000572.html


2. CardiAMP Cell Therapy Trial for Heart Failure: Clinical Leadership and Management Call. Webcast. BioCardia. October 5, 2022. https://event.choruscall.com/mediaframe/webcast.html?webcastid=9NhAJ6lm

The new, 2-year data is from a roll-in cohort of 10 patients presented at the HFSA 2022 meeting. 

CardiAMP Cell Therapy Yields 100% Response Rate in Heart Failure

The FDA has granted investigational new drug (IND) clearance for a phase 1/2 dose escalation study of Oncternal Therapeutics’ chimeric antigen receptor (CAR) T therapy ONCT-808 for treating aggressive 

“We are very pleased with the clearance of our IND application for our lead autologous CAR T product candidate, ONCT-808,” James Breitmeyer, MD, PhD, president and chief executive officer, Oncternal, said in a statement.

“This will be our second clinical program focusing on the important ROR1 cancer target, following the initiation of our phase 3 study for our ROR1 antibody zilovertamab, announced last week.”

ONCT-808 is an autologous CAR T therapy that targets ROR1. The study will enroll patients with aggressive B NHL, including those whose disease has been refractory to previous CD19 CAR T treatment.

“ROR1 is an exciting and promising target that is highly expressed in a wide range of cancers and is an ideal candidate for cell therapy applications due to its highly specific tumor expression, and association with tumor survival mechanisms. Our initial dose finding study will enroll patients with aggressive B NHL, including those that have failed prior CD19 therapy, which represent a significant unmet need in the market today. We expect to initiate the study in the coming months and to present interim results at a scientific conference in 2023,” Breimeyer added.

Allogeneic CAR T Recognized for Cutaneous T-Cell Lymphomas

Oncternal previously presented positive preclinical data on ONCT-808 at the European Hematology Association (EHA) 2022 Hybrid Congress in June 2022.

 The data were from preclinical studies conducted by Oncternal’s collaborator, the Karolinska Institute in Stockholm. The data presented demonstrated ROR1 CAR mediated target recognition and cell activation when expressed in either T cells or NK cells. Also, ROR1 CAR-T cells demonstrated dose-dependent anti-tumor activity in a mantle cell lymphoma mouse model.

Oncternal’s lead programs are zilovertamab, a monoclonal antibody that inhibits ROR1, which is in phase 2 trials, primarily for mantle cell lymphoma, and ONCT-216, a small molecule inhibitor of ETS-family oncoproteins, which is in phase 2 studies, primarily for Ewing sarcoma. Also in the pipeline is the preclinical Dual-Action Androgen Receptor Inhibitor (DAARI) ONCT-534for advanced prostate cancer resistant to available therapies.

“Despite recent significant advances in treating hematological malignancies with current CAR-based cell therapies, certain limitations remain, such as treatment failures due to tumor antigen escape, and toxicities including induction of immunodeficiencies like B-cell aplasia. Patients are in need of more effective treatment options” Evren Alici, MD, PhD, associate professor and group leader, Cell and Gene Therapy Group, Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, said in a statement at that time.

“The ROR1-targeting cell therapies have shown strong activity in our lymphoma models. We are now working with our Oncternal colleagues to evaluate the therapies in models of other tumor indications. With our strong focus on NK cells, we are excited to further study ROR1 CAR-NK cells within our NextGnNK competence center."

”Oncternal’s lead programs are zilovertamab, a monoclonal antibody that inhibits ROR1, which is in phase 2 trials, primarily for mantle cell lymphoma, and ONCT-216, a small molecule inhibitor of ETS-family oncoproteins, which is in phase 2 studies, primarily for Ewing sarcoma. Also in the pipeline is the preclinical Dual-Action Androgen Receptor Inhibitor (DAARI) ONCT-534for advanced prostate cancer resistant to available therapies.

REFERENCES
1. Oncternal Therapeutics receives IND clearance for ONCT-808, its autologous CAR T product candidate targeting ROR1 for the treatment of aggressive B cell lymphoma. News release. Oncternal. October 3, 2022. 

https://investor.oncternal.com/news-releases/news-release-details/oncternal-therapeutics-receives-ind-clearance-onct-808-its


2. Oncternal Therapeutics presents new preclinical data from its anti-ROR1 cell therapy collaboration with the Karolinska Institutet at the EHA2022 Congress. News release. Oncternal Therapeutics. June 10, 2022. https://investor.oncternal.com/news-releases/news-release-details/oncternal-therapeutics-presents-new-preclinical-data-its-anti

Oncternal will soon initiate a phase 1/2 dose-escalation study of ONCT-808. 

B-NHL Cell Therapy Cleared for Trials 

) was well-tolerated and yielded functional improvements in adult and pediatric patients with Danon disease, according to data from a phase 1 trial (NCT03882437) presented at the Heart Failure Society of America (HFSA) Annual Scientific Meeting 2022.

“Today’s Danon Disease trial results, the most comprehensive investigational gene therapy dataset for any cardiac condition, demonstrate positive early findings in pediatric patients and continued robust activity in adults that represent potential freedom from the devastating effects of this disease, including those that lead to heart transplantation or death,” Gaurav Shah, MD, chief executive officer, Rocket Pharma, said in a statement. “Results showed RP-A501 was generally well tolerated with evidence of durable treatment effect and improvement of Danon Disease, including for both pediatric patients with up to nine months of follow-up and four adult patients with up to 36 months of follow-up. Further, efficacy data from the pediatric patients are following similar or more favorable positive trends as in the adults at a similar timeframe. Pediatric patients showed vacuole clearance and marked reductions in brain natriuretic peptide (BNP) and troponin. We also observed improvement in New York Heart Association (NYHA) class and early improvements in the Kansas City Cardiomyopathy Questionnaire (KCCQ) for both patients.”

RP-A501 consists of a recombinant adeno-associated serotype 9 (AAV9) capsid that delivers a functional version of the human 

transgene (AAV9.LAMP2B). The new data from the phase 1 trial evaluating RP-A501 presented at the meeting has a data cutoff of September 27, 2022, and includes early efficacy data with updated safety data from the low-dose (6.7 x 10

 GC/kg; n = 2) pediatric cohort, as well as updated efficacy and safety data from young adult and adolescent patients in the low-dose (n = 3) and high-dose (1.1 x 10

RP-A501 was well-tolerated in the low-dose cohorts. In the 2 pediatric patients with 6 and 11 months of follow-up, there were no complement-related adverse events (AEs) and minimal complementactivation. These patients had normal-range platelets and no significant toxicities, skeletal myopathy, or late transaminase elevations. They had also received a modified immunomodulatory regimen to mitigate AEs. RP-A501 has continued to be well-tolerated in adult cohorts as well.

Gene Therapy for Rare Diseases: Latest Updates

“Data collected in adults from biomarker, clinical and functional parameters trend towards improvement in the initial months following gene therapy and appear durable for two to three years after treatment. I am particularly excited that 5 out of 5 currently enrolled pediatric and adult patients with a closely monitored immunomodulatory regimen showed improvement in NYHA class (from 2 to 1) with a follow-up of six to 36 months,” Shah added. “Simply put, these data indicate that these patients are no longer afflicted with cardiac disease symptoms during regular activity or cardiac-related limitations in physical activity. In this devastating disease with markedly shortened life span, stabilization alone may be considered meaningful, so the sustained improvements we’ve seen exceed our expectations and could be transformative for patients receiving gene therapy.”

gene expression was 21.1% in the first pediatric patient and 34.7% in the second via immunohistochemistry. Both pediatric and adult patients had evidence of durable and meaningful cardiac 

expression at 3 months through 24 months. These findings are consistent with earlier efficacy data observed.

Other positive efficacy findings included a decrease in vacuolar area, a decrease in BNP, decreases in troponin, improvements in NYHA class, improvements in KCCQ, and reductions in left ventricular wall thickness in pediatric and adult patients.

“Taken together, we believe the totality of data from the six patients currently enrolled in the Phase 1 trial will support advancement toward a Phase 2 pivotal study,” Shah added. “We recently convened an advisory board of international experts who endorsed our planned Phase 2 study design and endpoints, and we look forward to further discussions with the FDA later this year.”

REFERENCE
Rocket Pharmaceuticals announces positive updates from phase 1 clinical trial for RP-A501 in Danon disease at the Heart Failure Society of America (HFSA) Annual Scientific Meeting 2022. News release. Rocket Pharmaceuticals. September 30, 2022. https://www.businesswire.com/news/home/20220930005139/en/%C2%A0Rocket-Pharmaceuticals-Announces-Positive-Updates-from-Phase-1-Clinical-Trial-for-RP-A501-in-Danon-Disease-at-the-Heart-Failure-Society-of-America-HFSA-Annual-Scientific-Meeting-2022

Rocket Pharma presented updated data from adult and pediatric patients at the 2022 HFSA meeting. 

Gene Therapy Yields Improvements in Danon Disease 

Solid Biosciences has acquired AavantiBio, a company whose lead program, AVB-202, is a gene therapy candidate in preclinical studies for 

The combined company will now focus on advancing Solid’s preclinical gene therapy program SGT-003 for the potential treatment of Duchenne muscular dystrophy (DMD) as well as AVB-202 under the leadership of AavantiBio’s current chief executive officer (CEO), Bo Cumbo. Aavanti’sadditional programs in development include AVB-401 for BAG3-mediated dilated cardiomyopathy and undisclosed programs for other cardiac indications.

“I created Solid with my wife, Annie, and our co-founders nearly 10 years ago, to bring meaningful treatment options to patients and families who, like ours, live with the devastating consequences of DMD,”

 Ilan Ganot, president, chief executive officer and co-founder, Solid Biosciences

 “This acquisition provides exciting opportunities to bring our potentially best-in-class Duchenne gene transfer candidate, SGT-003, to patients and to expand our portfolio with innovative gene therapies designed to address significant unmet need in additional, adjacent rare disease indications. Bo Cumbo will assume the role of president and CEO and is a seasoned biotech executive with extensive expertise in bringing products through development and commercialization. I look forward to helping Bo with the leadership transition following the acquisition, and I am grateful to the investors who continue to support Solid’s critical efforts.”

Solid Biosciences also announced that it has entered into a securities purchase agreement with investors for a $75 million private placement expected to close concurrently with the merger. With the funding, thecombined company is expected to have approximately $215 million to be able to fund it into 2025 and advance the gene therapy programs.

Craig M. McDonald, MD, on Developing Gene Therapy for Different Populations of DMD

“I am excited for the opportunity to lead Solid Biosciences and to help build a leading genetic medicine company with a focus on neuromuscular and cardiac rare diseases,” said Bo Cumbo, president and chief executive officer, AavantiBio, said in a statement.

 “The Solid team has done incredible work in advancing Duchenne gene therapy, and its commitment to the Duchenne community aligns with AavantiBio’s patient-centric mission of bringing new therapies that can positively improve the quality of life of rare disease patients and their families. I also look forward to advancing our library of next generation cardiac and skeletal muscle capsids to extend our opportunities to bring treatment options to more people in need.”

Solid previously announced in a company update that it would be pausing development on SGT-001, its previous lead candidate for DMD, in favor of SGT-003, its next-generation candidate.2 The company stated that it would be switching to a scaled transient transfection-based manufacturing process of SGT-001 and that its phase 1/2 IGNITE-DMD trial (NCT03368742) would continue dosing in mid-2023. Solid also plans to be able to submit an investigational new drug application for SGT-003 in mid-2023.

Prior to the reprioritization, Solid had presented positive 2-year data from the IGNITE-DMD study at the 2022 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, held March 13-16, in Nashville, Tennessee.

 These data, from the first 3 patients treated in the high-dose cohort (2E14vg/kg), were in line with previous data reported from the 12- and 18-month time points.

Participants exhibited improved motor function, with a mean 16-meter improvement (range, -12 to 39; mean difference from natural history, +100.6) in 6-Minute Walk Test from baseline and a –1.7 change (range, -3 to –1; mean difference from natural history, +4.3) in North Star Ambulatory Assessment from baseline. They also showed improvements from baseline differing from natural history in pulmonary function with a mean 9.2% improvement in forced vital capacity (range, -1.4 to 29.0; mean difference from natural history, +19.2) and a 6.5% improvement in peak expiratory flow (range, -5.8 to 14.8; mean difference from natural history, +16.5). Patient-reported outcomes also improved and the therapy was well-tolerated.

While Solid’s progress in the DMD space seems to have stalled for the time being, other competitors such as Sarepta, Dystrogen, and CRISPR Therapeutics, are racing ahead with their respective DMD programs in recent months. CRIPSR received

 for its CRISPR therapeutic CRD-TMH-001 in August 2022, and in September, Dystrogen 

 for SRP-9001 (delandistrogene moxeparvovec).

1. Solid Biosciences announces acquisition of AavantiBio and concurrent $75 million private placement. News release. Solid Biosciences. September 30, 2022. https://www.solidbio.com/about/media/press-releases/solid-biosciences-announces-acquisition-of-aavantibio-and-concurrent-75-million-private-placement
2. Solid Biosciences provides second quarter 2022 business update and financial results. News release. Solid Biosciences. August 11, 2022. 

https://www.solidbio.com/about/media/press-releases/solid-biosciences-provides-second-quarter-2022-business-update-and-financial-results


3. Dreghici R, Redican S, Lawrence J, et al. Ignite DMD phase I/II study of SGT-001 microdystrophin gene therapy for DMD: 2-year outcomes update. Presented at MDA Clinical and Scientific Conference; March 13-16. Poster 46.
4. Cure Rare Disease Receives FDA Approval to Administer First-in-Human CRISPR Therapeutic. News release. Cure Rare Disease. August 10, 2022. 

https://www.biospace.com/article/releases/cure-rare-disease-receives-fda-approval-to-administer-first-in-human-crispr-therapeutic/


5. Sarepta Therapeutics submits biologics license application for SRP-9001 for the treatment of ambulant patients with Duchenne muscular dystrophy. News release. Sarepta Therapeutics. Septemebr 29, 2022. 

https://www.globenewswire.com/news-release/2022/09/29/2525189/36419/en/Sarepta-Therapeutics-Submits-Biologics-License-Application-for-SRP-9001-for-the-Treatment-of-Ambulant-Patients-with-Duchenne-Muscular-Dystrophy.html


6. Dystrogen Therapeutics investigational chimeric cell therapy DT-DEC01 for Duchenne muscular dystrophy demonstrates clinically significant functional and biomarker improvements. News release. Dystrogen Therapeutics, Corp. September 26, 2022. https://www.prnewswire.com/news-releases/dystrogen-therapeutics-investigational-chimeric-cell-therapy-dt-dec01-for-duchenne-muscular-dystrophy-demonstrates-clinically-significant-functional-and-biomarker-improvements-301633161.html

Solid has also pivoted from developing SGT-001 to SGT-003 for treating Duchene muscular dystrophy. 

Solid Bio Adds Friedreich Ataxia to Pipeline With Aavanti Acquisition

RGX-314, REGENXBIO’s investigational gene therapy for 

wet age-related macular degeneration (AMD)

, was well-tolerated and reduced treatment burden in participants treated in the phase 2 AAVIATE trial (NCT04514653).

These data were presented at the American Academy of Ophthalmology (AAO) annual meeting taking place September 30 – October 1 in Chicago, Illinois. Participants experienced no treatment-related serious adverse events (TEAEs) and REGENXBIO is adding a sixth cohort to the AAVIATE trial to evaluate a prophylactic ocular steroid regimen.

"Today's announcements come nearly a year into our collaboration with AbbVie to advance RGX-314 in wet AMD and other retinal diseases. These new subretinal and suprachoroidal data highlight the potential impact of RGX-314 for the millions of patients facing vision loss from wet AMD," Kenneth T. Mills, president and chief executive officer, REGENXBIO, said in a statement. "I am pleased with the continued progress on and momentum for these programs. We remain on track to submit a BLA for RGX-314 in 2024, and we expect to provide an update on the ALTITUDE trial of RGX-314 for the treatment of diabetic retinopathy using suprachoroidal delivery at the upcoming Retina Society Meeting in November."

Investigators have reported that as of August 1, 2022, suprachoroidal delivery of RGX-314 has been well-tolerated across 5 cohorts of participants with wet AMD enrolled in AAVIATE. No TEAEs have been reported although there were 15 serious AEs (SAEs) unrelated to treatment. Common TEAEs included conjunctival hemorrhage, increased intraocular pressure, episcleritis, and conjunctival hyperemia in 65 patients in cohorts 1 through 4 and these were mild or moderate. Participants treated at the first or second dose level had similar incidences of mild intraocular inflammation while those treated at the third dose level (cohort 4; 1x10

 GC/eye) had increased incidence of mild to moderate inflammation, all of which resolved with topical corticosteroids.

First Patient Treated in Dry AMD iPSC Therapy Clinical Trial

The multicenter, open-label, randomized, dose-escalation AAVIATE trial is evaluating the safety and efficacy of suprachoroidal delivery of RGX-314. The trial is primarily evaluating mean change in vision at week 40 from baseline via Best Corrected Visual Acuity (BCVA) compared to patients receiving monthly injections of ranibizumab. The trial is also evaluating mean change in central retinal thickness (CRT) and the number of anti-vascular endothelial growth factor (anti-VEGF) intravitreal injections received after treatment with RGX-314.

Participants in the RGX-314 arm had a meaningful reduction in anti-VEGF treatment burden (range, -63.8% to –84.7%) compared to mean annualized injection rate during the 12 months prior to administration. Participants treated at the third dose level had the highest reduction in treatment burden, with a mean 1.3 injections over 6 months after RGX-314 treatment – an 84.7% reduction in anti-VEGDF treatment burden. Ten of these patients (67%) had no anti-VEGF injections in this time period while maintaining visual acuity and CRT. Data from the second dose level (cohorts 2 and 3) additionally suggest that there is no meaningful difference in safety and vision outcomes for patients who are neutralizing antibody (NAb) positive.

An additional cohort, cohort 6, will be enrolled at the third dose levelwith a short course of prophylactic ocular steroids to evaluate the effect on intraocular inflammation. Participants will be enrolled regardless of NAb status.

"We are pleased to share updated data from the AAVIATE trial, including new 6-month data from Cohorts 1-4 which provides continued evidence of the emerging clinical profile of RGX-314 for the treatment of wet AMD using suprachoroidal delivery," Steve Pakola, MD, chief medical officer, REGENXBIO, added to the statement. "RGX-314 continues to be well tolerated, with emerging evidence of treatment effect, including meaningful reduction in anti-VEGF treatment burden at all dose levels. We look forward to expanding this trial to further explore the third dose level."

REGENXBIO also presented data from a long-term follow-up (LTFU) study(NCT03999801) that evaluated subretinal delivery of RGX-314 in 37 patients with wet AMD. Investigators observed dose-dependent increases in treatment effect and 16 patients in cohorts 3 and 4 have continued to tolerate the treatment and have experienced a durable treatment effect for up to 4 years. Stable to improved visual acuity was observed, with a mean BCVA of +12 letters from baseline at four years for Cohort 3 patients and -5 letters from baseline at three years for Cohort 4 patients following RGX-314 administration.

Nine SAEs, none related to treatment, were reported. One participant, in cohort 5, had a significant decrease of vision during the LTFU study who had macular pigmentary changes after a superior bleb in the phase 1/2a trial.

The LTFU study also revealed a meaningful reduction in anti-VEGF treatment burden, with a decrease in mean annualized rate from 6.8 injections to 2.4 injection in cohort 3 (67% reduction) and from 10.2 injections to 4.4 injections in cohort 4 (58.4%). Altogether, these data are expected to support the anticipated biologic license application filing for RGX-314 in 2024.

"These positive interim data from the long-term follow-up and AAVIATE trials continue to reinforce the potential clinical benefit of a one-time administration of RGX-314 in the overall management of patients with neovascular AMD," Arshad M. Khanani, MD, MA, FASRS, director, clinical research, Sierra Eye Associates, Reno, Nevada, added to the statement. "I am extremely encouraged by this long-term data up to four years showing durable treatment effect and the potential of RGX-314 to meaningfully reduce injection burden for patients while maintaining vision outcomes. I look forward to the further investigation of RGX-314 in Cohort 6 of the AAVIATE trial, as in-office suprachoroidal delivery has the potential to be an important treatment option for patients."

The ATMOSPHERE (NCT04704921) and ASCENT (NCT05407636) pivotal trials are active and enrolling patients with wet AMD. REGENXBIO is also expecting to present new interim data on RGX-314 in diabetic retinopathy from ALTITUDE (NCT04567550) at the Retina Society 55th Annual Scientific Meeting in November 2022.

REGENXBIO announces additional positive interim data from trials of RGX-314 for the treatment of wet AMD. News release. REGENXBIO. October 3, 2022. https://regenxbio.gcs-web.com/news-releases/news-release-details/regenxbio-announces-additional-positive-interim-data-trials-rgx

Participants in the AAVIATE trial had up to an 85% decrease in treatment burden 6 months after treatment with RGX-314. 

Wet AMD Gene Therapy Reduces Anti-VEGF Treatment Burden 

The umbilical cord blood (UCB) cell therapy omidubicel (NiCord; 

) improved survival in patients with hematological malignancies receiving allogeneic hematopoietic stem cell transplantation (HSCT).

These data, from a phase 3 trial (NCT02730299) were presented at the 10th Annual Meeting of the Society of Hematologic Oncology (SOHO), taking place September 28- October 1 in Houston, Texas, by Chenyu Lin, MD, hematology/oncology fellow, malignant hematologist, Duke University.

“These data reinforce our commitment to advance transformational cell therapy research and underscore the potential of our NAM technology platform. Our lead stem cell therapy candidate, omidubicel, addresses the unmet need for patients with hematologic malignancies, demonstrated by the robust and growing body of encouraging clinical evidence, including the long-term follow up data and quality of life improvement,” Ronit Simantov, MD, chief medical officer, Gamida Cell, said in a statement.

“As we approach the PDUFA date of January 30, 2023, and upon potential FDA approval, we are prepared to execute our plan that ensures access to those patients who can benefit from omidubicel as quickly as possible.”

Lin and colleagues analyzed data from 105 participants across 2 academic transplant centers worldwide from the phase 3 study either as a standalone unit (n = 92) or together with an unmanipulated UCB (n = 24).

Eleven participants were excluded from an initial pool of 116. Most patients (n = 97; 93%) engrafted fully, 2 (2%) had mixed chimerism between omidubicel and UCB, 5 (5%) had primary graft failure, and 1 patient was not evaluable. All patients received myeloablative conditioning regimens and standard graft versus host disease (GVHD) prophylaxis with a calcineurin inhibitor and mycophenolate mofetil. There were no late cases of secondary graft failure reported after the 5 patients reported in the primary analysis.

Omidubicel BLA Accepted With Priority Review in Hematological Malignancies

Median follow-up was 22 months (range, 0.3-122.5) overall and 35.7 months (range, 11.7-122.5) among survivors.Treated participants had an overall survival of 63% (95% CI, 53%-73%) and disease-free survival of 56% (95% CI, 47%-67%). Quality of life assessments revealed that overall well-being scores were higher in these patients when compared to standard of care.

In terms of safety, most chronic GVHD cases were mild (54%), with 33% moderate and 13% severe cases. No deaths were primarily attributed to chronic GVHD. One participant developed donor-derived MDS which is consistent with previous reports of donor-derived myeloid neoplasms after cord blood transplants (0.6–2%). A case of donor-derived AML was also observed in the phase 3 control group.

Omidubicel has demonstrated fast engraftment, few infections, and short durations of hospitalization in previous trials. It is an ex vivo expanded stem cell therapy derived from UCB.

“In addition to the known early benefits, omidubicel demonstrated long-term graft durability, with preserved trilineage hematopoiesis and immune competence at up to 10 years of follow-up,” Lin and colleagues wrote in the poster.

REFERENCES
1. Long-term data from omidubicel phase 3 trial demonstrates overall survival and sustainable durable outcomes for patients with blood cancers at the Society of Hematologic Oncology Meeting. News release. Gamida Cell. September 29, 2022. 

https://www.businesswire.com/news/home/20220929005316/en/Long-Term-Data-from-Omidubicel-Phase-3-Trial-Demonstrates-Overall-Survival-and-Sustainable-Durable-Outcomes-for-Patients-with-Blood-Cancers-at-the-Society-of-Hematologic-Oncology-Meeting


2. Lin C, Schwarzbach A, Montesinos P, et al. Multicenter long-term follow-up of allogeneic hematopoietic cell transplantation with omidubicel: A pooled analysis of five prospective clinical trials. Presented at: 10th Annual Meeting of the SOHO, September 28- October 1, Houston, Texas.

Disease-free survival was 56% in 105 participants over 3 years. 

Omidubicel Improves Survival in Hematologic Malignancies With HSCT 

MIC-Lx cell therapy (TolerogenixX) induced long-term donor-specific immunosuppression and yielded a significant increase in regulatory B lymphocytes in 

recipients, according to 3-year follow-up data from a phase 1 study (NCT02560220).

Patients treated with the modified immune cell (MIC) therapy had no donor-specific human leukocyte antigen (HLA) antibodies or acute rejections. The 4 patients who received the highest dose of MIC-LX (1.5 × 10

) 7 days before surgery were on reduced immunosuppressive therapy and did not have in vitro lymphocyte reactivity against stimulatory donor blood cells while reactivity against third-party cells was preserved. These patients also had 75-fold and 7-fold higher numbers of transitional B lymphocytes than in 12 long-term survivors on minimal immunosuppression and 4 operationally tolerant patients, respectively (

"MIC treatment is leading to an operationally tolerant phenotype of patients with profound suppression of anti-donor T cell responses," first author Prof. Dr. Christian Morath, chief scientific officer, TolerogenixX, said in a statement.

 "The 1-year follow-up data published in 2020 already showed excellent safety and tolerability of our treatment, and we are very happy that these favorable results hold up in the three-year follow-up."

The study treated 10 patients with 1.5 × 10

 MIC per kg body weight on day -2 (n = 3, group A) or 1.5 × 10

 MIC per kg body weight on day -2 (n = 3, group B) or day -7 (n = 4, group C) prior to living donor kidney transplantation, in addition to post-transplant immunosuppression with CyA, EC-MPS, and methylprednisolone.

Tackling Deceased Kidney Transplant and Severe Scleroderma With Cell Therapy

Over 3 years of follow up, there were no cases of de novo donor-specific antibodies or acute rejection episodes. Investigators found that kidney graft function was stable with a median serum creatinine of 1.40 mg/dL (range, 1.04-2.10), a median estimated glomerular filtration rate (according to the Chronic Kidney Disease Epidemiology Collaboration score) of 61 mL/min/1.73 m

 (range 41–93), and a median urinary protein excretion of 14 g/moL creatinine (range 5–90).

There were no cases of opportunistic infections and no cytomegalovirus or BKV replications during posttransplant screening. Six patients had 12 non-opportunistic infections, 2 of which occurred during the second and third years of follow-up. There were no cases of malignancy or posttransplant lymphoproliferative disorders.

"The results once again demonstrate that we generate an immunoregulatory cell population which carries the promise of exerting a beneficial effect on kidney transplants," author Prof. Dr. Matthias Schaier, chief executive officer, TolerogenixX, added to the statement.

Investigators found that percentage of regulatory B lymphocytes increased from a median of 6% (range, 0-11) of the total lymphocyte pool to 20% (range, 5-40) on day 180 before dropping to a median of 8% (range, 5-13) by day 720 and remaining stable until day 1080. These levels were not only higher than baseline but also levels in literature for stable immunosuppressed (range, 0-5%) and operationally tolerant patients (range, 3-8%).

Gene expression analysis revealedthat 3 of 4 patients in Group C had the COMBINED-g7 consensus gene-expression signature of operational tolerance.They also determined that interleukin-10-producing transitional B lymphocytes were functionally relevant for donor-specific unresponsiveness.

"These new results show that the effect is long-lasting and associated with a striking increase in regulatory B lymphocytes. They underline the importance of MIC-Lx in paving the way for a novel cell therapy in organ transplantation,” PD Dr. Anita Schmitt, chief technical officer, TolerogenixX, added to the statement.

Investigators are now conducting a phase 2 study (NCT05365672) to expand the findings seen in the 4 patients in Group C, compared to patients treated with standard of care. Patients in the phase 2 study will hopefully develop an operationally tolerant-like phenotype.

1. Morath C, Schaier M, Ibrahim E, et al. Induction of long-lasting regulatory B lymphocytes by modified immune cells in kidney transplant recipients. 

 Published online September 22, 2022. doi: 10.1681/ASN.2022020210
2. TolerogenixX publishes three-year follow-up data from phase i trial of immune tolerance-inducing MIC-Lx cell therapy. News release. TolerogenixX. September 26, 2022. https://www.einnews.com/pr_news/592816864/tolerogenixx-publishes-three-year-follow-up-data-from-phase-i-trial-of-immune-tolerance-inducing-mic-lx-cell-therapy

Patients treated with the highest dose of MIC-Lx had lymphocyte reactivity against third-party cells but not stimulatory donor blood cells. 

Modified Immune Cell Therapy Induces Kidney-Donor-Specific Immunosuppression 

The FDA has granted orphan drug designation to 

 SynKIR-110, a killer immunoglobulin-like receptor - chimeric antigen receptor (KIR-CAR) T-cell therapy, for the treatment of mesothelin-expressing mesothelioma.

"Orphan Drug Designation is another major milestone for Verismo following the acceptance of our SynKIR-110™ IND," Bryan Kim, DMD chief executive officer, Verismo Therapeutics, said in a statement.

 "Mesothelioma is a rare and deadly disease for which few other treatment options currently exist. We look forward to working with the mesothelioma community to advance SynKIR-110 as a potential treatment while we continue to expand clinical investigation of this novel platform in other cancers in the solid tumor space.

SynKIR-110 is developed using Verismo’s next-generation KIR-CAR platform that is designed to improve persistence and efficacy against solid tumors.The therapy is being developed for indications including mesothelin-expressing ovarian cancer, mesothelioma and cholangiocarcinoma, which are areas of high unmet medical need, with 5-year survival rates of 49.7%, 30%, and 10%, respectively.

The multi-chain KIR-CAR construct that makes up the platform is based on natural killer (NK) cell receptors and is designed to reduce T cell exhaustion by utilizing the natural on/off switch that will allow cells to rest when not bound to the tumor. The construct is also designed to improve the performance of cells in the solid tumor microenvironment with enhanced surface stability and DAP12 costimulatory chains to aid additional T-cell stimulating pathways and further improve cell persistence.

Phase 2/3 Mesothelioma Cell Therapy Trial Completes Final Patient Active Follow-up

 for SynKIR-110 just a few days prior to this announcement.

 Verismo will initiate the phase 1, first-in-human trial STAR-101 (SynKIR T cell Advanced Research) of SynKIR-110 in the first quarter of 2023 for mesothelin-expressing ovarian cancer, mesothelioma and cholangiocarcinoma. The trial’s first clinical site will be the Hospital of the University of Pennsylvania.

"Pre-clinical data have shown enhanced efficacy in murine models with no additional safety concerns. The FDA's clearance of our SynKIR-110 IND represents a new chapter for Verismo as we initiate the first-ever clinical trial for KIR-CAR T cells. It also validates the years of innovative research and hard work by industry pioneers at Penn and the Verismo team," Kim said upon the IND clearance.

The KIR-CAR platform has demonstrated ongoing regression of solid tumors refractory to traditional CAR T-cell therapies in preclinical studies. Verismo believes the platform will be able to be combined with other emerging techniques including in vivo gene editing, allogeneic cell therapies, advanced T cell selection, and combination therapies to further improve options and outcomes for patients.

"SynKIR-110 is the first product to use the novel KIR-CAR platform. Our technology incorporates a natural on/off switch that allows KIR-CAR T cells to rest when not exposed to tumor antigens, as well as providing an enhanced cell-surface stability of the KIR-CAR," Laura Johnson, PhD, chief scientific officer, Verismo, added to the statement.

 "These enhancements will allow KIR-CAR T cells to better cope with the harsh tumor microenvironment of solid tumors and, potentially, lead to better outcomes for our patients."

1. Verismo Therapeutics receives U.S. FDA orphan drug designation for SynKIR-110™, a first-in-class KIR-CAR T cell immunotherapy candidate, for the treatment of mesothelioma. News release. Verisoma Therapeutics. September 28, 2022. 

https://www.prnewswire.com/news-releases/verismo-therapeutics-receives-us-fda-orphan-drug-designation-for-synkir-110-a-first-in-class-kir-car-t-cell-immunotherapy-candidate-for-the-treatment-of-mesothelioma-301635551.html


2. Verismo Therapeutics announces submission of IND application to the FDA for SynKIR-110, a KIR-CAR T-cell immunotherapy candidate. Verismo Therapeutics. News release. August 19, 2022. https://firstwordpharma.com/story/5640985

Verismo plans to initiate a phase 1, first-in-human trial of SynKIR-110 in the first quarter of 2023. 

KIR-CAR T-Cell Therapy Recognized for Mesothelioma Treatment 

 (BLA) for SRP-9001 (delandistrogene moxeparvovec), an investigational gene therapy developed in collaboration with Roche, for the potential treatment of ambulant patients with Duchenne muscular dystrophy (DMD).

SRP-9001 expresses the microdystrophin gene to combat the deleterious effects of the dysfunctional dystrophin produced in DMD. It has been granted fast track, rare pediatric, and orphan drug designations in the US as well as orphan drug status in the EU, Switzerland, and Japan. The BLA has been submitted using the accelerated approval pathway. 

“Every hour of every day, this ruthless disease, Duchenne, robs thousands of children in the United States of muscle as it steals their future from them. Sarepta’s BLA submission for an accelerated approval of SRP-9001 is a significant milestone in our quest to intervene with urgency on behalf of the children we serve,” Doug Ingram, president and chief executive officer, Sarepta Therapeutics, said in a statement.

 “If approved, SRP-9001 will be the first gene therapy available for Duchenne patients. We are enormously grateful to the courageous families who have participated in the SRP-9001 trials and to the participating clinical investigators and experts who have guided us and played a crucial part in reaching this milestone.”

 from the phase 1/2 Study SRP-9001-101 (NCT03375164), the phase 2 SRP-9001-102 study (NCT03769116), and the phase 1 ENDEAVOR study (SRP-9001-103; NCT04626674). At 1, 2, and 4 years after treatment, SRP-9001 was well-tolerated and yielded clinical improvements and biomarker expression. Sarepta also found evidence of clinical benefit by comparing an integrated analysis across the 3 studies to an external control.

DMD Cell Therapy Shows Promise in Early Clinical Trial Data

Biomarker findings were obtained by western blot and supported by immunofluorescence. Efficacy and clinical benefits were measured by the North Star Ambulatory Assessment (NSAA) and secondary timed tests.

SRP-9001 is currently being evaluated in the double-blind, randomized, plscaebo-controlled EMBARK study (Study SRP-9001-301; NCT05096221), which is being proposed at the post-marketing confirmatory study to support the accelerated approval. EMBARK is primarily assessing change in NSAA total score from baseline to week 52 compared to placebo. Secondary outcomes include microdystrophin expression, time to rise from floor, patient-reported outcomes, skills gained, incidence of adverse events, and changes in scores on 100- and 10-meter walk/run, Timed Stair Ascend 4 Steps, and Stride Velocity 95th Centile tests.

“The data from our 103 study is particularly important because it’s from our commercially-representative material,” Louise Rodino-Klapac, PhD, executive vice president and chief scientific officer, Sarepta, said on a conference call regarding data on July 6, 2022.

 “It can be extremely challenging to achieve the same level of safety and efficacy when scaling up from small-scale to commercial-scale, so we are thrilled to see that these results are not only consistent, but may be improved over previously reported results.”

1. Sarepta Therapeutics submits biologics license application for SRP-9001 for the treatment of ambulant patients with Duchenne muscular dystrophy. News release. Sarepta Therapeutics. Septemebr 29, 2022. 


2. SRP-9001: New clinical data and integrated analysis. Webcast. Sarepta Therapeutics. July 6, 2022. https://investorrelations.sarepta.com/events/event-details/sarepta-therapeutics-share-new-clinical-data-and-integrated-analysis-srp-9001

SRP-9001 has shown safety and efficacy across multiple studies compared to controls, with additional efficacy data expected in 2024 from the EMBARK trial. 