Autolus Therapeutics plc (Autolus) is a biopharmaceutical company developing next-generation programmed T cell therapies for the treatment of cancer and autoimmune diseases.
Using the company’s broad suite of proprietary and modular T cell programming technologies, the company is engineering precisely targeted, controlled and highly active T cell therapies that are designed to better recognize target cells, break down their defense mechanisms and attack and eliminate these cells. The company’s...
Autolus Therapeutics plc (Autolus) is a biopharmaceutical company developing next-generation programmed T cell therapies for the treatment of cancer and autoimmune diseases.
Using the company’s broad suite of proprietary and modular T cell programming technologies, the company is engineering precisely targeted, controlled and highly active T cell therapies that are designed to better recognize target cells, break down their defense mechanisms and attack and eliminate these cells. The company’s programmed T cell therapies have the potential to be best-in-class and offer patients substantial benefits over the existing standard of care, including the potential for cure in some patients.
The company’s T cell programming technologies allow the company to tailor its therapies to address the specific disease the company is targeting and introduce new programming modules in to a patient’s T cells to give those T cells improved properties to better recognize target cells and overcome fundamental disease defense mechanisms. Cancers in particular, thrive on their ability to fend off T cells by evading recognition by T cells and by establishing other defense mechanisms, such as checkpoint inhibition, and creating a hostile microenvironment. The company’s leadership in T cell programming technologies will provide the company with a competitive advantage as the company looks to develop future generations of T cell therapies targeting both hematological cancers, solid tumors and autoimmune diseases, including potential products that could have a tolerability profile such to make them amenable to be used in outpatient settings.
The company’s clinical-stage pipeline comprises five programs being developed in eight hematological and solid tumor indications and one autoimmune indication.
The company’s clinical-stage programs are:
Obe-cel (AUTO1)
Obe-cel (obecabtagene autoleucel) is a CD19-targeting programmed T cell investigational therapy with a CD19 binder designed to improve the efficacy and safety profile, as compared to other CD19 CAR T therapies.
The company initiated the FELIX study, a Phase 1b/2 clinical trial of obe-cel for the treatment of adult r/r B-Acute Lymphoblastic Leukemia (‘ALL’), in 2020. This trial is intended to serve as a registrational trial and support regulatory licensure. In November 2023, the company submitted a Biologics License Application (‘BLA’) to the U.S. FDA for obe-cel for the treatment of patients with r/r adult B-ALL. In January 2024, the FDA notified the company that they had accepted the BLA filing for review and under the Prescription Drug User Fee Act (‘PDUFA’), the FDA has set a target action date of November 16, 2024. The BLA submission is based on data from the Phase 2 cohort of FELIX study. The data were presented at the 2023 American Society of Clinical Oncology (‘ASCO’) Annual Meeting in June 2023, with updated data presented at the Annual Meeting of the American Society for Hematology (‘ASH’) in December 2023.
With the cut-off date of September 13, 2023, the data presented at the ASH 2023 meeting were from a pooled analysis of data from all patients across all cohorts in the FELIX Phase 1b/2 study (morphologic disease, minimal residual disease (‘MRD’), isolated extramedullary disease (‘EMD’)) (n=127, median follow-up time from first obe-cel infusion to data cut-off of 16.6 months). Median vein-to-release time was 22 days. Across all patients, treatment with obe-cel resulted in a high response rate with complete response (‘CR’)/complete remission with incomplete recovery (‘CRi’) rate of 78% in evaluable patients. Additionally, obe-cel showed a favorable safety profile; grade =3 cytokine release syndrome (‘CRS’) was 2% and grade =3 immune effector cell-associated neurotoxicity syndrome (‘ICANS’) was 7%, with most severe cases of immunotoxicity occurring in patients with high leukemic burden in the bone marrow (‘BM’). The event free survival estimate (‘EFS’) at 12-months was 50% across all patients, with only 17% of responders proceeding to stem cell transplant while in remission. Cellular kinetic data shows high expansion and long-term persistence of CAR T cells in most responders.
In collaboration with University College London (‘UCL’), adult patients with r/r, B-ALL and treated with obe-cel continue to be monitored in the Phase 1 ALLCAR19 trial. A pooled analysis of long-term follow-up data from ALLCAR19 and FELIX Phase 1b Studies were presented at the ASH 2023 meeting. Data from the pooled analysis of r/r ALL patients (n=36) treated with obe-cel in the ALLCAR19 and FELIX 1b studies demonstrate high remission rates of 81% (29/36). After a median follow-up of 3 years and without subsequent transplant, 41% of patients continue in CR. The estimated EFS rate with censoring of subsequent transplant or new treatment was 45% at 36 months; all patients in ongoing remission were MRD negative at last assessment and median duration of response was not reached.
Patients continue to be enrolled into the Phase 1 ALLCAR19 extension trial. Data presented at the 2023 ASH meeting demonstrated the potentially best-in-class profile of obe-cel supported by the data observed in other B-cell malignancies, with continued high levels of durable remission paired with a favorable tolerability profile across patients with diffuse large B-cell lymphoma (‘DLBCL’), mantle cell lymphoma (‘MCL’), follicular lymphoma (‘FL’), and chronic lymphocytic leukemia (‘CLL’).
Furthermore, obe-cel is being investigated for the treatment of primary CNS lymphoma, (‘PCNSL’), in an exploratory Phase 1 clinical trial called CAROUSEL. UCL presented initial data at the 27th Congress of the European Hematology Association (‘EHA’) in 2022 and data is currently being prepared for publication. The company has also initiated two Phase 1 studies, one in pediatric B-ALL and B-NHL and one in Systemic lupus erythematosus (SLE).
AUTO1/22
In collaboration with UCL, the company commenced a Phase 1 clinical trial in pediatric patients with the company’s academic partner at UCL in r/r B-ALL with the company’s next-generation product candidate, AUTO1/22, in the fourth quarter of 2020. AUTO1/22 is a dual-targeting CAR T which builds on the obe-cel approach utilizing the same CD19 CAR, alongside a novel CD22 CAR designed to reduce antigen negative relapse of disease. In a publication in Blood in October 2023, the company presented data demonstrating a high level of activity, with 83% of patients (10/12 patients evaluated) experiencing MRD negative complete remission, and a favorable tolerability profile in a very challenging patient population. Patients on study were high risk, with 4 patients who had failed prior CD19 CAR therapy, 3 patients with a CD19-negative disease component, 3 patients with non-CNS EMD and 6 patients who had received prior blinatumomab. Of 10 responding patients, 5 had emergence of MRD (2) or frank relapse (3) with CD19 and CD22 expressing disease associated with loss of CAR T cell persistence. Importantly, there were no cases of relapse due to antigen-negative escape, with a median follow-up of 8.7 months. Overall survival was 75% at 6 and 12 months. Six and 12-month EFS were 75% and 60% respectively. This study is no longer enrolling patients.
AUTO4
A programmed T cell investigational therapy for the treatment of peripheral T cell lymphoma targeting TRBC1. Unique targeting of TRBC1 potentially opens a new therapeutic approach. The preclinical study package suggested selective binding and anti-tumor activity of TRBC1 and TRBC2 CARs in vitro and in vivo. Data were presented at the International Conference on Malignant Lymphoma (‘ICML’) in June 2023 of the LibrA T1 Phase 1/2 study. At the cutoff date of April 28, 2023, 19 patients were enrolled into the study and 13 were dosed. Using manufacturing process A, 10 patients were dosed. Using manufacturing process B, 3 additional patients were dosed. Among the 13 patients dosed with AUTO4, the treatment was well tolerated with no dose limiting toxicities. Ongoing responses at 15 and 18 months post-dosing at the highest dose tested (450x106) are encouraging. Presence of CAR T cells in the lymph nodes of patients suggest fast homing of CAR T cells to the tumor site, despite absence in the blood. Efficacy data from Process B was not provided given median follow up is less than 3 months.
AUTO6NG
A programmed T cell investigational therapy targeting GD2 in development for the treatment of neuroblastoma utilizing a new binder designed to minimize on-target, off-tumor toxicity, humanized to reduce immunogenicity, including RQR8 safety switch. Findings from a Phase 1 clinical trial with AUTO6 were published in November 2020 and provide evidence that AUTO6 induces clinical activity in this solid tumor setting without inducing on-target off-tumor toxicity. The company since developed a next-generation product candidate, AUTO6NG, which builds on this approach utilizing the same GD2 CAR alongside additional programming modules to enhance the activity and persistence. In June 2020, the company presented preclinical data of AUTO6NG, including data from a tumor model in small cell lung cancer indicating that GD2 is an attractive target for programmed T cell therapies in that indication. The MAGNETO Phase 1 clinical trial of AUTO6NG in r/r neuroblastoma was initiated in December 2023.
AUTO8
A next-generation product candidate for multiple myeloma, which comprises two independent CARs for the multiple myeloma targets, BCMA and CD19. The company has developed an optimized BCMA CAR, which is designed for improved killing of target cell that express BCMA at low levels. This has been combined with fast off rate CD19 CAR from obe-cel. The design of AUTO8 has the potential to induce deep and durable responses and extend the durability of effect over other BCMA CARs in development. A Phase 1 clinical trial of AUTO8 was initiated in March 2022 with the company’s academic partner UCL. The MCARTY Phase 1 study is an iterative, staggered design trial with two separate parallel cohorts for direct comparison of the BCMA CAR alone and AUTO8 (the BCMA CAR in combination with the CD19 CAR from obe-cel). As of November 13, 2023 (data cut-off), 11 patients have been infused with either BCMA CAR at 50 million (n=3) or 150 million (n=3) cells, or AUTO8 at 50 million (n=3) or 150 million (n=2). At a median follow-up of 6 months the company observed 100% response rate (‘ORR’), with 3 partial response (‘PR’), 1 very good partial response (‘VGPR’), 7 CR/ stringent complete response (‘sCR’) (all evaluable MRD negative). Two patients remained in ongoing sCR > 12 months. No cases of ICANS or CRS = Gr 3 were observed across all subjects during the period. While persistence data from the dual targeting cohort is immature, it demonstrates expansion of three CAR populations and suggests a trend to increased persistence of D8 BCMA CAR expressing T cells. The study is ongoing and continues to recruit patients.
Pipeline
The company’s product pipeline is built on its core principles of modular innovation with protein-based cell programming focused on advanced targeting, pharmacological control and enhancement of activity. After identifying a target, the company selects the suite of programming modules that is suited to target that particular disease based on the latest clinical data and the results of the company’s research. The particular modules selected may vary, and not every product candidate, including the company’s product candidates, contain all categories of modules.
The company’s programs have been highly tailored and specifically engineered via the company’s proprietary modules, and have the potential to be truly differentiated assets that could address limitations of current treatments and provide innovative options for patients.
Obe-cel has an optimized engagement of the CD19 target designed to enhance its persistence. These properties may enable obe-cel to be a suitable candidate for the treatment of adult patients with ALL, who tend to be less tolerant of severe toxicity compared with children with ALL. There is one CAR T cell therapy approved for the treatment of adult ALL. AUTO1/22 builds on the obe-cel approach utilizing the same CD19 CAR alongside a novel CD22 CAR designed to reduce antigen negative relapse of disease seen in cancer patients treated with CD19 CAR T cell therapies.
AUTO4, which the company is developing for the treatment of peripheral T cell lymphoma, employs a novel and differentiated treatment approach. AUTO4 is designed to selectively kill cancerous T cells in a manner that will preserve a portion of the patient’s normal, healthy T cells to maintain immunity. It targets an antigen, TRBC1 found on approximately 40% of T cell lymphomas. Since the company’s AUTO4 approach is a novel mechanism to target T cells, the company has also programmed the product candidate with a ‘safety switch’ in order to allow physicians to manage toxicity by eliminating the programmed T cells if a patient experiences severe adverse side effects from the treatment.
AUTO5 is a preclinical TRBC2 programmed T cell product candidate for the treatment of peripheral T cell lymphoma. TRBC2 is found on approximately 60% of T cell lymphomas. Plans to progress AUTO5 are subject to clinical data from the AUTO4 program.
The company is developing AUTO6NG, which builds upon AUTO6 data by incorporating additional programming modules intended to enhance efficacy by aiming to extend persistence and to address the layers of defense that cancer cells deploy to evade T cell killing.
AUTO8 is the company’s next-generation product candidate for multiple myeloma, which comprises two independent CARs for the multiple myeloma targets, BCMA and CD19. The company has developed an optimized BCMA CAR which is designed for improved killing of target cell that express BCMA at low levels. This has been combined with fast off rate CD19 CAR from obe-cel. The design of AUTO8 has the potential to induce deep and durable responses and extend the durability of effect over other BCMA CARs in development.
Solution: Advanced T Cell Programming
The company’s technological approach is the development of advanced T cell engineering components designed to directly address clinical challenges. A focus in the company’s early-stage pipeline is incorporation of multiple components in a single product.
Advanced Targeting Technologies
The company has developed advanced antigen targeting technologies to improve the ability of the company’s programmed T cell therapies to selectively identify and target cancer cells and to deliver a sustained anti-tumor effect. These targeting technologies include fast off-rate CARs, novel targets, high avidity spacers, dual-targeting and pattern recognition.
Fast Off-Rate CARs
The company has designed programmed T cells with fast off-rate binders. These fast off-rate kinetics are similar to the behavior of naturally occurring T cells. Obe-cel has this enhanced kinetic profile, which, when compared to data reported for other CAR T cell product candidates in clinical development for ALL that use high affinity binders, appears to result in reduced Cytokine Release Syndrome and in increased T cell engraftment. The company uses Fast Off-Rate CARs targeting CD19 in the company’s obe-cel, AUTO1/22 and AUTO8 programs.
Dual-Targeting CARs
The company has developed product candidates that target two antigens on a cancer cell and are designed to reduce the chances for relapse due to antigen escape. Evidence suggests that it may also improve a response in those patients with low levels of expression of a target antigen on their cancer cells. The company uses Dual Targeting CARs in the company’s AUTO1/22 and AUTO8 programs.
Pharmacological Control of T Cell Activity
The company has developed multiple technologies designed to pharmacologically control T cell activity in the event a patient suffers certain serious adverse events related to the T cell therapy. Safety switches are designed to selectively eliminate the programmed T cells following administration of a pharmacological agent, whilst tuneable or controllable CAR T cells allow the activity of T cell therapy to be dialed down following administration of a pharmacological agent.
Rituximab Safety Switch (RQR8)
The RQR8 safety switch is designed to selectively eliminate the programmed T cells by the administration of the commercially available monoclonal antibody rituximab. Once administered, rituximab binds to the engineered CD20 epitopes on the surface of the programmed T cell and triggers cell death. The company uses the RQR8 safety switch in the company’s AUTO4, AUTO5 and AUTO6NG programs.
Rapamycin Safety Switch (RapaCasp9)
The RapaCasp9 safety switch is designed to selectively eliminate the programmed T cells by the administration of the commercially available drug rapamycin. Once administered, rapamycin heterodimerises caspase 9 via FRB and FKBP to activate a cell death cascade and selectively eliminate the programmed T cells.
Tetracycline Controllable CAR (TetCAR)
TetCAR is a controllable CAR T cell system designed to reversibly dampen the activity of the programmed T cells by the administration of the commercially available antibiotic tetracycline to a patient. Once administered, tetracycline temporarily dislocates the CAR signaling domain from the cancer antigen binding domain leading to deactivation of the T cell therapy. Activity is then restored on clearance of the pharmacological agent from the patient.
Tumor Microenvironment Shielding
The company has developed technologies designed to shield the company’s programmed T cells from these immunosuppressive pathways.
Checkpoint Shielding (dSHP2)
The company has developed a modified version of an adaptor protein, SHP2, that in preclinical studies has been shown to efficiently counteract the inhibition of T cells resulting from the PD-L1/PD-1 interaction. In addition, it is designed to simultaneously disarm multiple inhibitory receptors on the cancer cell. The company uses the dSHP shielding module in the company’s AUTO6NG program.
Enhanced Activity
However, systemic or local administration of cytokines can be toxic, therefore the company has developed programming modules that are designed to harness the enhanced activity of cytokines whilst avoiding the potential for toxicities.
Chimeric Cytokine Receptors (CCRs)
The company uses proteins from an antibody structure to stably heterodimerise two cytokine signaling domains together to deliver a proliferative and survival signal into the company’s T cells. Preclinical data has demonstrated the potential for the CCR to improve the persistence and activity of CAR T cell therapy against solid tumors. The company uses the CCR enhanced activity module in AUTO6NG.
Host Immune System Recruitment (ssIL12)
IL-12 is a potent anti-tumor cytokine that mediates the activity of many different anti-tumor immune cells. The majority of clinical studies involving treatment of patients with IL-12 were associated with severe systemic side effects mediated by high levels of IFNgamma. The company’s ssIL12 module is designed to secrete very low levels of IL-12 from the company’s T cells and the company’s preclinical data demonstrates the potential for ssIL12 to provide anti-tumor without systemic toxicity.
Engineering survival signal (Fas-TNFR)
The company’s Fas chimeras consist of the extracellular domain of Fas fused to the intracellular domain from different TNF receptor superfamily members. Expression of these chimeras in a CAR T cell not only blocks apoptosis triggered by FasL, but results in co-stimulation, which promotes CAR T cell survival and proliferation.
Product Candidates for the Treatment of Hematological Cancers and Autoimmune Diseases
The company’s clinical-stage product candidates targeting hematological cancers are obe-cel, AUTO1/22, AUTO4 and AUTO8. The company has an additional hematological product candidate, AUTO5, in preclinical development. Additionally, obe-cel is also being explored as a potential therapeutic approach targeting certain autoimmune diseases.
Obe-cel: The company’s Programmed T Cell Therapy for the Treatment of ALL, other B-cell malignancies and autoimmune diseases
Introduction to Obe-cel
Obe-cel, formerly known as AUTO1, is a gene therapy product consisting of autologous T cells that are transduced with a lentiviral vector to express a novel anti-CD19 Chimeric Antigen Receptor (CD19 (CAT) CAR). The transduced T cells express second-generation CARs in which the CD19 CAR construct uses 41BB- Zeta and CD3- Zeta endodomains.
CD19 is an ideal target for a CAR T cell therapy as it is a cell surface marker for B-precursor cells and B-lymphocytes that is present on most B cell malignancies. CD19 is also a cell surface marker expressed broadly on the autoreactive B-cells and plasma cells that are associated with autoimmune diseases such as lupus. Upon CD19 directed CAR T cell therapies, it also leads to B-cell aplasia which can be used as a pharmacodynamic marker. CD19 CAR T cell therapies have proven effective in treating B-cell leukemias, B-cell lymphoma and early evidence suggest they are effective in treating b-cell mediated autoimmune diseases. Efficacy is dependent on engraftment and expansion of the CAR T cells. However, rapid activation and expansion of CAR T cells can result in CRS and/or ICANS, which in some cases can be life-threatening, particularly for elderly patients and patients with comorbidities that have a poor tolerance for toxicity. Furthermore, excessive activation of CAR T cells can lead to cell exhaustion and limit their engraftment and expansion, which may impact the initial efficacy and durability of therapeutic effect. Obe-cel is an investigational therapy in which a patient’s T cells are genetically modified to express a novel CD19-specific binder designed to reduce side effects observed with this class of therapeutics.
Obe-cel has been designed to recognize CD19 and interact with the target with a fast off-rate enabled by the novel CAT scFv binding domain. This property allows the obe-cel cells to efficiently recognize target cells, inject cytotoxic proteins to initiate the natural self-destruction process present in all human cells and then rapidly disengage from them in order to engage the next target cell, a process also known as serial killing. Rapid disengagement from the target antigen is expected to minimize excessive activation of the programmed T cells, reduce toxicity and may also reduce T cell exhaustion.
Obe-cel is the subject of an ongoing Phase 1/2 trial (FELIX) in adult r/r B-ALL. The company has also initiated a Phase 1 study in pediatric B-ALL and B-NHL.
The company’s academic partner, UCL, has conducted separate Phase 1 clinical trials evaluating the safety and efficacy of obe-cel. The first Phase 1 clinical trial in pediatric ALL patients is named the CARPALL trial, the second Phase 1 clinical trial in adult ALL patients is named the ALLCAR19 trial. The ALLCAR19 trial has been extended to include patients with DBCL, MCL, FL, and CLL. UCL has also conducted the CAROUSEL study in a small cohort of patients with primary central nervous system lymphoma.
The company recently Autolus initiated a Phase 1 study (CARLYSLE) of obe-cel in patients with systemic lupus erythematosus (‘SLE’).
Clinical Development of Obe-cel in Adult ALL
Background of Adult ALL
Obe-cel is being tested in a Phase 1b/2 clinical trial for the treatment of adult ALL, which according to the American Cancer Society is predicted to affect approximately 6,500 adults in the United States in 2023. Combination chemotherapy enables 90% of adult patients to experience complete remission (‘CR’). However, the majority of these remissions are not long-lasting in adult patients.
Two targeted immunotherapies have been approved in a number of jurisdictions, including the United States and the EU, for the treatment of adult ALL: blinatumomab and inotuzumab ozogamicin. Both of these therapies achieve high CR rates, but durability is limited. In a randomized Phase 3 clinical trial of blinatumomab in heavily pretreated B-cell precursor ALL, the blinatumomab arm achieved a CR rate of 44%, of which 76% also achieved MRD-negative CR, and the median duration of remission was 7.3 months. The median OS in those patients, though significantly improved compared to chemotherapy, was still only 7.7 months. Similarly, in a Phase 3 clinical trial of inotuzumab ozogamicin, a higher percentage of patients achieved MRD-negative CR when treated with inotuzumab compared to standard-of-care chemotherapy, but the median duration of remission was 4.6 months and median OS was 7.7 months.
On October 1, 2021 the FDA approved the use of the CAR T cell therapy brexucabtagene autoleucel (‘Tecartus’) for adults with B-cell precursor ALL that has not responded to treatment (refractory) or has returned after treatment (relapsed). The European Commission approved Tecartus for adults aged 26 and over with relapsed or refractory B-cell precursor ALL in September 2022.
Obe-cel Phase 1b/2 Clinical Trial in Adult ALL (FELIX Trial)
The data were presented at the 2023 ASCO Annual Meeting in June 2023, with updated data presented at the Annual Meeting of the ASH in December 2023. With the cut-off date of September 13, 2023, the data presented at ASH were from a pooled analysis of data from all patients across all cohorts in the FELIX Phase Ib/II study (morphologic disease, MRD, isolated EMD) (n=127, median follow-up time from first obe-cel infusion to data cut-off of 16.6 months). Median vein-to-release time was 22 days. Across all patients, treatment with obe-cel resulted in a high ORR with CR/CRi rate of 78% in evaluable patients. Additionally, obe-cel showed a favorable safety profile; grade =3 CRS was 2% and grade =3 ICANS was 7%, with most severe cases of immunotoxicity occurring in patients with high leukemic burden in the BM. The EFS at 12-months was 50% across all patients, with only 17% of responders proceeding to stem cell transplant while in remission. Cellular kinetic data shows high expansion and long-term persistence of CAR T cells in most responders.
Obe-cel Phase 1 Clinical Trial in Adult ALL (ALLCAR19 Trial)
In the first quarter of 2018, the company’s academic partner UCL initiated a single-arm, open label, multi-center Phase 1 clinical trial of obe-cel, named the ALLCAR19 trial, in patients aged 16 to 65 years with high-risk, relapsed or refractory CD19 positive B-lineage ALL. The clinical trial was conducted at sites in the United Kingdom. The trial enrolled patients with a high tumor burden; 45% of treated patients had 50% or greater bone marrow blasts. In the trial, 20 patients received obe-cel; product for 14 of those patients was manufactured using a semi-automated, fully-enclosed process. The therapy was well tolerated, with no patients experiencing Grade 3 or higher CRS. Three patients (15%), all of whom had high leukemia burden (>50% blasts), experienced Grade 3 ICANS that resolved swiftly with steroids. Of the 20 patients evaluable for efficacy, 17 patients (85%) achieved minimum residual disease (‘MRD’)-negative CR at one month.
A pooled analysis of long-term follow-up data from ALLCAR19 and FELIX Phase 1b Studies were presented at the ASH, meeting in December 2023. Data from the pooled analysis of r/r ALL patients (n=36) treated with obe-cel in the ALLCAR19 and FELIX Phase 1b studies showed high remission rates of 81% (29/36). After a median follow-up of 3 years and without subsequent transplant, 41% of patients continued in complete remission. The estimated EFS rate with censoring of subsequent transplant or new treatment was 45% at 36 months; all patients in ongoing remission were MRD negative at last assessment and median duration of response was not reached.
Development Strategy for Adult ALL
In 2020, the company initiated a multi-center, single-arm Phase 1b/2 clinical trial of obe-cel in adult patients with relapsed or refractory ALL (‘r/r ALL’), referred to as the FELIX trial. Recruitment in the Phase 2 Cohort A of the FELIX trial for morphological adult r/r ALL patients has been completed.
In January 2023, the FELIX trial completed screening patients for entry into the morphological cohort, as the pre-specified goal of approximately 90 patients enrolled had been reached. The Phase 2 Cohort A includes approximately 90 patients with morphological disease (at least 5% blasts in the BM at screening), with ORR (CR/CRi) as the primary endpoint; and the secondary endpoints include CR rate, EFS, duration of response (‘DOR’) and MRD negative remission rate. Smaller cohorts were also included in the Phase 2 portion of the FELIX trial, in which patients with MRD positive disease in morphological remission (Cohort B), as well as patients with isolated EMD (Cohort C) were be treated with obe-cel.
Obe-cel has received a number of designations from regulatory authorities, as follows: FDA orphan drug designation for the treatment of ALL (October 2019), EMA PRIME designation (March 2021), MHRA ILAP designation (June 2021), European Commission orphan drug designation (March 2022), and FDA RMAT designation (April 2022). In November 2023, the company submitted a BLA to the U.S. FDA for obe-cel for the treatment of patients with r/r adult B-ALL. In January 2024, the FDA notified that they had accepted the BLA and the FDA has set a PDUFA target action date of November 16, 2024. The BLA submission is primarily based on data from the FELIX study. The company plans to submit the marketing authorization application (‘MAA’) to the EMA in the first half of 2024.
Obe-cel Phase 1 Clinical Trial in Pediatric ALL
The CARPALL trial was initiated by UCL in the second quarter of 2016 and is a single-arm, open label, multi-center Phase 1 trial enrolling patients aged 24 years or younger with high-risk relapsed or refractory CD19 positive B-lineage ALL. The main objective of the trial is to evaluate the safety and efficacy of obe-cel when administered at a single dose of 1 million cells/kg. The trial has completed enrollment with obe-cel. However, the extension arm is now open, and treating pediatric ALL patients with AUTO 1/22.
Notably, ongoing CAR T persistence appears to be important for ongoing response in FL. Longer follow-up and enrollment of additional MCL, DLBCL and CLL/SLL patients is ongoing.
UCL has also initiated a Phase 1 exploratory trial (CAROUSEL) of obe-cel in patients with relapsed or refractory PCNSL. CAROUSEL is evaluating the feasibility of generating obe-cel and safety of administration in this patient population. UCL presented initial data at the EHA meeting in June 2022. Expansion of obe-cel was observed in the peripheral blood by qPCR, with persistence in all treated patients at last follow-up. No Grade 3 or greater CRS was observed using intravenous (‘IV’) or intra-ventricular obe-cel administration. Two cases of Grade 3 ICANS were reported following IV infusion, whereby the first patient had several neurological deficits that evolved despite ICANS treatment and were compatible with progressive PCNSL, as confirmed with the month 1 MRI scan, and the second patient had neurological deficits that improved with steroids/anakinra. The company observed encouraging response rates in six patients evaluable for efficacy following IV administration of obe-cel. The ORR was four out of six patients (67%), with 2 CRs and 2 PRs. These four responding patients are without disease progression at the last follow up date. Two patients died from progressive PCNSL while part of the study. The company expects to report longer follow-up from this trial and enrollment of additional patients is ongoing.
Clinical Development of Obe-cel in Lupus and other Autoimmune diseases
Clinical Development in SLE and other Autoimmune Diseases
The CARLYSLE trial is a single-arm, open-label, Phase 1 Study to determine the safety, tolerability, and preliminary efficacy of obe-cel in patients with severe, refractory SLE. Six patients are expected to receive a target dose of 50 x 106 CD19 CAR-positive T cells. Beyond this initial cohort, the study has the option to add further cohorts of patients. The first CARLYSLE trial was initiated in early 2024.
Depending on the outcome of the dose conformation study in SLE, the company would plan to initiate further studies in SLE and LN. Furthermore, additional evidence of CD19 CAR T cell treatment in other autoimmune diseases has been shown by others, including efficacy in patients with idiopathic inflammatory myositis, systemic sclerosis, myasthenia gravis and multiple sclerosis. Depending on the outcome of the dose conformation study in SLE, the company would plan to investigate obe-cel in additional autoimmune disease indications.
AUTO1/22 The company’s Programmed T Cell Therapy for the Treatment of ALL, other B-cell malignancies
Introduction to AUTO1/22
AUTO1/22 is a dual-targeting CAR T which builds on the obe-cel approach utilizing the same CD19 CAR, alongside a novel CD22 CAR designed to reduce antigen negative relapse of disease. Antigen negative relapse is a common cause of relapse in patients with pediatric ALL.
AUTO1/22 Phase 1 Clinical Trial in Pediatric ALL (CARPALL Trial)
The company commenced a Phase 1 clinical trial in pediatric patients with relapsed or refractory ALL with the company’s next-generation product candidate, AUTO1/22 in the fourth quarter of 2020. In a publication in Blood in October 2023, the company presented data demonstrating a high level of activity, with 83% of patients (10 of 12 patients evaluated) experiencing MRD negative complete remissions, and a favorable tolerability profile in a very challenging patient population. Patients on study were high risk, with 4 patients who had failed prior CD19 CAR therapy, 3 patients with a CD19-negative disease component, 3 patients with non-CNS EMD and 6 patients who had received prior blinatumomab. Of 10 responding patients, 5 had emergence of MRD (2) or frank relapse (3) with CD19 and CD22 expressing disease associated with loss of CAR T-cell persistence. Importantly, there were no cases of relapse due to antigen-negative escape, with a median follow-up of 8.7 months. Overall survival was 75% at 6 and 12 months. Six and 12-month event free survival (EFS) were 75% and 60% respectively.
AUTO4: The company’s T Cell Lymphoma Program
Introduction to AUTO4
The company is developing a programmed T cell product candidate, AUTO4, as a potential treatment for T-cell lymphomas. The company is developing this product candidate with a unique targeting approach that is designed to avoid the severe immunosuppression typically associated with the current investigational CAR T-cell therapies which uses a pan t-cell antigen. for this disease.
T cells have one of two functionally identical genes, known as TRBC1 and TRBC2. A normal/healthy T cell population contains a mix of cells expressing either TRBC1 or TRBC2. Both forms are active and provide the body with natural immunity, including antiviral immunity. Because T-cell lymphomas are clonal tumors that develop from a single T cell, they are either entirely TRBC1-positive or entirely TRBC2-positive. Currently available products for the treatment of T-cell lymphoma indiscriminately target all T cells, leading to the severe immunosuppression associated with these treatments.
The company has designed AUTO4 as a programmed T cell to specifically target and deplete cells expressing TRBC1, while preserving healthy T cells that express TRBC2. A normal T cell population consists of varying amounts of TRBC1-positive and TRBC2-positive T cells. Based on the typical distribution of TRBC1-positive and TRBC2-positive T cells, patients treated with AUTO4 should be left with a population of healthy, functional polyclonal T cells, which provides the immune system of these patients the ability to respond to bacterial and viral infections and other pathogens. In addition, this product candidate will have a built-in safety switch designed to eliminate the programmed CAR T cells in the event a patient suffers certain serious adverse events related to the CAR T cell therapy, such as CRS or neurotoxicity.
Clinical Development of AUTO4
In the fourth quarter of 2018, the company began enrolling patients in a single-arm, open label, multi-center Phase 1/2 clinical trial, Libra T1, in patients with TRBC1 positive PTCL-NOS, AITL and ALCL, the three most common subtypes of PTCL, for which patients have failed, or have relapsed disease following, at least one prior therapy. The company refers to this trial as the LibrA-T1 trial, which was initiated at sites in the UK and Spain in 2018 and 2020 respectively. Patients were screened for TRBC status of tumor cells using a CE-marked next-generation sequencing (‘NGS’) method prior to full enrollment in the trial.
The main objective of the Phase 1 portion of the trial was to evaluate the safety of AUTO4 and to determine a recommended dose for the Phase 2 portion of the trial. The main objective of the Phase 2 portion will be to further evaluate the safety of the treatment and evaluate efficacy endpoints, such as ORR and CR rate.
The company designed the trial to evaluate up to five dose levels of AUTO4, beginning with a low dose of 25 million AUTO4 cells. If the company does not observe any dose limiting toxicities (‘DLT’), the dose escalation phase of the trial will continue to higher doses of 75 million AUTO4 cells, 225 million AUTO4 cells, 450 million and potentially 900 million AUTO4 cells.
Data from the first 13 patients dosed in the Libra T1 trial was presented at the ICML in June 2023. At the cutoff date of April 28, 2023, 19 patients were enrolled into the study and 13 were dosed. Using manufacturing process A, 10 patients were dosed. Using manufacturing process B, 3 additional patients were dosed. Among the 13 patients dosed with AUTO4, the treatment was well tolerated with no DLT. Ongoing responses at 15 and 18 months post-dosing at the highest dose tested (450x106) are encouraging. Presence of CAR T cells in the lymph nodes of patients suggest fast homing of CAR T cells to the tumor site, despite absence in the blood. Efficacy data from Process B was not provided given median follow up is <3 months.
AUTO8: The company’s Multiple Myeloma Program
Introduction to AUTO8
AUTO8 is a next-generation product candidate for multiple myeloma, which comprises two independent CARs for the multiple myeloma targets, BCMA and CD19. The company has developed an optimized BCMA CAR which is designed for improved killing of target cell that express BCMA at low levels. This has been combined with fast off-rate CD19 CAR from obe-cel. The design of AUTO8 has the potential to induce deep and durable responses and extend the durability of effect over other approved BCMA CARs and those in development.
Clinical Development of AUTO8
In collaboration with UCL, the company commenced a Phase 1 clinical trial in patients with relapsed or refractory multiple myeloma in March 2022. The phase 1 study is an iterative, staggered design trial with two separate parallel cohorts for direct comparison of the BCMA CAR alone and AUTO8 (the BCMA CAR in combination with the CD19 CAR from obe-cel). As of November 13, 2023 (data cut-off), 11 patients have been infused with either BCMA CAR at 50 million (n=3) or 150 million (n=3) cells, or AUTO8 at 50 million (n=3) or 150 million (n=2). At a median follow-up of 6 months the company observed 100% response rate (ORR), with 3 PR, 1 VGPR, 7 CR/sCR (all evaluable MRD negative). Two patients remained in ongoing sCR > 12 months. No cases of ICANS or CRS = Gr 3 were observed across all subjects during the period. While persistence data from the dual targeting cohort is immature, it demonstrates expansion of three CAR populations and suggests a trend to increased persistence of D8 BCMA CAR expressing T cells. The study is ongoing and continues to recruit patients.
Solid Tumor Programs
In addition to the programs the company is pursuing described below, the company intends to continue to evaluate other possible solid tumor indications.
AUTO6: The company’s Neuroblastoma Program
Introduction to AUTO6 and AUTO6NG
Under the company’s license agreement with University College of London Business Ltd. (‘UCLB’), the company has been granted an exclusive, worldwide license to AUTO6 (1RG-CART), a programmed T cell product candidate targeting the glycosphingolipid GD2. Cancer Research UK (‘CRUK’) has completed an exploratory Phase 1 clinical trial of AUTO6 in pediatric patients with neuroblastoma. The company is developing a next-generation product candidate, which the company refers to as AUTO6NG, incorporating additional programming modules designed to improve efficacy, safety and persistence of AUTO6.
Preclinical Studies of AUTO6/6NG
In preclinical in vitro studies, AUTO6 selectively, effectively and efficiently killed GD2-expressing tumor cells while sparing cells that did not express GD2. In addition, the RQR8 safety switch activation by rituximab was tested in vitro, where the addition of rituximab was shown to activate the safety switch and eliminate the programmed T cells from the culture, and residual cells did not possess any intrinsic anti-GD2 activity. This safety switch activation was also observed in vivo in a mouse model, where the murine analogue of rituximab was able to deplete the GD2-targeting programmed T cell product candidate from the bone marrow, blood, lymph node and spleen of animals that had previously been engrafted with programmed T cells.
In 2016, in collaboration with Cancer Research UK’s Centre for Drug Development the company initiated a single-arm Phase 1 dose escalation trial of AUTO6 in relapsed or refractory neuroblastoma at two pediatric cancer centers in the UK. The trial evaluated the safety and efficacy of AUTO6. In 2020 the data from the AUTO6 Phase 1 clinical trial was published in Science Translational Medicine. The results from the study showed that AUTO6 can induce rapid regression of bulky disease in a solid tumor setting without inducing on-target, off-tumor toxicity, despite dose dependent CAR T expansion. CAR T cell expansion was observed in all 6 patients treated at the higher cell dose cohorts in this Phase 1 study. Three of these six patients demonstrated evidence of transient CAR T cell activity, including CRS, and regression of soft tissue and BM disease activity.
The GD2 binder used in AUTO6 has been designed to minimize on-target, off-tumor neurotoxicity associated with GD2 expression at low levels in pain fibers and the brain. Despite the presence of clear CAR T cell activity, no neurotoxicity was observed. The publication also suggests that, whilst AUTO6 is a valid and safe strategy for targeting neuroblastoma, further modifications are required to promote CAR T cell persistence and induce deeper and more durable responses for these patients.
In November 2019, the company reported preclinical data of AUTO6NG. Building on AUTO6, in AUTO6NG the company introduced additional programming modules in order to help the programmed T cells persist in and withstand the hostile tumor microenvironment. AUTO6NG is a programmed T cell therapy incorporating the GD2-targeted CAR T and RQR8 safety switch from AUTO6 but also incorporating three additional programming modules: (i) an IL7 CCR designed to increase persistence, (ii) a dominant negative TGFbRII protein designed to block inhibitor signals from TGFb and (iii) a truncated SHP2 protein designed to block inhibitor signals from PD1. These modules are delivered, or transduced, into the T cells via two viral vectors. Both single- and dual-transduced CAR T cells were evaluated in vitro for anti-tumor activity, cytokine secretion, T cell proliferation, survival, and resistance to immunosuppressive pathways.
The addition of these three modules in the AUTO6NG product candidate significantly augmented its function by extending T cell persistence and rendering modified T cells resistant to TGFb- and PD1/PDL1-driven immune inhibition when compared to AUTO6 in vitro. Additionally, intravenous delivery of AUTO6NG in mice with established tumor burden exhibited potent anti-tumor activity and extended survival, whereas AUTO6 showed no activity in that model.
The company presented new preclinical data for AUTO6NG in June 2020 at the AACR Virtual Annual Meeting 2020. GD2 was evaluated as a therapeutic CAR T target antigen in SCLC. The company observed that AUTO6 alone has demonstrated efficacy in an in vitro SCLC model; however, successful tumor targeting alone was not sufficient to drive meaningful in vivo efficacy in the same SCLC model. The company presented new preclinical data demonstrating the ability to target GD2 in SCLC cell line models in vitro, and the requirement for enhancing modules, designed to overcome TME suppressive mechanisms, to drive superior in vivo efficacy in a SCLC mouse model. The data suggests that AUTO6NG can overcome the immune suppressive mechanisms in the TME.
Clinical Development Strategy of AUTO6NG
GD2 is expressed in numerous pediatric and adult tumors, including neuroblastoma, osteosarcoma, soft tissue sarcoma, melanoma, astrocytoma and small cell lung cancer (‘SCLC’). A Phase 1 clinical trial of AUTO6NG in r/r neuroblastoma was initiated in December 2023 in collaboration with UCL.
Manufacture and Delivery of Programmed T Cell Therapies to Patients
The company is devoting significant resources to process development and manufacturing in order to optimize the safety and efficacy of the company’s product candidates, to ensure high quality and reliable product supply to patients, as well as to reduce the company’s per unit manufacturing costs and time to market if the company obtains regulatory approval for any of the company’s programmed T cell product candidates.
The manufacture and delivery of programmed T cell therapies to patients involves complex, integrated processes, including harvesting T cells from patients, manufacturing viral vectors with nucleic acid content encoded with the company’s programming modules, manufacturing programmed T cells using the viral vectors ex vivo, multiplying the T cells to obtain the desired dose, and ultimately infusing the T cells back into a patient’s body.
Commercial success in T cell therapies requires a manufacturing process that is reliable, scalable and economical. The company has established a manufacturing process that is scalable and serves as a manufacturing platform designed to support rapid development of the company’s programmed T cell therapy product candidates through clinical trial phases and regulatory approval processes. The company is using a semi-automated, fully enclosed system for cell manufacturing, which is designed to provide a common platform suitable for manufacturing all of the company’s product candidates. This platform allows for parallel processing having the ability to scale for commercial supply in a controlled environment at an economical cost. The company has established reliable and consistent viral vector production and viral transduction processes further, also a key to the company’s process reproducibility and reliability.
The company’s manufacturing and logistics process is designed to ensure that product integrity is maintained during shipment along with accurate tracking and tracing of shipments. The company is expanding internal manufacturing and supply capabilities as well as the use of expert service providers on maturing the company’s vein-to-vein logistics and the company’s gradual capacity expansion in the support of commercial operations. Chain of identity and chain of custody electronic systems are now in place to ensure transport and processing reliability and further adding to patient safety.
Manufacturing Agreements
The company has manufacturing agreements with King’s College London for early phase vector manufacturing. Autolus also has an internal capability to produce vector for early and late-stage trials. Additionally, the company has an agreement with AGC Biologics for late stage clinical and commercial supply of vector. All vector manufacturing is done in accordance with current Good Manufacturing Practice (‘cGMP’) in compliant manufacturing facilities. The manufacturing agreements governing the external supply arrangements also provide for access to services, including quality management systems, qualified persons for product release, office space, frozen storage and warehousing services.
For clinical trial supply, the company has established its initial cell and vector manufacturing capacity at the Cell and Gene Therapy Catapult in Stevenage, UK. The company has a cell manufacturing suite capable of supporting clinical supply operations, as well as a vector production suite capable of supplying clinical supplies.
In March 2018, the company entered into a strategic, long-term supply agreement with Miltenyi Biotec GmbH (‘Miltenyi’), for the supply of Miltenyi’s CliniMACS Prodigy instruments, reagents and disposables for the manufacture of the company’s programmed T cell therapies for preclinical and clinical use, and if approved, for commercial use, as well as support services. The supply agreement sets forth procedures to ensure continuity of supply to the company of Miltenyi’s products, both during the clinical phase and any future commercial phase of the company’s product candidates. After the initial ten-year term of the agreement, the company has two separate options to renew the agreement, each for an additional five-year term.
Commercialization
Based on the U.S. FDA acceptance of the BLA for obe-cel for patients with r/r Adult B-ALL, the company is in the process of establishing its commercial infrastructure and distribution capabilities in preparation for a potential approval. Under PDUFA, the FDA has set a target action date of November 16, 2024, a standard review timeline consistent with recently approved CAR T therapies. The company is developing its clinical-stage programs for the treatment of patients with late-stage or rare hematological cancers and solid tumors, most of whom are treated in specialized treatment centers or hospitals. With the company’s experience in gene therapy, transplantation and oncology, the company intends to provide high levels of service and scientific engagement at these treatment centers, and to pilot and establish systems necessary for product delivery by the time of launch. By focusing on these centers, the company can begin to build its commercialization capabilities with limited resources.
The company has retained worldwide commercial rights for certain of the company’s product candidates. The company plans to build its global commercialization capabilities internally over time such that the company is able to commercialize any product candidate for which the company may obtain regulatory approval. The company may pursue strategic collaborations with third parties in order to maximize the commercial potential of the company’s product candidates. Under the terms of the License and Option Agreement with BioNTech, BioNTech has certain options to co-promote or co-commercialize AUTO1/22 and AUTO6NG. The company generally expects to launch any of its products that receive regulatory approval in the United States first, followed by the EU and subsequently in other major markets.
Intellectual Property
As of December 31, 2023, the company’s patent portfolio is consisted of 81 patent families, of which 17 patent families originated from UCLB, the technology-transfer company of UCL, 3 patent families are in-licensed from Noile-Immune Biotech, Inc., and 61 patent families the company owns and has originated from its own research. Of the 17 live patent families that were originally in-licensed from UCL, 16 have been assigned to the company. Because the company has acquired or licensed certain of the company’s patents from UCLB, and licensed certain of other patents from third parties, the company must rely on their prior practices with regard to the assignment of such intellectual property.
Commercially or strategically important non-U.S. jurisdictions in which certain patent applications that the company has in-licensed are pending include: Europe, Australia, Canada, Japan, China, Brazil, Chile, Israel, India, Republic of Korea, Hong Kong, Mexico, New Zealand, Russia, Singapore, South Africa, Colombia, Peru, Cuba, Indonesia, Malaysia and Philippines. ‘AUTOLUS’ is the company’s registered trademark.
The company’s strategy is to develop and obtain additional intellectual property covering innovative manufacturing processes and methods for genetically engineering T cells expressing new constructs with properties that are designed to improve the ability of the company’s programmed T cells to recognize and kill cancer cells. To support this effort, the company has established expertise and development capabilities focused in the areas of T cell programming, preclinical and clinical research and development, and manufacturing and manufacturing process scale-up, and the company expect that the company’s ongoing research and development activities will yield additional patentable inventions and patent applications that will expand the company’s intellectual property portfolio.
License and Option Agreement with BioNTech SE
In February 2024, the company entered into a License and Option Agreement (the ‘BioNTech License Agreement’) with BioNTech pursuant to which the company granted to BioNTech an exclusive, worldwide, sublicensable license (the ‘License’) to certain binders and to exploit products that express in vivo such binders (collectively, the ‘Binder Licensed Products’).
License Agreement with UCL Business Ltd.
In September 2014, the company entered into an exclusive license agreement with UCLB, the technology transfer company of UCL, for the development and commercialization rights to certain T cell programming modules (the ‘UCLB Agreement’). The UCLB Agreement was amended and restated in March 2016 to also include certain development and commercialization rights to improvements and new T cell programming modules. The UCLB Agreement was further amended and restated in March 2018 to include a license to AUTO1, for which UCL is conducting Phase 1 clinical trials in pediatric and adult ALL patients. The UCLB Agreement was further amended and restated in October 2020 to reflect the company’s election to have various patent rights assigned to the company, and to include a license to new technology and further licenses to obe-cel for which UCL is conducting Phase 1 clinical trials in PCNSL patients. Under the UCLB Agreement, subject to certain limitations, exceptions and retained rights of UCLB, the company received an exclusive license of certain patent rights and know-how owned by UCLB covering T cell programming modules. The licensed rights cover obe-cel, AUTO4/5 and AUTO6 targeting modules, as well as additional T cell programming modules and technologies, including dual-targeting technology, pattern recognition technology, safety switches (including RQR8), tunable T cells, manufacturing processes, as well as certain technology for evading tumor micro-environments. The company also has option rights and rights of first negotiation to obtain an exclusive license for development and commercialization rights to certain new T cell programming modules.
Government Regulation and Product Approval
The company’s product candidates must be approved by the FDA before they may be legally marketed in the United States and by the appropriate foreign regulatory agency before they may be legally marketed in foreign countries.
The company relies on third parties for the production of clinical and commercial quantities of the company’s products and some intermediates in accordance with cGMP regulations.
The U.S. Foreign Corrupt Practice Act, as amended (the ‘FCPA’) prohibits any U.S. individual or business, as well as their employees, officers, agents, and representatives, from paying, offering, or authorizing payment or offering of anything of value, directly or indirectly, to any foreign, non-U.S. official, political party or candidate for the purpose of influencing any act or decision of the foreign entity in order to assist the individual or business in obtaining or retaining business. The FCPA also obligates companies whose securities are listed in the United States to comply with accounting provisions requiring the company to maintain books and records that accurately and fairly reflect all transactions of the corporation, including international subsidiaries, and to devise and maintain an adequate system of internal accounting controls.
The company’s operations are also subject to non-U.S. anti-corruption laws such as the UK Bribery Act 2010 (the ‘UK Bribery Act’). As with the FCPA, these laws generally prohibit the company and its employees and intermediaries from authorizing, promising, offering, or providing, directly or indirectly, improper or prohibited payments, or anything else of value, to government officials or other persons to obtain or retain business or gain some other business advantage.
Research and Development
The company’s research and development expenses were $130.5 million for the year ended December 31, 2023.
History
Autolus Therapeutics plc was founded in 2014. The company was incorporated pursuant to the laws of England and Wales in 2014.
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