On December 12, 2021 Silence Therapeutics plc, Nasdaq: SLN ("Silence" or "the Company"), a leader in the discovery, development and delivery of novel short interfering ribonucleic acid (siRNA) therapeutics for the treatment of diseases with significant unmet medical need, reported that additional positive data from the SLN124 healthy volunteer study at the 2021 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Atlanta, Georgia (USA) (Press release, Silence Therapeutics, DEC 12, 2021, View Source [SID1234596939]). SLN124, a siRNA targeting the liver expressed TMPRSS6 gene, is currently in development for iron loading anemia conditions, thalassemia and myelodysplastic syndrome (MDS).

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The phase 1, randomized, double-blind, placebo-controlled, single-ascending dose study evaluated the safety and tolerability of SLN124 (1.0, 3.0 and 4.5 mg/kg doses) in 24 healthy volunteers. Pharmacokinetic parameters and pharmacodynamic biomarkers of iron metabolism were also measured to assess reduction in iron.

Giles Campion, M.D., EVP, Chief Medical Officer and Head of Research & Development at Silence, said: "We developed our proprietary mRNAi GOLD platform with the focus on delivering targeted, precision medicines for many diseases that lack effective treatments. The healthy volunteer study represents the first clinical data from our platform and demonstrated our ability to translate strong preclinical results in humans. By modulating endogenous hepcidin in a highly controlled manner, we believe SLN124 has the potential to address the needs of patients in a broad range of hematological diseases. We look forward to data from the ongoing studies in patients with thalassemia and MDS anticipated in the third quarter of next year."

Lead author, John Porter, M.D., Professor and Consultant Hematologist, Red Cell Disorders Unit, University College London and University of College London Hospitals, commented: "Silencing the TMPRSS6 gene represents a new and promising therapeutic approach to manipulating hepcidin, which in turn has the potential to control a number of hematological conditions. I look forward to further development of SLN124 in people with iron-loading anemias, who could positively benefit from the effects we’ve seen in healthy volunteers."

New data presented at ASH (Free ASH Whitepaper) today showed SLN124 was rapidly distributed (median tmax was 4.0 or 5.0 hours) and largely eliminated from plasma within 24 hours post-dose in all dosing groups. SLN124 plasma concentrations increased in a greater than dose-linear fashion between dosing groups.

Dose-related increases in circulating hepcidin, a key endogenous regulator of iron balance and distribution, were evident by Day 8; all doses resulted in sustained increments throughout the period of the study consistent with robust target engagement and TMPRSS6 gene knockdown. SLN124 induced durable reductions in serum iron; percentage change from baseline was ~50% at Day 29 with 3.0 and 4.5 mg/kg doses.

All SLN124 doses induced marked reductions in transferrin saturation (TSAT); absolute levels of TSAT achieved (10–16%) are below the level (< 20%) where iron availability to tissue is restricted and at or below that (< 16%) required to support normal erythropoiesis in health.

As previously reported, results showed all doses of SLN124 were well-tolerated with no serious or severe treatment emergent adverse events (TEAEs) or TEAEs leading to withdrawal. TEAEs did not appear to be dose dependent and the majority were mild, including transient injection site reactions which resolved without intervention.

The poster entitled, "SLN124 a GalNAc Conjugated 19-mer Double Stranded siRNA Reduces Iron and Increases Hepcidin Levels of Healthy Volunteers in a Phase 1 Clinical Study," is available here.

SLN124 is being evaluated in two phase 1 single-ascending dose studies in patients with thalassemia and MDS. SLN124 has Orphan Drug Designation for both conditions and rare pediatric disease designation for beta thalassemia. Silence plans to initiate a phase 1 study of SLN124 in polycythemia vera in the second half of 2022.

About Thalassemia and Myelodysplastic Syndrome (MDS)

Thalassemia and MDS are both rare diseases that prevent a person from producing enough healthy red blood cells. Low levels of healthy red blood cells, known as anemia, result in less oxygen being delivered to different parts of the body. This can cause symptoms such as excessive tiredness and weakness. It can also lead to other serious health problems, such as heart disease. People living with thalassemia or MDS can also store too much iron in their bodies, leading to a phenomenon called ‘iron overload’, which can damage organs such as the liver, heart and the endocrine system.

Both conditions are often treated with repeated blood transfusions, which add to the problem of iron overload. Iron chelation therapy removes excess iron from the body using special medicines. While it helps reduce the amount of body iron for people with thalassemia or MDS, it does not treat the underlying cause of the anemia or stop this from progressing. There is, therefore, a need for therapies that directly address the biological drivers of the anemia.

About Polycythemia Vera (PV)

PV is a rare blood cancer and one of a related group known as "myeloproliferative neoplasms"

(MPNs). Unlike in thalassemia and MDS where the body does not produce enough red blood cells, people with PV produce too many red blood cells. This makes the blood thicker and less able to travel around the body, causing a variety of issues ranging from headaches and dizziness to more serious complications, such as blood clots.

Current treatments are focused on treating the symptoms of PV to reduce the number of red blood cells and reduce the risk of blood clots. They do not target the underlying genetic cause of the disease.

About SLN124

SLN124 is a gene ‘silencing’ therapy – one that is designed to temporarily block a specific gene’s message that would otherwise trigger an unwanted effect. In this case, SLN124 aims to temporarily ‘silence’ TMPRSS6, a gene that prevents the liver from producing a central regulator of iron balance and distribution in the body – hepcidin. Silencing TMPRSS6 by SLN124 increases endogenous hepcidin, with potential beneficial effects in several hematological disorders. SLN124 has demonstrated safety and proof-of-mechanism in a healthy volunteer study and is currently being studied in patients with thalassemia and MDS. SLN124 has orphan drug designation for both conditions and rare pediatric disease designation for beta thalassemia. Silence plans to initiate a phase 1 study of SLN124 in polycythemia vera in the second half of 2022.

On December 12, 2021 MorphoSys AG (FSE: MOR; NASDAQ: MOR) reported that the latest data from the ongoing MANIFEST study, an open-label, Phase 2 clinical trial of pelabresib, an investigational BET inhibitor, in patients with myelofibrosis, a rare bone marrow cancer for which only limited treatment options are available (Press release, MorphoSys, DEC 12, 2021, View Source [SID1234596932]). These latest results, which included more patients and longer-term follow-up than previously reported data, suggest the potential of pelabresib in the treatment of myelofibrosis. These findings were presented during poster and oral sessions at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (ASH 2021), held December 11 – 14, 2021 in Atlanta, Georgia and virtually.

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"These data reconfirm previously published results and reinforce the role pelabresib may play, if approved, in overcoming some of the challenges we face in treating myelofibrosis," said Malte Peters, M.D., MorphoSys Chief Research and Development Officer. "We are further exploring the effectiveness and safety of pelabresib as a first-line treatment for myelofibrosis in MANIFEST-2, an ongoing Phase 3 study. The latest results reaffirm our confidence in the MANIFEST-2 study, and we look forward to sharing findings from this trial once they become available."

At ASH (Free ASH Whitepaper) 2021, the latest data evaluating pelabresib as a first-line combination with ruxolitinib – the current standard of care – for patients with myelofibrosis who had not previously been treated with a JAK inhibitor (JAK inhibitor-naïve) were presented. As of September 10, 2021, the data cut-off, a total of 84 JAK inhibitor-naïve patients have been enrolled and received the combination. The data showed 68 percent (n=57) of patients treated with the combination achieved a ≥35 percent reduction in spleen volume (SVR35) from baseline at week 24 and 60 percent (n=47) maintained SVR35 at week 48. Most patients also saw their symptoms reduced, with 56 percent (n=46) achieving ≥50 percent reduction in total symptom score (TSS50) from baseline at week 24. At the time of the data cut-off, 53 patients (63 percent of the 84 patients) were still on treatment. No new safety signals were identified in the study. The most common hematologic adverse events were thrombocytopenia (12 percent, grade 3/4) and anemia (34 percent, grade 3/4). Non-hematological events included dyspnea (5 percent, grade 3) and respiratory tract infections (8 percent, grade 3/4).

Additionally, analyses from an exploratory endpoint presented at ASH (Free ASH Whitepaper) 2021 showed a reduction of megakaryocyte clustering in bone marrow and correlation with spleen volume reduction. Megakaryocytes are the cells in the bone marrow responsible for making platelets, and the clustering of these cells are one of the signs of myelofibrosis. The exploratory data, which require further evaluation, suggest the potential pelabresib may have in changing the course of myelofibrosis treatment, if approved.

"In my opinion, a challenge in treating myelofibrosis is knowing that despite available treatment options the disease will ultimately progress in the majority of patients diagnosed," said Srdan Verstovsek, M.D., Ph.D., professor of medicine and hematologist-oncologist at the MD Anderson Cancer Center and a MANIFEST investigator. "Identifying new, first-line treatment options will improve physicians’ ability to better manage the disease from the time of diagnosis. These latest data, although early in the investigational process, suggest that by

combining pelabresib and ruxolitinib, we may have the potential to enhance the current standard of care in the first-line treatment of myelofibrosis."

Additional data from Arm 1 of the MANIFEST study were also presented in an oral presentation at ASH (Free ASH Whitepaper) 2021. In Arm 1, pelabresib is being evaluated as a monotherapy in patients with advanced myelofibrosis who are ineligible to receive, intolerant of, or refractory to JAK inhibitors, a population with very limited therapeutic options. Patients were divided into two cohorts, transfusion-dependent (TD) and non-transfusion-dependent (non-TD). For the TD cohort, the primary endpoint was conversion to transfusion independence (TI) for 12 consecutive weeks. In the non-TD cohort, the primary endpoint was SVR35 at week 24. At week 24, 11 percent (n=7) of patients reached SVR35. In addition, we observed 31 percent of patients had a spleen volume reduction of 25 percent or more (n=20) at week 24. Across all cohorts, 28 percent (n=18) of patients achieved TSS50. No new safety signals were identified in the study. The most common hematologic adverse events were thrombocytopenia (23 percent, grade 3/4) and anemia (15 percent, grade 3). Non-hematological events included diarrhea (6 percent, grade 3) and respiratory tract infections (5 percent, grade 3).

About Pelabresib
Pelabresib (CPI-0610) is an investigational selective small-molecule designed to promote anti-tumor activity by inhibiting the function of bromodomain and extra-terminal domain (BET) proteins to decrease the expression of abnormally expressed genes in cancer. Pelabresib is currently being investigated as a treatment for myelofibrosis and has not yet been evaluated or approved by any regulatory authorities.

About MANIFEST
MANIFEST is an open-label, Phase 2 clinical trial of pelabresib (CPI-0610) in patients with myelofibrosis (MF), a rare cancer of the bone marrow that disrupts the body’s normal production of blood cells.

Constellation Pharmaceuticals, an affiliate of MorphoSys, is evaluating pelabresib in combination with ruxolitinib in JAK-inhibitor-naïve MF patients (Arm 3), with a primary endpoint of the proportion of patients with a ≥35% spleen volume reduction from baseline (SVR35) after 24 weeks of treatment. Constellation Pharmaceuticals is also evaluating pelabresib either as a monotherapy in patients who are resistant to, intolerant of, or ineligible for ruxolitinib and no longer on the drug (Arm 1) or as add-on therapy in combination with ruxolitinib in patients with a suboptimal response to ruxolitinib or MF progression (Arm 2). Patients in Arms 1 and 2 are being stratified based on transfusion-dependent (TD) status. The primary endpoint for the patients in cohorts 1A and 2A, who were TD at baseline, is conversion to transfusion independence for 12 consecutive weeks. The primary endpoint for patients in cohorts 1B and 2B, who were not TD at baseline, is the proportion of patients with a ≥35% spleen volume reduction from baseline after 24 weeks of treatment.

On December 12, 2021 Protagonist Therapeutics (Nasdaq: PTGX) ("Protagonist" or "the Company") reported that updated data from two ongoing Phase 2 studies evaluating rusfertide in patients with polycythemia vera (PV), demonstrating its ability to essentially eliminate the need for phlebotomies in patients (Press release, Protagonist, DEC 12, 2021, View Source [SID1234596881]). Rusfertide also showed rapid and sustained hematocrit control in patients requiring frequent phlebotomies or those having high baseline hematocrit levels (>48%). The data were presented in two oral presentations at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2021 Annual Meeting, in addition to the Company’s three poster presentations: one describing the Phase 3 study design for rusfertide in PV; one presenting pre-clinical findings with a hepcidin analog in a mouse model of PV; and another poster on the Phase 2 clinical proof-of-concept data for rusfertide in hereditary hemochromatosis (HH).

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"The latest data continues to demonstrate rusfertide’s potential to maintain rapid and durable control of hematocrit and essentially eliminate the need for phlebotomies in phlebotomy-dependent PV patients, while offering meaningful improvements across various quality of life measures," said Ronald Hoffman, MD, Director of the Myeloproliferative Disorders Research Program at the Icahn School of Medicine at Mount Sinai, and principal investigator for the study. "Early findings for rusfertide induction therapy also demonstrate its ability to rapidly control hematocrit in patients with elevated hematocrit levels above 48 percent, and to sustain those effects in maintenance, highlighting rusfertide’s potential efficacy in a wider spectrum of PV patients."

"We are extremely encouraged by the totality and consistency of the positive results presented today at ASH (Free ASH Whitepaper) for rusfertide in polycythemia vera, and by the support we are garnering from the physician community as we continue to execute against our goal of addressing unmet medical needs through this natural hormone mimetic therapy," said Dinesh V. Patel, PhD, President and Chief Executive Officer of Protagonist. "The upcoming double-blinded, placebo-controlled Phase 3 PV study is a transformative step in the progressive journey of rusfertide, from de novo discovery to a registrational study. In addition, we look forward to providing clarity on our next steps in HH and other iron-overload related diseases in 2022, thereby expanding the potential utility of rusfertide into multiple indications."

Summary of Key Results

Updated Results from Phase 2 Study Evaluating Rusfertide in Patients with PV

In this Phase 2 study, 63 phlebotomy-dependent PV patients were treated with rusfertide for up to 18 months. The results of the study demonstrated the essential elimination of the need for therapeutic phlebotomy (TP). Rapid, sustained, and durable control of hematocrit levels below 45% was observed without a significant increase in white blood cell numbers or PV-related thromboses. During the first 28 weeks on treatment, 84% of patients required no phlebotomies, 14% required one, and 2% required two phlebotomies. The most frequent adverse events were injection site reactions which were transient in nature. Importantly, none of the treated PV patients suffered from thrombotic events. Serious and Grade 3-4 events were limited in number, less than 10 at the time of data cut-off. Two SAEs were previously reported as possible related to study drug.

Among patient reported outcomes, a third of the patients in the study also saw at least a 40% reduction in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Scores (MPN-SAF-TSS) from baseline at week 28. Sixty-nine percent of patients reported improvement in Patient Global Impression of Change from baseline at week 8.

New Results from Phase 2 Study Evaluating Rusfertide as an Induction Therapy in Patients with PV

In this Phase 2 study, induction therapy with twice weekly rusfertide was administered alone to patients with confirmed high hematocrit levels above 48%. In all 16 erythrocytotic PV patients, rusfertide demonstrated rapid reduction of hematocrit below 45% within weeks, without the need for TP. The drug was well tolerated. Post-induction, weekly rusfertide treatment maintained hematocrit levels without the need for TP. While this study remains ongoing, most reported drug related adverse events to date were grade 1-2, with injection site reactions being the most common adverse event.

Additional Poster Presentations

The design of Protagonist’s planned three-part, multicenter, global, double-blinded, placebo-controlled Phase 3 clinical trial was presented in a poster. This Phase 3 study is expected to commence in Q1 2022 and will evaluate rusfertide in patients with PV compared to placebo when added onto current therapy. The primary endpoint of the study will be the absence of phlebotomy during weeks 20-32 for patients on rusfertide.

Also presented in a poster were results from a pre-clinical study demonstrating that a rusfertide peptide analog reduced erythrocytosis by restricting iron needed for red blood cell production while normalizing body iron distribution in a murine model with JAK2-V617F mutations. These effects support the use of a hepcidin mimetic, such as rusfertide, for potential utility in PV through dose titration treatment to maintain hematocrit below 45%.

Results from a Phase 2a proof-of-concept study evaluating rusfertide in patients with HH were also presented in a poster, demonstrating that rusfertide reduced serum iron and maintained transferrin saturation below 45% with corresponding significant reductions in phlebotomies. Liver iron concentration measured by MRI were also maintained at pre-study levels in patients at the end of the six-month study. Rusfertide was generally well tolerated in patients with HH, with the most common adverse events being injection site reactions that were mild or moderate.

Details for ASH (Free ASH Whitepaper) 2021 presentations are as follows:

Oral Presentations

Title: "Rusfertide (PTG-300) Controls Hematocrit Levels and Essentially Eliminates Phlebotomy Requirement in Polycythemia Vera Patients"
Session Title: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Novel Therapies for MPNs and JAK inhibitors for Myelofibrosis
Authors: Ronald Hoffman, MD, et al.

Title: "Rusfertide (PTG-300) Induction Therapy Rapidly Achieves Hematocrit Control in Polycythemia Vera Patients without the Need for Therapeutic Phlebotomy"
Session Title: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Novel Therapies for MPNs and JAK inhibitors for Myelofibrosis
Authors: Yelena Ginzburg, MD, et al.

Posters

Title: "A Phase 3 Study of the Hepcidin Mimetic Rusfertide (PTG-300) in Patients with Polycythemia Vera"
Session Title: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Poster I
Authors: Srdan Verstovsek, MD, PhD, et al.

Title: "Regulation of Iron Homeostasis and Efficacy of Rusfertide Analog Peptide in a Mouse Model for Polycythemia Vera"
Session Title: 102. Iron Homeostasis and Biology: Poster II
Authors: Roopa Taranath, PhD, et al.

Title: "Rusfertide (PTG-300), a Hepcidin Mimetic, Maintains Liver Iron Concentration in the Absence of Phlebotomies in Patients with Hereditary Hemochromatosis"
Session Title: 102. Iron Homeostasis and Biology: Poster I
Authors: Kris V. Kowdley, MD, et al.

On December 12, 2021 Antengene Corporation Limited ("Antengene" SEHK: 6996.HK), a leading innovative, global biopharmaceutical company dedicated to discovering, developing and commercializing first-in-class and/or best-in-class medicines for cancer and other life-threatening diseases, reported a clinical trial collaboration to evaluate the safety, pharmacokinetics and preliminary efficacy of ATG-017 in combination with Bristol Myers Squibb’s PD-1 checkpoint inhibitor, Opdivo (nivolumab) (Press release, Antengene, DEC 12, 2021, View Source [SID1234596876]). The open-label Phase 1/2 trial will evaluate the investigational combination as a potential treatment option for patients with advanced solid tumors.

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"Our clinical collaboration with Bristol Myers Squibb underscores Antengene’s commitment to explore combination regimens from our portfolio with other mechanisms of action that might transform cancer care", said Jay Mei, M.D., Ph.D., Founder and CEO of Antengene. "We are excited to enter this clinical collaboration with Bristol Myers Squibb and look forward to initiating enrollment in this exciting combination regimen in the first half of 2022."

ATG-017 is an oral and selective inhibitor of extracellular signal–regulated protein kinase 1 and 2 (ERK1/2). Opdivo is a human programmed death receptor-1 (PD-1) blocking antibody that binds to the PD-1 receptor expressed on activated T-cells. This collaboration builds on Antengene’s preclinical data set, some of which was presented at the Society for Immunotherapy in Cancer (SITC) (Free SITC Whitepaper) 2021, which showed that the combination of an ERK1/2 inhibitor and an immune checkpoint inhibitor (CPI) worked synergistically to produce improved efficacy in preclinical immune CPI-resistant cancer models.

"Antengene believes that rational combination of targeted therapies and immuno-oncology drugs may offer the greatest chance of success in the next advances of cancer treatments," said Kevin Lynch, M.D., Antengene’s Chief Medical Officer. "We believe ATG-017 could be useful in multiple combination regimens. In preclinical studies, the combination of ATG-017 and an immune CPI demonstrated promising synergy in resistant and refractory murine tumor models. With the initiation of our Phase 1/2 combination trial, we will be working to validate these promising findings in the clinic. We believe these data will inform the design of future studies and, if positive, demonstrate ATG-017’s potential to synergize with immuno-oncology agents and turn "cold" tumors "hot". Potent inhibition of ERK has the potential to reverse an immune-suppressed tumor microenvironment, or block ERK-mediated disease progression that may characterize CPI-resistance and hyper-progressive disease. This represents a major unmet need in cancer therapy," continued Dr. Lynch.

ATG-017 is currently being investigated in a Phase 1/2 open-label, multicenter dose-finding study, the "ERASER" study, in patients with identified mutations in the RAS-MAPK pathway. The trial is being conducted in two parts, with dose-escalation and dose-expansion parts exploring both monotherapy and as a combination therapy, with a PD-1 checkpoint inhibitor as the first partner drug.

Under the terms of the Agreement, Antengene will sponsor and fund the study and Bristol-Myers Squibb will provide Opdivo for the combination dose escalation and combination dose expansion portions of the trial. Antengene has global commercial and development rights to ATG-017. Opdivo is a trademark of Bristol-Myers Squibb Company.

About ATG-017

ATG-017 is a potent and selective small molecule extracellular signal-regulated kinases 1 and 2 (ERK1/2) inhibitor. ERK1/2 are related protein-serine/threonine kinases that function as terminal kinases in the RAS-MAPK signal transduction cascade. This cascade regulates a large variety of cellular processes, including proliferation. The RAS-MAPK pathway is dysregulated in more than 30% of human cancers with the most frequent alterations being observed in RAS or BRAF genes across multiple tumor types. An ERK inhibitor enables the targeting of both RAS and BRAF mutant diseases.

Antengene recently presented data at the 2021 Society for Immune Therapy in Cancer meeting (SITC 2021) detailing compelling preclinical results showing the combination of ATG-017 and an anti-PD-L1 monoclonal antibody (atezolizumab) in an aggressive immune checkpoint resistant murine cancer model rendered "cold" tumors "hot."

On December 12, 2021 IASO Biotherapeutics ("IASO Bio"), a clinical-stage biopharmaceutical company focused on discovering, developing, and manufacturing innovative medicines and Innovent Biologics, Inc. ("Innovent", HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of cancer, metabolic, autoimmune and other major diseases, reported the latest data from the phase 1/2 clinical study of a fully human B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy in an oral presentation at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Abstract # 547) (Press release, IASO Biotherapeutics, DEC 12, 2021, View Source [SID1234596873]). BCMA CAR-T therapy was co-developed by the two companies (IASO Bio: CT103A, Innovent: IBI326) for the treatment of patients with relapsed/refractory multiple myeloma (RRMM). Presentation title: A Phase 1/2 Study of a Novel Fully Human B-Cell Maturation Antigen-Specific CAR T Cells (CT103A) in Patients with Relapsed and/or Refractory Multiple Myeloma with Professor Chunrui Li, MD, PhD, from Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology (HUST) in China as the oral presenter.

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The updated data is based on a single-arm, open-label, multi-center phase 1/2 study being conducted in China. The study mainly enrolled patients with BCMA-positive RRMM who had an Eastern Cooperative Oncology Group (ECOG) performance score of 0-1 and received ≥3 lines of prior therapy. The study’s primary endpoint is objective response rate (ORR), with secondary endpoints including duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, tolerability, pharmacokinetics and pharmacodynamics (PK/PD). As the data cutoff date of Oct.12, 2021, this study included 79 subjects treated with the recommended Phase II dose (RP2D) of 1.0×106 CAR-T cells/kg (9 from the exploratory investigator-initiated trial [IIT] and 70 from the registrational study [Trial Registration# NCT05066646]).

Study results showed that CT103A has excellent safety and efficacy profiles, as corroborated by long in vivo persistence, indicating that CT103A has the potential to be a breakthrough therapy for patients with RRMM.

CT103A demonstrated a favorable and manageable safety profile: Among the 79 patients, 75 (94.9%) experienced cytokine release syndrome (CRS). The majority of them experienced 1~2 CRS; only 2 experienced grade 3 CRS (all occurred during the IIT phase of the study, while the 70 patients in the registrational study did not report any grade 3 or higher CRS). The median time to CRS onset was 6.0 days after infusion, and the median duration of CRS was 5.0 days. Only 1 patient experienced grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS) manifested as transient decrease in consciousness and soon resolved without intervention. All patients with CRS or ICANS have resolved, among which 20% and 34.7% were treated with tocilizumab and steroids respectively.

CT103A showed favorable and durable efficacy: Of the 79 patients, the ORR was 94.9% and the complete response/stringent complete response (CR/sCR) rate was 58.2%, with a trend suggesting a correlation between deeper responses and longer follow-ups. PFS at 6, 9, and 12 months after infusion was 78.0%, 76.0%, and 71.0%, respectively. CT103A also demonstrated favorable efficacy in 11 patients with EMM, achieving an ORR of 100% and a CR/sCR rate of 72.7%. In all 79 patients, 93.7% achieved minimal residual disease (MRD)-negativity with a sensitivity of 10-5 at least once after infusion.

CT103A also demonstrated favorable efficacy in patients who had received prior CAR-T therapy: Among the 13 patients who previously received CAR-T therapy, the ORR was 76.9%, with 61.5% of those patients achieving very good partial response (VGPR) or deeper responses, and 46.2% achieved CR/sCR.

CT103A demonstrated robust expansion and prolonged persistence: The expansion of CT103A in peripheral blood reached the peak at a median of 12 days, with a median Cmax of 92,000 copies/ug DNA. CT103A was still detectable in 10 (55.6%) of the 18 patients who completed 12-month follow-up after infusion. The first enrolled patient still had detectable CT103A transgene (4,040 copies/ug DNA) 34 months (1,030 days) after infusion, and remained in sCR during this time. Soluble BCMA in peripheral blood of patients rapidly declined after CT103A infusion and persistently remained below the detectable limit.

CT103A has low immunogenicity: Only 1.3% (1/79) of patients were tested anti-drug antibody (ADA)-positive within three months after CT103A infusion. At a median follow-up duration of seven months, only 12.7% (10/79) of patients tested ADA-positive.

"While a high rate of relapse remains a major clinical challenge in RRMM, BCMA-targeted CAR-T has thus far showed great promise in its treatment. CT103A is a fully-human BCMA-specific CAR-T therapy that can reduce relapse by bypassing potential anti-CAR immunogenicity in the host. This CT103A study demonstrated favorable efficacy, safety, PK/PD, and low immunogenicity, signifying enormous therapeutic value for the treatment of RRMM as potentially a clinical breakthrough," said the two principal investigators at the primary centers of the study – Prof. Lugui Qiu, MD, from the Chinese Academy of Medical Science Hematology Hospital and Prof. Chunrui Li, MD, PhD, from Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology.

Dr. Wen (Maxwell) Wang, Chief Executive Officer and Chief Medical Officer of IASO Bio, said: "This is our second time reporting CT103A results during an oral session at ASH (Free ASH Whitepaper) Meeting. And this year’s new data for safety and efficacy of CT103A is particularly exciting. It includes some of the results from the registrational study at 11 sites which is worth emphasizing since it’s globally the first registrational study that enrolled patients who had failed prior CAR-T treatment. For these patients, who have no approved treatment options, CT103A also demonstrated favorable and durable efficacy, once again highlighting the enormous therapeutic potential of this innovative candidate. At present, we are also advancing the clinical development of CT103A for early-line treatments, combination therapies and autoimmune diseases, while expanding the development program globally. We’ll submit the new drug application (NDA) soon and look forward to launching this cell therapy to benefit even more patients in the future. "

Dr. Hui Zhou, Senior Vice President of Innovent, said: "Multiple myeloma (MM) is a common hematology malignant disease with high incidence rate, and relapse and refractory are inevitable after current treatments. There’s an urgent unmet need requesting a treatment with well-tolerated and long persistence for patients. We are glad the results from the Phase I/II study of CT-103A (Innovent R&D code: IBI326) were announced in an oral presentation at this year’s ASH (Free ASH Whitepaper) Annual Meeting. These results looks very promising as they have demonstrated favorable and durable efficacy and manageable efficacy of IBI326. We will further accelerate this clinical development of IBI326 to bring forth a treatment option that will bring new hope to patients with MM."

About Multiple Myeloma (MM)
Multiple Myeloma is a deadly blood cancer that often infiltrates the bone marrow causing anemia, kidney failure, immune problems, and bone fractures. For multiple myeloma patients, common first-line drug treatments include proteasome inhibitors, immunomodulatory drugs, and alkylating agents. While treatment may result in remission, most patients will inevitably enter the relapsed or refractory stage as there’s currently no cure. As a result, there is a significant unmet need for patients with relapsed/refractory multiple myeloma. In the United States, MM accounts for nearly 2% of all cancer cases, and more than 2% of cancer-related deaths.

According to Frost & Sullivan, the number of new MM cases in the United States rose from 30,300 in 2016 to 32,300 in 2020 and is expected to increase to 37,800 by 2025. The total number of patients diagnosed with MM in the United States increased from 132,200 in 2016 to 144,900 in 2020 and is expected to rise to 162,300 by 2025.

The number of new MM cases in China rose from 18,900 in 2016 to 21,100 in 2020 and is expected to increase to 24,500 by 2025. The total number of patients diagnosed with MM in China increased from 69,800 in 2016 to 113,800 in 2020 and is expected to rise to 182,200 by 2025.

About CT103A (BCMA CAR-T)
CT103A is an innovative therapy co-developed by IASO Bio and Innovent Biologics. Previous studies indicate subjects with relapsed/refractory multiple myeloma (RRMM) who received high-dose BCMA-targeting CAR-T cells may achieve better remission but have worse adverse events. Moreover, once the disease progresses again, the re-infusion of CAR-T cells will not be effective. To solve this dilemma, CT103A has been developed, a lentiviral vector containing a CAR structure with a fully human scFv, CD8a hinger and transmembrane, 4-1BB co-stimulatory and CD3ζ activation domains. Based on strict selection and screening, utilizing a proprietary in-house optimization platform and integrated in house manufacture process improvement, the construct of the BCMA CAR-T is potent and CT103A shows prolonged persistency in patients. In February 2021, CT103A was granted Breakthrough Therapy Designation (BTD) by China’s National Medical Products Administration (NMPA) for the treatment of RRMM. In addition to multiple myeloma, IASO Bio is investigating CT103A in patients with autoimmune diseases.