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Item 1. Business

2025-03-20 compared with 2024-03-21 · 348 added, 352 removed, 966 unchanged (42% of the section changed)

Business Overview

We are a biopharmaceutical company developing next-generation programmed T cell therapies for the treatment of cancer and autoimmune diseases.

Using our broad suite of proprietary and modular T cell programming technologies, we are 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.

We are an early commercial-stage biopharmaceutical company developing next-generation programmed T cell therapies for the treatment of cancer and autoimmune diseases.

On November 8, 2024, the U.S.

Food and Drug Administration, or FDA, granted marketing approval for our first approved commercial product, AUCATZYL/obe-cel (obecabtagene autoleucel) for the treatment of adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia, or r/r B-ALL.

We commercially launched AUCATZYL in the United States in January 2025, and we plan to initiate sales of AUCATZYL/obe-cel in the European Union, or EU, and the United Kingdom, or UK, once regulatory approval is received.

Marketing authorization submissions for AUCATZYL/obe-cel were accepted by the European Medicines Agency, or EMA, in April 2024 and the U.K.

Medicines and Healthcare products Regulatory Agency, or MHRA, in August 2024, and we expect to receive notification of approval status from these authorities in the second half of 2025.

AUCATZYL 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 chimeric antigen receptor T cell, or CAR T, therapies.

Adult r/r/ B- ALL is an extremely aggressive type of blood cancer with a high unmet medical need in the treatment of patients once they relapse, where historically patients suffer from poor outcomes.

AUCATZYL is manufactured at our dedicated commercial manufacturing site, the Nucleus, in Stevenage, UK.

If we receive approval to commercialize AUCATZYL outside of the United States, we intend for the Nucleus to meet the global supply demands of AUCATZYL, with Cardinal Health serving as our commercial distribution partner in the United States.

In addition to AUCATZYL/obe-cel for the treatment of adult r/r B-ALL, we are advancing obe-cel in other oncology indications including pediatric B-ALL and B-NHL, for which we have initiated Phase 1 studies.

Obe-cel is also being developed for the treatment of autoimmune indications and we have initiated a Phase 1 study in patients with severe, refractory systemic lupus erythematosus (“SLE”).

Using our broad suite of proprietary and modular T cell programming technologies, we are also developing five programs in seven hematological and solid tumor indications and one autoimmune indication.

We are 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.

We believe our 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.

Our T cell programming technologies allow us to tailor our therapies to address the specific disease we are 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.

Our T cell programming technologies allow us to tailor our therapies to address the specific disease we are targeting and introduce new programming modules into 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.

We believe our leadership in T cell programming technologies will provide us with a competitive advantage as we look 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..

Our current clinical-stage pipeline comprises five programs being developed in eight hematological and solid tumor indications and one autoimmune indication.

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Our current 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.

We 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, we 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 us 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.

We have also initiated two Phase 1 studies, one in pediatric B-ALL and B-NHL and one in Systemic lupus erythematosus (SLE).

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In collaboration with UCL, we commenced a Phase 1 clinical trial in pediatric patients with our academic partner at UCL in r/r B-ALL with our 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, we 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.

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 (450x10 6 ) 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.

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.

We 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, we 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.

A next-generation product candidate for multiple myeloma, which comprises two independent CARs for the multiple myeloma targets, BCMA and CD19.

We have 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.

We believe that the design of AUTO8 has the potential to induce deep and durable responses and extend the durability of effect over other BCMA CARs currently in development.

A Phase 1 clinical trial of AUTO8 was initiated in March 2022 with our 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 we 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.

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We believe our leadership in T cell programming technologies will provide us with a competitive advantage as we look to develop future generations of T cell therapies targeting both hematological cancers, solid tumors and autoimmune diseases, including potential products that could have a sufficient tolerability profile to enable use in outpatient settings.

Our current clinical-stage pipeline comprises five programs being developed in seven hematological and solid tumor indications and one autoimmune indication.

Our current pipeline is below:

Our product pipeline is built on our core principles of modular innovation with protein-based cell programming focused on advanced targeting, pharmacological control and enhancement of activity.

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Our programs have been highly tailored and specifically engineered via our 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.

We believe that 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 currently 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 we are 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 we believe 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 our AUTO4 approach is a novel mechanism to target T cells, we have 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.

We are 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 our next-generation product candidate for multiple myeloma, which comprises two independent CARs for the multiple myeloma targets, BCMA and CD19.

We have 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.

We believe that the design of AUTO8 has the potential to induce deep and durable responses and extend the durability of effect over other BCMA CARs currently in development.

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Our strategic priorities include:

• Execute on the U.S.

launch and commercialization of AUCATZYL/obe-cel for adult r/r B-ALL

• Subject to receiving regulatory approval, launch AUCATZYL/obe-cel for adult r/r B-ALL in the U.K.

and European Union

• Develop obe-cel for treatment of potential additional indications, including Lupus

• Build our research and development pipeline

Background on T Cells and Cancer

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More recently, genetically programmed redirected T cell therapies have been approved.

These include the CD19 targeting therapies Kymriah®, Yescarta® and Tecartus®, and Breyanzi®, developed by Novartis AG, Kite Pharma, Inc.

These include the CD19 targeting therapies Kymriah®, Yescarta®, Tecartus®, and Breyanzi®, developed by Novartis AG, Kite Pharma, Inc.

and Bristol Myers Squibb Inc., respectively, for the treatments of B-ALL and B-NHL.

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We believe that improving efficacy and durability over the products currently on the market or in development for the treatment of cancers requires addressing target antigen loss, countering checkpoint inhibition and adding novel targets to expand the range of indications amenable to programmed T cell therapy.

We believe our clinical-stage product candidates and our approach to T cell programming have the potential to address these limitations.

We believe our commercial product and our clinical-stage product candidates and our approach to T cell programming have the potential to address these limitations.

Programmed T Cell Therapies

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These receptors combine the tumor recognition domain of an antibody with the activation and costimulatory domains from the T cell receptor to rearm a patient’s T cells to recognize and kill their cancer cells.

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CAR T Cell Production

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Finally, realization of the potential of this approach across a broad range of solid tumor types will require multiple technology solutions in order to address limitations of the current generation of therapies.

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Emerging Promise of T Cell Immunotherapies for the Treatment Autoimmune Diseases

Autoimmune diseases are the result of an immune system that is overactive, causing it to attack and damage the patient’s own tissues.

Autoimmune diseases can affect multiple organs throughout the body and can in some cases be life threatening.

Autoimmune diseases can affect multiple organs throughout the body and can be life threatening in some cases.

The presence of autoreactive B cells that produce autoreactive antibodies, antibodies that attack the body’s own tissues, are a common feature of these diseases.

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It may be possible that CD19 is a better target than CD20 or BAFF, as it is expressed more broadly on the autoreactive plasma cells and plasma blasts as well as B cells.

Additionally, CAR T cells may be better at depleting the B cells than the antibodies, as they can penetrate into all tissues including some that antibodies can’t reach.

Additionally, CAR T cells may be better at depleting the B cells than the antibodies, as they can penetrate into all tissues including some that antibodies cannot reach.

The future promise of CAR T cell therapy for autoimmune diseases will be driven by efficacy, safety and cost effectiveness.

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A focus in our early-stage pipeline is incorporation of multiple components in a single product.

The diagram in this section following the table summarizing our clinical programs shows how our programming modules relate to our product candidates.

Advanced Targeting Technologies

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We use Dual Targeting CARs in our AUTO1/22 and AUTO8 programs.

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Pharmacological Control of T Cell Activity

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The CCR is a programming module that is designed to deliver a cytokine signal directly inside T cells without administration or secretion of cytokines themselves.

We use proteins from an antibody structure to stably heterodimerise two cytokine signaling domains together to deliver a proliferative and survival signal into our T cells.

We use proteins from an antibody structure to stably heterodimerize two cytokine signaling domains together to deliver a proliferative and survival signal into our 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.

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Our ssIL12 module is designed to secrete very low levels of IL-12 from our T cells and our preclinical data demonstrates the potential for ssIL12 to provide anti-tumor without systemic toxicity.

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Engineering survival signal (Fas-TNFR)

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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.

Our Product Candidates for the Treatment of Hematological Cancers and Autoimmune Diseases

Our clinical-stage product candidates targeting hematological cancers are obe-cel, AUTO1/22, AUTO4 and AUTO8.

We have 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.

Our 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).

Our Commercial Product:

AUCATZYL for Adult r/r B-ALL

AUCATZYL/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-ζ and CD3- ζ endodomains.

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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.

Obe-cel is an autologous 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.

AUCATZYL/obe-cel recognizes and interacts with the CD19 target with a fast off-rate enabled by the novel CAT scFv binding domain.

This property allows the AUCATZYL/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 currently the subject of an ongoing Phase 1/2 trial (FELIX) in adult r/r B-ALL.

We have also initiated a Phase 1 study in pediatric B-ALL and B-NHL.

Our 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 D BCL, MCL, FL, and CLL .

UCL has also conducted the CAROUSEL study in a small cohort of patients with primary central nervous system lymphoma.

We recently Autolus initiated a Phase 1 study (CARLYSLE) of obe-cel in patients with systemic lupus erythematosus ( “ SLE ” ), as described below .

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The US FDA granted marketing approval for obe-cel for the treatment of adult patients with r/r B-ALL on November 8, 2024 under the brand name AUCATZYL.

Marketing authorization applications (“MAA”) for AUCATZYL/obe-cel in adult r/r ALL are being reviewed by the regulators in both EU and the U.K., with a submission to the EMA accepted in March 2024, and a submission accepted by the U.K.

MHRA in August 2024.

We expect to receive notification of approval status from these authorities in the second half of 2025.

Clinical Development of Obe-cel in Adult ALL

Background of Adult ALL

Obe-cel is currently 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.

Obe-cel was 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”).

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The European Commission approved Tecartus for adults aged 26 and over with relapsed or refractory B-cell precursor ALL in September 2022.

On November 8, 2024 the FDA approved the use of obe-cel for the treatment of adults with r/r B-ALL.

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.

We initiated the FELIX study, a Phase 1b/2 clinical trial of obe-cel for the treatment of adult r/r B-Acute Lymphoblastic Leukemia, in 2020.

Most recently the data were published in the New England Journal of Medicine in December 2024.

The published data were from a pooled analysis of data from all patients across all cohorts in the FELIX Phase 1b/2 study.

Of the 153 r/r B-ALL patients enrolled patients in the FELIX study, 127 (83.0%) received at least one obe-cel infusion and were evaluable.

Eligible patients underwent leukapheresis, and bridging therapy, except blinatumomab, was permitted at the investigator’s discretion.

Obe-cel was administered in a bone marrow (“BM”) burden adjusted split dose following lymphodepletion, with a BM mandated prior to lymphodepletion to guide dosing.

The second obe-cel dose was given in the absence of severe/unresolved toxicity.

The primary end point was overall remission (“CR/Cri”).

In the pivotal cohort of patients, (cohort IIA (n=94)), the CR/CRi for patients who received at least one infusion of obe-cel was 76.6%.

Across all infused patients (n=127), of the 91/127 with ≥5% BM blasts pre-lymphodepletion, the CR/CRi was 74.7%.

Median response duration for all infused patients was 21.2 months.

Median event-free survival (EFS) was 11.9 months and the estimated 6- and 12-month event-free survival rates were 65.4% and 49.5%, respectively.

BM burden pre-lymphodepletion correlated with median event-free survival;

patients with low (<5% BM blasts), intermediate (≥5–≤75% blasts), and high (>75% blasts) BM burden had event-free survival rates at 12 months of 68.0%, 54.9% and 25.0%, respectively.

Median overall survival (“OS”) was 15.6 months and estimated 6- and 12-month overall survival rates were 80.3% and 61.1%, respectively.

BM burden pre-lymphodepletion correlated with overall survival;

patients with low, intermediate, and high BM burden had an overall survival rate at 12 months of 71.5%, 58.7% and 55.0%, respectively.

BM burden before enrollment also influenced event-free and overall survival.

Of the 127 patients infused (pooled across all study cohorts), 99 patients responded.

Of the responders, 18 patients (18.2%) proceeded to allo-Stem Cell Transplant (“allo-SCT”) while in remission at a median of 101 days post-obe-cel infusion.

In 6/18 (33.3%), this was a second allo-SCT.

Of 11 patients who had persisting CAR T cells before allo-SCT, and who had samples available post, none had CAR T cells detected following allo-SCT.

There was no difference in event-free and overall survival observed between patients who received allo-SCT and those who did not.

Median duration of CAR T persistence by droplet digital PCR (ddPCR) in peripheral blood was 17.8 months.

Obe-cel was associated with minimal immunotoxicity.

CRS and Immune effector cell-associated neurotoxicity syndrome (“ICANS”) rates (Grade ≥3) were 2.4% and 7.1%, respectively.

Overall, 87 (68.5%) patients developed CRS, and 29 (22.8) developed ICANS.

Severe ICANS post-obe-cel were seen as largely limited to patients with high BM burden pre-lymphodepletion.

Intensive care unit (ICU) admissions occurred in 20 (15.7%) patients for a median of 5.5 days (range,1−37) of which 7/20 were admitted due to immunotoxicity management (5 ICANS, 2 CRS).

Obe-cel Phase 1 Clinical Trial in Adult ALL (ALLCAR19 Trial)

In the first quarter of 2018, our 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.

In the first quarter of 2018, our academic partner University College London (“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.

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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).

Data from the pooled analysis of r/r B-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.

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all patients in ongoing remission were MRD negative at last assessment and median duration of response was not reached.

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Development Strategy for Adult ALL

In 2020, we 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.

Regulatory Status and Plans

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, we 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.

We plan to submit the marketing authorization application (“MAA”) to the EMA in the first half of 2024.

The US FDA granted marketing approval for obe-cel on November 8, 2024 under the brand name AUCATZYL for the treatment of adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (r/r B-ALL) without the need for a Risk Evaluation and Mitigation Strategy (REMS).

The approval is based on data from the Phase 2 cohort of FELIX study.

MAAs for obe-cel in r/r B-ALL are being reviewed by the regulators in both the EU and the UK, with a submission to the EMA accepted in March 2024, and a submission accepted by the U.K.

MHRA in August 2024.

Based on prior regulatory timelines, we expect to hear from the MHRA and EMA regarding potential marketing approvals in the second half of 2025.

Commercialization Strategy for AUCATZYL

FDA has granted marketing approval for AUCATZYL for the treatment of patients with r/r B-ALL.

We are now in the process of launching the product in the US.

In addition to the standard sales & marketing elements and medical affairs activities required to successfully commercialize an oncology/hematology product, there are several additional requirements needed for commercializing CAR-T cell therapies.

This required several bespoke elements, including the processes for distribution, patient scheduling, center engagement and service hub to be established.

It is a requirement that the product is administered only by authorized centers that are specialized in hematology and have the necessary infrastructure and capabilities for administering CAR-T therapies.

We achieved our target 33 centers fully authorized to deliver AUCATZYL by end of January 2025, covering 60% of the accessible patient population, and this number of centers will steadily increase with the expectation it will be over 50 centers by mid-2025.

We expect to complete authorization of 60 treatment centers, covering approximately 90% of the target patient population, by the end of 2025.

In December 2024, the National Comprehensive Cancer Network®, or NCCN, added AUCATZYL to its Clinical Practice Guidelines in Oncology, or NCCN Guidelines®, for the treatment of adult r/r B-ALL.

The NCCN is a not-for-profit alliance of 30 leading cancer centers devoted to patient care, research, and education.

The NCCN Guidelines are a comprehensive set of guidelines detailing the sequential management decisions and interventions that currently apply to 97% of cancers affecting patients in the U.S and are intended to ensure that all patients receive preventive, diagnostic, treatment, and supportive services that reflect the latest evidence in oncological patient care.

We have retained worldwide commercial rights for AUCATZYL.

We plan to expand our global commercialization capabilities over time such that we are able to commercialize any product candidate in a broader number of countries over time, but with a focus on achieving an early presence in the U.S., U.K.

and parts of Europe, i.e.

countries where we expect to obtain a regulatory approval.

We may pursue strategic collaborations with third parties in order to maximize the commercial potential of AUCATZYL.

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.

We generally expect to launch any of our products that receive regulatory approval in the United States first, followed by the U.K., EU and subsequently in other major markets.

The product option for AUTO1/22 was not exercised and has expired as of February 8, 2025.

See “Risk Factors–Risks Related to our Intellectual Property–Third parties may initiate legal proceedings alleging that we are infringing their intellectual property rights, the outcome of which would be uncertain and could significantly harm our business.”

Our Manufacturing and Logistics Capabilities

We are devoting significant resources to process development and manufacturing in order to optimize the safety and efficacy of AUCATZYL, to ensure high quality and reliable product supply to patients, as well as to reduce our per unit manufacturing costs and time to market for AUCATZYL and any of our programmed T cell product candidates for which we obtain regulatory approval.

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 our 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.

We have established a manufacturing process that is scalable and serves as a manufacturing platform designed to support rapid development of our programmed T cell therapy product candidates through clinical trial phases and regulatory approval processes.

We are using a semi-automated, fully enclosed system for cell manufacturing, which is designed to provide a common platform suitable for manufacturing all of our product candidates.

This platform allows for parallel processing having the ability to scale for commercial supply in a controlled environment at an economical cost.

We have established reliable and consistent viral vector production and viral transduction processes further, also a key to our process reproducibility and reliability.

Our manufacturing and logistics process is designed to ensure that product integrity is maintained during shipment along with accurate tracking and tracing of shipments.

We are expanding internal manufacturing and supply capabilities as well as the use of expert service providers on maturing our vein-to-vein logistics and our gradual capacity expansion in 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.

Our manufacturing and commercialization strategy requires a fully integrated vein-to-vein product delivery cycle.

We believe having established manufacturing processes suitable for commercialization early in the development of AUCATZYL will allow us to focus on expanding manufacturing capacity during our early commercial launch needs.

Over time, we expect to establish regional manufacturing hubs to meet projected near-, mid- and long-term commercial product requirements for commercialization.

Our first purpose-built facility, the Nucleus, is located in Stevenage, U.K..

This facility, which has a global reach, can meet our near and mid-term clinical and commercial needs allowing ample time for expanding our manufacturing footprint.

Our plan is to establish our manufacturing infrastructure in a manner that would minimize logistical complexities and costs for all regions going forward.

The licensure and commercial supply of our cell products will be from our 70,000 square foot facility called the Nucleus, in Stevenage, United Kingdom.

We believe this facility, which has a global reach, can meet our near and mid-term clinical and commercial needs allowing ample time for expanding our manufacturing footprint.

In March 2024, following the most recent GMP inspection by the MHRA in February 2024, the Nucleus facility obtained a Manufacturer’s Importation Authorization (MIA) together with the accompanying GMP certificate.

These licenses enable us to manufacture both commercial and clinical autologous drug products in the facility.

The Nucleus provides multiple clean rooms, QC labs, warehouse and administrative space and is being fitted out in a phased manner as demand requires.

At full capacity, we expect the Nucleus facility to provide manufacturing capacity for approximately 2,000 batches annually, Additional fallow space for the expansion of manufacturing capacity is available if required.

Our plan is to establish our manufacturing infrastructure in a manner that would minimize logistical complexities and costs for all regions going forward.

We believe our scalable closed-system manufacturing process, along with our proprietary and modular T cell programming technologies, would be challenging and costly for potential competitors to replicate.

Our Manufacture and Delivery Performance

Data on manufacturing and delivery performance for obe-cel in the FELIX clinical trial were presented at the 2023 ASCO Annual Meeting in June 2023, with updated data presented at the ASH Annual Meeting in December 2023.

The FELIX study successfully demonstrated the robust operability of obe-cel manufacturing, QC and logistics processes, meeting target V2C (time from leukapheresis to quality release) and V2D (time from leukapheresis to delivery of product to the hospital).

Median V2C and V2D times were 21 and 24 days, respectively.

All apheresis starting material was successfully processed despite the multitude of constraints posed by the COVID-19 pandemic.

In total, 96% of manufactured obe-cel batches reached their target dose of 410 x 106 CAR T cells.

Further optimization and improvements made during the study increased reliability, consistency, and precision of the manufacturing process, and supported the development of the Nucleus manufacturing facility with greater production capacity that aims to achieve a ≥95% manufacturing success rate with ≤15-day V2C times.

Manufacturing Agreements with Third Parties

We obtain viral vector for commercial supply of AUCATZYL and for late stage clinical trials from our partner AGC Biologics.

We also have manufacturing agreements with King’s College London for early phase vector manufacturing, and some internal capability to produce vector for early and late-stage trials.

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.

In March 2018, we 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 our programmed T cell therapies, including for commercial production of AUCATZYL as well as for preclinical and clinical use, as well as support services.

The supply agreement sets forth procedures to ensure continuity of supply to us of Miltenyi’s products, both during the clinical phase and any future commercial phase of our product candidates.

After the initial ten-year term of the agreement, we have two separate options to renew the agreement, each for an additional five-year term.

The supply agreement contains customary termination provisions, allowing for termination by a party upon the other party’s uncured material breach, upon the other party’s bankruptcy or insolvency or upon the other party being subject to an extended period of force majeure events.

We may also terminate the supply agreement upon advance written notice, if we decide to suspend or discontinue the development or commercialization of our product candidates.

The supply agreement is governed under the laws of Germany.

There are two direct in class competitors to AUCATZYL approved for the treatment of adult patients with r/r B-ALL:

the autologous CAR therapies Tecartus and Kymriah.

Tecartus is approved for use in adult B-ALL and Kymriah is approved for use in adolescents and young adults, (i.e., patients up to the age of 25).

We believe obe-cel has a differentiated safety profile and shows potential for longer term outcomes when compared to these current approved therapies.

In addition, it is possible that companies could take other autologous CAR T cell products forward in adult ALL or allogeneic “off-the-shelf” CAR T cell therapies could be developed which would be considered direct competitors.

Allogeneic products are in early development in indications other than B-ALL, and, because these products are not made from the patient's own cells, they might be more convenient to deliver, without the need to wait for a product to be manufactured (typical manufacturing times for autologous products are currently 18-25 days).

However, this class of product has not shown the same levels of durable activity and the products in clinical trials are therefore likely to require periodic repeat dosing as opposed to autologous products, which allow for the therapy to be given as a one-time treatment.

Our Product Candidates for the Treatment of Hematological Cancers and Autoimmune Diseases

Our clinical-stage product candidates targeting hematological cancers are obe-cel, AUTO1/22, AUTO4 and AUTO8.

We have 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 for the Treatment of Pediatric ALL, B-NHL and other B-cell malignancies

Background of Pediatric ALL

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In adult ALL, however, one of the major challenges has been severe toxicity, including death due to CAR T cell-mediated toxicity observed in the clinical trials of these products.

Obe-cel has been designed to reduce toxicity but still sustain durable CRs, and we believe it has the potential to become a standalone therapy for adult ALL.

Obe-cel has been designed to reduce toxicity but still sustain durable CRs.

Obe-cel Phase 1 Clinical Trial in Pediatric ALL

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Median follow-up for patients in cohort 2 was seven months.

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None of the patients experienced Grade 3 or higher CRS and one patient out of 21 patients (5%) experienced Grade 4 neurotoxicity, which was deemed more consistent with fludarabine than CAR-associated neurotoxicity.

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In CLL, four of the five treated patients achieved undetectable minimal residual disease ( “ uMRD ” ) in the bone marrow, with all ongoing at the last follow-up date.

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.

We continue to evaluate obe-cel's potential to address current unmet medical needs in these indications.

UCL has also initiated a Phase 1 exploratory trial (CAROUSEL) of obe-cel in patients with relapsed or refractory PCNSL .

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We expect 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

Obe-cel for Lupus and Other Autoimmune Diseases

In addition to advancing AUCATZYL/obe-cel for oncology indications, we are advancing obe-cel for the treatment of Lupus and other autoimmune diseases.

We have initiated the Phase 1 CARLYSLE trial to determine the safety, tolerability, and preliminary efficacy of obe-cel in patients with severe, refractory systemic lupus erythematosus.

Background of SLE

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The disease onset is generally between the ages of 20 and 40, and it affects predominantly young women.

The prevalent population of SLE patients in the United States, United Kingdom, Germany, France Spain, Italy and Japan is approximately 550,000 patients ~60% (330,000 patients) with moderate to severe disease.

The estimated prevalent population of SLE patients in the United States, United Kingdom, Germany, France Spain, Italy and Japan is approximately 550,000 patients ~60% (330,000 patients) with moderate to severe disease.

~15% will be refractory to standard therapies;

potentially addressable by CAR T therapy.

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Currently available treatments are not curative and are associated with certain safety concerns.

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Another strategy to induce deeper depletion of the B cell compartment originates from the highly effective treatment of patients with B cell malignancies using CD19 CAR T cells.

A clinical study by Mackensen and colleagues showed a deep depletion of CD19+ B cells and plasma blasts in SLE-affected tissues could trigger an immune reset that could allow the cessation of immunosuppressive treatment in patients with SLE.

A clinical study by Mackensen and colleagues published in 2023 showed a deep depletion of CD19+ B cells and plasma blasts in SLE-affected tissues could trigger an immune reset that could allow the cessation of immunosuppressive treatment in patients with SLE.

In this study, autologous T cells from 8 patients with SLE were transduced with a lentiviral anti-CD19 CAR vector, expanded and reinfused at a dose of 1×10x6 CAR T cells per kg body weight into the patients after lymphodepletion with fludarabine and cyclophosphamide.

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Remission of SLE according to standard criteria was achieved in all patients after 3 months, and drug-free remission was maintained during longer follow-up after CAR T cell administration.

Based on the important role of B cells in the SLE disease pathogenesis and the preliminary evidence of safety and activity of CD19 CAR T cell therapy in this disease, it is hypothesized that treatment with a single infusion of obe-cel may have the potential to eliminate the malfunctioning autoreactive B cells and ameliorate disease in SLE patients in a similar fashion.

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 10 6 CD19 CAR-positive T cells.

Based on the important role of B cells in the SLE disease pathogenesis and the preliminary evidence of safety and activity of CD19 CAR T cell therapy in this disease, we have hypothesized that treatment with a single infusion of obe-cel may have the potential to eliminate the malfunctioning autoreactive B cells and ameliorate disease in SLE patients in a similar fashion.

We believe obe-cel's potential advantages over other autoimmune therapies that are approved or in development include its differentiated mechanism of action via its fast-off rate CD19 binder, the existing clinical data and approval in r/r B-ALL and our established manufacturing and commercial capabilities.

In particular, the favorable safety profile, with low rates of high-grade CRS and ICANS in the cancer setting, have the potential to drive acceptability of a cell therapy approach in the rheumatology setting.

Additionally, the fast-off rate kinetics observed with obe-cel in the cancer setting show increased T-cell engraftment and profound B-cell depletion.

These properties have the potential to drive a deeper cut into CD19+ B cells and plasma blasts in SLE-affected tissues, and could potentially trigger an immune reset in patients.

Obe-cel is the only autologous CD19 CAR T-cell therapy being developed for lupus with an approval in another indication.

We expect that data supporting the safety and manufacture of obe-cel in r/r B-ALL could potentially be useful to support the development of obe-cel in autoimmune indications.

Finally, our established commercial systems and manufacturing infrastructure for AUCATZYL/obe-cel could be leveraged to support an autoimmune indication.

Clinical Development in SLE, LN and other Autoimmune Diseases

The CARLYSLE trial is a single-arm, open-label, Phase 1 trial to determine the safety, tolerability, and preliminary efficacy of obe-cel in patients with severe, refractory SLE.

The primary goal of this trial is to confirm the fixed dose of obe-cel in adult SLE patients.

Six patients received 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, we would plan to initiate further studies in SLE and LN.

The first CARLYSLE trial was initiated in early 2024 and we completed patient doing in early 2025.

We expect to provide initial data at our R&D Investor Event in April 2025 and follow up presentation of full data at a medical conference in the second half of 2025.

Depending on the outcome of the dose confirmation study in SLE, we 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, we would plan to investigate obe-cel in additional autoimmune disease indications.

Depending on the outcome of the dose confirmation study in SLE, we would plan to investigate obe-cel in additional autoimmune disease indications.

AUTO1/22 Our Programmed T Cell Therapy for the Treatment of ALL, other B-cell malignancies

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Antigen negative relapse is a common cause of relapse in patients with pediatric ALL.

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AUTO1/22 Phase 1 Clinical Trial in Pediatric ALL (CARPALL Trial)

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Six and 12-month event free survival (EFS) were 75% and 60% respectively .

This study is no longer enrolling patients.

Our T Cell Lymphoma Program

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A large proportion of T cell lymphoma patients are refractory to or relapse following treatment with standard therapies and there remains a need to develop an effective therapy for this currently unmet medical need.

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Unlike B cell lymphomas, T cell lymphomas have not benefited from advances in immunotherapeutic approaches.

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In the fourth quarter of 2018, we 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.

We refer to this trial as the LibrA-T1 trial, which was initiated at sites in the UK and Spain in 2018 and 2020 respectively.

We refer to this trial as the LibrA-T1 trial, which was initiated at sites in the U.K.

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.

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Efficacy data from Process B was not provided given median follow up is <3 months.

This study is no longer enrolling patients.

Our Multiple Myeloma Program

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Patients with relapsed or refractory disease typically have a poor prognosis.

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Recently approved therapeutic approaches include products that target BCMA on multiple myeloma cells, including redirected T cell therapies such as T cell engagers and CAR T cell therapies.

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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 we 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.

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Three of these six patients demonstrated evidence of transient CAR T cell activity, including CRS, and regression of soft tissue and BM disease activity.

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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.

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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.

We presented new preclinical data for AUTO6NG in June 2020 at the AACR Virtual Annual Meeting 2020.

We presented new preclinical data for AUTO6NG in June 2020 at the American Association for Cancer Research (“AACR ” ) Virtual Annual Meeting 2020.

GD2 was evaluated as a therapeutic CAR T target antigen in SCLC.

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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

We are devoting significant resources to process development and manufacturing in order to optimize the safety and efficacy of our product candidates, to ensure high quality and reliable product supply to patients, as well as to reduce our per unit manufacturing costs and time to market if we obtain regulatory approval for any of our programmed T cell product candidates.

Commercial success in T cell therapies requires a manufacturing process that is reliable, scalable and economical.

We are using a semi-automated, fully enclosed system for cell manufacturing, which is designed to provide a common platform suitable for manufacturing all of our product candidates.

This platform allows for parallel processing having the ability to scale for commercial supply in a controlled environment at an economical cost.

We have established reliable and consistent viral vector production and viral transduction processes further, also a key to our process reproducibility and reliability.

Our manufacturing and logistics process is designed to ensure that product integrity is maintained during shipment along with accurate tracking and tracing of shipments.

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.

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Our manufacturing and commercialization strategy requires a fully integrated vein-to-vein product delivery cycle.

We believe having established manufacturing processes suitable for commercialization early in the development of our T cell therapies will allow us to focus on expanding manufacturing capacity during our clinical trials and early commercial launch needs.

Over time, we expect to establish regional manufacturing hubs to meet projected near-, mid- and long-term commercial product requirements for commercialization.

Our first purpose-built facility is located in Stevenage, UK.

This facility, which has a global reach, can meet our near and mid-term clinical and commercial needs allowing ample time for expanding our manufacturing footprint.

Our plan is to establish our manufacturing infrastructure in a manner that would minimize logistical complexities and costs for all regions going forward.

Manufacturing Agreements

We have 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, we have 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.

For clinical trial supply, we have established our initial cell and vector manufacturing capacity at the Cell and Gene Therapy Catapult in Stevenage, UK.

We have 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, we 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 our 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 us of Miltenyi’s products, both during the clinical phase and any future commercial phase of our product candidates.

After the initial ten-year term of the agreement, we have two separate options to renew the agreement, each for an additional five-year term.

We may also terminate the supply agreement upon advance written notice, if we decide to suspend or discontinue the development or commercialization of our product candidates.

The supply agreement is governed under the laws of Germany.

Manufacturing Facilities

The licensure and commercial supply of our cell products will be from a new 70,000 square foot facility called the Nucleus.

These licenses enable us to manufacture both commercial and clinical autologous drug products in the facility.

The Nucleus provides multiple clean rooms, QC labs, warehouse and administrative space and is being fitted out in a phased manner as demand requires.

Manufacture and Delivery Performance

Median V2C and V2D times were 21 and 24 days, respectively.

All apheresis starting material was successfully processed despite the multitude of constraints posed by the COVID-19 pandemic.

In total, 96% of manufactured obe-cel batches reached their target dose of 410 x 10 6 CAR T cells.

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Commercialization

Based on the U.S.

FDA acceptance of the BLA for obe-cel for patients with r/r Adult B-ALL, we are in the process of establishing our 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.

This study is currently enrolling patients

Commercialization and Manufacturing Plans for our Clinical-Stage Programs

We are developing our 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.

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By focusing on these centers, we can begin to build our commercialization capabilities with limited resources.

We have retained worldwide commercial rights for certain of our product candidates.

We currently plan to build our global commercialization capabilities internally over time such that we are able to commercialize any product candidate for which we may obtain regulatory approval.

We are also planning to advance obe-cel in autoimmune indications, and plan to leverage our established clinical and commercial manufacturing infrastructure, including our purpose-built manufacturing facility, the Nucleus.

We have retained worldwide commercial rights for our product candidates.

and parts of Europe, i.e.

countries where we expect to obtain a regulatory approval.

We may pursue strategic collaborations with third parties in order to maximize the commercial potential of our 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.

We generally expect to launch any of our products that receive regulatory approval in the United States first, followed by the EU and subsequently in other major markets.

We generally expect to launch any of our products that receive regulatory approval in the United States first, followed by the U.K., EU and subsequently in other major markets.

The product option for AUTO1/22 was not exercised as of February 8, 2025 and has expired.

In addition to the Nucleus, we maintain separate manufacturing capabilities for clinical-stage programs separate to The Nucleus (which is used exclusively for commercial manufacturing of AUCATZYL) to support further clinical trials of obe-cel in autoimmune conditions and potentially future hematological indications.

For clinical trial supply, we have established our internal cell and vector manufacturing capacity at the Cell and Gene Therapy Catapult in Stevenage, United Kingdom.

We have a cell manufacturing suite capable of supporting clinical supply operations.

Our early-stage programs such as AUTO1/22 and AUTO6NG are manufactured in collaboration with the UCL study teams.

However, phase-appropriate Process Development activities have been initiated within our laboratories in order to leverage our existing manufacturing capabilities for progression to a late-stage clinical program.

Intellectual Property

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A portion of our patent portfolio is directed to certain current product candidates or technologies deployed in certain product candidates, and the remainder of the portfolio is directed to alternative approaches, technologies or modules that are not currently deployed in our current product candidates.

As of December 31, 2023, our patent portfolio is comprised 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 we own and have originated from our own research.

As of December 31, 2024, our patent portfolio is comprised of 83 patent families, of which 17 patent families originated from UCLB, the technology-transfer company of UCL and 63 patent families we own and have originated from our own research.

Of the 17 live patent families that were originally in-licensed from UCL, 16 have been assigned to us.

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To support this effort, we have 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 we expect that our ongoing research and development activities will yield additional patentable inventions and patent applications that will expand our intellectual property portfolio.

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The term of individual patents depends upon the legal term of the patents in the countries in which they are obtained.

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To the extent that our consultants, contractors or collaborators use intellectual property owned by others in their work for us, disputes may arise as to the rights in related or resulting know-how and inventions.

We also protect our brand via the use of trademarks.

As of December 31, 2024, our trademark portfolio consists of 5 trademark families covering our core brand and product.

These families include protection in commercially relevant jurisdictions, including the U.S.

We have established internal guidelines for the use of our brands and monitor for the registration of similar marks by third parties.

Our License and Option Agreement with BioNTech SE

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This maximum amount includes the potential milestone payments for the Binder Licensed Products described below, all option exercise fees and potential milestone payments for licenses to optioned products and technologies, and additional payments that BioNTech may pay to us for an increased revenue interest with respect to obe-cel as described below.

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License and Options

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• an option to obtain exclusive rights to co-fund development costs of our development-stage programs AUTO1/22 and AUTO6NG, in return for agreed upon economic terms, including an option exercise fee, milestone payments and a profit-sharing arrangement for each such product candidate, with additional options to co-promote or co-commercialize such product candidate.

The product option for AUTO1/22 was not exercised and has expired as of February 8, 2025 ;

• an option to obtain an exclusive worldwide license to exploit products that express certain additional binders in vivo or, with respect to certain binders, in an antibody drug conjugate (“Binder Option”);

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Obe-cel Product Revenue Interest

Under the BioNTech License Agreement, BioNTech has also agreed to financially support the expansion of the clinical development program for, and planned commercialization of, obe-cel.

Under the BioNTech License Agreement, BioNTech has also agreed to financially support the expansion of the clinical development program and planned commercialization of, obe-cel.

In exchange for the grant of rights to future revenues from the sales of obe-cel, BioNTech has made an upfront payment to us of $40 million (representing the remainder of the $50 million total upfront payment).

We will pay BioNTech a low single-digit percentage of annual net sales of obe-cel, which may be increased up to a mid-single digit percentage in exchange for milestone payments of up to $100 million in the aggregate on achievement of certain regulatory events for specific new indications upon BioNTech's election.

We will pay BioNTech a low single-digit percentage of annual net sales of obe-cel, including revenues from sales of AUCATZYL, which may be increased up to a mid-single digit percentage in exchange for milestone payments of up to $100 million in the aggregate on achievement of certain regulatory events for specific new indications upon BioNTech's election.

We expect to make initial payments of the revenue interest to BioNTech in 2025.

Manufacturing and Commercial Agreement

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BioNTech may terminate the agreement, in whole or in part, for any or no reason upon a specified period of prior written notice.

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Our License Agreement with UCL Business Ltd.

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On a per-product basis, these milestone payments range from £1 million to £18.5 million, depending on which T cell programming modules are used in the product achieving the milestone.

On November 8, 2024 we were notified by the FDA that our obe-cel BLA was approved, allowing for the marketing of AUCATZYL in the US for the treatment of adult patients (18 years and older) with r/r B-ALL.

Consequently, we paid a regulatory milestone payment of £10.0 million to UCLB.

Under the terms of the license, we have the right to grant sub-licenses to third parties, subject to certain restrictions.

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Failure to achieve diligence obligations may result in loss of exclusivity or termination of the license on a program-by-program basis.

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The UCLB Agreement expires on a product-by-product and country-by-country basis upon the expiration of the royalty term with respect to each product in each country.

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Patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse

Adult patients with relapsed or refractory (r/r) LBCL after two or more lines of systemic therapy, including DLBCL

Adult patients with LBCL after two or more lines of systemic therapy, including DLBCL

Adult patients with relapsed or refractory FL after two or more lines of systemic therapy.

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Adult patients with relapsed or refractory MCL.

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Four of these products, Tecartus and Yescarta from Kite/Gilead, Kymriah from Novartis and Breyanzi from BMS are anti-CD19 CAR T cell therapies, the same class as obe-cel.

However, only Tecartus is approved for use in adult ALL.

However, only Tecartus is approved for use in adult ALL with Kymriah also being an option for adolescents and young adults, (i.e., patients up to the age of 25 years old).

We believe there will be a market for obe-cel in this indication due to its differentiated safety profile when compared to current approved therapies.

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The process for obtaining regulatory marketing approvals and the subsequent compliance with applicable federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial resources.

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Government Regulation

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• FDA acceptance, review and approval, of the BLA, which might include review by an advisory committee, a panel typically consisting of independent clinicians and other experts who provide recommendations as to whether the application should be approved and under what conditions.

Before testing any biological product candidate, including our product candidates, in humans, the product candidate must undergo rigorous the preclinical testing.

Before testing any biological product candidate, including our product candidates, in humans, the product candidate must undergo rigorous preclinical testing.

Preclinical tests, also referred to as nonclinical studies, include laboratory evaluations as well as in vitro and animal studies to assess the potential safety and efficacy of the product candidate.

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Accordingly, we cannot be sure that submission of an IND will result in the FDA allowing clinical trials to begin, or that, once begun, issues will not arise that suspend or terminate such trials.

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Further, each clinical trial must be reviewed and approved by an independent institutional review board (“IRB”), at or servicing each institution at which the clinical trial will be conducted.

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Because this is a relatively new and expanding area of novel therapeutic interventions, there can be no assurance as to the length of the trial period, the number of patients the FDA will require to be enrolled in the trials in order to establish the safety, efficacy, purity and potency of immunotherapy products, or that the data generated in these trials will be acceptable to the FDA to support marketing approval.

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Concurrently with clinical trials, companies usually complete additional nonclinical studies and must also develop additional information about the physical characteristics of the biological product as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.

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To assure cGMP, GTP and GCP compliance, an applicant must incur significant expenditure of time, money and effort in the areas of training, recordkeeping, production, and quality control.

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Notwithstanding the submission of relevant data and information, the FDA may ultimately decide that the BLA does not satisfy its regulatory criteria for approval and deny approval.

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Also, new government requirements, including those resulting from new legislation, may be established, or the FDA’s policies may change, which could delay or prevent regulatory approval of our products under development.

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Marketing Exclusivity

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In the United States and markets in other countries, sales of any products for which we receive regulatory approval for commercial sale will depend, in significant part, on the extent to which third-party payors provide coverage, and establish adequate reimbursement levels for such products.

In the United States, third-party payers include federal and state healthcare programs, private managed care organizations, health insurers and other organizations.

The process for determining whether a third-party payer will provide coverage for a product may be separate from the process of establishing the reimbursement rate that such a payor will pay for the product.

In the United States, third-party payors include federal and state healthcare programs, private managed care organizations, health insurers and other organizations.

The process for determining whether a third-party payor will provide coverage for a product may be separate from the process of establishing the reimbursement rate that such a payor will pay for the product.

Third-party payors may limit coverage to specific products on an approved list, also known as a formulary, which might not include all of the FDA-approved products for a particular indication.

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In addition, in some countries, cross-border imports from low-priced markets exert a commercial pressure on pricing within a country.

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The downward pressure on healthcare costs in general, particularly prescription drugs and biologics, has become very intense.

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federal Anti-Kickback Statute, the ACA amended the intent standard for certain healthcare fraud under HIPAA such that a person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

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HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act (“HITECH”), and their implementing regulations, impose certain requirements on “covered entities,” including certain healthcare providers, health plans and healthcare clearinghouses, as well as their respective “business associates” that create, receive, maintain or transmit individually identifiable health information for or on behalf of a covered entity, and their covered subcontractors, relating to the privacy, security, transmission and breach of individually identifiable health information.

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Additionally, the federal Physician Payments Sunshine Act, created under the ACA, and its implementing regulations, require certain manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) to annually report to the Centers for Medicare and Medicaid Services (“CMS”), information related to certain payments or other transfers of value provided to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), certain other healthcare providers (such as physicians assistants and nurse practitioners) and teaching hospitals, or to entities or individuals at the request of, or designated on behalf of, the physicians and teaching hospitals as well as certain ownership and investment interests held by physicians and their immediate family members.

Additionally, similar healthcare laws and regulations in the European Union and other jurisdictions, including reporting requirements detailing interactions with and payments to healthcare providers and laws governing the data privacy and security of certain protected information, such as the EU GDPR and the UK GDPR, which imposes obligations and restrictions on the collection and use of personal data relating to individuals located in the European Union and the United Kingdom (including health data).

GDPR, which imposes obligations and restrictions on the collection and use of personal data relating to individuals located in the European Union and the United Kingdom (including health data).

Finally, the majority of states also have statutes or regulations similar to the aforementioned federal laws, some of which are broader in scope and apply to items and services reimbursed under Medicaid and other state programs, or, in several states, apply regardless of the payor.

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Over the last several years, there have been federal and state proposals and legislation enacted regarding the pricing of pharmaceutical and biopharmaceutical products, limiting coverage and reimbursement for drugs and other medical products, and making changes to healthcare financing and the delivery of care in the United States.

Recently, there have been a number of health reform measures by the Biden administration that we expect will have a significant impact on the pharmaceutical industry.

In July 2021, the Biden administration released an executive order, “Promoting Competition in the American Economy,” with multiple provisions aimed at prescription drugs.

In response to Biden’s executive order, on September 9, 2021, U.S.

Department of Health and Human Services (“HHS”), released a Comprehensive Plan for Addressing High Drug Prices that outlines principles for drug pricing reform and sets out a variety of potential legislative policies that Congress could pursue to advance these principles.

Further, on August 16, 2022, President Biden signed the Inflation Reduction Act of 2022 (“IRA”), into law, which among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025.

Recently, there have been a number of health reform measures that we expect will have a significant impact on the pharmaceutical industry.

For example, on August 16, 2022, the Inflation Reduction Act of 2022 (“IRA”), was signed into law, which among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025.

The IRA also eliminates the “donut hole” under the Medicare Part D program beginning in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost and creating a new manufacturer discount program.

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In addition, the IRA (i) directs HHS to negotiate the price of certain high-expenditure, single-source drugs and biologics covered under Medicare and (ii) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.

On August 29, 2023, HHS announced the list of the first ten drugs that will be subject to price negotiations, although the Medicare drug price negotiation program is currently subject to legal challenges.

It is currently unclear how the IRA will be implemented but is likely to have a significant impact on the pharmaceutical industry.

In response to the Biden administration’s October 2022 executive order, on February 14, 2023, HHS released a report outlining three new models for testing by the CMS Innovation Center which will be evaluated on their ability to lower the cost of drugs, promote accessibility, and improve quality of care.

It is unclear whether the models will be utilized in any health reform measures in the future.

Further, on December 7, 2023, the Biden administration announced an initiative to control the price of prescription drugs through the use of march-in rights under the Bayh-Dole Act.

In addition, the IRA (i) directs HHS to negotiate the price of certain high-expenditure, single-source biologics that have been on the market for at least 11 years covered under Medicare (the “Medicare Drug Price Negotiation Program”) and (ii) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.

These provisions began to take effect progressively starting in fiscal year 2023.

On August 15, 2024, HHS announced the agreed-upon prices of the first ten drugs that were subject to price negotiations, although the Medicare Drug Price Negotiation Program is currently subject to legal challenges.

On January 17, 2025, HHS selected fifteen additional products covered under Part D for price negotiation in 2025.

Each year thereafter more Part B and Part D products will become subject to the Medicare Drug Price Negotiation Program.

Further, on December 7, 2023, an initiative to control the price of prescription drugs through the use of march-in rights under the Bayh-Dole Act was announced.

On December 8, 2023, the National Institute of Standards and Technology published for comment a Draft Interagency Guidance Framework for Considering the Exercise of March-In Rights which for the first time includes the price of a product as one factor an agency can use when deciding to exercise march-in rights.

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Further, there remains heightened Congressional scrutiny in the United States of pharmaceutical pricing practices designed to, among other things, bring more transparency in product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for products.

At the state level, legislatures have increasingly enacted legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

In addition, regional healthcare authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other healthcare programs.

The current Trump administration is pursuing policies to reduce regulations and expenditures across government including at HHS, the FDA, CMS and related agencies.

These actions, presently directed by executive orders or memoranda from the Office of Management and Budget, may propose policy changes that create additional uncertainty for our business.

These actions may include, for example, directives to reduce agency workforce, rescinding a Biden administration executive order tasking the Center for Medicare and Medicaid Innovation (“CMMI”) to consider new payment and healthcare models to limit drug spending and eliminating the Biden administration’s executive order that directed HHS to establishing an AI task force and developing a strategic plan.

Additionally, in its June 2024 decision in Loper Bright Enterprises v.

Raimondo (“Loper Bright”), the U.S.

Supreme Court overturned the longstanding Chevron doctrine, under which courts were required to give deference to regulatory agencies’ reasonable interpretations of ambiguous federal statutes.

The Loper Bright decision could result in additional legal challenges to current regulations and guidance issued by federal agencies applicable to our operations, including those issued by the FDA.

Congress may introduce and ultimately pass health care related legislation that could impact the drug approval process and make changes to the Medicare Drug Price Negotiation Program created under the IRA.

In addition to the IRA, other federal health reform measures have been proposed and adopted in the United States that could impact cell therapy.

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This “best price” takes into consideration any rebates or concessions manufacturers offer, with some exceptions.

The final rule would exempt value-based or outcomes-based payment arrangements from the definition of “best price” which provides manufacturers more flexibility to work with commercial payers and states on innovate payment mechanisms for high-cost cell and gene therapies.

The final rule exempts value-based or outcomes-based payment arrangements from the definition of “best price” which provides manufacturers more flexibility to work with commercial payors and states on innovate payment mechanisms for high-cost cell and gene therapies.

While Medicaid is not a significant driver of cell therapy sales it is a bellwether program and one we watch closely.

Foreign Corrupt Practice Act, the UK Bribery Act 2010 and Other Anti-corruption Laws

Foreign Corrupt Practice Act, the U.K.

Bribery Act 2010 and Other Anti-corruption and Trade Control Laws

Foreign Corrupt Practice Act, as amended (the “FCPA”) prohibits any U.S.

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Activities that violate the FCPA, even if they occur wholly outside the United States, can result in criminal and civil fines, imprisonment, disgorgement, oversight, and debarment from government contracts.

In addition to the FCPA, other U.S.

laws such as the U.S.

domestic bribery statute and U.S.

Travel Act prohibit the provision of improper payments and benefits to government and private-sector recipients within the United States.

Our operations are also subject to non-U.S.

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Under the UK Bribery Act, we may also be liable for failing to prevent a person associated with us from committing a bribery offense.

We are also subject to other laws and regulations governing our international operations, including regulations administered by the governments of the UK and the United States and authorities in the EU, including applicable export control regulations, economic sanctions and embargoes on certain countries and persons, anti-money laundering laws, import and customs requirements and currency exchange regulations, collectively referred to as trade control laws.

We are also subject to other laws and regulations governing our international operations, including regulations administered by the governments of the U.K.

and the United States and authorities in the EU, including applicable export control regulations, economic sanctions and embargoes on certain countries and persons, anti-money laundering laws, import and customs requirements and currency exchange regulations, collectively referred to as trade control laws.

Failure to comply with the UK Bribery Act, the FCPA and other anti-corruption laws and trade control laws could subject us to criminal and civil penalties, disgorgement and other sanctions and remedial measures, and legal expenses.

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Data Privacy and Security Laws

In the ordinary course of our business, we process personal or sensitive data, including data we collect in connection with our clinical trial activities.

In the ordinary course of our business, we and the third parties with whom we work process personal or sensitive data, including data we collect in connection with our clinical trial activities.

Accordingly, we are subject to certain data privacy and security obligations, including U.S.

and foreign laws, regulations, and rules, contractual obligations, industry standards, policies and other obligations related to data privacy and security.

Such obligations may include, without limitation, the Federal Trade Commission Act, HIPAA, as amended by the HITECH, the EU’s General Data Protection Regulation 2016/679 (“EU GDPR”), the EU GDPR as it forms part of UK law by virtue of section 3 of the EU (Withdrawal) Act 2018 (“UK GDPR”), and the ePrivacy Directive.

In the past few years, several states within the United States—including California, Virginia, Colorado, Connecticut, and Utah—have enacted comprehensive privacy laws that impose certain obligations on covered businesses.

law by virtue of section 3 of the EU (Withdrawal) Act 2018 (“UK GDPR”), and the ePrivacy Directive and local implementations thereof, including the U.K.’s Privacy and Electronic Communications Regulations 2003.

In the past few years, several states within the United States have enacted comprehensive privacy laws that impose certain obligations on covered businesses.

We may in the future become subject to these laws.

Additionally, we are, or may become, subject to various U.S.

Additionally, we are, and may become in the future, subject to various U.S.

federal and state consumer protection laws which require us to publish statements that accurately and fairly describe how we handle personal data and choices individuals may have about the way we handle their personal data.

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mandating notice of certain personal data breaches to the relevant supervisory authority(ies) and affected individuals;

and mandating the appointment of representatives in the UK and/or the EU in certain circumstances.

See the risk factor captioned “We are subject to stringent and evolving U.S.

and mandating the appointment of representatives in the U.K.

and/or the EU in certain circumstances.

See the risk factor captioned “We and the third parties with whom we work are subject to stringent and evolving U.S.

and foreign laws, regulations, and rules, contractual obligations, industry standards, policies and other obligations related to data privacy and security.

Our actual or perceived failure to comply with such obligations could lead to regulatory investigations or actions;

Our (or the third parties with whom we work) actual or perceived failure to comply with such obligations could lead to regulatory investigations or actions;

litigation (including class claims) and mass arbitration demands;

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and other adverse business consequences” In Part I, Item 1A.

of this report for additional information about the laws and regulations to which we may become subject and about the risks to our business associated with such laws and regulations.

of this report for additional information about the laws and regulations to which we are or may become subject and about the risks to our business associated with such laws and regulations.

EU Regulation

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We anticipate that our T cell therapy products will be regulated as ATMPs in the EU.

There is legislation at a EU level relating to the standards of quality and safety for the collection and testing of human blood and blood components for use in cell-based therapies, which could apply to our products.

There is legislation at an EU level relating to the standards of quality and safety for the collection and testing of human blood and blood components for use in cell-based therapies, which could apply to our products.

Additionally, there may be local legislation in various EU Member States, which may be more restrictive than the EU legislation, and we would need to comply with such legislation to the extent it applies.

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Individual EU Member States retain the power to authorize the conduct of clinical trials on their territory.

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The extent to which on-going clinical trials will be governed by the CTR will depend on the duration of the individual clinical trial.

For clinical trials in relation to which an application for approval was made on the basis of the CTD before January 31, 2023, the CTD will continue to apply on a transitional basis until January 31, 2025.

By that date, all ongoing trials will become subject to the provisions of the CTR.

The CTR will apply to clinical trials from an earlier date if the related clinical trial application was made on the basis of the CTR or if the clinical trial has already transitioned to the CTR framework before January 31, 2025.

The CTR foresaw a three-year transition period that ended on January 31, 2025.

Since this date, all new or ongoing trials are subject to the provisions of the CTR.

In all cases, clinical trials must be conducted in accordance with GCP and the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.

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The sponsor must take out a clinical trial insurance policy, and in most EU countries, the sponsor is liable to provide “no fault” compensation to any study subject injured in the clinical trial.

During the development of a medicinal product, the EMA and national medicines regulators within the EU provide the opportunity for dialogue and guidance on the development program.

During the development of a medicinal product, the EMA and national competent authorities of EU Member States provide the opportunity for dialogue and guidance on the development program.

At the EU level, developers of medicinal products can ask the EMA for scientific advice and protocol assistance at any stage of development and regardless of whether the medicinal product is eligible for the centralized authorization procedure or not.

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Marketing Authorizations

In order to market a new medicinal product in the EU, a company must submit and obtain approval from regulators of a marketing authorization application (“MAA”).

The process for doing this depends, among other things, on the nature of the medicinal product.

The centralized procedure results in a single marketing authorization (“MA”), granted by the European Commission that is valid throughout the EEA (i.e., the EU as well as Iceland, Liechtenstein and Norway).

The centralized procedure is compulsory for human drugs that are:

(i) derived from biotechnology processes, such as genetic engineering, (ii) contain a new active substance indicated for the treatment of certain diseases, such as HIV/AIDS, cancer, diabetes, neurodegenerative diseases, autoimmune and other immune dysfunctions and viral diseases, (iii) products designated as orphan medicinal products and (iv) advanced-therapy medicines (“ATMPs”), such as gene therapy, somatic cell therapy or tissue-engineered medicines.

In the EU, medicinal products can only be commercialized after a related marketing authorization (“MA”), has been granted.

To obtain an MA for a product in the EU, an applicant must submit a Marketing Authorization Application (“MAA”), either under a centralized procedure administered by the European Medicines Agency (“EMA”), or one of the procedures administered by the competent authorities of EU Member States (decentralized procedure, national procedure or mutual recognition procedure).

A MA may be granted only to an applicant established in the EU.

The centralized procedure provides for the grant of a single MA by the European Commission that is valid throughout the EEA (which is comprised of the 27 EU Member States plus Iceland, Liechtenstein and Norway).

Pursuant to Regulation (EC) No 726/2004, the centralized procedure is compulsory for specific products, including for (i) medicinal products derived from biotechnological processes, (ii) products designated as orphan medicinal products, (iii) advanced therapy medicinal products (“ATMPs”), and (iv) products with a new active substance indicated for the treatment of HIV/AIDS, cancer, neurodegenerative diseases, diabetes, auto-immune and other immune dysfunctions and viral diseases.

For products with a new active substance indicated for the treatment of other diseases and products that are highly innovative or for which a centralized process is in the interest of patients, authorization through the centralized procedure is optional on related approval.

Therefore, the centralized procedure would be mandatory for the products we are developing.

As a result, the information in this section focuses solely on this procedure.

Under the centralized procedure in the EU, the EMA’s Committee for Medicinal Products for Human Use (“CHMP”) conducts the initial assessment of a product.

Under the centralized procedure, the EMA’s Committee for Medicinal Products for Human Use (“CHMP”), conducts the initial assessment of a product.

The CHMP is also responsible for several post-authorization and maintenance activities, such as the assessment of modifications or extensions to an existing MA.

The maximum timeframe for the evaluation of an MAA under the centralized procedure is 210 days.

This excludes so-called clock stops, during which additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP.

At the end of the review period, the CHMP provides an opinion to the European Commission.

If this opinion is favorable, the European Commission may then adopt a decision to grant an MA.

Accelerated assessment may be granted by the CHMP in exceptional cases, when a medicinal product targeting an unmet medical need is expected to be of major interest from the point of view of public health and, in particular, from the viewpoint of therapeutic innovation.

If the CHMP accepts a request for accelerated assessment, the time limit of 210 days will be reduced to 150 days (excluding clock stops).

The CHMP can, however, revert to the standard time limit for the centralized procedure if it considers that it is no longer appropriate to conduct an accelerated assessment.

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An MA has, in principle, an initial validity of five years.

The maximum timeframe for the evaluation of a MAA under the centralized procedure is 210 days, excluding clock stops when additional information or written or oral explanation is to be provided by the applicant in response to questions of the CHMP.

A MA has, in principle, an initial validity of five years.

The MA may be renewed after five years on the basis of a re-evaluation of the risk-benefit balance by the EMA or by the competent authority of the EU Member State in which the original MA was granted.

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However, if the conditions are not fulfilled within the timeframe set by the EMA and approved by the European Commission, the MA will cease to be renewed.

The European Commission may grant an MA “under exceptional circumstances”.

Such authorization is intended for products for which the applicant can demonstrate that it is unable to provide comprehensive data on the efficacy and safety under normal conditions of use even after the product has been authorized and subject to specific procedures being introduced.

This may be because the indications for which the product in question is intended are encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence, or in the present state of scientific knowledge, comprehensive information cannot be provided, or it would be contrary to generally accepted principles of medical ethics to collect such information.

Like a conditional MA, an MA granted under exceptional circumstances is reserved to medicinal products intended to be authorized for treatment of rare diseases or unmet medical needs for which the applicant does not hold a complete data set that is required for the grant of a standard MA.

A MA may also be granted “under exceptional circumstances” where the applicant can show that it is unable to provide comprehensive data on efficacy and safety under normal conditions of use even after the product has been authorized and subject to specific procedures being introduced.

These circumstances may arise in particular when the intended indications are very rare and, in the state of scientific knowledge at that time, it is not possible to provide comprehensive information, or when generating data may be contrary to generally accepted ethical principles.

Like a conditional MA, a MA granted under exceptional circumstances is reserved to medicinal products intended to be authorized for treatment of rare diseases or unmet medical needs for which the applicant does not hold a complete data set that is required for the grant of a standard MA.

However, unlike the conditional MA, an applicant for authorization in exceptional circumstances is not subsequently required to provide the missing data.

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Advanced Therapy Medicinal Products

ATMPs include gene therapy products as well as somatic cell therapy products and tissue engineered products.

Advanced Therapy Medicinal Products, or ATMPs, include gene therapy products as well as somatic cell therapy products and tissue engineered products.

The grant of marketing authorization in the EU for products containing viable human tissues or cells such as gene therapy medicinal products is governed by Regulation (EC) No.

1394/2007 on ATMPs, read in combination with Directive (EC) No.

2001/83 of the European Parliament and of the Council.

2001/83 of the European Parliament and of the Council, commonly known as the Community code on medicinal products.

Regulation (EC) No.

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Manufacturers of advanced therapy medicinal products must demonstrate the quality, safety and efficacy of their products to the EMA which is required to provide an opinion regarding the application for marketing authorization.

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The European Commission grants or refuses marketing authorization in light of the opinion delivered by the EMA.

The Committee for Advanced Therapies (“CAT”) is responsible in conjunction with the CHMP for the evaluation of ATMPs.

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Although these guidelines are not legally binding, we believe that our compliance with them is likely necessary to gain and maintain approval for any of our product candidates.

Cell-based products must also comply with Directive (EC) No.

2004/23 of the European Parliament and of the Council of March 31, 2004 on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells (the “Tissues and Cells Directive”), as well as its technical implementing directives.

The Tissues and Cells Directive describes the conditions and quality requirements which must be applied when sourcing the cells intended for manufacturing of the cell-based medicinal product.

The EU Member States have transposed the Tissues and Cells Directive into their national laws.

However, various interpretations of the Tissue and Cells Directive have occurred and are reflected in individual EU Member States national implementing legislation which have led to diverging approaches.

Products made from substances of human origin must also comply with Regulation (EU) 2024/1938 on standards of quality and safety for substances of human origin intended for human application.

This Regulation describes the conditions and quality requirements which must be applied when sourcing the substances of human origin intended for manufacturing of such medicinal products and removed divergences between EU Member States that were present under the (now repealed) Directive (EC) No.

Data Exclusivity

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Pediatric Development

In the EU, companies developing a new medicinal product must agree to a Pediatric Investigation Plan (“PIP”), with the EMA’s Pediatric Committee (“PDCO”) during drug development and, at the latest, before submission of an MA, and must conduct pediatric clinical trials in accordance with that PIP, unless a deferral or waiver applies (e.g., because the relevant disease or condition occurs only in adults).

The MAA for the product must include the results of pediatric clinical trials conducted in accordance with the PIP, unless a waiver applies, or a full or partial deferral has been granted.

In the EU, Regulation (EC) No 1901/2006 provides that all MAAs for new medicinal products have to include the results of trials conducted in the pediatric population, in compliance with a pediatric investigation plan (“PIP”), agreed with the EMA’s Pediatric Committee (“PDCO”).

The PIP sets out the timing and measures proposed to generate data to support a pediatric indication of the medicinal product for which MA is being sought.

The PDCO can grant a deferral of the obligation to implement some or all of the measures provided in the PIP until there are sufficient data to demonstrate the efficacy and safety of the product in adults.

Further, the obligation to provide pediatric clinical trial data can be waived by the PDCO when these data are not needed or appropriate because the product is likely to be ineffective or unsafe in children, the disease or condition for which the product is intended occurs only in adult populations, or when the product does not represent a significant therapeutic benefit over existing treatments for pediatric patients.

Products that are granted an MA on the basis of the pediatric clinical trials conducted in accordance with the PIP are eligible for a six-month extension of the protection under a supplementary protection certificate (if any is in effect at the time of approval) or, in the case of orphan medicinal products, a two-year extension of the orphan market exclusivity.

This pediatric reward is subject to specific conditions and is not automatically available when data in compliance with the PIP are developed and submitted.

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Once the MA is obtained in all EU Member States and study results are included in the product information, even when negative, the product is eligible for a six-month extension to the Supplementary Protection Certificate, or SPC, if any is in effect at the time of authorization or, in the case of orphan medicinal products, a two-year extension of orphan market exclusivity.

In the United States, companies developing a new medicinal product must agree to a Pediatric Study Plan, or PSP, with the FDA during development (except for non-oncology medicinal product with an Orphan Drug Designation) and, at the latest, before submission of a marketing authorization application, and must conduct pediatric clinical trials in accordance with that PSP as agreed, unless a deferral or waiver applies (e.g., because the relevant disease or condition occurs only in adults).

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Manufacturing Regulation

In addition to an MA, various other requirements apply to the manufacturing and placing on the EU market of medicinal products.

In addition to a MA, various other requirements apply to the manufacturing and placing on the EU market of medicinal products.

The manufacturing of medicinal products in the EU requires a manufacturing authorization and import of medicinal products into the EU requires a manufacturing authorization allowing for import.

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Regulation (EC) No 847/2000 sets out further provisions for implementation of the criteria for designation of a medicinal product as an orphan medicinal product.

An application for the designation of a medicinal product as an orphan medicinal product must be submitted at any stage of development of the medicinal product but before filing of an MAA.

An MA for an orphan medicinal product may only include indications designated as orphan.

An application for the designation of a medicinal product as an orphan medicinal product must be submitted at any stage of development of the medicinal product but before filing of a MAA.

A MA for an orphan medicinal product may only include indications designated as orphan.

For non-orphan indications treated with the same active pharmaceutical ingredient, a separate marketing authorization has to be sought.

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Orphan medicinal product designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

The period of market exclusivity may, however, be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria on the basis of which it received orphan medicinal product destination, including where it can be demonstrated on the basis of available evidence that the original orphan medicinal product is sufficiently profitable not to justify maintenance of market exclusivity or where the prevalence of the condition has increased above the threshold.

Additionally, an MA may be granted to a similar medicinal product with the same orphan indication during the 10 year period if:

The period of market exclusivity may, however, be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria on the basis of which it received orphan medicinal product designation, including where it can be demonstrated on the basis of available evidence that the original orphan medicinal product is sufficiently profitable not to justify maintenance of market exclusivity or where the prevalence of the condition has increased above the threshold.

Additionally, a MA may be granted to a similar medicinal product with the same orphan indication during the 10 year period if:

(i) if the applicant consents to a second original orphan medicinal product application, (ii) if the manufacturer of the original orphan medicinal product is unable to supply sufficient quantities;

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A company may voluntarily remove a product from the register of orphan products.

Tab le o f co ntents

Post-Approval Controls

Where an MA is granted in relation to a medicinal product in the EU, the holder of the MA is required to comply with a range of regulatory requirements applicable to the manufacturing, marketing, promotion and sale of medicinal products.

Where a MA is granted in relation to a medicinal product in the EU, the holder of the MA is required to comply with a range of regulatory requirements applicable to the manufacturing, marketing, promotion and sale of medicinal products.

Similar to the United States, both MA holders and manufacturers of medicinal products are subject to comprehensive regulatory oversight by the EMA, the European Commission and/or the competent regulatory authorities of the individual EU Member States.

The holder of an MA must establish and maintain a pharmacovigilance system and appoint an individual qualified person for pharmacovigilance who is responsible for oversight of that system.

The holder of a MA must establish and maintain a pharmacovigilance system and appoint an individual qualified person for pharmacovigilance who is responsible for oversight of that system.

Key obligations include expedited reporting of suspected serious adverse reactions and submission of periodic safety update reports (“PSURs”).

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However, the details are governed by regulations in individual EU Member States and can differ from one country to another.

For example, applicable laws require that promotional materials and advertising in relation to medicinal products comply with the product’s Summary of Product Characteristics (“SmPC”), which may require approval by the competent national authorities in connection with an MA.

The SmPC is the document that provides information to physicians concerning the safe and effective use of the product.

The SmPC is the document that provides information to physicians and other healthcare professionals concerning the safe and effective use of the product.

Promotional activity that does not comply with the SmPC is considered off-label and is prohibited in the EU.

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In the EU, pricing and reimbursement schemes vary widely from country to country.

EU Member States will approve the gross price set by the manufacturer and attempt to negotiate discount schemes to manage product acquisitions costs and monitor and control prescription volumes and issue guidance to physicians to limit prescriptions to the label indication.

In addition, some EU Member States may require the submission of dossiers that compare the cost-effectiveness of a particular medicinal product candidate to currently available therapies.

Some EU Member States may approve a specific price for a product, or they may instead adopt a system of direct or indirect controls on the profitability of the company placing the product on the market.

Other EU Member States allow companies to fix their own prices for products but monitor and control prescription volumes and issue guidance to physicians to limit prescriptions.

In addition, some EU Member States may require the completion of additional studies that compare the cost-effectiveness of a particular medicinal product candidate to currently available therapies.

This Health Technology Assessment (“HTA”) process is the procedure according to which the assessment of the public health impact, therapeutic impact and the economic and societal impact of use of a given medicinal product in the national healthcare systems of the individual country is conducted.

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The HTA Regulation is intended to boost cooperation among EU Member States in assessing health technologies, including new medicinal products, and providing the basis for cooperation at EU level for joint clinical assessments in these areas.

When it enters into application in 2025, the HTA Regulation will be intended to harmonize the clinical benefit assessment of HTA across the EU.

In light of the fact that the UK has left the EU, Regulation No 2021/2282 on HTA will not apply in the UK.

However, the UK Medicines and Healthcare products Regulation Agency (“MHRA”) is working with UK HTA bodies and other national organizations, such as the Scottish Medicines Consortium (“SMC”), the National Institute for Health and Care Excellence (“NICE”), and the All-Wales Medicines Strategy Group, to introduce new pathways supporting innovative approaches to the safe, timely and efficient development of medicinal products.

The HTA Regulation has applied from January 12, 2025 although it will enter into force iteratively and initially apply to new active substances to treat cancer and to all advanced therapy medicinal products (ATMPs), it will then be expanded to orphan medicinal products in January 2028, and to all centrally authorized medicinal products as of 2030.

Selected high-risk medical devices will also be assessed under the HTA Regulation as of 2026.

The HTA Regulation is intended to harmonize the clinical benefit assessment of HTA across the EU.

In light of the fact that the U.K.

has left the EU, Regulation No 2021/2282 on HTA does not apply in the U.K..

However, the U.K.

Medicines and Healthcare products Regulation Agency (“MHRA”) is working with U.K.

HTA bodies and other national organizations, such as the Scottish Medicines Consortium (“SMC”), the National Institute for Health and Care Excellence (“NICE”), and the All-Wales Medicines Strategy Group, to introduce new pathways supporting innovative approaches to the safe, timely and efficient development of medicinal products, including, effective as of 31 March 2025, relaunching the Innovative Licensing and Access Pathway with more predictable timelines and closer involvement of the National Health Service.

Regulation of Companion Diagnostics

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Compliance with these requirements is a prerequisite to be able to affix the CE mark to devices, without which they cannot be marketed or sold in the EEA.

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To demonstrate compliance with the GSPR laid down in Annex I to the IVDR, and obtain the right to affix the CE mark, IVD manufacturers must conduct a conformity assessment procedure, which varies according to the type of IVD and its classification.

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Companion diagnostics must undergo a conformity assessment by a Notified Body.

If the related medicinal product has, or is in the process of, been authorised through the centralized procedure for the authorization of medicinal products, the notified body will, before it can issue a CE Certificate of Conformity, be required to seek a scientific opinion from the EMA on the suitability of the companion diagnostic for use in relation to the medicinal product concerned.

For medicinal products that have or are in the process of authorisation through any other route provided in EU legislation, the Notified Body must seek the opinion of the national competent authority of an EU Member State.

If the related medicinal product has, or is in the process of, been authorized through the centralized procedure for the authorization of medicinal products, the notified body will, before it can issue a CE Certificate of Conformity, be required to seek a scientific opinion from the EMA on the suitability of the companion diagnostic for use in relation to the medicinal product concerned.

For medicinal products that have or are in the process of authorization through any other route provided in EU legislation, the Notified Body must seek the opinion of the national competent authority of an EU Member State.

Brexit and the Regulatory Framework in the United Kingdom

The UK’s withdrawal from the EU on January 31, 2020, commonly referred to as Brexit, has changed the regulatory relationship between the UK and the EU.

The Medicines and Healthcare products Regulatory Agency (“MHRA”) is now the UK’s standalone regulator for medicinal products and medical devices.

Great Britain (England, Scotland and Wales) is now a third country to the EU.

Northern Ireland will, with regard to EU regulations, continue to follow the EU regulatory rules for now.

The UK regulatory framework in relation to clinical trials is governed by the Medicines for Human Use (Clinical Trials) Regulations 2004, as amended, which is derived from the CTD, as implemented into UK national law through secondary legislation.

On January 17, 2022, the MHRA launched an eight-week consultation on reframing the UK legislation for clinical trials, and which aimed to streamline clinical trials approvals, enable innovation, enhance clinical trials transparency, enable greater risk proportionality, and promote patient and public involvement in clinical trials.

The UK Government published its response to the consultation on March 21, 2023 confirming that it would bring forward changes to the legislation.

These resulting legislative amendments will determine how closely the UK regulations will align with the CTR.

The United Kingdom’s, or U.K., withdrawal from the EU on January 31, 2020, commonly referred to as Brexit, has changed the regulatory relationship between the U.K.

The Medicines and Healthcare products Regulatory Agency, or MHRA, is now the U.K.’s standalone regulator for medicinal products and medical devices.

The United Kingdom is now a third country to the EU.

regulatory framework in relation to clinical trials is governed by the Medicines for Human Use (Clinical Trials) Regulations 2004, as amended, which is derived from the CTD, as implemented into U.K.

national law through secondary legislation.

On January 17, 2022, the MHRA launched an eight-week consultation on reframing the U.K.

legislation for clinical trials, and which aimed to streamline clinical trials approvals, enable innovation, enhance clinical trials transparency, enable greater risk proportionality, and promote patient and public involvement in clinical trials.

Government published its response to the consultation on March 21, 2023 confirming that it would bring forward changes to the legislation.

Government published its response to the consultation on March 21, 2023 confirming that it would bring forward changes to the legislation and such changes were laid in parliament on December 12, 2024.

These resulting legislative amendments will, if implemented in their current form, bring the U.K.

into closer alignment with the CTR.

In October 2023, the MHRA announced a new Notification Scheme for clinical trials which enables a more streamlined and risk-proportionate approach to initial clinical trial applications for Phase 4 and low-risk Phase 3 clinical trial applications.

Marketing authorizations in the UK are governed by the Human Medicines Regulations (SI 2012/1916), as amended.

Since January 1, 2021, an applicant for the EU centralized procedure marketing authorization can no longer be established in the UK.

As a result, since this date, companies established in the UK cannot use the EU centralized procedure and instead must follow one of the UK national authorization procedures or one of the remaining post-Brexit international cooperation procedures to obtain a marketing authorization to market products in the UK.

All existing EU marketing authorizations for centrally authorized products were automatically converted or grandfathered into UK marketing authorization, effective in Great Britain only, free of charge on January 1, 2021, unless the marketing authorization holder opted-out of this possibility.

Northern Ireland currently remains within the scope of EU authorizations in relation to centrally authorized medicinal products.

Accordingly, until the Windsor Framework is implemented in Northern Ireland on January 1, 2025, products falling within the scope of the EU centralized procedure can only be authorized through UK national authorization procedures in Great Britain.

The MHRA has also introduced changes to national marketing authorization procedures.

This includes introduction of procedures to prioritize access to new medicines that will benefit patients, including a 150-day assessment route, a rolling review procedure and the International Recognition Procedure.

Since January 1, 2024, the MHRA may rely on the International Recognition Procedure, or IRP, when reviewing certain types of marketing authorization applications.

This procedure is available for applicants for marketing authorization who have already received an authorization for the same product from a reference regulator.

These include the FDA, the EMA, and national competent authorities of individual EEA countries.

A positive opinion from the EMA and CHMP, or a positive end of procedure outcome from the mutual recognition or decentralized procedures are considered to be authorizations for the purposes of the IRP.

Marketing authorizations in the United Kingdom are governed by the Human Medicines Regulations (SI 2012/1916), as amended.

Since January 1, 2021, an applicant for the EU’s centralized procedure marketing authorization can no longer be established in the United Kingdom.

As a result, since this date, companies established in the United Kingdom cannot use the EU’s centralized procedure.

In order to obtain a United Kingdom MA to commercialize products in the United Kingdom, an applicant must be established in the United Kingdom and must follow one of the United Kingdom national authorization procedures or one of the remaining post-Brexit international cooperation procedures.

Applications are governed by the Human Medicines Regulations (SI 2012/1916) and are made electronically through the MHRA Submissions Portal.

The MHRA has introduced changes to national licensing procedures, including procedures to prioritize access to new medicines that will benefit patients, a 150-day assessment (subject to clock-stops) and a rolling review procedure.

The rolling-review procedure permits the separate or joint submission of quality, non-clinical, and clinical data to the MHRA which can be reviewed on a rolling basis.

After an application under the rolling-review procedure has been validated, the decision should be received within 100 days (subject to clock-stops).

In addition, since January 1, 2024, the MHRA may rely on the International Recognition Procedure (“IRP”), when reviewing certain types of MAAs.

Pursuant to the IRP, the MHRA will take into account the expertise and decision-making of trusted regulatory partners (e.g., the regulatory in Australia, Canada, Switzerland, Singapore, Japan, the U.S.A.

The MHRA will conduct a targeted assessment of IRP applications but retain the authority to reject applications if the evidence provided is considered insufficiently robust.

The IRP allows medicinal products approved by such trusted regulatory partners that meet certain criteria to undergo a fast-tracked MHRA review to obtain and/or update a MA in the United Kingdom.

Applications should be decided within a maximum of 60 days if there are no major objections identified that cannot be resolved within such 60 day period and the approval from the trusted regulatory partner selected has been granted within the previous 2 years or if there are such major objections identified or such approval hasn’t been granted within the previous 2 years within 110 days.

Applicants can submit initial MAAs to the IRP but the procedure can also be used throughout the lifecycle of a product for post-authorization procedures including line extensions, variations and renewals.

All existing marketing authorizations of the EU for centrally authorized products were automatically converted or grandfathered into the United Kingdom’s marketing authorization, effective in Great Britain only, free of charge on January 1, 2021, unless the marketing authorization holder opted-out of this possibility.

Northern Ireland remained within the scope of authorizations of the EU in relation to centrally authorized medicinal products until January 1, 2025.

However, on January 1, 2025, a new arrangement as part of the so-called “Windsor Framework” came into effect and reintegrated Northern Ireland under the regulatory authority of the MHRA with respect to medicinal products.

The Windsor Framework removes EU licensing processes and EU labelling and serialization requirements in relation to Northern Ireland and introduces a U.K.-wide licensing process for medicines.

There is no pre-marketing authorization orphan designation for medicinal products in the UK.

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The criteria are essentially the same as those in the EU, but have been tailored for the market.

This includes the criterion that prevalence of the condition in Great Britain, rather than the EU, must not be more than five in 10,000.

This includes the criterion that prevalence of the condition in the United Kingdom, rather than the EU, must not be more than five in 10,000.

Upon the grant of a marketing authorization with orphan status, the medicinal product will benefit from up to 10 years of market exclusivity from similar products in the approved orphan indication.

The start of this market exclusivity period will be set from the date of first approval of the product in Great Britain.

Tab le o f co ntents

The start of this market exclusivity period will be set from the date of first approval of the product in the United Kingdom.

Post-Approval Controls

Where a MA is granted in relation to a medicinal product in the U.K., the holder of the MA is required to comply with a range of regulatory requirements applicable to the manufacturing, marketing, promotion and sale of medicinal products.

Similar to the United States and the EU, both MA holders and manufacturers of medicinal products are subject to comprehensive regulatory oversight by the MHRA.

The holder of a MA must establish and maintain a pharmacovigilance system and appoint an individual qualified person for pharmacovigilance who is responsible for oversight of that system.

Key obligations include expedited reporting of suspected serious adverse reactions and submission of periodic safety update reports (“PSURs”).

All new MAAs must include a risk management plan (“RMP”), describing the risk management system that the company will put in place and documenting measures to prevent or minimize the risks associated with the product.

The regulatory authorities may also impose specific obligations as a condition of the MA.

Such risk-minimization measures or post-authorization obligations may include additional safety monitoring, more frequent submission of PSURs, or the conduct of additional clinical trials or post-authorization safety studies.

In the U.K., the advertising and promotion of medicinal products are subject to U.K.

laws governing promotion of medicinal products, interactions with physicians and other healthcare professionals, misleading and comparative advertising and unfair commercial practices.

General requirements for advertising and promotion of medicinal products, such as direct-to-consumer advertising of prescription medicinal products are established in U.K.

SPC is the document that provides information to physicians concerning the safe and effective use of the product.

Promotional activity that does not comply with the U.K.

SPC is considered off-label and is prohibited in the U.K.

Corporate Information

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Employees and Human Capital Resources

As of December 31, 2023, we had 463 full-time employees as shown in the table below:

As of December 31, 2024, we had 647 full-time employees, 65 of whom hold Ph.D.

degrees, as shown in the table below:

At December 31,

2023 2022 2021

Administration

Research and development

Sales and general administration

Research and development including manufacturing

Total 647 463

Switzerland and Germany

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The principal purposes of our equity incentive plans are to attract, retain and motivate selected employees, consultants and directors through the granting of equity-based compensation awards.

Tab le o f co ntents

As of December 31, 2024.

the Company added the manufacturing function following the BLA approval granted by the FDA.

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business