“There were lower rates of CRS and ICANS than in ZUMA-2 and most side effects were grade 1. These real-world experiences are very helpful, because clinical trials use a selected population of patients. We're seeing similar responses and toxicities in the real-world setting as the clinical trials. I think it’s very encouraging data.”

Currently approved chimeric antigen receptor (CAR) T-cell therapies for hematologic malignancies include lisocabtagene maraleucel (Breyanzi), axicabtagene cliolecleucel (Yescarta), brexucabtagene autoleucel (Tecartus)and ciltacabtagene autoleucel (Carvykti). As more CAR T therapies come to market, clinicians are beginning to see the long-term impact of these treatments in the clinic.

Among these clinicians is Nilanjan Ghosh, MD, PhD, chief of the lymphoma division and oncologist at Levine Cancer Institute. Ghosh has first-hand experience with these CAR T therapies on the clinic side and has seen their impact in patients with hematologic malignancies such as lymphomas.

 spoke to Ghosh to learn more about the future trajectory of CAR T-cell therapies in lymphomas. He discussed recent data seen in real-world experience studies of CAR T-cell therapies.

Videos

The chief of the lymphoma division and oncologist at Levine Cancer Institute discussed data from real-world experience studies. 

Nilanjan Ghosh, MD, PhD, on Real-World Efficacy of CAR T-Cell Therapies 

The FDA has approved Bristol Myers Squibb’s supplemental biologics license application for 

 (liso-cel; Breyanzi) as second-line therapy for patients with large B-cell lymphoma (LBCL).

The chimeric antigen receptor (CAR) T-cell therapy was originally approved in February 2021 for adults with relapsed or refractory diffuse LBCL who have not responded to at least 2 other treatments based off data from the pivotal 

In the second-line setting, liso-cel recently showed good efficacy and patient-reported outcome (PRO) data in the 

(NCT03483103), updated data from which were presented at the 

2022 American Society of Clinical Oncology (ASCO) meeting, held June 3-7, 2022, in Chicago, Illinois

The TRANSCEND study dosed 61 participants that had disease that relapsed after or was refractory to first-line chemotherapy. These participants were followed-up for a median of 12.3 months (range, 1.2–26.5). Investigators found that overall response rate (ORR) was 80% and complete response rate (CR) was 54%. Median duration of response (DOR) was 12.1 months, progression-free survival (PFS) was 9.0 months, and median overall survival (OS) has not been reached.

Frederick Locke, MD, on the Impact Potential of CAR T-Cell Therapies in Hematologic Malignancies

Investigators assessed PROs and found that completion rates were high (≥ 80%) across most visits for all measures. Baseline European Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients (EORTC QLQ-C30) mean fatigue scores were worse by at least 10 points at baseline compared to a general noncancer population. These scores, along with pain domain scores, Functional Assessment of Cancer Therapy – lymphoma subscale, and EuroQol Visual Analogue Scale scores improved significantly by least square means through day 545. 

Patients also reported that lymphoma symptoms improved in a clinically meaningful way. No outcomes significantly worsened and 70% of patients demonstrated meaningful improvement in FACT-LymS at month 6. 

Liso-cel has been well-tolerated, with treatment-emergent adverse events (TEAE) in TRANSCEND that included neutropenia (51%), fatigue (39%), and CRS (38%), including 1 case of grade 3 CRS (2%). Neurological events occurred in 31% of participants, 5% (n = 3) of which were grade 3 cases. AEs resolved with the use of tocilizumab (7%), corticosteroids (3%), or both (20%). Overall, grade 3 TEAEs occurred in 79% of participants, with grade 5 cases in 2 patients due to COVID-19. Two patients (3%) had grade 3/4 infections and 15 (25%) had at least grade 3 neutropenia at Day 29.

Liso-cel's supplemental biologics license application 

 in April 2022 for the treatment of relapsed/refractory DLBCL, primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma grade 3B (FL3B) in patients who have received 2 or more lines of systemic treatment.

1.U.S. FDA Approves Bristol Myers Squibb’s CAR T Cell Therapy Breyanzi® for Relapsed or Refractory Large B-cell Lymphoma After One Prior Therapy. News release. Bristol Myers Squibb. June 24, 2022. https://news.bms.com/news/details/2022/U.S.-FDA-Approves-Bristol-Myers-Squibbs-CAR-T-Cell-Therapy-Breyanzifor-Relapsed-or-Refractory-Large-B-cell-Lymphoma-After-One-Prior-Therapy/default.aspx
2. FDA Approves New Treatment For Adults With Relapsed Or Refractory Large-B-Cell Lymphoma. News release. FDA. February 5, 2021. https://www.prnewswire.com/news-releases/fda-approves-new-treatment-for-adults-with-relapsed-or-refractory-large-b-cell-lymphoma-301223275.html
3. Sehgal A, Hoda D, Riedell PA, et al. Lisocabtagenemaraleucel (liso-cel) as second-line (2L) therapy for R/R large B-cell lymphoma (LBCL) in patients (pt) not intended for hematopoietic stem cell transplantation (HSCT): Primary analysis from the phase 2 PILOT study. Presented at: 2022 ASCO Annual Meeting, June 3-7, 2022, Chicago, Illinois. Abstract #7062
4. Gordon LI, Hoda D, Shi L, et al. Lisocabtagenemaraleucel (liso-cel) as second-line (2L) treatment (tx) for R/R large B-cell lymphoma (LBCL) in patients (pt) not intended for hematopoietic stem cell transplantation (HSCT): Patient-reported outcomes (PRO) from the phase 2 PILOT study. Presented at: 2022 ASCO Annual Meeting, June 3-7, 2022, Chicago, Illinois. Abstract #6567
5. US Food and Drug Administration (FDA) accepts for priority review Bristol Myers Squibb’s supplemental biologics license application for Breyanzi (lisocabtagenemaraleucel) as a second-line therapy for relapsed or refractory large B-cell lymphoma. News release. Bristol Myers Squibb; February 17, 2022. Accessed February 17, 2022. 


6. Bristol Myers Squibb receives European Commission approval for CAR T cell therapy Breyanzi (lisocabtagenemaraleucel) for certain forms of relapsed or refractory large B-cell lymphoma. News release. Bristol Myers Squibb. April 5, 2022. Accessed April 8, 2022. https://bit.ly/3LPwb0l

Articles

The approval builds off of liso-cel's (Breyanzi) previous indication for third-line or later treatment in LBCL.

Liso-Cel Approved for Second-Line Large B-Cell Lymphoma 

 Weekly Rewind! We’ve compiled 5 highlights from this week’s coverage of advances in gene and cell therapies, including FDA actions, notable research, and interviews with experts across the field.

1. Krystal Seeks Approval for Dystrophic Epidermolysis Bullosa Gene Therapy

Krystal Biotech has submitted a biologics license application for B-VEC (beremagene geperpavec), its gene therapy for the potential treatment of dystrophic epidermolysis bullosa.

2. Steven W. Pipe, MD, on Challenges in Gene Therapy Trials for Hemophilia

The director of the Pediatric Hemophilia and Coagulation Disorders Program at CS Mott Children’s Hospital discussed common challenges with gene therapy clinical trials.

3. Gene-Mediated Immunotherapy for Ovarian Cancer Clears Safety Hurdle, Will Continue Dosing

Celsion’s GEN-1, an IL-12 DNA plasmid vector, was determined to have a satisfactory safety profile and acceptable risk/benefit by an independent Data Safety Monitoring Board (DSMB) that has recommended dosing to continue.

4. Thomas Martin, MD, on Exciting Cell Therapy Options in Multiple Myeloma

The clinical professor of medicine, Helen Diller Family Comprehensive Cancer Center, UCSF, discussed cilta-cel and upcoming cell therapies.

5. Children Treated With Zolgensma for Presymptomatic SMA Achieve Age-Appropriate Motor Milestones

All children in the phase 3 SPR1NT study achieved the primary end point of independent sitting. 

Review top news and interview highlights from the week ending June 24, 2022. 

CGTLive’s Weekly Rewind – June 24, 2022 

The EMA’s Committee for Medicinal Products for Human Use (CHMP) has given a positive opinion to BioMarin’s valoctocogene roxaparvovec (val-rox; Roctavian) gene therapy for the potential treatment of 

"Today's positive CHMP opinion for Roctavian addresses the unmet medical needs in severe hemophilia A by providing a treatment option that has been shown in clinical studies can maintain effective levels of endogenously produced coagulation Factor VIII over multiple years with a single intravenous administration. Currently available treatment options require long-term, chronic use with a high degree of compliance to a prescribed schedule to be effective," Hank Fuchs, MD, president, worldwide research and development, BioMarin, said in a statement.

A final decision on val-rox's approval is expected from the European Commission in the third quarter of 2022. Meanwhile, in the US, the filing of BioMarin’s biologic license application was 

 with the FDA requesting additional durability and safety data on the gene therapy.

 The BLA was previously rejected in August 2020 with requests for 2-year follow-up data.

BioMarin is working to collect the new data from ongoing trials, including GENEr8-1 (NCT03370913), GENEr8-3 (NCT04323098), and the non-clinical study GENEr8, and plans to resubmit the BLA by the end of September 2022 instead of June.

Steven W. Pipe, MD, on Challenges in Gene Therapy Trials for Hemophilia

"The positive CHMP opinion offers hope for a new treatment option for people with severe hemophilia A, who have been bound to lifelong treatment and still experience serious health complications, such as breakthrough bleeding, pain, and joint damage, as well as having to constantly consider their condition in all aspects of their lives," Johannes Oldenburg, MD, PhD, director, Institute of Experimental Haematology and Transfusion Medicine and Haemophilia Centre, University Clinic, Bonn, Germany, added to the statement.

 "The robust data set from the clinical trial program underscores the potential impact of gene therapy for patients, including a substantial and sustained reduction in bleeding that would have previously required Factor VIII infusions."

In March 2022, BioMarin announced the publication of results from the GENEr8-1 study in the 

 that demonstrated val-rox's ability to 

restore endogenous factor VIII production

 and significantly reduce bleeding and use of enzyme replacement therapy in patients with hemophilia A.

Investigators found that 132 human immunodeficiency virus–negative participants in GENEr8-1 had mean chromogenic substrate factor VIII activity levels during weeks 49 through 52 were 42.9 IU per deciliter (standard deviation [SD], 45.5) and median chromogenic substrate factor VIII activity levels were 23.9 IU per deciliter (interquartile range [IQR], 11.9-62.3). The mean change in factor VIII activity from baseline was 41.9 IU per deciliter (95% CI, 34.1-49.7; 

 <.001) and median change was 22.9 IU per deciliter (IQR, 10.9-61.3). Val-rox's safety profile was manageable, with all participants experiencing at least 1 mild adverse event (AE) and 5 participants experiencing treatment-related serious AEs.

1. BioMarin receives positive CHMP opinion in Europe for valoctocogene roxaparvovec gene therapy to treat adults with severe hemophilia A. News release. BioMarin. June 24, 2022. 

https://investors.biomarin.com/2022-06-24-BioMarin-Receives-Positive-CHMP-Opinion-in-Europe-for-Valoctocogene-Roxaparvovec-Gene-Therapy-to-Treat-Adults-with-Severe-Hemophilia-A


2. BioMarin delays hemophilia a therapy valoctocogene roxaparvovec filing as FDA calls for more data. News release. BioMarin. May 31, 2022. 

https://www.biospace.com/article/fda-needs-more-data-for-biomarin-s-hemophilia-a-therapy/


3. Ozelo MC, Mahlangu J, Pasi J, et al. Valoctocogene roxaparvovec gene therapy for hemophilia A. 

. 2022; 386: 1013-1025. doi: 10.1056/NEJMoa2113708

BioMarin received a positive CHMP opinion after the FDA delayed val-rox's BLA filing for the second time. 

Val-Rox Approval Favored in Europe, Stalled in US

Krystal Biotech has submitted a biologics license application (BLA) for B-VEC (beremagene geperpavec), its gene therapy for the potential treatment of dystrophic epidermolysis bullosa (DEB).

The BLA submission is based off positive data from the phase 1/2 GEM-1/2 study (NCT03536143) and the 

 (NCT04491604). Positive data from the GEM-3 study were recently presented at the American Academy of Dermatology (AAD) 2022 Annual Meeting, March 25-29, Boston, Massachusetts, by principal investigator M. Peter Marinkovich, MD, associate professor, department of dermatology, Stanford University.

“The unmet medical need for DEB patients remains very high and our relentless pursuit of a treatment for this disease continues with the same sense of urgency that we have always had since the founding of Krystal Biotech,” Suma Krishnan, president, research & development, Krystal, said in a statement.

 “We look forward to working with the FDA in its review of our BLA submission.”

B-VEC is a topical, re-dosable gene therapy. It is directly applied to DEB wounds and delivers 2 copies of the COL7A1 gene directly to the skin to make functional COL7 protein. Krystal plans to submit a marketing authorization application with the EMA in the second half of 2022.

Assessing Gene Therapy in Recessive Dystrophic Epidermolysis Bullosa

The GEM-1/2 trial was a single-center, randomized, intra-patient placebo-controlled, open-label trial that enrolled 9 patients with dystrophic epidermolysis bullosa patients evaluated over 12 weeks. The trial met both its mechanistic and clinical endpoints and investigators found that B-VEC was well-tolerated with no serious treatment-related adverse events (AEs).

Recently in the GEM-3 study, investigators found that a significantly greater proportion of wounds treated with B-VEC exhibited complete wound healing compared with placebo at 3 months (absolute difference, 50.3% [95% CI, 28.7-72.0]; 

 <.005) and 6 months (absolute difference, 45.8% [95% CI, 23.6-68.0%]; 

 Almost half (49.7%) of wounds treated with B-VEC were completely healed at both 3 and 6 months compared with 7.1% of wounds treated with placebo, demonstrating durability of response. Most wounds (66.7%; n = 14) closed at 3 months were also closed at 6 months, compared with 33.3% of placebo-treated wounds meeting the same endpoint (

Pain and patient-reported outcome data were also positive, with a significant change from baseline in pain response at week 22 (

 = .02), and near-significant changes at weeks 24 (

 = .06). There was also a trend toward decreased pain in B-VEC versus placebo treated wounds. Improvements from baseline were also seen in patient-reported outcome measures such as EQ-5D-5L and Skindex-29. Safety findings were similar between GEM-1/2 and GEM-3, and the therapy continues to be well-tolerated.

“It’s the very first topical gene replacement therapy in dermatology... We've seen success in the phase 3 trial and it may be the case that more dermatologists will be seeing these patients come in since the therapy is so easy to do,” Marinkovich said in an 

1. Krystal Biotech submits biologics license application to U.S. FDA seeking approval of B-VEC for the treatment of patients with dystrophic epidermolysis bullosa. News release. Krystal Biotech. June 22, 2022. 

https://ir.krystalbio.com/news-releases/news-release-details/krystal-biotech-submits-biologics-license-application-us-fda


2. Marinkovich MP, Gonzalez ME, Guide S, et al. GEM-3: A phase 3 study of beremagene geperpavec (B-VEC), an investigational, topical gene therapy, for the treatment of dystrophic epidermolysis bullosa (DEB). Presented at: AAD 2022 Annual Meeting, March 25-29, Boston, Massachusetts.

B-VEC recently showed efficacy in the phase 3 GEM-3 trial. 

Krystal Seeks Approval for Dystrophic Epidermolysis Bullosa Gene Therapy 

“As it stands right now, the safety and efficacy look quite encouraging. We believe that at least 1 platform for hemophilia A and 1 for hemophilia B will be submitted for regulatory review this year. I'm fully preparing our clinic to the fact that we may be doing commercial gene therapy either late in 2022 or early in 2023.”

Multiple companies are targeting hemophilia A and B indications for gene and cell therapy programs, with the goal of addressing Factor VIII deficiency in hemophilia A and Factor IX deficiency in hemophilia B.

 had the opportunity to speak with Steven W. Pipe, MD, a veteran of the field who has been involved with multiple gene therapy investigations. Pipe is director of the Pediatric Hemophilia and Coagulation Disorders Program at CS Mott Children’s Hospital and is also a professor at University of Michigan Health.

Among Pipe’s investigations are the pivotal GENEr8-1 (NCT03370913) study of valoctocogene roxaparvovec (val-rox; Roctavian; BioMarin), the BLA filing for which was recently delayed by the FDA, as well as studies on etranacogene dezaparvovec by UniQure and another program by Bayer.

 A paper coauthored by Pipe was published in January 2022 exploring novel approaches to treating hemophilia A.

 In this clip, Pipe discussed the challenges of conducting gene therapy investigations in hemophilia.

1. BioMarin delays hemophilia a therapy valoctocogene roxaparvovec filing as FDA calls for more data. News release. BioMarin. May 31, 2022. https://www.biospace.com/article/fda-needs-more-data-for-biomarin-s-hemophilia-a-therapy/
2. Pipe SW, Gonen-Yaacovi G, Segurado OG. Hemophilia A gene therapy: current and next-generation approaches. Expert Opin Biol. Published online January 6, 2022. doi:10.1080/14712598.2022.2002842

The director of the Pediatric Hemophilia and Coagulation Disorders Program at CS Mott Children’s Hospital discussed common challenges with gene therapy clinical trials. 