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ADC Therapeutics Announces FDA Approval of ZYNLONTA™ (loncastuximab tesirine-lpyl) in Relapsed or Refractory Diffuse Large B-Cell Lymphoma

On April 23, 2021 ADC Therapeutics SA (NYSE: ADCT) reported that the U.S. Food and Drug Administration (FDA) has approved ZYNLONTA (loncastuximab tesirine-lpyl) for the treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), DLBCL arising from low grade lymphoma and high-grade B-cell lymphoma (Press release, ADC Therapeutics, APR 23, 2021, View Source [SID1234578403]).1 ZYNLONTA, a CD19-targeted antibody drug conjugate (ADC), has been granted accelerated approval by the FDA based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

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"There is a significant unmet need for treatment options for patients with r/r DLBCL, including those who have been heavily pretreated and have difficult-to-treat disease," said Paolo F. Caimi, MD, University Hospitals Cleveland Medical Center and Case Comprehensive Cancer Center, Case Western Reserve University. "Single-agent ZYNLONTA demonstrated clinically important outcomes in the pivotal LOTIS-2 study across several disease subtypes. Notably, this included transplant eligible and ineligible patients and patients who previously received stem cell transplant or CAR-T cell therapy."

The FDA approval was based on data from LOTIS-2, a large (n=145) Phase 2 multinational, single-arm clinical trial of ZYNLONTA for the treatment of adult patients with r/r DLBCL following two or more prior lines of systemic therapy. Results from the trial demonstrated an overall response rate (ORR) of 48.3% (70/145 patients), which included a complete response (CR) rate of 24.1% (35/145 patients) and a partial response (PR) rate of 24.1% (35/145 patients). Patients had a median time to response of 1.3 months and the median duration of response (mDoR) for the 70 responders was 10.3 months (inclusive of patients who were censored). In a pooled safety population the most common adverse reactions (≥20%) were thrombocytopenia, gamma-glutamyltransferase increased, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea and musculoskeletal pain. In LOTIS-2, the most common (≥10%) grade ≥3 treatment-emergent adverse events were neutropenia (26.2%), thrombocytopenia (17.9%), gamma-glutamyltransferase increased (17.2%) and anemia (10.3%).

"The FDA approval of ZYNLONTA is an exciting advancement for patients with r/r DLBCL and a transformational event for ADC Therapeutics," said Chris Martin, Chief Executive Officer of ADC

Therapeutics. "We extend our deepest gratitude to the patients who participated in our LOTIS-1 and LOTIS-2 clinical trials, their families, the study investigators and our employees, as their commitment made this important milestone possible."

DLBCL, the most common type of non-Hodgkin lymphoma in the United States, is a rapidly progressing, aggressive disease that is heterogeneous with multiple subtypes.2 More than 40% of first-line DLBCL treatments fail.3 For patients who fail first-line therapy, prognoses are poor, worsening with each line of therapy as the chance for cure or long-term disease-free survival diminishes.4,5

ZYNLONTA will be commercially available in the United States shortly. ADC Therapeutics has launched the Advancing Patient Support Program, a comprehensive patient support program offering financial assistance, ongoing education and other resources to eligible patients who are prescribed ZYNLONTA.

Please see full Prescribing Information at www.adctherapeutics.com for ZYNLONTA.

Conference Call Details

ADC Therapeutics management will host a conference call and live audio webcast on Friday, April 23, 2021 at 4 p.m. ET. To access the live call, please dial (833) 303-1198 (domestic) or +1 914 987 7415 (international) and provide conference ID 6867157. The live webcast will be available under "Events & Presentations" in the Investors section of the ADC Therapeutics website at ir.adctherapeutics.com. The archived webcast will be available for 30 days following the call.

Important Safety Information

WARNINGS AND PRECAUTIONS

Effusion and Edema

Serious effusion and edema occurred in patients treated with ZYNLONTA. Grade 3 edema occurred in 3% (primarily peripheral edema or ascites) and Grade 3 pleural effusion occurred in 3% and Grade 3 or 4 pericardial effusion occurred in 1%.

Monitor patients for new or worsening edema or effusions. Withhold ZYNLONTA for Grade 2 or greater edema or effusion until the toxicity resolves. Consider diagnostic imaging in patients who develop symptoms of pleural effusion or pericardial effusion, such as new or worsened dyspnea, chest pain, and/or ascites such as swelling in the abdomen and bloating. Institute appropriate medical management for edema or effusions.

Myelosuppression

Treatment with ZYNLONTA can cause serious or severe myelosuppression, including neutropenia, thrombocytopenia, and anemia. Grade 3 or 4 neutropenia occurred in 32%, thrombocytopenia in 20%, and anemia in 12% of patients. Grade 4 neutropenia occurred in 21% and thrombocytopenia in 7% of patients. Febrile neutropenia occurred in 3%.

Monitor complete blood counts throughout treatment. Cytopenias may require interruption, dose reduction, or discontinuation of ZYNLONTA. Consider prophylactic granulocyte colony-stimulating factor administration as applicable.

Infections

Fatal and serious infections, including opportunistic infections, occurred in patients treated with ZYNLONTA. Grade 3 or higher infections occurred in 10% of patients, with fatal infections occurring in 2%. The most frequent Grade ≥3 infections included sepsis and pneumonia.

Monitor for any new or worsening signs or symptoms consistent with infection. For Grade 3 or 4 infection, withhold ZYNLONTA until infection has resolved.

Cutaneous Reactions

serious Cutaneous reactions occurred in patients treated with ZYNLONTA. Grade 3 cutaneous reactions occurred in 4% and included photosensitivity reaction, rash (including exfoliative and maculo-papular), and erythema.

Monitor patients for new or worsening cutaneous reactions, including photosensitivity reactions. Withhold ZYNLONTA for severe (Grade 3) cutaneous reactions until resolution. Advise patients to minimize or avoid exposure to direct natural or artificial sunlight including exposure through glass windows. Instruct patients to protect skin from exposure to sunlight by wearing sun-protective clothing and/or the use of sunscreen products. If a skin reaction or rash develops, dermatologic consultation should be considered.

Embryo-Fetal Toxicity

Based on its mechanism of action, ZYNLONTA can cause embryo-fetal harm when administered to a pregnant woman because it contains a genotoxic compound (SG3199) and affects actively dividing cells.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ZYNLONTA and for 9 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ZYNLONTA and for 6 months after the last dose.

ADVERSE REACTIONS

In a pooled safety population of 215 patients (Phase 1 and LOTIS-2), the most common (>20%) adverse reactions, including laboratory abnormalities, were thrombocytopenia, increased gamma-glutamyltransferase, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain.

In LOTIS-2, serious adverse reactions occurred in 28% of patients receiving ZYNLONTA. The most common serious adverse reactions that occurred in ≥2% receiving ZYNLONTA were febrile neutropenia, pneumonia, edema, pleural effusion, and sepsis. Fatal adverse reactions occurred in 1%, due to infection.

Permanent treatment discontinuation due to an adverse reaction of ZYNLONTA occurred in 19% of patients. Adverse reactions resulting in permanent discontinuation of ZYNLONTA in ≥2% were gamma-glutamyltransferase increased, edema, and effusion.

Dose reductions due to an adverse reaction of ZYNLONTA occurred in 8% of patients. Adverse reactions resulting in dose reduction of ZYNLONTA in ≥4% was gamma-glutamyltransferase increased.

Dosage interruptions due to an adverse reaction occurred in 49% of patients receiving ZYNLONTA. Adverse reactions leading to interruption of ZYNLONTA in ≥5% were gamma-glutamyltransferase increased, neutropenia, thrombocytopenia, and edema.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to ADC Therapeutics at 1-855-690-0340.

FDA filing acceptance and priority review received for SH-111

On April 23, 2021 Shorla Pharma Limited (‘Shorla’), a specialty pharmaceutical company, reported today that it has submitted, and the U.S. Food and Drug Administration (FDA) has accepted for filing, its application for its SH-111 oncology drug designed to treat T-cell leukemia (Press release, Shorla Pharma, APR 23, 2021, View Source [SID1234578402]). SH-111 is a lifesaving treatment that is often in shortage and the company looks forward to working closely with FDA to bring this much needed product to market later this year.

"We’re very proud that SH-111 will have a significant clinical benefit particularly for children with leukemia," said Sharon Cunningham, CEO and Co-founder of Shorla Pharma. "It’s a desperately needed product and a life-changing treatment that we are honored to bring to patients in the United States, and later, worldwide."

Founded in Ireland, Shorla specializes in developing innovative oncology drugs, with a focus on orphan and pediatric cancers. With strong support from scientists and clinicians, plus an extensive industry network that includes the Children’s Oncology Group in the U.S., the company has an advanced pipeline of oncology therapies to treat a number of unmet patient needs.

T-cell leukemia is an aggressive blood and bone marrow cancer which progresses quickly. While most leukemias target older people, T-cell leukemia is most common among children, with this particular treatment often in shortage. The expedited review granted for this filing recognizes the urgent need for the product.

Added Orlaith Ryan, Shorla Pharma CTO and Co-founder, "Reaching this milestone is an important step as we continue to make progress across our growing pipeline. Our focus is on developing innovative oncology treatments for women and children, with a focus on rare cancers where existing treatments are limited, in short supply or inadequate."

The company is also developing a drug for treating breast and ovarian cancers, and an oral solution to treat patients with glioblastoma who have trouble swallowing.

Dr. Reddy’s to release Q4 and full year FY 21 results on May 14th, 2021 Earnings call slated for May 14th @ 5:30 PM IST / 8:00 AM EDT

On April 23, 2021 Dr. Reddy’s Laboratories Ltd. (BSE: 500124, NSE: DRREDDY, NYSE: RDY, NSEIFSC: DRREDDY) reported that it will announce results for the fourth quarter and full year ended March 31, 2021 on Friday, May 14th, 2021 after the Board Meeting (Press release, Dr Reddy’s, APR 23, 2021, View Source [SID1234578401]).

Summary of Events

Event Date and Time Medium
Release of financial results May 14th, after the Board Meeting Stock Exchange, Media, Company website, Business wire, Email
Press meet presentation Will be available on the Company’s website Company’s website
www.drreddys.com
Earnings Call May 14th, 5:30 PM IST / 8:00 AM EDT
Hosted by the Company

(Details below)

Playback of Earnings Call After the earnings call till May 21st, 2021 Details below
Transcript of the Earnings call Will be available on the Company’s website Company’s website
www.drreddys.com

Earnings Call

Following the release, the management of the Company will host an earnings call to discuss the Company’s financial performance. (Dial In and other details given below)

Play Back

The play back will be available after the earnings call, till May 21st, 2021. For play back dial in phone No: +91 22 7194 5757 | +91 22 6663 5757, and Playback Code is 40700.

European Commission Approves JEMPERLI (dostarlimab), the First Anti-PD-1 Therapy Approved for Recurrent or Advanced dMMR/MSI-H Endometrial Cancer in Europe

On April 23, 2021 AnaptysBio, Inc. (Nasdaq: ANAB), a clinical-stage biotechnology company developing first-in-class antibody product candidates focused on emerging immune control mechanisms applicable to inflammation and immuno-oncology indications, reported that the European Commission has granted conditional marketing authorization for JEMPERLI (dostarlimab) for use in women with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) recurrent or advanced endometrial cancer who have progressed on or following prior treatment with a platinum containing regimen (Press release, AnaptysBio, APR 23, 2021, View Source [SID1234578400]). The approval makes dostarlimab the first anti-PD-1 therapy available for endometrial cancer in Europe.

JEMPERLI was generated by AnaptysBio using its proprietary somatic hypermutation (SHM) antibody platform and subsequently developed by TESARO, Inc., now a part of GSK, under a collaboration agreement. Eight AnaptysBio-generated therapeutic antibodies have advanced into clinical development to date, and JEMPERLI is the first AnaptysBio-generated antibody to obtain regulatory approval.

"We are delighted that JEMPERLI is the first AnaptysBio-generated antibody to be approved in Europe and look forward to meaningful potential future milestone and royalty revenue from our collaboration with GSK," said Hamza Suria, president and chief executive officer of AnaptysBio. "These revenues will continue to support AnaptysBio’s primary value-creation strategy, which is focused on advancing wholly-owned first-in-class therapeutic antibodies through multiple upcoming clinical catalysts in 2021 and 2022."

JEMPERLI is indicated as a monotherapy for treatment of adult patients with recurrent or advanced dMMR/MSI-H endometrial cancer, who have progressed on, or are being dosed following, prior treatment with a platinum-containing regimen, and is the first indication approved by the European Commission for JEMPERLI. AnaptysBio has earned a $10.0 million milestone payment as a result of this approval. Earlier this month, AnaptysBio earned a $20.0 million milestone payment as a result of approval by the U.S. Food and Drug Administration for JEMPERLI in endometrial cancer. In 2020, AnaptysBio received milestone payments of $10.0 million and $5.0 million for the FDA’s and EMA’s acceptances of the BLA and Marketing Authorisation Application (MAA) filings for JEMPERLI, respectively.

Earlier this year, FDA accepted a subsequent BLA filing for JEMPERLI for the treatment of adult patients with dMMR recurrent or advanced solid tumors who have progressed on or following prior treatment. AnaptysBio recently received a $10.0 million payment from GSK as a result of this milestone. Payments totaling an additional $35 million will be due to AnaptysBio upon the achievement of future regulatory milestones for JEMPERLI in the United States and Europe. Furthermore, $165 million in sales milestones are due to AnaptysBio upon achievement of certain annual JEMPERLI net sales revenues. Royalties due to AnaptysBio for dostarlimab range from 8% to 25% of global net sales, where AnaptysBio will receive 8% of annual global net sales below $1 billion, and 12-25% of net sales above $1 billion. JEMPERLI is also being developed by GSK for the treatment of other tumor types and treatment settings, including currently ongoing phase III trials in recurrent or primary advanced endometrial cancer in combination with chemotherapy standard of care (RUBY) and the phase III FIRST study of platinum-based therapy with dostarlimab and niraparib versus standard of care platinum-based therapy as first-line treatment of stage III or IV non-mucinous epithelial ovarian cancer.

In addition, JEMPERLI is being evaluated as monotherapy and in combination therapy across multiple tumor types and other cancers, including platinum-resistant ovarian cancer, non-small cell lung cancer, multiple myeloma and melanoma.

GSK continues to develop additional antibodies partnered with AnaptysBio, including cobolimab, an AnaptysBio-generated anti-TIM-3 antagonist antibody, and GSK4074386, an anti-LAG-3 antagonist antibody. Under the terms of the collaboration, AnaptysBio is due to receive development and regulatory milestone payments for each of the first two indications for each of these antibodies. AnaptysBio can potentially receive a total of $1.1 billion in aggregate milestone payments under this collaboration. In addition, AnaptysBio will receive royalties ranging from 4% to 8% on global net sales of cobolimab and GSK4074386 and 1% of GSK’s global net sales of ZEJULATM.

Important Information for JEMPERLI in the EU

Indication
JEMPERLI is indicated as monotherapy for the treatment of adult patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) recurrent or advanced endometrial cancer (EC) that has progressed on or following prior treatment with a platinum-containing regimen.

Immune-Mediated Adverse Reactions
Immune-related adverse reactions, which may be severe or fatal, can occur in patients treated with antibodies blocking the programmed cell death protein-1 / programmed death-ligand 1 (PD-1/PD-L1) pathway, including JEMPERLI. While immune-related adverse reactions usually occur during treatment with PD-1/PD-L1 blocking antibodies, symptoms can also manifest after discontinuation of treatment. Immune-related adverse reactions may occur in any organ or tissue and may affect more than one body system simultaneously. Important immune-related adverse reactions listed in this section are not inclusive of all possible severe and fatal immune-related reactions.

Early identification and management of immune-related adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Patients should be monitored for symptoms and signs of immune-related adverse reactions. Clinical chemistries, including liver tests and thyroid function tests, should be evaluated at baseline and periodically during treatment. For suspected immune-related adverse reactions, adequate evaluation including specialty consultation should be ensured.

Based on the severity of the adverse reaction, treatment with JEMPERLI should be withheld or permanently discontinued and corticosteroids (1 to 2 mg/kg/day prednisone or equivalent) or other appropriate therapy administered. Upon improvement to Grade ≤1, corticosteroid taper should be initiated and continued for 1 month or longer. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Hormone replacement therapy for endocrinopathies should be instituted as warranted.

Treatment with JEMPERLI should be permanently discontinued for any Grade 3 immune-related adverse reaction that recurs and for any Grade 4 immune-related adverse reaction toxicity, except for endocrinopathies that are controlled with replacement hormones and unless otherwise specified in the Summary of Product Characteristics (SmPC).

Immune-Related Pneumonitis
Pneumonitis has been reported in patients receiving JEMPERLI. Patients should be monitored for signs and symptoms of pneumonitis. Suspected pneumonitis should be confirmed with radiographic imaging and other causes excluded. Patients should be managed with JEMPERLI treatment modifications and corticosteroids.

Immune-related pneumonitis occurred in 7 (1.4%) of 515 patients, including Grade 2 (1.2%) and Grade 3 (0.2%) pneumonitis. Pneumonitis led to discontinuation of JEMPERLI in 3 (0.6%) patients. Systemic corticosteroids (prednisone ≥ 40 mg per day or equivalent) were required in all 7 patients experiencing pneumonitis. Pneumonitis resolved in 6 (85.7%) patients.

Immune-Related Colitis
JEMPERLI can cause immune-related colitis. Patients should be monitored for signs and symptoms of colitis and managed with treatment modifications, anti-diarrhoeal agents and corticosteroids.

Colitis occurred in 8 (1.6%) patients, including Grade 2 (1.0%) and Grade 3 (0.6%) colitis. Colitis did not lead to discontinuation of JEMPERLI in any patients. Systemic corticosteroids (prednisone ≥ 40 mg per day or equivalent) were required in 2 (28.6%) patients. Colitis resolved in 6 (75.0%) patients experiencing colitis.

Immune-Related Hepatitis
JEMPERLI can cause immune-related hepatitis. Patients should be monitored for changes in liver function periodically as indicated, based on clinical evaluation and managed with JEMPERLI treatment modifications and corticosteroids.

Hepatitis occurred in 1 (0.2%) patient, which was Grade 3. Systemic corticosteroids (prednisone ≥ 40 mg per day or equivalent) were required. Hepatitis did not lead to discontinuation of JEMPERLI and resolved.

Immune-Mediated Endocrinopathies

Hypothyroidism occurred in 37 (7.2%) patients, all of which were Grade 2. Hypothyroidism did not lead to discontinuation of JEMPERLI and resolved in 13 (35.1%) patients.

Hyperthyroidism occurred in 10 (1.9%) patients, including Grade 2 (1.7%) and Grade 3 (0.2%). Hyperthyroidism did not lead to discontinuation of JEMPERLI and resolved in 8 (80%) patients.

Thyroiditis occurred in 2 (0.4%) patients; both were Grade 2. Neither event of thyroiditis resolved; there were no discontinuations of JEMPERLI due to thyroiditis.

Adrenal insufficiency occurred in 7 (1.4%) patients, including Grade 2 (0.8%), and Grade 3 (0.6%). Adrenal insufficiency resulted in discontinuation of JEMPERLI in 1 (0.2%) patient and resolved in 2 (28.6%) patients.

Immune-Mediated Nephritis
Nephritis, including tubulointerstitial nephritis, occurred in 3 (0.6%) patients; all were Grade 2. Systemic corticosteroids (prednisone ≥ 40 mg per day or equivalent) were required in 2 (66.7%) patients experiencing nephritis. Nephritis led to discontinuation of JEMPERLI in 1 (0.2%) patient and resolved in 2 of 3 (66.7%) patients.

Immune-Related Rash
Immune-related rash occurred in 17 (3.3%) patients, including Grade 3 in 6 (1.2%) patients receiving JEMPERLI. The median time to onset of rash was 41 days (range 2 days to 407 days). Systemic corticosteroids (prednisone ≥ 40 mg per day or equivalent) were required in 5 (29%) patients experiencing rash. Rash did not lead to discontinuation of JEMPERLI and resolved in 13 (76.5%) patients.

Immune-Related Arthralgia
Immune-related arthralgia occurred in 21 (4.1%) patients. Grade 3 immune-related arthralgia was reported in 3 (0.6%) patients receiving JEMPERLI. The median time to onset of arthralgia was 87 days (range 1 day to 783 days). Systemic corticosteroids (prednisone ≥ 40 mg per day or equivalent) were required in 2 (9.5%) patients experiencing arthralgia. Arthralgia did not lead to discontinuation of JEMPERLI and resolved in 8 (38%) patients experiencing arthralgia.

Other Immune-Related Adverse Reactions
Given the mechanism of action of JEMPERLI other potential immune-related adverse reactions may occur, including potentially serious events [e.g. myositis, myocarditis, encephalitis, demyelinating neuropathy (including Guillain Barré syndrome), sarcoidosis].

Clinically significant immune-related adverse reactions reported in less than 1% of patients treated with JEMPERLI as monotherapy in clinical studies include autoimmune haemolytic anaemia, pancreatitis, iridocyclitis, uveitis and diabetic ketoacidosis. Patients should be monitored for signs and symptoms of immune-related adverse reactions and managed as described in the SmPC.

Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with PD-1 inhibitors. Treatment with JEMPERLI may increase the risk of rejection in solid organ transplant recipients. The benefit of treatment with JEMPERLI versus the risk of possible organ rejection should be considered in these patients.

Fatal and other serious complications can occur in patients who receive allogeneic haematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1–blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GvHD), acute GvHD, chronic GvHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1–blocking antibody prior to or after an allogeneic HSCT.

Infusion-Related Reactions
Infusion-related reactions including hypersensitivity occurred in 7 (1.4%) patients, including Grade 2 (1.2%) and Grade 3 (0.2%) infusion-related reactions. All patients recovered from the infusion-related reaction.

Immunogenicity
Anti-drug antibodies (ADA) were tested in 315 patients who received JEMPERLI and the incidence of JEMPERLI treatment-emergent ADAs was 2.5%. Neutralising antibodies were detected in 1.3% of patients. In the patients who developed anti-JEMPERLI antibodies, there was no evidence of altered efficacy or safety of JEMPERLI.

Elderly population
Of the 515 patients treated with JEMPERLI monotherapy, 50.7% were under 65 years, 37.9% were 65-75 years, and 11.5% were 75 years or older. No overall differences in safety were reported between elderly (≥ 65 years) and younger patients (< 65 years).

Pregnancy, Lactation and Fertility
JEMPERLI is not recommended during pregnancy and in women of childbearing potential not using contraception. JEMPERLI should not be used during breast-feeding and breast-feeding should be avoided for at least 4 months after the last dose of JEMPERLI. Fertility studies have not been conducted with JEMPERLI.

COMMON ADVERSE REACTIONS
JEMPERLI is most commonly associated with immune-related adverse reactions. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of JEMPERLI.

In patients with advanced or recurrent solid tumours (N = 515), the most common adverse reactions (> 10%) were anaemia (25.6%), nausea (25.0%), diarrhoea (22.5%), vomiting (18.4%), arthralgia (13.8%), pruritus (11.5%), rash (11.1%), pyrexia (10.5%) and hypothyroidism (10.1%). JEMPERLI was permanently discontinued due to adverse reactions in 17 (3.3%) patients; most of them were immune-related events. Adverse reactions were serious in 8.7% of patients; most serious adverse reactions were immune-related adverse reactions.

AbbVie Receives Positive CHMP Opinion for VENCLYXTO® (venetoclax) as a Combination Regimen for Adult Patients with Newly Diagnosed Acute Myeloid Leukemia Who Are Ineligible for Intensive Chemotherapy

On April 23, 2021 AbbVie (NYSE: ABBV) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion for VENCLYXTO (venetoclax) in combination with hypomethylating agents for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy (Press release, AbbVie, APR 23, 2021, View Source [SID1234578398]). The positive CHMP opinion is a scientific recommendation for marketing authorization to the European Commission (EC), which is expected to deliver its final decision on VENCLYXTO combination therapy for use in AML in the first half of 2021.

The positive CHMP opinion represents the third for an extension of indications for VENCLYXTO. The opinion is based on results from the double-blind, placebo-controlled VIALE-A (M15-656) and the Phase 1b open-label, nonrandomized, multicenter M14-358 trial.

"This positive CHMP opinion for VENCLYXTO in acute myeloid leukemia is a critical step to providing new therapeutic options in the European Union for patients with this devastating disease," said Mohamed Zaki, M.D., Ph.D., vice president and global head of oncology development at AbbVie. "Enabling improved outcomes including potentially prolonging the lives of patients with malignant diseases such as acute myeloid leukemia is part of our mission and an objective we pursue relentlessly every day."

AML is the most common acute leukemia in the world.1 An estimated 160,000 people are currently living with the disease globally. 1 The rate of new cases of acute myeloid leukemia is 4.3 per 100,000 men and women per year.3 It is also among the most difficult blood cancers to treat.2 Despite advances in available therapies and care, the five-year survival rate for patients diagnosed with AML remains approximately 29 percent.3 AML typically worsens quickly, and due to age and comorbidities, not all patients can tolerate intensive chemotherapy.4

"AML is an incredibly aggressive form of cancer, and patients who are diagnosed with this disease are often so ill that they cannot tolerate the intensive chemotherapy that healthcare providers would typically prescribe," said Hartmut Döhner, M.D., Professor of Medicine and Director, Department of Hematology, Oncology, Palliative Care, Rheumatology and Infectious Diseases at University Hospital in Ulm, Germany. "VENCLYXTO combination therapy is a promising advancement for patients and their healthcare providers facing this challenging, lethal form of cancer."

Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S.

About the VENCLYXTO AML Clinical Trial Program
AbbVie’s clinical trial program to evaluate VENCLYXTO combination therapy in patients with newly diagnosed acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy included two studies conducted around the world.

VIALE-A (M15-656) Phase 3 Trial
The randomized, double-blind, placebo-controlled VIALE-A (M15-656) trial evaluated the efficacy and safety of VENCLYXTO in combination with azacitidine in patients with newly diagnosed AML who were ineligible for intensive chemotherapy. The study met its primary endpoints of statistically significant improvement of overall survival (OS) and complete remission rate and complete remission with incomplete hematologic recovery (CR + CRi). OS was 14.7 months for the VENCLYXTO plus azacitidine arm versus 9.6 months in the placebo plus azacitidine arm. The study also met secondary endpoints, with the VENCLYXTO plus azacitidine arm resulting in a CR rate of 36.7 percent vs. 17.9 percent in the placebo plus azacitidine arm and a composite complete remission rate (CR + CRi) of 66.4 percent versus 28.3 percent. The safety profile of VENCLYXTO plus azacitidine was consistent with the known side-effect profiles of both agents, and adverse events (AEs) were consistent with expectations for an older AML population; no differences between the two treatment arms with respect to quality-of-life measures were seen. The most frequently reported serious AEs in the VENCLYXTO plus azacitidine arm and placebo plus azacitidine arm were febrile neutropenia (in 30 percent and 10 percent), pneumonia (in 17 percent and 22 percent), sepsis (in 6 percent and 8 percent), and haemorrhage (in 9 percent and 6 percent).5

M14-358 Phase 1b Trial
The non-randomized, open-label M14-358 trial evaluated VENCLYXTO in combination with azacitidine or decitabine in patients with newly diagnosed AML. The trial showed patients treated with VENCLYXTO in combination with azacitidine achieved a CR rate of 44 percent and a CR+CRi rate of 71 percent. The median duration of response for patients treated with VENCLYXTO in combination with azacitidine who achieve a CR or CRi was 21.9 months. Median time to first CR or CRi was 1.2 months (range: 0.7 to 7.7 months). Patients who received VENCLYXTO in combination with decitabine achieved a CR rate of 55 percent and a CR+CRi rate of 74 percent. The median duration of response for patients treated with VENCLYXTO in combination with decitabine who achieved a CR or CRi was 15 months. Median time to first CR or CRi was 1.9 months (range: 0.9 to 5.4 months). The most frequently reported serious AEs in patients receiving VENCLYXTO in combination with azacitidine were febrile neutropenia (31 percent) and pneumonia (26 percent). The most frequently reported serious AEs in patients receiving VENCLYXTO in combination with decitabine were febrile neutropenia (42 percent), pneumonia (29 percent), bacteraemia (16 percent) and sepsis (6 percent).6

About VENCLYXTO (venetoclax)

VENCLYXTO (venetoclax) is a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers, BCL-2 prevents cancer cells from undergoing their natural death or self-destruction process, called apoptosis. VENCLYXTO targets the BCL-2 protein and works to help restore the process of apoptosis.

VENCLYXTO is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research and to studying venetoclax in clinical trials across several blood and other cancers. Venetoclax is approved in more than 80 countries, including the U.S.

Indication and Important VENCLYXTO (venetoclax) EU Safety Information7

Indication

Venclyxto in combination with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL).

Venclyxto in combination with rituximab is indicated for the treatment of adult patients with CLL who have received at least one prior therapy.

Venclyxto monotherapy is indicated for the treatment of CLL:

In the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor, or
In the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.
Contraindications

Hypersensitivity to the active substance or to any of the excipients is contraindicated. Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase due to increased risk for tumor lysis syndrome (TLS). Concomitant use of preparations containing St. John’s wort as VENCLYXTO efficacy may be reduced.

Special Warnings & Precautions for Use

TLS, including fatal events, has occurred in patients with CLL when treated with VENCLYXTO.

Patients should be assessed for risk and should receive appropriate prophylaxis, monitoring, and management for TLS. The risk of TLS is a continuum based on multiple factors, including comorbidities. VENCLYXTO poses a risk for TLS in the initial 5-week dose-titration phase. Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLYXTO and at each dose increase.

Neutropenia (grade 3 or 4) has been reported and complete blood counts should be monitored throughout the treatment period.

Serious infections including sepsis with fatal outcome have been reported. Monitoring of any signs and symptoms of infection is required. Suspected infections should receive prompt treatment including antimicrobials and dose interruption or reduction as appropriate.

Live vaccines should not be administered during treatment or thereafter until B-cell recovery.

Drug Interactions

CYP3A inhibitors may increase VENCLYXTO plasma concentrations. At initiation and dose-titration phase: Strong CYP3A inhibitors are contraindicated due to increased risk for TLS and moderate CYP3A inhibitors should be avoided. If moderate CYP3A inhibitors must be used, physicians should refer to the SmPC for dose adjustment recommendations. At steady daily dose: moderate or strong CYP3A inhibitors must be used, physicians should refer to the VENCLYXTO summary of product characteristics (SmPC) for dose adjustment recommendations.

Avoid concomitant use of P-gp and BCRP inhibitors at initiation and during the dose titration phase.

CYP3A4 inducers may decrease VENCLYXTO plasma concentrations. Avoid coadministration with strong or moderate CYP3A inducers. These agents may decrease venetoclax plasma concentrations.

Co-administration of bile acid sequestrants with VENCLYXTO is not recommended as this may reduce the absorption of VENCLYXTO.

Adverse Reactions

The most commonly occurring adverse reactions (>=20%) of any grade in patients receiving venetoclax in the combination studies with obinutuzumab or rituximab were neutropenia, diarrhoea, and upper respiratory tract infection. In the monotherapy studies, the most common adverse reactions were neutropenia/neutrophil count decreased, diarrhoea, nausea, anaemia, fatigue, and upper respiratory tract infection.

The most frequently occurring serious adverse reactions (>=2%) in patients receiving venetoclax in combination with obinutuzumab or rituximab were pneumonia, sepsis, febrile neutropenia, and TLS. In the monotherapy studies, the most frequently reported serious adverse reactions (>=2%) were pneumonia and febrile neutropenia.

Discontinuations due to adverse reactions occurred in 16% of patients treated with venetoclax in combination with obinutuzumab or rituximab in the CLL14 and Murano studies, respectively. In the monotherapy studies with venetoclax, 11% of patients discontinued due to adverse reactions.

Dosage reductions due to adverse reactions occurred in 21% of patients treated with the combination of venetoclax and obinutuzumab in CLL14, in 15% of patients treated with the combination of venetoclax and rituximab in Murano, and in 14% of patients treated with venetoclax in the monotherapy studies. The most common adverse reaction that led to dose interruptions was neutropenia.

Specific Populations

Patients with reduced renal function (CrCl <80 mL/min) may require more intensive prophylaxis and monitoring to reduce the risk of TLS at initiation and during the dose-titration phase. Safety in patients with severe renal impairment (CrCl <30 mL/min) or on dialysis has not been established, and a recommended dose for these patients has not been determined.

For patients with severe (Child-Pugh C) hepatic impairment, a dose reduction of at least 50% throughout treatment is recommended.

VENCLYXTO may cause embryo-fetal harm when administered to a pregnant woman. Advise nursing women to discontinue breastfeeding during treatment.

This is not a complete summary of all safety information. See VENCLYXTO (venetoclax) SmPC at www.ema.europa.eu. Globally, prescribing information varies; refer to the individual country product label for complete information.

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