On December 12, 2022 AvenCell Therapeutics, Inc. reported updated safety and efficacy data from its lead CD-123-directed Universal CAR T Cell Candidate ("UniCAR") (Press release, AvenCell Therapeutics, DEC 12, 2022, View Source [SID1234625187]). These data, based on AvenCell’s Universal Targeting platform, were presented at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in New Orleans, Louisiana.

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The oral presentation (#979) included updated data from the first-in-human phase I dose escalation study of AVC-101 in patients with relapsed/refractory acute myeloid leukemia (r/r AML) designed to assess safety and tolerability and identify an MTD. Secondary and exploratory objectives include efficacy, biological activity, and PK.

As of October 13, 2022, of 16 patients treated with AVC-101, five patients (31%) achieved complete response with incomplete count recovery (CRi) or MRD negative conversion and the overall response rate was 56% (n=9). Of evaluable patients with minimal residual disease (MRD+; n=2), both converted to MRD negative status after the treatment.

"The AVC-101 [UniCAR CD123] program shows extremely promising results in the most challenging AML patients who have exhausted all options," said Prof. Dr. med. Martin Wermke, head of Early Clinical Trial Unit at University Hospital Carl Gustav Carus in Dresden, Germany. "This study shows preliminary evidence of clinical efficacy including multiple CRs in the dose escalation stage, manageable toxicity, and proof of principle that the switchable technology can be turned on and off to manage toxicities thereby enabling targets too challenging for traditional CAR Ts. We are hopeful for additional trials of this platform to build on this encouraging data."

The presentation reports results from 16 heavily pre-treated R/R AML patients with a median of six prior lines of therapies (min-max: 2-9 lines), with nine patients having received a prior allogeneic hematopoietic stem cell transplantation. Median age of patients was 64.5 (range 18-80), with four patients over the age of 70.

"We are excited to be at ASH (Free ASH Whitepaper) for the first time as AvenCell and to showcase the Universal Targeting platform, which has the potential to address some of the most difficult efficacy and safety challenges with cell therapies seen to date," said Andrew Schiermeier, Ph.D., chief executive officer, AvenCell Therapeutics. "The data presented by Dr. Gerhard Ehninger is indicative of the promise of the platform to treat a multitude of difficult cancer targets, where the ability to precisely and reliably control CAR T cell activity in vivo after administration is critical."

About AVC-101

AVC-101 is an investigational CD-123-directed cell therapy targeting acute myeloid leukemia, that utilizes AvenCell’s proprietary Universal Targeting platform, a regulatable CAR T cell technology that can turn CAR T cells "OFF" and "ON" by means of a separately infused Targeting Module. With AVC-101, AvenCell is aiming to create a solution to address the heterogeneity and aggressive nature of acute myeloid leukemia. CD123 is a target in acute myeloid leukemia, but its on-target off-tumor toxicity makes a conventional CD-123-directed CAR very challenging.

AvenCell’s proprietary Universal Targeting Platform is part of a new paradigm in cell therapy through one-time engraftment of Universal CAR T Cells, which can then be controlled in vivo with the separate administration of Targeting Modules that direct the Universal CAR T cells to cancer cells for activation and killing. The platform’s ability to control CAR T activity after infusion via repeatable, titratable, and switchable Targeting Module infusion provides extensive flexibility to address such issues as avoiding T cell exhaustion, antigen escape, and reacting rapidly to any potential adverse events.

AVC-101 is not approved for any indication in any geography and has not been demonstrated safe or effective for any use.

On December 12, 2022 reported that updated clinical data for its CD20xCD3 T-cell engaging bispecific antibodies, including five oral presentations, were presented at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition, December 10-13, 2022 (Press release, Genentech, DEC 12, 2022, View Source [SID1234625185]). Updated results for the investigational bispecific glofitamab in people with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) suggest glofitamab has the potential to be the first off-the-shelf CD20xCD3 T-cell engaging bispecific antibody that can be given for a fixed period of time to people with heavily pretreated aggressive lymphoma. These data will be presented at the meeting and simultaneously published online in the New England Journal of Medicine (NEJM). Additionally, updated data for mosunetuzumab continued to demonstrate clinically meaningful outcomes in people with heavily pretreated follicular lymphoma (FL). Mosunetuzumab is a fixed-duration treatment that can be administered in the outpatient setting, which could allow people the possibility of experiencing a lasting remission with a treatment-free period.

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"We pioneered the development of T-cell engaging bispecific antibodies for lymphoma with the aim of expanding treatment options for people with difficult-to-treat blood cancers," said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. "New glofitamab and mosunetuzumab data continue to demonstrate durable and impressive patient responses, including complete remissions, when given for a fixed period of time. We believe these medicines could potentially transform treatment and offer new hope for people with lymphomas."

Pivotal Phase II Glofitamab Data Presented at ASH (Free ASH Whitepaper) 2022 and Published in NEJM

Updated data from the pivotal Phase II NP30179 study in people with R/R LBCL showed glofitamab given as a fixed course induced early and durable responses that were maintained beyond the end of treatment. Most patients who had achieved a complete response (CR; a disappearance of all signs of cancer) at the end of treatment experienced durable responses, with a median CR follow-up from end of treatment of 11.5 months (95% confidence interval [CI]: 10.5-16.4). Twelve months after the end of treatment with glofitamab, 61% of patients (n=37/61) maintained a CR, 92.6% remained progression-free, and only one patient (n=1/44) experienced disease progression.

Simultaneously, an earlier data cut from the Phase II NP30179 study in R/R diffuse large B-cell lymphoma (DLBCL) was published online in NEJM.

Data from this pivotal Phase II study have been submitted for review to the European Medicines Agency, and submissions to additional health authorities worldwide, including the U.S. Food and Drug Administration (FDA), are ongoing.

Updated Pivotal Phase II Mosunetuzumab Data Presented at ASH (Free ASH Whitepaper) 2022

An updated analysis from the pivotal Phase II GO29781 study of mosunetuzumab in people with R/R FL who had received two or more prior therapies showed 60.0% (n=54/90; 95% CI: 49.1–70.2) achieved a CR and 77.8% (95% CI: 67.8–85.9) achieved an objective response (a CR or a partial response, a decrease in the amount of cancer in their body) at a median follow-up of 28.3 months. After 24 months of achieving a CR, 62.7% of patients remained in remission (95% CI: 37.7–87.7). Overall, 48.3% of patients remained progression-free (95% CI: 36.2-60.3). The median duration of response, median duration of CR, and median progression-free survival were not reached. Safety was consistent with the previous analysis of study data, with no new cytokine release syndrome (CRS) events or Grade 3 or higher adverse events (AEs) reported. CRS events were experienced by 44% of patients and were predominately low grade and during cycle one.

The European Commission granted conditional marketing authorization for mosunetuzumab for the treatment of people with R/R FL who have received at least two prior systemic therapies in June 2022, making it the first and only fixed-duration bispecific antibody to be approved in Europe for lymphoma. Mosunetuzumab is under Priority Review with the FDA, with a decision expected by December 29, 2022.

Additional Mosunetuzumab and Glofitamab Data Presented at ASH (Free ASH Whitepaper) 2022

Genentech continues to evaluate mosunetuzumab and glofitamab as part of its commitment to providing off-the-shelf therapies for people with lymphomas that can meet their diverse needs, including fixed-duration treatment options. Additional data presented at ASH (Free ASH Whitepaper) 2022 include the following:

A subcutaneous (SC) formulation of mosunetuzumab (administered as an injection given under the skin) demonstrated comparable efficacy with the intravenous formulation and a manageable safety profile in people with R/R non-Hodgkin’s lymphoma (NHL). The most common AEs were injection site reactions (60.9%; n=53/87) and CRS events (27.6%; n=24/87), which were all Grade 1 or 2. These findings suggest that a SC formulation of mosunetuzumab may offer patients a treatment option that could reduce their time spent in treatment centers.
Updated results from the Phase I/II G050554 study of mosunetuzumab monotherapy in elderly/unfit patients with previously untreated DLBCL and additional analyses from the Phase I/II G040516 study of mosunetuzumab in combination with Polivy (polatuzumab vedotin-piiq) in heavily pretreated people with DLBCL continued to show promising efficacy and manageable safety, highlighting the potential of mosunetuzumab in these patient populations.
Results from the Phase I/II NP30179 study evaluating glofitamab as a monotherapy following pretreatment with obinutuzumab in patients with heavily pretreated R/R mantle cell lymphoma continued to show early, high and durable response rates in this difficult-to-treat disease. After a median follow-up of eight months, the overall response rate (ORR) was 83.8%, with the majority of patients showing durable complete responses at the data cut off (74.1%; n=20/27). The most common AE was CRS (75.5%; n=28/37), with the majority low grade.
Data from the safety and expansion cohorts of the Phase Ib NP40126 study evaluating glofitamab in combination with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in patients with previously untreated DLBCL showed, after a median follow-up of 8.5 months, a best ORR of 92.7% (n=51/55) and a complete metabolic response rate of 72.7% (n=40/55). In the safety cohort, CRS events were all low grade (Grade 1 or 2 [10.7%; n=6/56]), and serious AEs were reported in 18 patients (32.1%).
Both mosunetuzumab and glofitamab are being investigated as SC formulations and in Phase III studies that will expand the understanding of their impact in earlier lines of treatment, with the aim of continuing to address the diverse needs and preferences of people with blood cancers. This includes the confirmatory Phase III CELESTIMO study investigating mosunetuzumab plus lenalidomide as a chemotherapy-free option for patients with R/R FL; the Phase III SUNMO study investigating mosunetuzumab plus Polivy versus rituximab in combination with gemcitabine plus oxaliplatin (R-GemOx) in patients with R/R aggressive B-cell NHL who are ineligible for autologous stem cell transplant (ASCT); and the Phase III STARGLO study evaluating glofitamab in combination with gemcitabine and oxaliplatin (GemOx) versus rituximab in combination with GemOx in patients with R/R DLBCL who are ineligible for ASCT.

About Glofitamab

Glofitamab is an investigational CD20xCD3 T-cell engaging bispecific antibody designed to target CD3 on the surface of T cells and CD20 on the surface of B cells. Glofitamab was designed with a novel 2:1 structural format. This T-cell engaging bispecific antibody is engineered to have one region that binds to CD3, a protein on T cells, a type of immune cell, and two regions that bind to CD20, a protein on B cells, which can be healthy or malignant. This dual-targeting brings the T cell in close proximity to the B cell, activating the release of cancer cell-killing proteins from the T cell. A robust clinical development program for glofitamab is ongoing, investigating the molecule as a monotherapy and in combination with other medicines for the treatment of people with B-cell non-Hodgkin’s lymphomas, including diffuse large B-cell lymphoma and other blood cancers.

About Mosunetuzumab

Mosunetuzumab is a first-in-class CD20xCD3 T-cell engaging bispecific antibody designed to target CD20 on the surface of B cells and CD3 on the surface of T cells. This dual targeting activates and redirects a patient’s existing T cells to engage and eliminate target B cells by releasing cytotoxic proteins into the B cells. A robust clinical development program for mosunetuzumab is ongoing, investigating the molecule as a monotherapy and in combination with other medicines, for the treatment of people with B-cell non-Hodgkin’s lymphomas, including follicular lymphoma and diffuse large B-cell lymphoma, and other blood cancers.

About Polivy (polatuzumab vedotin-piiq)

Polivy is a first-in-class anti-CD79b antibody-drug conjugate (ADC). The CD79b protein is expressed specifically in the majority of B cells, an immune cell impacted in some types of non-Hodgkin’s lymphoma (NHL), making it a promising target for the development of new therapies. Polivy is designed to bind to CD79b on B cells and destroys them through the delivery of an anti-cancer agent, which is thought to minimize the effects on normal cells. Polivy is being developed by Genentech using Seagen ADC technology and is currently being investigated for the treatment of several types of NHL.

Polivy U.S. Indication

Polivy is a prescription medicine used with other medicines, bendamustine and a rituximab product, to treat diffuse large B-cell lymphoma in adults who have progressed after at least two prior therapies.

The accelerated approval of Polivy is based on a type of response rate. There are ongoing studies to confirm the clinical benefit of Polivy.

Important Safety Information

Possible serious side effects

Everyone reacts differently to Polivy therapy, so it’s important to know what the side effects are. Some people who have been treated with Polivy have experienced serious to fatal side effects. A patient’s doctor may stop or adjust a patient’s treatment if any serious side effects occur. Patients must contact their healthcare team if there are any signs of these side effects.

Nerve problems in arms and legs: This may happen as early as after the first dose and may worsen with every dose. If a patient already has nerve pain, Polivy may make it worse. The patient’s doctor will monitor for signs and symptoms, such as changes in sense of touch, numbness or tingling in hands or feet, nerve pain, burning sensation, any muscle weakness, or changes to walking patterns
Infusion-related reactions: A patient may experience fever, chills, rash, breathing problems, low blood pressure, or hives within 24 hours of the infusion
Infections: Patients should contact their healthcare team if they experience a fever of 100.4°F or higher, chills, cough, or pain during urination. Also, a patient’s doctor may give medication before giving Polivy, which may prevent some infections, and monitor blood counts throughout treatment with Polivy. Treatment with Polivy can cause severe low blood cell counts
Rare and serious brain infections: A patient’s doctor will monitor the patient closely for signs and symptoms of these types of infections. Patients should contact their doctor if they experience confusion, dizziness or loss of balance, trouble talking or walking, or vision changes
Tumor lysis syndrome: Caused by the fast breakdown of cancer cells. Signs include nausea, vomiting, diarrhea, and lack of energy
Potential harm to liver: Some signs include tiredness, weight loss, pain in the abdomen, dark urine, and yellowing of the skin or the white part of the eyes. Patients may be at higher risk if they already have liver problems or are taking other medication
Side effects seen most often

The most common side effects during treatment were:

Low blood cell counts (platelets, red blood cells, white blood cells)
Nerve problems in arms and legs
Tiredness or lack of energy
Diarrhea
Nausea
Fever
Decreased appetite
Infections
Polivy may not be for everyone. A patient should talk to their doctor if they are:

Pregnant or may be pregnant: Data have shown that Polivy may harm an unborn baby
Planning to become pregnant: Women should avoid getting pregnant while taking Polivy. Women should use effective contraception during treatment and for at least 3 months after their last Polivy treatment. Men taking Polivy should use effective contraception during treatment and for at least 5 months after their last Polivy treatment
Breastfeeding: Women should not breastfeed while taking Polivy and for at least 2 months after the last dose
These may not be all the side effects. Patients should talk to their healthcare provider for more information about the benefits and risks of Polivy treatment.

Report side effects to the FDA at (800) FDA-1088 or View Source Report side effects to Genentech at (888) 835-2555.

Please visit View Source for the full Prescribing Information for additional Important Safety Information.

On December 12, 2022 Orca Bio, a late-stage biotechnology company developing high-precision cell therapies for the treatment of cancer, genetic blood disorders and autoimmune diseases, reported that interim clinical data from its Phase 1 multi-center trial of its second investigational cell therapy, Orca-Q, were unveiled in an oral presentation at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Orca Bio, DEC 12, 2022, View Source [SID1234625184]).

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The data from the ongoing clinical trial show that Orca-Q reduced the incidence and severity of graft versus host disease (GvHD) and improved graft-versus-host disease-free, relapse-free survival (GRFS) rates in 26 patients matched to haploidentical allogeneic hematopoietic stem cell donors. Unlike standard of care haploidentical allogeneic hematopoietic stem transplant (alloHSCT), Orca-Q does not require post-transplant cyclophosphamide (PTCy).

"Patients and transplant physicians are in urgent need of a novel treatment option that improves the chances of survival and the quality of that survival. This is the key limitation of haploidentical transplant, which is currently the only treatment option for the vast majority of blood cancer patients in need of a transplant," said Amandeep Salhotra, M.D., associate professor, Division of Leukemia, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope. "These results suggest Orca-Q’s promise to overcome this serious challenge by offering a novel investigational high-precision cell therapy with the potential to significantly improve patient outcomes and reduce serious transplant-related risks."

Orca-Q is an investigational high-precision cell therapy that is a proprietary composition of enriched CD34+ stem cells combined with specific T cell subsets. The findings presented at ASH (Free ASH Whitepaper) are from patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndromes (MDS) and chronic myeloid leukemia (CML) who were matched to haploidentical allogeneic donors, defined as matched across at least 4/8 but fewer than 7/8 human leukocyte antigen (HLA) loci. Historical controls from the literature of patients who received standard of care haploidentical alloHSCT with PTCy GvHD prophylaxis were used for comparison purposes1,2,3,4.

Interim results from the Phase 1 single-arm, open-label trial showed:

A reduction of grade 2-4 acute GvHD (aGvHD) at 6 months as compared to literature controls (13% vs 21-63%), with only one patient developing grade 3 aGvHD and no incidence of grade 4 aGvHD.
No patients experienced moderate-to-severe chronic GvHD (cGvHD), compared to 24%-33% in the literature control. There was only one case of mild cGvHD.
GRFS was 75% at one year after Orca-Q, which compares favorably to a GRFS of 46% in patients in the literature control.
Patients treated with Orca-Q also experienced a low adverse event profile, suggesting Orca-Q has the potential to offer a new treatment option for patients undergoing haploidentical alloHSCT.

Today, approximately 70% of blood cancer patients do not have access to a fully matched related donor. Haploidentical transplant, which uses healthy, blood-forming cells from a partially matched donor to replace the unhealthy ones, is one of the few treatment options currently available to those without a fully matched donor. However, its use remains significantly limited because of the conditioning regimens that are required. Haploidentical transplant patients receiving higher intensity myeloablative conditioning treatments have a higher risk of cGvHD post-transplant, while patients receiving lower intensity pre-transplant conditioning have a greater risk of relapse.

"These interim results from our second clinical program demonstrate Orca-Q’s potential to overcome the challenges of haploidentical alloHSCT by providing a solution with which patients and physicians may no longer have to compromise between the risk of relapse and the risk of GvHD," said Scott McClellan, M.D., Ph.D., chief medical officer of Orca Bio. "This novel approach, along with our growing body of clinical evidence demonstrating Orca-T’s improved GvHD and relapse-free survival rates in patients with HLA-matched donors, underscore the potential of our high-precision platforms to deliver cell therapies that can greatly expand the number of patients who receive life-saving treatment, whether their donor is a full or partial match."

The full presentation will be made available on www.orcabio.com.

About Orca-Q
Orca-Q is Orca Bio’s second investigational high-precision allogeneic cellular therapy to enter clinical development for hematological malignancies. Orca-Q is a proprietary composition of enriched CD34+ stem cells combined with specific T cell subsets derived from haploidentical—or partially matched—donors that are purified through Orca Bio’s high-precision platform. Orca-Q is a first-in-class therapy that has the potential to improve patient outcomes and reduce the risks of graft versus host disease, without the use of post-transplant cyclophosphamide (PTCy) in patients for whom a full human leukocyte antigen (HLA) match cannot be found.

About Orca-T
Orca-T is an investigational high-precision allogeneic cellular therapy consisting of infusions containing regulatory T-cells, conventional T-cells and CD34+ stem cells derived from peripheral blood from either related or unrelated matched donors. Orca-T has received Regenerative Medicine Advanced Therapy (RMAT) designation from the U.S. Food and Drug Administration and is being studied to treat multiple hematologic malignancies.

On December 12, 2022 Asher Biotherapeutics, Inc., a biotechnology company focused on developing therapies to precisely engage specific immune cells to fight cancer, reported new preclinical data demonstrating proof-of-concept for cis-targeted cytokines as a novel strategy for enhancing chimeric antigen receptor T cell (CAR-T) engraftment, expansion, and functionality culminating in the delivery of improved anti-tumor activity (Press release, Asher Biotherapeutics, DEC 12, 2022, View Source [SID1234625183]). This data will be presented in a poster at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting being held in New Orleans, Louisiana, December 10-13, 2022.

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"We are delighted to share new preclinical data with our cell therapy program, further highlighting the versatility of our cis-targeting cytokine platform, as well as its potential applicability across a range of hematologic malignancies and solid tumors," said Ivana Djuretic, Ph.D., Founder and Chief Scientific Officer of Asher Bio. "These data demonstrate our ability to selectively activate only CAR-T cells post-adoptive transfer and, as a result, to improve anti-tumor activity. We are particularly pleased to observe these results using two different cytokines, interleukin-2 (IL-2) and interleukin-21 (IL-21), which act through distinct, potentially complementary, mechanisms. Over time, our ability to deliver different, supportive cytokine signals could enable us to target a diverse set of cell therapies, including those based on T cell receptors, tumor-infiltrating lymphocytes, natural killer cells and regulatory T cells, to support the use of cell therapies in a diverse set of tumor types. We look forward to advancing this program as we aim to maximize the reach of our platform, with the goal of delivering better outcomes to cancer patients who remain underserved by existing therapeutic options."

CAR-T cell therapies have recently transformed the treatment of some hematological malignancies and are showing promise in solid tumors. In the clinic, the successful expansion and persistence of CAR-T cells has correlated with improved therapeutic outcomes, including durable complete responses and survival; in preclinical studies, the administration of IL-2 has been observed to enhance CAR-T engraftment, persistence and functionality. However, the clinical potential of utilizing existing IL-2 molecules in combination with CAR-T therapies is limited due to the severe toxicity of high dose IL-2 and the inadequate selectivity of existing engineered IL-2 variants, which expand multiple endogenous cell types in addition to the transferred CAR-T cells.

In order to overcome these challenges, Asher Bio developed two cis-targeted fusion molecules, one using IL-2 and the other using IL-21, which are designed to selectively activate CAR-T cells by recognizing an extracellular tag, while exhibiting minimal effects on non-engineered or endogenous cells. Both cis-targeted cytokine fusions are comprised of a targeting antibody directed against a tag expressed on the CAR-T surface, that is co-expressed with the CAR, and a cytokine mutein with attenuated binding to its cognate cytokine receptor.

In a poster titled, "Selective Support of CAR-T Cell Therapies by Cis-Targeted IL-2 or IL-21 Cytokines Results in Enhanced Anti-Tumor Activity," Asher Bio scientists and collaborators at the Perelman School of Medicine at the University of Pennsylvania presented preclinical in vitro and in vivo data that support the development of cis‑targeted cytokines directed by anti-tag antibodies as a promising approach to enhance CAR-T cell therapies. The data show:

– Cis-targeted IL-2 or IL-21 molecules targeting an exogenous tag selectively activated CAR‑T cells in vitro and enhanced anti-tumor activity and survival in vivo.
– CAR-T cell targeted IL-2 and IL-21 enhanced anti-tumor activity through distinct mechanisms.
– Cis-targeted cytokine therapies allowed for temporal control, while avoiding the negative pleiotropic effects associated with systemically administered wild-type cytokines.

The poster presentation will be available in the "Presentations and Posters" section of Asher Bio’s website: View Source

On December 12, 2022 Rocket Pharmaceuticals, a leading late-stage biotechnology company advancing an integrated and sustainable pipeline of genetic therapies for rare childhood disorders with high unmet need, reported positive clinical data from its lentiviral (LV)-based gene therapy programs at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, taking place in New Orleans, Louisiana, from December 10-13 (Press release, Rocket Pharmaceuticals, DEC 12, 2022, View Source [SID1234625182]).

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Lentiviral-mediated Gene Therapy for Patients with Fanconi Anemia [Group A]: Updated Results from Global RP-L102 Clinical Trials

The poster presentation includes positive updated data (cut-off October 26, 2022) from the ongoing Phase 2 pivotal trial of RP-L102, Rocket’s ex vivo lentiviral gene therapy candidate for Fanconi Anemia (FA).

RP-L102 conferred phenotypic correction in at least six of 10 evaluable patients with ≥12 months of follow-up as demonstrated by increased resistance to mitomycin-C (MMC) in bone marrow (BM)-derived colony forming cells, concomitant genetic correction and hematologic stabilization.
A seventh patient has displayed evidence of progressively increasing genetic correction as demonstrated by peripheral blood and BM vector copy numbers (VCNs), with recent development of MMC resistance and indicators of hematologic stability after 36 months of follow-up.
The primary endpoint has been achieved, based on a trial protocol in which statistical and clinical significance requires a minimum of five patients to attain increased MMC resistance at least 10% above baseline at two or more timepoints and concomitant evidence of genetic correction and clinical stabilization.
The safety profile of RP-L102 has been highly favorable, and the treatment, administered without any cytotoxic conditioning, has been well tolerated. No signs of bone marrow dysplasia, clonal dominance or insertional mutagenesis related to RP-L102 have been observed.
As previously disclosed, one patient experienced a Grade 2 transient infusion-related reaction, which resolved; one patient with confirmed engraftment developed a T-cell lymphoblastic lymphoma that was conclusively determined by the investigator, sponsor and the independent data monitoring committee to be related to FA (a cancer predisposition syndrome) and unrelated to RP-L102 gene therapy.
Based on the positive efficacy and safety data from the Phase 2 pivotal FA trial, Rocket anticipates regulatory filing in the second half of 2023.
Lentiviral-mediated Gene Therapy for Adults and Children with Severe Pyruvate Kinase Deficiency: Results from an Ongoing Global Phase 1 Study

The poster presentation includes positive updated data (cut-off October 26, 2022) from two adult patients with significant anemia who were treated with RP-L301, Rocket’s ex vivo lentiviral gene therapy candidate for Pyruvate Kinase Deficiency (PKD).

At 24 months post-infusion, both patients have robust and sustained efficacy demonstrated by normalized hemoglobin (from baseline levels in the 7.0-7.5 g/dL range), improved hemolysis parameters, independence from red blood cell transfusions and improved quality of life both reported anecdotally and as documented via formal quality of life assessments.
The safety profile appears highly favorable, with no RP-L301-related serious adverse events through 24 months post-infusion in both adult patients.
Insertion site analyses in peripheral blood and bone marrow in both adult patients up to 12 months post-RP-L301 demonstrated highly polyclonal patterns and there has been no evidence of insertional mutagenesis.
Adult and pediatric enrollment is completed in the Phase 1 study. Phase 2 pivotal trial initiation is anticipated in 2023.
Interim Results from an Ongoing Phase 1/2 Study of Lentiviral-mediated Ex-vivo Gene Therapy for Pediatric Patients with Severe Leukocyte Adhesion Deficiency-I

The poster presentation includes previously disclosed top-line data at three to 24 months of follow-up after RP-L201 infusion for all patients and overall survival data for seven patients at 12 months or longer after infusion. RP-L201 is Rocket’s ex vivo lentiviral gene therapy candidate for severe Leukocyte Adhesion Deficiency-I (LAD-I).

Observed 100% overall survival at 12 months post-infusion via Kaplan Meier estimate and a statistically significant reduction in all hospitalizations, infection- and inflammatory-related hospitalizations and prolonged hospitalizations for all nine LAD-I patients with three to 24 months of available follow-up. Data also shows evidence of resolution of LAD-I-related skin rash and restoration of wound repair capabilities.
The safety profile of RP-L201 has been highly favorable in all patients with no RP-L201-related serious adverse events to date. Adverse events related to other study procedures, including busulfan conditioning, have been previously disclosed and consistent with the safety profiles of those agents and procedures.
Based on the positive efficacy and safety data from the Phase 2 pivotal LAD-I trial, Rocket has initiated discussions with the FDA and anticipates regulatory filing in the first half of 2023.
About Fanconi Anemia

Fanconi Anemia (FA) is a rare pediatric disease characterized by bone marrow failure, malformations and cancer predisposition. The primary cause of death among patients with FA is bone marrow failure, which typically occurs during the first decade of life. Allogeneic hematopoietic stem cell transplantation (HSCT), when available, corrects the hematologic component of FA, but requires myeloablative conditioning. Graft-versus-host disease, a known complication of allogeneic HSCT, is associated with an increased risk of solid tumors, mainly squamous cell carcinomas of the head and neck region. Approximately 60-70% of patients with FA have a Fanconi Anemia complementation group A (FANCA) gene mutation, which encodes for a protein essential for DNA repair. Mutations in the FANCA gene leads to chromosomal breakage and increased sensitivity to oxidative and environmental stress. Increased sensitivity to DNA-alkylating agents such as mitomycin-C (MMC) or diepoxybutane (DEB) is a ‘gold standard’ test for FA diagnosis. Somatic mosaicism occurs when there is a spontaneous correction of the mutated gene that can lead to stabilization or correction of a FA patient’s blood counts in the absence of any administered therapy. Somatic mosaicism, often referred to as ‘natural gene therapy’ provides a strong rationale for the development of FA gene therapy because of the selective growth advantage of gene-corrected hematopoietic stem cells over FA cells.

About Pyruvate Kinase Deficiency

Pyruvate kinase deficiency (PKD) is a rare, monogenic red blood cell disorder resulting from a mutation in the PKLR gene encoding for the pyruvate kinase enzyme, a key component of the red blood cell glycolytic pathway. Mutations in the PKLR gene result in increased red cell destruction and the disorder ranges from mild to life-threatening anemia. PKD has an estimated prevalence of 4,000 to 8,000 patients in the United States and the European Union. Children are the most commonly and severely affected subgroup of patients. Currently available treatments include splenectomy and red blood cell transfusions, which are associated with immune defects and chronic iron overload. Recently, mitapivat, an oral enzyme activator, was approved for use in the least severely-afflicted adult patients (those who are not transfusion-dependent and do not have mutations known to cause severe disease).

RP-L301 was in-licensed from the Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) and Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz (IIS-FJD).

About Leukocyte Adhesion Deficiency-I

Severe Leukocyte Adhesion Deficiency-I (LAD-I) is a rare, autosomal recessive pediatric disease caused by mutations in the ITGB2 gene encoding for the beta-2 integrin component CD18. CD18 is a key protein that facilitates leukocyte adhesion and extravasation from blood vessels to combat infections. As a result, children with severe LAD-I are often affected immediately after birth. During infancy, they suffer from recurrent life-threatening bacterial and fungal infections that respond poorly to antibiotics and require frequent hospitalizations. Children who survive infancy experience recurrent severe infections including pneumonia, gingival ulcers, necrotic skin ulcers, and septicemia. Without a successful bone marrow transplant, mortality in patients with severe LAD-I is 60-75% prior to the age of 2 and survival beyond the age of 5 is uncommon. There is a high unmet medical need for patients with severe LAD-I.

Rocket’s LAD-I research is made possible by a grant from the California Institute for Regenerative Medicine (Grant Number CLIN2-11480). The contents of this press release are solely the responsibility of Rocket and do not necessarily represent the official views of CIRM or any other agency of the State of California.