On December 10, 2023 Molecular Partners AG (SIX: MOLN; NASDAQ: MOLN), a clinical-stage biotech company developing a new class of custom-built protein drugs known as DARPin therapeutics, reported positive initial clinical data from its ongoing Phase 1/2a trial of MP0533, a novel tetra-specific T cell engager, in a poster at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, Molecular Partners, DEC 10, 2023, View Source [SID1234638383]). These data, which highlight encouraging initial safety and antitumor activity, expand upon those previously disclosed in the conference abstract.

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"We are excited to share these initial data for MP0533, where we see antileukemic activity, already at these low doses, with a favorable safety profile. We look forward to the continuation of this study and evaluating the full potential of MP0533 for patients," said Patrick Amstutz, CEO of Molecular Partners. "For the first time ever, a non-antibody-based T-cell engager shows clinical activity, opening the door for next-generation DARPin drugs, such as tetra-specifics and logic-gated molecules."

As of the data cut-off (October 24, 2023), 11 patients had been enrolled in the first four dosing regimens (DR) of the ongoing Phase 1/2a trial of MP0533 monotherapy in patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS/AML). The trial enrollment remains on track with patients currently being treated in the fifth of seven dose-escalation cohorts planned.

MP0533 continues to demonstrate an acceptable safety profile across all four DRs studied. No dose-limiting toxicities (DLTs) were observed as of data cut-off, and all patients were able to receive their full dose of MP0533. The most frequently reported MP0533-related adverse events were infusion-related reactions and cytokine release syndrome (all Grade 1-2).

Two responders have been observed to date, including a patient achieving complete response (CR) in DR 4 and another patient with morphological leukemia-free state (MLFS) in DR 3 (initially identified as CRi at the time of abstract submission, data cutoff July 2023). These responses are particularly notable for having occurred at dose levels below those predicted for therapeutically relevant activity.

Details of the poster presenting these results from the ongoing Phase 1/2a trial of MP0533 at the 65th ASH (Free ASH Whitepaper) Annual Meeting and Exposition can be found below. The poster will be made available on Molecular Partners’ website after the presentation. For more information on the trial, please visit clinicaltrials.gov (NCT05673057).

Session Name: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster 2
Publication Number: 2921
Title: MP0533, a CD3-Engaging DARPin Targeting CD33, CD123, and CD70 in Patients with Relapsed/Refractory AML or MDS/AML: Preliminary Results of a Phase 1/2a Study
Session Location & Date: San Diego Convention Center, Halls G-H; Sunday, December 10, 2023
Presentation Time: 6:00–8:00 pm PT

About MP0533
MP0533 is a novel, avidity-driven, tetra-specific T cell-engaging, half-life extended, DARPin, which simultaneously targets the tumor-associated antigens CD33, CD123 and CD70 as well as the immune activator CD3 on T cells. MP0533’s affinity to each tumor-associated antigen is tuned to preferentially kill AML cells which commonly co-express at least two of these three target antigens whereas most healthy blood cells only express one or none. MP0533’s unique avidity-driven mode of action therefore enables targeted T cell-mediated killing of AML cells while preserving a therapeutic window that minimizes damage to healthy cells.

On December 10, 2023 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported that new data from its CD20xCD3 T-cell engaging bispecific antibody program, including eight oral presentations, were presented at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition, December 9-12, 2023 (Press release, Genentech, DEC 10, 2023, View Source [SID1234638382]). Based on 32-month and 3-year follow-ups of two pivotal studies for fixed-duration treatments of Columvi (glofitamab-gxbm) and Lunsumio (mosunetuzumab-axgb), respectively, data show that remissions were maintained in the majority of patients with heavily pre-treated lymphomas. Additionally, new early-phase data of novel Columvi or Lunsumio combination regimens support ongoing investigation in Phase III studies in earlier lines of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL).

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"Updated data from pivotal studies of Columvi and Lunsumio continue to provide compelling evidence for how fixed-duration therapies can deliver sustained, long-term benefit for people with difficult-to-treat lymphomas," said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. "Our data at ASH (Free ASH Whitepaper) also demonstrate progress in evaluating our bispecific antibodies in earlier stages of disease and additional types of lymphoma so more people can benefit from our therapies."

Longer follow-up data from pivotal studies of fixed-duration Columvi and Lunsumio show benefit is maintained beyond the end of treatment
Extended follow-up data from the pivotal Phase II NP30179 study of Columvi administered for up to 12 cycles (approximately eight months) in patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) who have received at least two prior lines of therapy showed favorable long-term outcomes. After a median follow-up of 32 months, 55% of patients with a complete response (CR) were in remission at 24 months. Most of these patients remained progression-free and alive 18 months after completing the fixed-duration treatment. In patients who had received prior chimeric antigen receptor (CAR) T-cell therapy, the median duration of CR was 22.0 months (95% confidence interval [CI]: 6.7–not reached). No new safety signals were observed since the previous analysis.

Data from a three-year follow-up analysis of the pivotal Phase II GO29781 study of Lunsumio in patients with R/R FL who have received at least two prior lines of therapy were presented. Results showed continued durable responses and a manageable safety profile after treatment (up to approximately 12 months), with 59% of patients completing treatment after eight cycles (approximately five months). 72.7% of patients with a CR were alive and without disease progression 30 months after their first response. In the overall population, median progression-free survival (PFS) was 24 months (95% CI: 12.0–not evaluable [NE]) and overall survival (OS) not yet reached. No new safety signals were observed since the previous analysis.

Additional data presented reinforce the potential of novel combination regimens in earlier treatment settings
Diffuse large B-cell lymphoma
Data from the Phase Ib/II GO40516 study of Lunsumio plus Polivy (polatuzumab vedotin-piiq) in patients with R/R LBCL were presented and simultaneously published in Nature Medicine. Results showed that at 24 months median follow-up, the median PFS was 11.4 months (95% CI: 6.2–18.7), and median OS was 23.3 months (95% CI: 14.8–NE), highlighting the combination’s potential in R/R LBCL. The overall safety profile of patients with R/R LBCL treated with Lunsumio plus Polivy was manageable. Cytokine release syndrome (CRS) events were generally low grade (Grade 1: 10.2%; Grade 2: 5.1%; Grade 3: 3.1%). Lunsumio in combination with Polivy is being evaluated as an outpatient therapy for patients with R/R DLBCL in the ongoing Phase III SUNMO study.

Results from both arms of the Phase Ib NP40126 study evaluating Columvi in combination with Rituxan (rituximab), cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), and Columvi in combination with Polivy plus Rituxan, cyclophosphamide, doxorubicin and prednisone (Pola+R-CHP) in previously untreated DLBCL were presented. After a median of 12 months follow-up, data from the Columvi plus Pola+R-CHP arm showed that 91.7% of patients had a CR with no progression observed. Of the patients with a CR, 95.5% were still in remission, with a 12-month PFS rate of 91.5%. Safety profiles were highly consistent with earlier analyses from this study. These data support the ongoing Phase III SKYGLO study in previously untreated DLBCL.

Follicular lymphoma
The Phase II MorningSun study, evaluating a subcutaneous (SC) formulation of Lunsumio in patients with selected B-cell non-Hodgkin’s lymphomas , showed that SC Lunsumio is active and has a manageable safety profile in patients with first-line (1L) low-tumor burden FL. Data showed that 83.3% of patients achieved a complete metabolic response (95% CI: 62.6-95.3), and responses were ongoing at data cut-off. CRS was generally low grade (Grade 1: 36.7%; Grade 2: 6.7%) and occurred in cycle one only. Subcutaneous Lunsumio is also being investigated in combination with oral lenalidomide in 1L FL in the Phase Ib/II CO41942 study. New data demonstrated promising efficacy and manageable safety; data showed that 89.2% of patients achieved a CR, and CRS events were either Grade 1 (47.5%) or 2 (2.5%), all of which were confined to cycles one to two. The data support further investigation of this SC formulation of Lunsumio and highlight its potential as a tailored monotherapy or combination outpatient therapy for FL, including in community practices.

Totality of data presented underscores the strength of Genentech’s broad, industry-leading development program, which aims to address the diverse needs, preferences and experiences of people with blood cancers
Both Columvi and Lunsumio are being investigated in Phase III studies that will expand the understanding of their impact in earlier lines of treatment. This includes the Phase III STARGLO study evaluating Columvi in combination with GemOx in patients with R/R DLBCL who are ineligible for autologlous stem cell transplant; the Phase III SKYGLO study evaluating the efficacy and safety of Columvi plus Pola+R-CHP in previously untreated DLBCL; the Phase III GLOBRYTE study evaluating Columvi monotherapy in R/R mantle cell lymphoma; the Phase III SUNMO study investigating Lunsumio plus Polivy in R/R DLBCL; and the Phase III CELESTIMO study investigating Lunsumio plus lenalidomide in patients with R/R FL.

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

Columvi U.S. Indication

Columvi (glofitamab-gxbm) is a prescription medicine to treat adults with certain types of diffuse large B-cell lymphoma (DLBCL) or large B-cell lymphoma (LBCL) that has come back (relapsed) or that did not respond to previous treatment (refractory), and who have received 2 or more prior treatments for their cancer.

It is not known if Columvi is safe and effective in children.

The conditional approval of Columvi is based on response rate and durability of response. There are ongoing studies to establish how well the drug works.

What is the most important information I should know about Columvi?

Columvi can cause Cytokine Release Syndrome (CRS), a serious side effect that is common during treatment with Columvi, and can also be serious and lead to death.

Call your healthcare provider or get emergency medical help right away if you develop any signs or symptoms of CRS, including:

fever of 100.4°F (38°C) or higher
chills or shaking
fast or irregular heartbeat
dizziness or light-headedness
trouble breathing
shortness of breath
Due to the risk of CRS, you will receive Columvi on a "step-up dosing schedule".

A single dose of a medicine called obinutuzumab will be given to you on the first day of your first treatment cycle (Day 1 of Cycle 1).
You will start the Columvi step-up dosing schedule a week after the obinutuzumab dose. The step-up dosing schedule is when you receive smaller "step-up" doses of Columvi on Day 8 and Day 15 of Cycle 1. This is to help reduce your risk of CRS. You should be hospitalized during your infusion and for 24 hours after receiving the first step-up dose on Day 8. You should be hospitalized during your infusion and for 24 hours after receiving the second step-up dose on Day 15 if you experienced CRS during the first step-up dose.
You will receive your first full dose of Columvi a week after the second step-up dose (this will be Day 1 of Cycle 2).
If your dose of Columvi is delayed for any reason, you may need to repeat the "step-up dosing schedule".
If you had more than mild CRS with your previous dose of Columvi, you should be hospitalized during and for 24 hours after receiving your next dose of Columvi.
Before each dose of Columvi, you will receive medicines to help reduce your risk of CRS and infusion-related reactions.

Your healthcare provider will monitor you for CRS during treatment with Columvi and may treat you in a hospital if you develop signs and symptoms of CRS. Your healthcare provider may temporarily stop or completely stop your treatment with Columvi if you have severe side effects.

Carry the Columvi Patient Wallet Card with you at all times and show it to all of your healthcare providers. The Columvi Patient Wallet Card lists the signs and symptoms of CRS you should get emergency medical help for right away.

What are the possible side effects of Columvi?

Columvi may cause serious side effects, including:

Cytokine Release Syndrome.
Neurologic problems. Columvi can cause serious neurologic problems that may lead to death. Your healthcare provider will monitor you for neurologic problems during treatment with Columvi. Your healthcare provider may also refer you to a healthcare provider who specializes in neurologic problems. Tell your healthcare provider right away if you develop any signs or symptoms of neurologic problems, including:
headache
confusion and disorientation
difficulty paying attention or understanding things
trouble speaking
sleepiness
memory problems
numbness, tingling, or weakness of the hands or feet
dizziness
shaking (tremors)
Serious Infections. Columvi can cause serious infections that may lead to death. Your healthcare provider will monitor you for signs and symptoms of infection and treat you as needed. Tell your healthcare provider right away if you develop any signs of an infection, including: fever, chills, weakness, cough, shortness of breath, or sore throat.
Growth in your tumor or worsening of tumor related problems (tumor flare). Tell your healthcare provider if you get any of these signs or symptoms of tumor flare:
tender or swollen lymph nodes
pain or swelling at the site of the tumor
chest pain
cough
trouble breathing

The most common side effects of Columvi include: CRS, muscle and bone pain, rash, and tiredness.

The most common severe abnormal lab test results with Columvi include: decreased white blood cells, decreased phosphate (an electrolyte), increased uric acid levels, and decreased fibrinogen (a protein that helps with blood clotting).

Your healthcare provider may temporarily stop or completely stop treatment with Columvi if you develop certain side effects.

Before receiving Columvi, tell your healthcare provider about all of your medical conditions, including if you:

have an infection
have kidney problems
are pregnant or plan to become pregnant. Columvi may harm your unborn baby
Females who are able to become pregnant:

Your healthcare provider should do a pregnancy test before you start treatment with Columvi.
You should use effective birth control (contraception) during treatment and for 1 month after your last dose of Columvi. Talk to your healthcare provider about what birth control method is right for you during this time.
Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with Columvi.
are breastfeeding or plan to breastfeed. Columvi may pass into your breast milk. Do not breastfeed during treatment and for 1 month after your last dose of Columvi.

Tell your health care provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

What should I avoid while receiving Columvi?

Do not drive, operate heavy machinery, or do other dangerous activities if you develop dizziness, confusion, shaking (tremors), sleepiness, or any other symptoms that impair consciousness until your signs and symptoms go away. These may be signs and symptoms of neurologic problems.

These are not all the possible side effects of Columvi. Talk to your health care provider for more information about the benefits and risks of Columvi.

You may report side effects to the FDA at (800) FDA-1088 or View Source You may also report side effects to Genentech at (888) 835-2555.

Please see Important Safety Information, including Serious Side Effects, as well as the Columvi full Prescribing Information and Medication Guide or visit View Source

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

Lunsumio U.S. Indication

Lunsumio (mosunetuzumab-axgb) is a prescription medicine used to treat adults with follicular lymphoma whose cancer has come back or did not respond to previous treatment, and who have already received two or more treatments for their cancer.

It is not known if Lunsumio is safe and effective in children.

The conditional approval of Lunsumio is based on response rate. There are ongoing studies to establish how well the drug works.

What is the most important information I should know about Lunsumio?

Lunsumio may cause Cytokine Release Syndrome (CRS), a serious side effect that is common during treatment with Lunsumio and can also be severe or life-threatening.

Get medical help right away if you develop any signs or symptoms of CRS at any time, including:

fever of 100.4°F (38°C) or higher
chills
low blood pressure
fast or irregular heartbeat
tiredness or weakness
difficulty breathing
headache
confusion
feeling anxious
dizziness or light-headedness
nausea
vomiting

Due to the risk of CRS, you will receive Lunsumio on a "step-up dosing schedule."

The step-up dosing schedule is when you receive smaller "step-up" doses of Lunsumio on Day 1 and Day 8 of your first cycle of treatment
You will receive a higher dose of Lunsumio on Day 15 of your first cycle of treatment
If your dose of Lunsumio is delayed for any reason, you may need to repeat the step-up dosing schedule
Before each dose in Cycle 1 and Cycle 2, you will receive medicines to help reduce your risk of CRS

Your healthcare provider will check you for CRS during treatment with Lunsumio and may treat you in a hospital if you develop signs and symptoms of CRS. Your healthcare provider may temporarily stop or completely stop your treatment with Lunsumio, if you have severe side effects.

What are the possible side effects of Lunsumio?

Lunsumio may cause serious side effects, including:

Neurologic problems. Your healthcare provider will check you for neurologic problems during treatment with Lunsumio. Your healthcare provider may also refer you to a healthcare provider who specializes in neurologic problems. Tell your healthcare provider right away if you develop any signs or symptoms of neurologic problems during or after treatment with Lunsumio, including:
headache
numbness and tingling of the arms, legs, hands, or feet
dizziness
confusion and disorientation
difficulty paying attention or understanding things
forgetting things or forgetting who or where you are
trouble speaking, reading, or writing
sleepiness or trouble sleeping
tremors
loss of consciousness
seizures
muscle problems or muscle weakness
loss of balance or trouble walking
Serious infections. Lunsumio can cause serious infections that may lead to death. Your healthcare provider will check you for signs and symptoms of infection before and during treatment. Tell your healthcare provider right away if you develop any signs or symptoms of infection during treatment with Lunsumio, including:
fever of 100.4° F (38° C) or higher
chest pain
tiredness
shortness of breath
painful rash
sore throat
pain during urination
feeling weak or generally unwell
Low blood cell counts. Low blood cell counts are common during treatment with Lunsumio and can also be severe. Your healthcare provider will check your blood cell counts during treatment with Lunsumio. Lunsumio may cause the following low blood cell counts:
low white blood cell counts (neutropenia). Low white blood cells can increase your risk for infection
low red blood cell counts (anemia). Low red blood cells can cause tiredness and shortness of breath
low platelet counts (thrombocytopenia). Low platelet counts can cause bruising or bleeding problems
Growth in your tumor or worsening of tumor related problems (Tumor flare). Lunsumio may cause serious or severe worsening of your tumor. Tell your healthcare provider if you develop any of these signs or symptoms of tumor flare during your treatment with Lunsumio: tender or swollen lymph nodes, chest pain, cough, trouble breathing, and pain or swelling at the site of the tumor

Your healthcare provider may temporarily stop or permanently stop treatment with Lunsumio if you develop severe side effects.

The most common side effects of Lunsumio include: tiredness, rash, fever, and headache.

The most common severe abnormal lab test results with Lunsumio include: decreased phosphate, increased glucose, and increased uric acid levels.

Before receiving Lunsumio, tell your healthcare provider about all of your medical conditions, including if you:

have ever had an infusion reaction after receiving Lunsumio
have an infection, or have had an infection in the past which lasted a long time or keeps coming back
have or have had Epstein-Barr Virus
are pregnant or plan to become pregnant. Lunsumio may harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with Lunsumio
Females who are able to become pregnant:

your healthcare provider should do a pregnancy test before you start treatment with Lunsumio
you should use an effective method of birth control during your treatment and for 3 months after the last dose of Lunsumio
are breastfeeding or plan to breastfeed. It is not known if Lunsumio passes into your breast milk. Do not breastfeed during treatment and for 3 months after the last dose of Lunsumio

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

What should I avoid while receiving Lunsumio?

Do not drive, operate heavy machinery, or do other dangerous activities if you develop dizziness, confusion, tremors, sleepiness, or any other symptoms that impair consciousness until your signs and symptoms go away. These may be signs and symptoms of CRS or neurologic problems.

These are not all the possible side effects of Lunsumio. Talk to your healthcare provider for more information about the benefits and risks of Lunsumio.

You may report side effects to the FDA at (800) FDA-1088 or View Source You may also report side effects to Genentech at (888) 835-2555.

Please see Important Safety Information, including Serious Side Effects, as well as the Lunsumio full Prescribing Information and Medication Guide or visit View Source

About Polivy (polatuzumab vedotin-piiq)

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

Polivy U.S. Indication
Polivy is a prescription medicine used with other medicines (a rituximab product, cyclophosphamide, doxorubicin, and prednisone) as a first treatment for adults who have moderate to high risk diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) or high-grade B-cell lymphoma (HGBL).

Polivy is a prescription medicine used with other medicines, bendamustine and a rituximab product, to treat DLBCL in adults who have progressed after at least 2 prior therapies.

Important Safety Information

Possible serious side effects

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

Nerve problems in your arms and legs: This may happen as early as after your first dose and may worsen with every dose. Your doctor will monitor for signs and symptoms, such as changes in your sense of touch, numbness or tingling in your hands or feet, nerve pain, burning sensation, any muscle weakness, or changes to your walking pattern
Infusion-related reactions: You may experience fever, chills, rash, breathing problems, low blood pressure, or hives within 24 hours of your infusion
Low blood cell counts: Treatment with Polivy can cause severe low blood cell counts. Your doctor will monitor your blood counts throughout treatment with Polivy
Infections: If you have a fever of 100.4°F (38°C) or higher, chills, cough, or pain during urination, contact your healthcare team. Your doctor may also give you medication before giving you Polivy, which may prevent some infections, and will monitor your blood counts throughout treatment with Polivy. Treatment with Polivy can cause severe low blood cell counts
Rare and serious brain infections: Your doctor will monitor closely for signs and symptoms of these types of infections. Contact your doctor if you experience confusion, dizziness or loss of balance, trouble talking or walking, or vision changes
Tumor lysis syndrome: Caused by the fast breakdown of cancer cells. Signs include nausea, vomiting, diarrhea, and lack of energy
Potential harm to liver: Some signs include tiredness, weight loss, pain in the abdomen, dark urine, and yellowing of your skin or the white part of your eyes. You may be at higher risk if you already had liver problems or you are taking other medication

Side effects seen most often

The most common side effects of Polivy when used as a first treatment in DLBCL with the medicines rituximab product, cyclophosphamide, doxorubicin, and prednisone include

Nerve problems in arms and legs
Nausea
Tiredness or lack of energy
Diarrhea
Constipation
Hair loss
Redness and sores of the lining of the mouth, lips, throat, and digestive tract

Polivy may lower your red or white blood cell counts and increase uric acid levels.

The most common side effects of Polivy when used in DLBCL after at least 2 prior therapies with other medicines, bendamustine and a rituximab product include

Low blood cell counts (platelets, red blood cells, white blood cells)
Nerve problems in arms and legs
Tiredness or lack of energy
Diarrhea
Nausea
Fever
Decreased appetite
Infections
Polivy may not be for everyone. Talk to your doctor if you are

Pregnant or think you are pregnant: Data have shown that Polivy may harm your unborn baby
Planning to become pregnant: Women should avoid getting pregnant while taking Polivy. Women should use effective contraception during treatment and for 3 months after their last Polivy treatment. Men taking Polivy should use effective contraception during treatment and for 5 months after their last Polivy treatment
Breastfeeding: Women should not breastfeed while taking Polivy and for 2 months after the last dose

These may not be all the side effects. Talk to your healthcare provider for more information about the benefits and risks of Polivy treatment.

You may report side effects to the FDA at (800) FDA-1088 or View Source You may also report side effects to Genentech at (888) 835-2555.

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

On December 10, 2023 Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, reported long-term follow up of treatment-naïve patients with myelofibrosis (MF) who participated in the Phase 1 portion of its study evaluating once-weekly selinexor in combination with ruxolitinib (NCT04562389) (Press release, Karyopharm, DEC 10, 2023, View Source,-with-no-SVR-or-TSS-Progressions-Observed-As-of-the-Data-C [SID1234638381]). The data, featured in an oral presentation at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (ASH 2023), show patients treated with 60mg selinexor, and who achieved ≥35% reduction in spleen volume (SVR35) at week 24, continued to remain in radiographic response. In addition, all patients who achieved TSS50 at Week 24 remained in response as of the data cut-off.

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The data included in the oral presentation for ASH (Free ASH Whitepaper) 2023 were based on the Phase 1 portion of the Phase 1/3 study evaluating the safety and efficacy of once-weekly selinexor in combination with ruxolitinib in patients with treatment-naïve MF (NCT04562389). As of August 1, 2023, 24 patients had been assigned to either selinexor 40mg (N= 10) or 60mg (N=14), in combination with ruxolitinib. The maximum duration of follow-up was 78 weeks with a median duration of 32 weeks for SVR35 durability, and a maximum duration of follow-up was 64 weeks with a median duration of 51 weeks for TSS50 durability.

An exploratory biomarker analysis showed a reduction of variant allele frequency (VAF) at week 24 for all three MF driver genes (CALR, MPL, and JAK2) and rapid and sustained reduction of pro-inflammatory cytokine production. Early cytokine reduction at Week 4 was associated with spleen volume reduction (SVR) at Week 24 and was sustained until the end of treatment. The clinical efficacy associated with biomarkers impacting MF biological hallmarks may suggest disease modification.

"The growing body of data from this study suggests that selinexor in combination with ruxolitinib may provide spleen reduction, symptom improvement, long-term durability and disease modification, expanding the benefit this combination may provide to patients with treatment-naïve myelofibrosis, " said Reshma Rangwala, MD, PhD, Chief Medical Officer of Karyopharm. "We’re excited about the potential to change treatment paradigms for these patients – and expand the number of patients who benefit from first-line therapy."

The safety profile was consistent with previous data cuts with no new safety signals observed as of Aug 1st.

"The current standard of care is not associated with consistent molecular or pathologic responses," said Dr. Sri Tantravahi, University of Utah. "The long-term findings are very exciting as they underscore the potential for durable, clinically relevant responses and modification of disease course. The wait for new options has been long and difficult for the myelofibrosis community, and we welcome this important research to help advance the understanding of XPO1 and JAK inhibitor combinations as a meaningful treatment option for patients."

"We are encouraged by the attention MPNs (Myeloproliferative Neoplasms) are getting in recent years from companies like Karyopharm," said Kapila Viges, Chief Executive Officer of MPN Research Foundation. "With patients waiting for more answers to these chronic yet serious blood cancers, we look forward to the data readouts at ASH (Free ASH Whitepaper) this year. Efforts to develop better therapies and now combinations of therapies bring hope to the myelofibrosis community and open the potential for more options in the treatment paradigm. For patients, options matter."

About XPOVIO (selinexor)

XPOVIO is a first-in-class, oral exportin 1 (XPO1) inhibitor and the first of Karyopharm’s Selective Inhibitor of Nuclear Export (SINE) compounds to be approved for the treatment of cancer. XPOVIO functions by selectively binding to and inhibiting the nuclear export protein XPO1. XPOVIO is approved in the U.S. and marketed by Karyopharm in multiple oncology indications, including: (i) in combination with Velcade (bortezomib) and dexamethasone (XVd) in patients with multiple myeloma after at least one prior therapy; (ii) in combination with dexamethasone in patients with heavily pre-treated multiple myeloma; and (iii) in patients with diffuse large B-cell lymphoma (DLBCL), including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. XPOVIO (also known as NEXPOVIO in certain countries) has received regulatory approvals in various indications in a growing number of ex-U.S. territories and countries, including but not limited to the European Union, the United Kingdom, China, South Korea, Canada, Israel and Taiwan. XPOVIO and NEXPOVIO is marketed by Karyopharm’s partners, Antengene, Menarini, Neopharm and FORUS in China, South Korea, Singapore, Australia, Hong Kong, Germany, Austria, Israel and Canada.

Please refer to the local Prescribing Information for full details.

Selinexor is also being investigated in several other mid- and late-stage clinical trials across multiple high unmet need cancer indications, including in endometrial cancer and myelofibrosis.

For more information about Karyopharm’s products or clinical trials, please contact the Medical Information department at:

Tel: +1 (888) 209-9326
Email: [email protected]

SELECT IMPORTANT SAFETY INFORMATION

Warnings and Precautions

Thrombocytopenia: Monitor platelet counts throughout treatment. Manage with dose interruption and/or reduction and supportive care.
Neutropenia: Monitor neutrophil counts throughout treatment. Manage with dose interruption and/or reduction and granulocyte colony‐stimulating factors.
Gastrointestinal Toxicity: Nausea, vomiting, diarrhea, anorexia, and weight loss may occur. Provide antiemetic prophylaxis. Manage with dose interruption and/or reduction, antiemetics, and supportive care.
Hyponatremia: Monitor serum sodium levels throughout treatment. Correct for concurrent hyperglycemia and high serum paraprotein levels. Manage with dose interruption, reduction, or discontinuation, and supportive care.
Serious Infection: Monitor for infection and treat promptly.
Neurological Toxicity: Advise patients to refrain from driving and engaging in hazardous occupations or activities until neurological toxicity resolves. Optimize hydration status and concomitant medications to avoid dizziness or mental status changes.
Embryo‐Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential and males with a female partner of reproductive potential, of the potential risk to a fetus and use of effective contraception.
Cataract: Cataracts may develop or progress. Treatment of cataracts usually requires surgical removal of the cataract.
Adverse Reactions

The most common adverse reactions (≥20%) in patients with multiple myeloma who receive XVd are fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, decreased weight, cataract and vomiting. Grade 3‐4 laboratory abnormalities (≥10%) are thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia and neutropenia. In the BOSTON trial, fatal adverse reactions occurred in 6% of patients within 30 days of last treatment. Serious adverse reactions occurred in 52% of patients. Treatment discontinuation rate due to adverse reactions was 19%.
The most common adverse reactions (≥20%) in patients with multiple myeloma who receive Xd are thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea and upper respiratory tract infection. In the STORM trial, fatal adverse reactions occurred in 9% of patients. Serious adverse reactions occurred in 58% of patients. Treatment discontinuation rate due to adverse reactions was 27%.
The most common adverse reactions (incidence ≥20%) in patients with DLBCL, excluding laboratory abnormalities, are fatigue, nausea, diarrhea, appetite decrease, weight decrease, constipation, vomiting, and pyrexia. Grade 3‐4 laboratory abnormalities (≥15%) are thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia. In the SADAL trial, fatal adverse reactions occurred in 3.7% of patients within 30 days, and 5% of patients within 60 days of last treatment; the most frequent fatal adverse reactions was infection (4.5% of patients). Serious adverse reactions occurred in 46% of patients; the most frequent serious adverse reaction was infection (21% of patients). Discontinuation due to adverse reactions occurred in 17% of patients.
Use In Specific Populations

Lactation: Advise not to breastfeed.

For additional product information, including full prescribing information, please visit www.XPOVIO.com.

To report SUSPECTED ADVERSE REACTIONS, contact Karyopharm Therapeutics Inc. at 1‐888‐209‐9326 or FDA at 1‐800‐FDA‐1088 or www.fda.gov/medwatch.

On December 10, 2023 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) reported that the primary analysis of the Phase III HAVEN 7 study reinforced the efficacy and safety of Hemlibra (generic name: emicizumab) in previously untreated or minimally treated infants with severe hemophilia A without factor VIII inhibitors (Press release, Chugai, DEC 10, 2023, View Source;category= [SID1234638380]). Results showed that Hemlibra achieved meaningful bleed control in babies up to 12 months of age, and was well tolerated.1 The new data were presented at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition taking place 9-12 December 2023, in San Diego, California, and included in the press program.

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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"Hemlibra, which can be administered subcutaneously, is an option to reduce the treatment burden for infants who have difficulty with intravenous administration in the treatment of severe hemophilia A to prevent bleeding. In this study, Hemlibra demonstrated effective bleeding control in infants for the first time. This complements data across a wide range of ages shown in previous clinical trials and supports earlier initiation of Hemlibra treatment aimed at preventing bleeding in infants. We remain committed to building evidence including long-term data to support the safe use of this drug for those who need it," said Dr. Osamu Okuda, Chugai’s President and CEO.

The burden of severe hemophilia A in babies and on their parents and caregivers is significant. The World Federation of Hemophilia treatment guidelines consider the standard of care in hemophilia to be regular prophylaxis initiated at a young age, as studies have shown this improves long-term outcomes, while reducing the risk of intracranial hemorrhage.2-4 However, for many babies with hemophilia A, prophylaxis is not started until after the first year of life.5-8 Hemlibra, which is already approved and being used to treat babies with hemophilia A, provides a flexible treatment option that can be administered subcutaneously from birth at different dosing frequencies for maintenance dosing.9

The HAVEN 7 study is a Phase III, descriptive, single-arm study, set up in collaboration with the hemophilia A community to evaluate the efficacy, safety, pharmacokinetics and pharmacodynamics of subcutaneous Hemlibra in infants with severe hemophilia A without factor VIII inhibitors. These results, which included data from 55 participants, showed that at 101.9 weeks median follow-up, 54.5% of participants (n=30) did not have any bleeds that required treatment, while 16.4% (n=9) did not have any treated or untreated bleeds at all. There were no spontaneous bleeds requiring treatment in any participant, and all treated bleeds were as a result of trauma. A total of 207 bleeds occurred in 46 participants (83.6%); 87.9% of these were as a result of trauma. Model-based annualized bleeding rate (95% CI) was 0.4 (0.30-0.63) for treated bleeds. No new safety signals were observed and there were no treatment-related serious adverse events, intracranial hemorrhages or deaths reported. 3.6% of participants (n=2) tested positive for factor VIII inhibitors which may be a consequence of reduced factor VIII usage in participants treated with Hemlibra, and no participant tested positive for anti-drug antibodies.1 Results were consistent with positive results from the interim analysis and from previous Phase III HAVEN studies.10-14

The results of additional research on biomarkers in the HAVEN 7 study were also presented at ASH (Free ASH Whitepaper), and were supportive of the study’s primary efficacy analysis. This additional research showed that the pharmacodynamic profiles of Hemlibra in babies were consistent with those previously observed in older children and adults with hemophilia A. The data showed that Hemlibra exhibits the expected pharmacodynamic response, despite the reduced presence of the clotting factors that Hemlibra binds to in this age group.15

The HAVEN 7 study results complement data from the broader, pivotal HAVEN clinical program, providing insights into the evolution of hemophilia A in babies, and the impact of initiating preventative treatment from birth. The primary analysis is being followed by a seven year extension period.1

About Hemlibra
Hemlibra is a bispecific monoclonal antibody created with Chugai’s proprietary antibody engineering technologies. The drug is designed to bind factor IXa and factor X. In doing so, Hemlibra provides the cofactor function of factor VIII in people with hemophilia A, who either lack or have impaired coagulation function of factor VIII.16,17 The product was approved by the U.S. Food and Drug Administration (FDA) in November 2017, for the first time in the world, for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A (congenital factor VIII deficiency) with factor VIII inhibitors. Hemlibra has been approved in more than 115 countries for congenital hemophilia A with and without factor VIII inhibitors. In Japan, it was first approved in March 2018 for congenital hemophilia A with factor VIII inhibitors, and its indication was later expanded to include congenital hemophilia A without factor VIII inhibitors, and acquired hemophilia A.

On December 10, 2023 MorphoSys AG (FSE: MOR; NASDAQ: MOR) reported comprehensive results from the Phase 3 MANIFEST-2 study investigating pelabresib, an investigational BET inhibitor, in combination with the JAK inhibitor ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis (Press release, MorphoSys, DEC 10, 2023, View Source [SID1234638379]). These findings were presented in an oral presentation at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego, California.

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Myelofibrosis is characterized by four hallmarks: an enlarged spleen, anemia, bone marrow fibrosis and disease-associated symptoms. In MANIFEST-2, all hallmarks were improved with the pelabresib and ruxolitinib combination versus placebo plus ruxolitinib, which is the standard of care in myelofibrosis. Ruxolitinib dosing was similar in both arms of the study and was determined based on its approved myelofibrosis indication.

"The MANIFEST-2 results demonstrated clear benefits across the four hallmarks of myelofibrosis, including a significant reduction in spleen size – a key finding given the known association between spleen volume reduction and patient survival," said Raajit K. Rampal, M.D., Ph.D., Director, Center for Hematologic Malignancies, and Director, Myeloproliferative Neoplasms Program, Memorial Sloan Kettering Cancer Center. "The comprehensive results presented at ASH (Free ASH Whitepaper) also show that the pelabresib combination improves anemia, disease-associated symptoms and bone marrow fibrosis, and that it is well-tolerated. These findings point to pelabresib and ruxolitinib as a potential paradigm-shifting first-line treatment of this debilitating disease."

MANIFEST-2 Comprehensive Findings

MANIFEST-2 is a global, multicenter, double-blind, Phase 3 study of 430 JAK inhibitor-naïve adults with myelofibrosis, randomized 1:1 to receive the pelabresib and ruxolitinib combination or placebo plus ruxolitinib. MANIFEST-2 is one of the largest studies in this disease to date.

Strong Reductions in Spleen Size and Symptoms

In the MANIFEST-2 study, pelabresib and ruxolitinib demonstrated a near doubling in the proportion of patients achieving a ≥35% reduction in spleen volume (SVR35) at 24 weeks, the primary endpoint, versus placebo plus ruxolitinib (p<0.001).

For the first key secondary endpoint assessing symptom reduction, absolute change in total symptom score (TSS) at 24 weeks, there was a strong numerical improvement for patients receiving pelabresib and ruxolitinib versus placebo plus ruxolitinib. The response rate for the second key secondary endpoint, proportion of patients achieving ≥50% reduction in symptom score (TSS50) at 24 weeks, was also numerically greater for patients receiving pelabresib and ruxolitinib. Significant improvements in both key secondary endpoints were observed with the pelabresib combination for patients classified as intermediate-risk (Dynamic International Prognostic Scoring System [DIPSS] Int-1 and Int-2), who account for over 90% of the MANIFEST-2 population.

The proportion of patients achieving both SVR35 and TSS50 at 24 weeks was doubled with pelabresib and ruxolitinib versus placebo plus ruxolitinib (40.2% vs. 18.5%, respectively).

Details are included in the table below.

Endpoint Pelabresib + Ruxolitinib
(N=214) Placebo +
Ruxolitinib
(N=216) Difference
SVR35 65.9% 35.2% 30.4%*
P-value: p<0.001
Absolute Change in TSS -15.99
(Mean Baseline: 28.26)
-14.05
(Mean Baseline: 27.36) -1.94**
P-value: 0.0545
TSS50 52.3% 46.3% 6.0%*
P-value: 0.216
*Difference calculated using Cochran–Mantel–Haenszel (CMH) common risk difference

**Least square mean estimate

Improvement in Anemia

Patients receiving pelabresib in combination with ruxolitinib reported fewer anemia adverse events (43.9%, grade ≥3: 23.1%) compared with placebo plus ruxolitinib (55.6%, grade ≥3: 36.4%). Additionally, by week 24, fewer patients in the pelabresib and ruxolitinib arm required red blood cell transfusions compared with the placebo arm (30.8% vs. 41.2%, respectively).

A greater proportion of patients achieved a hemoglobin response — defined as a ≥1.5 g/dL mean increase in hemoglobin levels over baseline in the absence of transfusions during the previous 12 weeks — with pelabresib and ruxolitinib versus placebo plus ruxolitinib (9.3% vs. 5.6%, respectively). Average hemoglobin levels were greater in patients receiving pelabresib and ruxolitinib than in those receiving placebo plus ruxolitinib, starting at week 9 and continuing to week 24. Anemia benefits were observed across all studied patient risk groups.

"Anemia can reduce patients’ quality of life by causing severe fatigue and necessitating blood transfusions," said Professor Claire Harrison, Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom. "In MANIFEST-2, patients receiving the combination therapy showed clear benefits on anemia, including greater hemoglobin levels, fewer red blood cell transfusions and fewer anemia and fatigue adverse events. Given its strong efficacy, safety profile and signs of disease modification, the pelabresib and ruxolitinib combination has the potential to become the new standard of care in the first-line treatment of myelofibrosis."

Improvement in Bone Marrow Fibrosis

Bone marrow fibrosis, or the replacement of bone marrow with fibrous scar tissue, is a central pathological feature of myelofibrosis. In MANIFEST-2, fibrosis was improved by at least one grade in a greater proportion of patients receiving pelabresib and ruxolitinib (38.5% vs. 24.2% with placebo plus ruxolitinib) and worsened by at least one grade in a smaller proportion of patients receiving pelabresib and ruxolitinib (16.3% vs. 28.3% with placebo plus ruxolitinib) at 24 weeks. Bone marrow fibrosis is graded on a scale from 0 (normal) to 3 (most severe) based on fiber density; studies suggest a correlation between the grade of bone marrow fibrosis and patient prognosis.

Biomarker Analysis Suggests Disease Modification

In a biomarker analysis, average plasma levels of inflammatory cytokines (IL-8, IL-6, TNF-α and NF-κB-regulated cytokines) were reduced in patients receiving pelabresib and ruxolitinib compared with placebo plus ruxolitinib at 24 weeks. Increased cytokine levels are associated with all four disease hallmarks; increased IL-8 levels are also associated with worse survival outcomes. These biomolecular improvements suggest early evidence of a disease-modifying effect.

Well-Tolerated Safety Profile

Overall, grade ≥3 treatment-emergent adverse events (TEAEs) were reported less frequently with pelabresib and ruxolitinib than with placebo plus ruxolitinib (49.1% vs. 57.5%, respectively).

In the pelabresib and ruxolitinib arm, the most common (≥10%) hematologic TEAEs were anemia (43.9%; grade ≥3: 23.1%), thrombocytopenia (32.1%; grade ≥3: 9.0%) and platelet count decrease (20.8%; grade ≥3: 4.2%). In the placebo plus ruxolitinib arm, the most common hematologic TEAEs were anemia (55.6%; grade ≥3: 36.4%), thrombocytopenia (23.4%; grade ≥3: 5.6%) and platelet count decrease (15.9%; grade ≥3: 0.9%).

The most common (≥10%) nonhematologic TEAEs in the pelabresib and ruxolitinib arm were diarrhea (23.1%; grade ≥3: 0.5%), dysgeusia (18.4%; grade ≥3: 0.5%), constipation (18.4%; grade ≥3: 0%), nausea (14.2%; grade ≥3: 0.5%), cough (12.7% grade ≥3: 0), asthenia (11.8% grade ≥3: 0.5%), fatigue (11.8%; grade ≥3: 0.5%), dizziness (11.3%; grade ≥3: 0%), headache (11.3% grade ≥3: 0.5%) and COVID-19 (11.3%; grade ≥3: 0%). The most common nonhematologic TEAEs in the placebo plus ruxolitinib arm were constipation (24.3%; grade ≥3: 0%), diarrhea (18.7%; grade ≥3: 1.4%), fatigue (16.8%; grade ≥3: 0.9%), COVID-19 (15.9%; grade ≥3: 1.9%), nausea (15.0%; grade ≥3: 0%), asthenia (13.6%; grade ≥3: 0%), dyspnea (13.1%; grade ≥3: 0.9%), cough (11.2%; grade ≥3: 0%) and headache (10.7%; grade ≥3: 0%). Discontinuation rates due to adverse events were 10.7% with pelabresib and ruxolitinib and 6.5% with placebo plus ruxolitinib.

The safety profile of the pelabresib and ruxolitinib combination therapy was consistent with previous clinical studies. No new safety signals were observed.

"The four hallmarks of myelofibrosis – enlarged spleen, anemia, bone marrow fibrosis and disease-associated symptoms – have a strong impact on a patient’s life. In MANIFEST-2, the combination of JAK and BET inhibition addressed all four of these hallmarks with the potential to modify the course of the disease," said Tim Demuth, M.D., Ph.D., MorphoSys Chief Research and Development Officer. "We are confident that the comprehensive data package will provide impactful insights into the promising and well-tolerated combination of pelabresib and ruxolitinib. Our goal now is to bring this first-line therapy to patients with intermediate- and high-risk myelofibrosis as quickly as possible. We look forward to meeting with regulatory agencies regarding these data and are diligently preparing regulatory filings with the intention of submitting applications to the U.S. Food and Drug Administration and the European Medicines Agency in the middle of 2024."

Investor Event at ASH (Free ASH Whitepaper) 2023

MorphoSys will host an in-person investor event to review these detailed findings and address questions with the company’s management team and medical experts, including Professor Claire Harrison, Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom, and Ruben Mesa, M.D., FACP, President and Executive Director, Atrium Health Levine Cancer Center and Atrium Health Wake Forest Baptist Comprehensive Cancer Center.

The event, taking place on Monday, December 11 at the Hilton San Diego Bayfront Hotel, will start with a networking breakfast at 6:30 a.m. PST and continue with a formal presentation at 7:00 a.m. PST (4:00 p.m. CET / 3:00 p.m. GMT / 10:00 a.m. EST). A webcast will also be available for those not attending ASH (Free ASH Whitepaper) 2023 in person.

Webcast participants may pre-register and will receive dial-in details to access the call easily and quickly: View Source;linkSecurityString=c1a71840b. Please dial in 10 minutes before the beginning of the conference.

The live webcast (audio and presentation) can be directly accessed via View Source or via the Investors section under "Events & Conferences" on the MorphoSys website, www.morphosys.com; after the call, a slide-synchronized audio replay of the conference call will be available at the same location.