Alicia Bigica

In a status update for its biologics license application (BLA) for valoctocogene roxaparvovec (val-rox), BioMarin disclosed that the gene therapy's PDUFA target action date may be delayed if the FDA deems the submission of new data from a phase 3 analysis as a major amendment to the application.

 A in adults, currently has a PDUFA date of March 31, 2023. In recent communications with the FDA, BioMarin noted that the agency has scheduled its inspection of the company's manufacturing facility in California and has requested the submission of expected 3-year data from on the ongoing phase 3 GENEr8-1 clinical trial. These data, once reviewed by the agency, could be considered a major amendment and therefore extend the review period by 3 months. 

"We appreciate the level of engagement from FDA this early in their BLA review cycle and are pleased to share that the inspection of our gene therapy manufacturing facility has now been scheduled. Additionally, with their request related to the upcoming three-year data analysis from our Phase 3 GENEr8-1 study, FDA stated that these data are expected to provide longer-term efficacy and safety information and would thus be useful to people with Hemophilia A and healthcare providers in making better and more informed decisions when considering valoctocogene roxaparvovec as a treatment choice should it be approved," said Hank Fuchs, MD, president of worldwide research and development, BioMarin, in a statement.

The FDA accepted BioMarin's resubmitted BLA for val-rox in October 2022, following 

 by the European Commission in August 2022. The gene therapy has received RMAT, breakthrough therapy, and orphan drug designations from the FDA.

Full 52-week results from the GENEr8-1 study were 

 demonstrating that a single dose of the infused gene therapy resulted in statistically significant increases in endogenous Factor VIII production (

 <.001) and signficantly reduced bleeding events and use of factor VIII concentrate (

<.001 for both), all while maintaining a relatively good safety profile (N = 134). 

 from a subset of the modifiend intent-to-treat population (n=17) of patients who had been dosed at least 3 years prior to data cutoff showed a mean factor VIII activity of 16.8 IU/dL by CS assay and 27 IU/dL by OS assay, with a mean cumulative annualized bleeding rate of 0.7 over the 174-week evaluation period and 0.6 during year 3. 

BioMarin is expected to publish its full 3-year data analysis from the entire cohort in early 2023. 

The FDA isn't the only agency waiting on long-term benefits of the drug. In its final 

, The Institute for Clinical and Economic Review (ICER) has concluded that the price of valoctocogene roxaparvovec (val-rox; Roctavian; BioMarin) should be capped at $1.9 million and the price of etranacogene dezaparvovec (EtranaDez; uniQure and CSL Behring) should be capped at $2.9 million,

noting the unknown long-term benefits of val-rox.

"The new gene therapies can result in successfully-treated patients appearing ‘cured’ for at least a period of time. During this period these gene therapies will eliminate the need for expensive prophylactic treatment," David Rind, MD, chief medical officer, ICER, said in a statement.

 "However, the duration of this ‘cure’ and the safety of therapies remain important uncertainties. At least with val-rox, patients will eventually return to needing prophylaxis.”

1. BioMarin Announces Incremental Progress on Biologics License Application (BLA) Review for Valoctocogene Roxaparvovec AAV Gene Therapy for Adults with Severe Hemophilia A Program. News release. BioMarin Pharmaceutical. November 7, 2022. https://www.prnewswire.com/news-releases/biomarin-announces-incremental-progress-on-biologics-license-application-bla-review-for-valoctocogene-roxaparvovec-aav-gene-therapy-for-adults-with-severe-hemophilia-a-program-301670773.html
2. Ozelo MC, Mahlangu J, Pasi J, et al. Valoctocogeneroxaparvovec gene therapy for hemophilia A. 

. 2022; 386: 1013-1025. doi: 10.1056/NEJMoa2113708
3. BioMarin Announces Stable and Durable Annualized Bleed Control in the Largest Phase 3 Gene Therapy Study in Adults with Severe Hemophilia A; 134-Participant Study Met All Primary and Secondary Efficacy Endpoints at Two Year Analysis. News release. BioMarin Pharmaceutical. January 9, 2022. 
4. Institute for Clinical and Economic Review. Gene therapy for hemophilia B and an update on gene therapy for hemophilia A: Effectiveness and value. November 3, 2022. https://icer.org/wp-content/uploads/2022/05/Hemophilia_Revised-Report_Updated_For-Publication_110322.pdf
5. ICER Publishes Evidence Report on Gene Therapies for Hemophilia A and B. News release. ICER. November 3, 2022. https://icer.org/news-insights/press-releases/icer-publishes-evidence-report-on-gene-therapies-for-hemophilia-a-and-b/

Articles

Recent communication with the FDA suggests that the agency's decision might be delayed past Q1 2023. 

BioMarin Prepares for PDUFA Delay for Val-Rox Hemophilia Gene Therapy

Terry Horgan, the primary patient in an N-of-1 clinical trial evaluating a CRISPR-based 

 for the treatment of Duchenne muscular dystrophy (DMD), has died, according to an announcement from Cure Rare Disease, the nonprofit biotech sponsoring the trial.

Horgan is the brother of Cure Rare Disease founder Rich Horgan, who started the nonprofit to help identify a potential treatment for his brother, who was diagnosed with the degenerative neuromuscular disorder in 1999. 

Back in August, the FDA gave the nonprofit the go-ahead to proceed with the trial (NCT05514249),

 which involved the intravenous administration of a CRISPR-based gene therapy intended to treat muscle promotor and exon 1 mutations on the dystrophin gene that would upregulate an isoform of the dystrophin protein in hopes of stabilizing an potentially reversing symptom progression in DMD. It has not been made abundantly clear whether or not Horgan actually received the therapy before his death. 

"We know the CRD-TMH-001 trial and the outcome have been closely followed by the rare disease community and many are eager for more details. While these details are currently being studied by multiple teams across the country, this is a complex undertaking and could take up to four months," Cure Rare Disease said in a statement. "The comprehensive work these teams are doing is critical to gaining a clear understanding of the outcome of the CRD-TMH-001 trial and to shedding additional light on the challenges of gene therapy broadly."

In an interview with CGTLive, Muscular Dystrophy Association VP of Public Policy & Advocacy spoke about the organization's work to advance gene therapies towards regulatory review. Watch Now. 

The investigational therapy, CRD-TMH-001, is 1 of several therapeautic pursuits being supported by Cure Rare Disease, although it is the only one to have reached the clinical trial stage so far. The nonprofit is currently exploring 19 different mutations associated with Duchenne and Becker muscular dystrophies, as well as several other pipeline candidates in limb girdle muscular dystrophy, adenylosuccinate synthase 1, and spinocerebellar ataxia. 

The news is yet another bump in the road for the close-knit DMD community, who have become increasingly vocal proponents of investigational therapies coming before regulators. Several companies are working on therapeutics with DMD-related targets, but few have hedged big successes. 

Most recently, Solid Biosciences presented new data on its gene therapy candidate SGT-001,

 which showed that treatment with the microdystrophin gene therapy was associated with improvements in stride velocity 95th centile at 1-year post-dose compared with baseline. Patients treated demonstrated an average improvement of 8.8%-9.5% from baseline, 23.9%-24.6% compared to natural history, and 26.0%-26.7% compared to the control patient. Solid plans to initiate clinical trial evaluation of another gene therapy candidate, SGT-003, in late 2023. 

Further along in the process is Sarepta Therapeutics, who recently submitted a biologics license application to the FDA for the accelerated approval of SRP-001 (delandistrogene moxeparvovec), its gene therapy candidate for the treatment of ambulatory patients with DMD.

 The application is based on the expression of a shortened, functional version of the dystrophin protein as a surrogate end point that will likely result in clinical benefit. If accepted, Sarepta could expect a decision in May 2023. 

1. An Update to the CRD community. News release. Cure Rare Disease. November 1, 2022. https://www.cureraredisease.org/blog-posts/update-to-crd-community
2. Cure Rare Disease Receives FDA Approval to Administer First-in-Human CRISPR Therapeutic. News release. Cure Rare Disease. August 9, 2022. https://www.cureraredisease.org/fda-approval
3. Solid Biosciences Presents New SGT-001 IGNITE DMD Study Results at World Muscle Society 2022 Congress Demonstrating Improvements in Ambulatory Function. News release. Solid Biosciences. October 13, 2022. https://www.solidbio.com/about/media/press-releases/solid-biosciences-presents-new-sgt-001-ignite-dmd-study-results-at-world-muscle-society-2022-congress-demonstrating-improvements-in-ambulatory-function
4. Sarepta Therapeutics Submits Biologics License Application for SRP-9001 for the Treatment of Ambulant Patients with Duchenne Muscular Dystrophy. News release. Sarepta Therapeutics. September 29, 2022. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-submits-biologics-license-application-srp

The trial was launched through a partnership between Cure Rare Disease and UMass Chan Medical School. 

DMD Patient Dies in CRISPR Gene Therapy Trial Led By Nonprofit Biotech Cure Rare Disease

When thinking about the current state of advanced therapeutics for rare diseases, many of which are gene or cell-based therapies, the expression “cart before the horse” may come to mind. That is, the incredible rate of advances being made in the lab and in the clinic sometime seem leaps ahead of where realistic clinical practice currently lies.

, awareness of their disease is severely lacking among health care providers, especially those in the community setting. Access to specialists can be equally as limiting, with hundreds of miles often between patients and specialists at academic institutions. Add to that limited education on clinical trials, prohibitive costs, and travel restrictions due to health or other circumstances, many of the treatments currently or soon to be available might never reach their intended audience.

“Translation” in this field often means from lab to clinic, but in the case of rare diseases, translation also needs to happen from clinic to community, as improving access to advanced therapies for rare diseases is not just about developing successful therapies, but effectively involving and educating providers at all levels.

This topic was the focus of a dynamic panel discussion at the 

, October 17-18, 2022 in Washington, DC. Illustrating the different steps and players involved in the rare disease diagnosis and treatment process, the panel featured key speakers representing advocacy, industry, and academia.

Representing advocacy, Michelle Davis, executive director of the International FOP Association, recounted the work completed to boost awareness of fibrodysplasia ossificans progressive (FOP), a very rare degenerative musculoskeletal disorder. From her perspective, she noted that “creating a registry is the most important step, as it allows you to understand the size of your patient population and gather data, and that data becomes valuable and something that you can leverage in academia or pharma.”

Working with a very limited pool of FOP specialists, the International FOP Association supports extensive education efforts to better equip the community provider, including physicians, advanced practice providers, and nurses, with information about the rare disease, including presentations to look out for and continuing education opportunities.

Davis’ efforts are a small part of recognition and diagnosis, which can be particularly challenging in rare diseases. Those exhibiting perplexing presentations may land in the hands of Vinaya Murthy, MPH, MS, LCGC, and her colleagues at Indiana University Health’s Undiagnosed Rare Disease Clinic (URDC). Murthy, an assistant professor of clinical medical and molecular genomics, is a genetic counselor who helped launch the rare disease clinic which focuses on providing extensive genetic counseling services for patients who likely have an undiagnosed rare disease of genetic origin. The clinic, which includes a staff of medical geneticists and genetic counselors, serves to close the loop for patients who have yet to receive a definitive diagnosis despite extensive testing and seeing multiple providers.

For those who receive a confirmed diagnoses, Murthy and colleagues can then go on to referring them to a broader network of support, including helping unite them with advocacy organizations and clinical trial sites.

Patient recruitment for rare disease clinical trials involves its own set of unique challenges. Health, financial, and geographic limitations can quickly whittle away a pool of prospective participants, especially given that many rare disease patients live upwards of 2 hours away from major academic medical centers where clinical trials typically take place.

On the momentum of COVID-19 and the dissemination of telehealth, a large effort to decentralize clinical trials is underway, moving more trials outside of academic institutions to community settings, going as far to provide hybrid and fully virtual trial experiences. This patient-centric approach is key to improving clinical trial enrollment for advanced therapies for rare diseases.

Elevating the patient voice as part of the drug development process can help close a lot of the gaps that currently exist in terms of patient awareness of and willingness to participate in clinical trials, according to Nerissa Kreher, MD, MBA, chief medical officer, Entrada Therapeutics. Kreher spoke of emphasizing a ‘hub-and-spoke’ model to increase community-based clinical trials. “By training community [primary investigators] to be more involved in the trial, they learn about the clinical trial process and execution but also the disease. Ultimately, they will be more equipped to deliver care when treatments are approved.”

Ultimately, all 3 points go back to education, and the panel participants all agreed that adjustments to medical school curriculum are in order to better equip providers with the knowledge and decision-making tools needed to navigate the immense uncertainty that a rare disease diagnosis can conjure.

If We Build It, Will They Come? Presented at: 2022 NORD Breakthrough Summit. October 17-18, 2022. Washington, DC.

With so many therapies on the horizon, the clinical and patient communities need to be adequately prepared to support them. 

Bridging the Gap: Education, Awareness Key to Translating Medical Innovation to Community Health Care in Rare Diseases

The FDA has granted accelerated approval to bluebird bio's elivaldogene autotemcel (eli-cel; Lenti-D) for the treatment of early, active cerebral adrenoleukodystrophy (CALD) in patients without an HLA-matched donor.

 The approval follows similar action by the FDA in August when it approved the biotech company's gene therapy 

 (beti-cel; Zynteglo) intended for the treatment of transfusion-dependent β-thalassemia.

After a challenging start to 2022, bluebird bio has seemingly bounced back on the heels of 2 very favorable meetings of the FDA Cellular, Tissue, and Gene Therapies Advisory Committee, who cast a 

 in support of both eli-cel and beti-cel, stating that the benefits of the lentiviral vector gene therapies 

"For the ALD community, this long-awaited approval represents significant hope and offers families a new option where, for many, there had been none," Andrew Obenshain, chief executive officer, bluebird bio, said in a statement.

  "We are grateful to every individual who was involved in the development of SKYSONA and are committed to working with providers and payers to make this important treatment option available to patients and their families."

Eli-cel, which is currently on clinical hold and is continuing to be evaluated in the phase 3 ALD-104 study (NCT03852498), was granted priority review in December 2021 based on positive data from 23 participants in ALD-104 as well as 32 participants from the completed phase 2/3 Starbeam study (ALD-102; NCT01896102).

 An additional long-term follow-up study (LTF-304; NCT02698579) is ongoing.

The Starbeam study met its primary end point of Major Functional Disabilities (MFD)-free survival at 24 months, with 29 patients (90.6%) achieving this end point. Two participants withdrew at investigator discretion and 1 participant experienced rapid disease progression, MFD, and death. Median follow-up, including the long-term follow-up study, is 3.5 years (42.3 months; range, 13.4-83.7).

In August 2021, the FDA placed the first in class, one-time gene therapy product on hold due the report of a suspected unexpected serious adverse reaction of myelodysplastic syndrome in a patient treated with the therapy.

 The hematologic malignancy, of which 2 other cases have since developed, is thought to be mediated by the use of the lentiviral vector. 

David A. Williams, MD, associate chairman, department of pediatric oncology, Dana-Farber Cancer Institute, and chief, hematology/oncology, Boston Children's Hospital, who presented an analysis of the cases earlier this year at the 

2022 American Society of Gene and Cell Therapy Annual Meeting

, concluded that more study is necessary of the LVV-mediated oncogenesis but that the gene therapy offers significant clinical benefit to patients with CALD.

Insertion site analysis (ISA) revealed that both patients that developed MDS from ALD-104 had clonal predominance at 6 months postinfusion that included a single insertion in the 

 gene. Further analysis revealed no typical driver mutation of myeloid neoplasms. The patient from ALD-102 had insertions in multiple genes, including 

 and another patient with benign clonal predominance did have insertion in 

Notably, both eli-cel and beti-cel were previously approved in Europe; however, bluebird bio 

 late last year due to payor challenges. Upon 

, beti-cel's one-time treatment was priced at $2.8 million, making it the most expensive gene therapy available. The company launched a 

 earlier this year, citing the "tough biotech market" in its move to cut its workforce by 30% and slow its cash burn in order to continue supporting its efforts in gene therapy development and commercialization. 

1. bluebird bio Receives FDA Accelerated Approval for SKYSONA® Gene Therapy for Early, Active Cerebral Adrenoleukodystrophy (CALD). News release. bluebird bio. September 16, 2022. https://finance.yahoo.com/news/bluebird-bio-receives-fda-accelerated-035100645.html
2. bluebird bio Announces FDA approval of ZYNTEGLO® , the first gene therapy for people with beta-thalassemia who require regular red blood cell transfusions. News release. bluebird bio. August 17, 2022.
3. bluebird bio announces FDA priority review of biologics license application for eli-cel gene therapy for cerebral adrenoleukodystrophy (CALD) in patients without a matched sibling donor. News release. bluebird bio. December 17, 2021. 

https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-announces-fda-priority-review-biologics-license-0


4. bluebird bio reports second quarter financial results and provides operational update. News release. bluebird bio. August 9, 2021. 

https://www.businesswire.com/news/home/20210809005334/en/bluebird-bio-Reports-Second-Quarter-Financial-Results-and-Provides-Operational-Update


5. Williams DA, Bledsoe JR, Duncan CN, et al. Myelodysplastic syndromes after eli-cel gene therapy for cerebral adrenoleukodystrophy (CALD). Presented at: ASGCT 25th Annual Meeting; May 16-19, 2022. Washington DC.

The approval follows unanimous support of eli-cel's benefits in CALD from an FDA AdComm meeting and an approval for beti-cel in beta-thalassemia.  

Eli-Cel Approved for CALD, Marking Second Gene Therapy Win for bluebird bio

Intellia has reported positive interim data from 2 ongoing clinical trials examining their in vivo CRISPR/Cas9 gene editing therapies, one for the treatment of transthyretin (ATTR) amyloidosis with cardiomyopathy and the other for hereditary angioedema (HAE). 

Interim results from the phase 1 clinical trial of NTLA-2001, Intellia Therapeutics' and Regeneron Pharmaceuticals' investigational CRISPR/Cas9 gene editing therapy for the treatment of ATTR amyloidosis with cardiomyopathy demonstrate deep reductions in serum TTR over a 28-day period after patient's received the single-dose therapy. 

Patients in the low-dose cohort (0.7 mg/kg; n=9) who had either Class I/II or Class III New York Heart Association (NYHA) heart failure saw a mean TTR serum reduction by day 28 of 93%, with a mean reduction of 92.5% in the high-dose cohort (1.0 mg/kg; NYHA Class I/II; n=3). These reductions were sustained through follow-up, which ranged from 2 to 6 months as of the July 1, 2022 data cutoff. 

“Together with the previously reported data from the polyneuropathy arm of this landmark study, these results strongly suggest that NTLA-2001 could serve as a single-dose treatment regardless of disease manifestation. At these deep and consistent levels of protein reduction, we believe NTLA-2001 has the potential to halt and even reverse the underlying cause of ATTR amyloidosis," said John Leonard, MD, president and chief executive officer, Intellia, in a statement. "Given the similarly robust TTR reductions observed at the two doses tested, we have selected a fixed dose comparable to the 0.7 mg/kg level for evaluation across both arms in the ongoing dose-expansion portion of the study. We look forward to completing the Phase 1 study as we advance closer to a potential pivotal trial, which we expect will include patients in the US.”

In terms of adverse events (AEs), 2 of 12 patients treated reported transient infusion reactions, one of which was grade 3 and resolved without consequence. Notably, no significant liver findings were observed in patients in either dose level. 

In the ongoing phase 1/2 clinical trial of NTLA-2002, Intellia's systemically administered CRISPR gene editing candidate, data from the ongoing dose escalation study demonstrated a dose dependent reduction in plasma kallikrein, the protein responsible for the overproduction of bradykinin which leads to debilitating swelling. Among 6 adult patients, single doses of 25 mg and 75 mg NTLA-2002 administered via intravenous infusion resulted in 65% and 92%, mean reductions in plasma kallikrein, respectively, with max reductions reached by week 8. Reductions were sustained through at least 16 weeks in the 25 mg cohort (n=3) and 8 weeks in the 75 mg cohort (n=3). 

In addition, treatment with NTLA-2002 resulted in a mean reduction of HAE attacks of 91% in the 25 mg cohort through 16 weeks of observation, with 2 of 3 patients not having any HAE attacks since treatment and all 3 being HAE attack-free since week 10. Data for the 75 mg cohort is not yet available. Notably, 2 patients who were on prophylactic therapy prior to treatment have since had that they withdrawn with no HAE attacks. 

“We are strongly encouraged by the greater than 90% reduction in HAE attacks observed in the 25 mg dose cohort, as these interim results support our belief that a single dose of NTLA-2002 has the potential to permanently prevent the debilitating swelling attacks associated with HAE," Leonard added. 

The most frequent AEs were infusion-related reactions, most of which were grade 1, and no dose-limiting toxicities, serious AEs or AEs grade 3 or higher have been recorded, including no significant elevations of liver enzymes. 

Based on these findings, Intellia introduced a third, 50-mg dose to the phase 1/2 study and will plan to include up to 2 doses for evaluation in the phase 2, placebo-controlled, dose-expansion study that is set to begin in early 2023. 

1. Intellia and Regeneron Announce Initial Data from the Cardiomyopathy Arm of Ongoing Phase 1 Study of NTLA-2001, an Investigational CRISPR Therapy for the Treatment of Transthyretin (ATTR) Amyloidosis. News release. Intellia Therapeutics. September 16, 2022. https://ir.intelliatx.com/news-releases/news-release-details/intellia-and-regeneron-announce-initial-data-cardiomyopathy-arm
2. Intellia Therapeutics Announces Positive Interim Clinical Data for its Second Systemically Delivered Investigational CRISPR Candidate, NTLA-2002 for the Treatment of Hereditary Angioedema (HAE). News release. Intellia Therapeutics. September 16, 2022. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-announces-positive-interim-clinical-data

Administration of NTLA-2001 led to rapid and deep reductions in serum TTR by day 28.

Intellia Nets Positive Data Across In Vivo CRISPR Therapies for ATTR Amyloidosis Cardiomyopathy, Angioedema

BioMarin revealed in an SEC filing that it is investigating a case of b-cell acute lymphoblastic leukemia (B-ALL) in a patient who received its investigational gene therapy for hemophilia, valoctocogene roxaparvovec (val-rox; BMN-270).

Genetic testing of the patient's leukemic cells showed that 85% carried a Philadelphia-like chromosomal translocation, a known driver in leukemic cells. In addition, leukemic cells enriched to 90% purity from peripheral blood carried negligible levels of the gene therapy BMN-270 vector DNA.

"These negligible, near background levels of BMN 270 indicate that BMN 270 is not clonally expanding in these leukemic cells," the company said in the filing.

 "Additional genomic analyses are underway, which BioMarin expects to confirm the absence of BMN 270 vector integration events contributing to leukemic growth, as well as to provide further insights into the underlying genetic etiology of this case."

At this time, neither the FDA nor the EU has imposed a hold on the study, and the independent Data Safety Monitoring Board has not recommended any changes to study protocols. 

The patient participated in one of the company's ongoing phase 3 clinical trials, GENEr8-1 study (NCT03370913) and GENEr8-3 (NCT04323098). Both studies  are evaluating a single administration of the val-rox gene therapy at a dose of 6x10

 vg/kg, though the GENEr8-3 couples the gene therapy with prophylactic corticosteroids. The primary end point of both studies is change from baseline in median FVIII activity at 52 weeks post-infusion. 

Results from GENEr8-1 were published earlier this year in the 

 demonstrating a statistically significant increase in mean factor VIII activity level at weeks 49 through 52 (41.9 IU per deciliter; 95% CI, 34.1-49.7; 

<.001) as well as a 98.6% and 83.8% decrease in rates of factor VIII concentrate use and treated bleeding after week 4, respectively (

 <.001). All participants experienced at least 1 adverse event (AE), with 16.4% experiencing a serious AE. Elevations in alanine aminotransferase levels occurred in 85.8% of participants, with other common AEs including headache, nausea, and elevations in aspartate aminotransferase levels. 

These findings supported the val-rox marketing authorization in the EU,

 which was granted on August 25, 2022 under conditions, including an indication for adult patients with severe hemophilia A without a history of factor VIII inhibitors and without detectable antibodies to adeno-associated virus (AAV) serotype 5. Roctavian will retain its orphan drug designation and was also granted 10-year market exclusivity. 

Meanwhile in the US, the FDA's call for additional data has delayed BioMarin's biologics license application submission for val-rox twice,

 with the company intending on resubmitting by the end of September. 

1. Securities and Exchange Commission, Form 8-K. BioMarin Pharmaceuticals. September 12, 2022. Accessed September 14, 2022. https://app.quotemedia.com/data/downloadFiling?webmasterId=101533&ref=116942054&type=HTML&symbol=BMRN&companyName=BioMarin+Pharmaceutical+Inc.&formType=8-K&dateFiled=2022-09-12&CK=1048477 
2. Ozelo MC, Mahlangu J, Pasi KJ, et al; GENEr8-1 Trial Group. Valoctocogene roxaparvovec gene therapy for hemophilia A. 

. 2022;386(11):1013-1025. doi:10.1056/NEJMoa2113708
3. First gene therapy for adults with severe hemophilia A, BioMarin's ROCTAVIAN™ (valoctocogene roxaparvovec), approved by European Commission (EC). News release. BioMarin. August 24, 2022. 

https://investors.biomarin.com/2022-08-24-First-Gene-Therapy-for-Adults-with-Severe-Hemophilia-A,-BioMarins-ROCTAVIAN-TM-valoctocogene-roxaparvovec-,-Approved-by-European-Commission-EC


4. BioMarin delays hemophilia a therapy valoctocogeneroxaparvovec 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/

The gene therapy received a conditional marketing approval in the European Union in August 2022. 

BioMarin to Investigate B-ALL Case in Val-Rox Gene Therapy Clinical Trial

Following the report of promising 12-month data for the lower-dose cohort in the Phase 1/2 study of gene therapy AMT-130 for the treatment of Huntington disease, UniQure has announced that it has since paused enrollment in its higher-dose cohort due to the occurrence of suspected unexpected severe adverse reactions (SUSARs). 

The pause in enrollment is pending a safety review by the independent Data Safety Monitoring Board, which is expected to take place in Q4 of this year. Enrollment in the lower-dose cohort continues, as the company also plans to start crossing over control patients in Q3 2022. 

The SUSARs consisted of localized inflammatory responses and other related symptoms observed in 3 patients treated with the higher dose of AMT-130; 2 patients from a single clinical site in the European cohort and 1 patient in the US cohort. Notably, the US-based patient's symptoms, which occurred following treatment in March 2022, were originally deemed unrelated to the therapy but a consequence of the procedure, which involves administering AMT-130 into the striatum of the brain through 2 to 6 small holes in the skull via micro-catheter. Following the European SUSAR reports in July, UniQure reclassified and reported the event as a SUSAR. 

“While these patients have fully or substantially recovered, and no clear root cause has yet been identified, we believe it’s prudent to temporarily delay additional higher-dose procedures until we put additional monitoring and treatment plans in place and complete our safety review early in the fourth quarter of 2022," said UniQure chief executive officer Matt Kapusta in a statement. "The delay is not expected to impact any future lower-dose procedures, as no serious adverse events related to AMT-130 have been reported in any of the additional 12 patients treated at the lower dose, and no impact is expected on the timing of previously guided data read-outs in 2023, including the presentation of 1 to 2-year follow-up on both low and high-dose cohorts in the second quarter of 2023.” 

The company previously reported encouraging 12-month data from the US-based lower-dose cohort, noting that the treatment was generally well-tolerated with no serious adverse events reported that were deemed related to treatment. Among the 12 patients treated, 4 with evaluable data showed a decline in mutant Huntingtin protein (mHTT) in cerebrospinal fluid at all timepoints compared with baseline, culminating in a mean 53.8% decrease at 12-month follow-up. This is compared with control patients, 3 of whom with available data showed an increase in mean mHTT at 1, 3, 6 and 9 months, ultimately with a mean decrease of 16.8% at 12-month follow-up. 

In addition, 6 patients' neurofilament light chain (NfL) neared baseline levels at 12-month follow-up after an expected increase following the treatment procedure. At 12 months, a mean increase in NfL of 8% compared with baseline was recorded, with 2 of 6 patients having levels at or below baseline at 12-month follow-up, and 1 patient's levels falling below baseline at 15- and 18-month follow-up. 

UniQure plans to present 1- to 2-year follow-up data from the US cohort in Q2 2023, with 1-year data from the European low-dose cohort planned in 2023, as well. 

uniQure Announces Second Quarter 2022 Financial Results and Highlights Recent Company Progress. News release. UniQure. August 8, 2022. https://www.globenewswire.com/news-release/2022/08/08/2493736/0/en/uniQure-Announces-Second-Quarter-2022-Financial-Results-and-Highlights-Recent-Company-Progress.html

No such adverse events have occurred in the lower-dose group.

UniQure Pauses High Dose of AMT-130 Huntington Disease Gene Therapy for Severe Adverse Events

Tevogen Bio has completed enrollment in its phase 1 clinical trial evaluating allogeneic cytotoxic CD8+ T lymphocyte cells in elderly or high-risk patients with 

Thus far, no dose-limiting toxicities or signficant treatment-related adverse events have been reported among the 24 participants, some of whom were infected with the Delta and Omicron variants as well as other subvariants of COVID-19. Tevogen previously reported that all patients dosed in the first 3 cohorts experienced resolution of lymphopenia following treatment with the cell therapy. 

"Concluding patient enrollment in this trial is an exciting milestone and I believe a promising step forward in the advancement of potential new treatments for high risk patients with COVID-19," said trial principal investigator Dolores Grosso, DNP, CRNP, of Jefferson University Hospitals, in a statement.

Patients eligible for inclusion are elderly or have comorbid conditions including those associated with the heart, lungs, liver, kidneys, hypertension, diabetes, cancer, or obesity that put them at higher risk for infection-related complications. Importantly, patients must express the HLA A*02:01 allele that is in common with the cell therapy product in order to be eligible to receive the intravenous therapy. 

Patients enrolled received 1 of 4 dose levels: 1 x 10

/kg. Following 4 days of observation in the hospital, patients are discharged home where they will be monitored remotely over a 14-day period, including taking their own blood pressure, temperature, and oxygen levels. Patients will also provide blood samples at 7, 14, and 28 days and 2, 3, and 6 months post-treatment. Patients in the control arm will be monitored remotely by study personnel in their homes for the 14-day period, and can be treated with any standard or experimental COVID-19 therapy. 

Primary outcome measures include safety-related end points such as infusion reactions, grade 4 adverse events, graft versus host disease, marrow aplasia, neurotoxicity and/or cytokine release syndrome. Secondary end points include COVID-19 viral load, cell persistence following infusion, the development of endogenous COVID-19-specific T cells and/or antibodies, as well as quality of life end points such as the need for supplemental oxygen, the ability to return to work, fatigue, blood pressure support, performance status, grade of dyspnea, and survival up to 6 months post-treatment. 

"Completing this trial will allow us to proceed quickly with further testing of this product in a variety of additional patient groups, including those suffering from Long COVID," said 

, MD, Tevogen's chief scientific officer. 

Notably, TVGN-489 targets multiple internal and external proteins across the viral genome that are preserved regardless of variant since the cell therapy is not limited to the spike protein, which is the target of current vaccines and monoclonal antibodies. 

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

Elderly or high-risk patients with COVID-19 received 1 of 4 escalating dose levels.

COVID-19 Cell Therapy Trial Dosing Complete With Good Safety Profile

Celyad Oncology's phase 1b clinical trial, KEYNOTE-B79 (NCT04991948) in refractory metastatic colorectal cancer (mCRC) is back on track after the FDA lifted its clinical hold which was placed back in March 2022.

 that involved similar pulmonary findings,

 was lifted following adjustments made to the trial's eligibility criteria.

, a TCR inhibitory molecule (TIM)-based allogeneic NKG2D CAR T-cell therapy given concurrently with FOLFOX chemotherapy and followed by the anti-PD-1 therapy pembrolizumab (Keytruda; Merck) in adults with MCC with confirmed non-microsatellite instability high (non-MSI-H)/mismatch-repair proficient (pMMR) tumor status and recurrent or progressive diseases following at least 1 line of systemic therapy that must include FOLFOX chemotherapy. 

With a target enrollment of 34 participants, study investigators are seeking to establish the ocurrence of dose-limiting toxicities that occur up to 73 days post-first study treatment administration, as well as the objective response rate at day 94, 6 weeks after the first pembrolizumab treatment administration. 

CYAD-101 was previously evaluated in patients with mCRC in the phase 1 alloSHRINK clinical trial (NCT03692429), in which the agent demonstrated anti-tumor activity via partial responses in 2 out of 15 patients and stable disease in 9 patients. The median progression-free survival observed with CYAD-101 was 3.9 months and the treatment appeared to be safe and tolerable.

“We are pleased that the FDA lifted the clinical hold on this trial. We remain confident in the potential development of not only the candidate itself, but the continued development with our proprietary TIM technology," said Charles Morris, MD, chief medical officer of Celyad Oncology, in a statement. "CYAD-101 is currently our only clinical candidate co-expressing NKG2D and TIM, and we hope to continue to showcase our expertise with our non-gene edited technologies and explore additional opportunities to utilize NKG2D in allogeneic CAR T."

The company voluntarily paused the trial in February 2022 to investigate 2 reported deaths in the trial. 

Clinical Hold Lifted on Celyad's Phase 1b Trial in Refractory Metastatic Colorectal Cancer

The time is now for genetics to become much more clinically available and informative and hopefully something that will drive better therapies. 

As recent as 2 decades ago, the thought of applying genetic insights to clinical care was merely a pipe dream. Today, genetic testing is available and more accessible, and translational research continues to show the value of these insights into both personalized approaches to care as well as the development of new, targeted therapeutics. 

Yet, we still have so much to learn, and that is the motivation behind "In Our DNA SC," a community research project recently launched by the Medical University of South Carolina (MUSC) and Helix. The state-wide initiative will offer no-cost genetic testing for 100,000 individuals to assess for actionable information related to certain types of cancer and cardiovascular disease. Not only will patients be able to review these key findings with their providers, but participants will also be contributing to one of the largest clinical-genomic datasets that will be used for future research. 

To learn more about the initiative and the increasing role of genetics in everyday clinical care, CGTLive spoke with Daniel Judge, MD, professor of medicine in cardiology, MUSC. 

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MUSC recently launched In Your DNA SC, a 4-year study to collect and glean insights from genetic testing in the general population. 