On February 18, 2022 Atara Biotherapeutics, Inc. (Nasdaq: ATRA), a leader in T-cell immunotherapy, developing transformative therapies for patients with cancer and autoimmune diseases, reported Memorial Sloan Kettering Cancer Center’s (MSK) notification to the U.S. Food and Drug Administration (FDA) of a fatal serious adverse event (SAE) associated with a patient treated in the ongoing Phase 1, MSK-conducted dose-escalation clinical study of autologous mesothelin CAR T, ATA2271 (Press release, Atara Biotherapeutics, FEB 18, 2022, View Source [SID1234608314]). MSK has voluntarily paused enrollment of new patients in the study on a temporary basis while additional information regarding the case is gathered and reviewed. The FDA has notified MSK of its agreement with this approach.

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ATA2271 is a next-generation, autologous chimeric antigen receptor (CAR) T-cell therapy targeting mesothelin currently under clinical investigation in patients with malignant pleural mesothelioma. The single case involved a patient with a history of multiple malignancies and other comorbidities undergoing treatment for advanced recurrent mesothelioma. MSK is in the process of further evaluating the occurrence, including the extent of the relationship of the event to ATA2271.

"The safety of every patient participating in studies we are funding or conducting is of the utmost priority for Atara," said Jakob Dupont, MD, Head of Global Research & Development at Atara. "Clinical evaluation of the case remains ongoing, and we are working closely with investigators at MSK, who are conducting the ATA2271 study under their IND, to establish the underlying causes of the event. We anticipate providing a further update in the coming weeks following further discussion and consultation with MSK."

The median survival of treated patients with malignant pleural mesothelioma is 9-17 months even with successful completion of a combination of chemotherapy, aggressive surgical resection, and radiation therapy. The first six patients enrolled in the two lowest dose cohorts received either 1×106 cells/kg (patients 1-3) or 3×106 cells/kg (patient 4-6) intrapleural ATA2271. Within these two cohorts, no dose limiting toxicities have been reported to date. The patient event being reported relates to the first patient in a third, higher-dose cohort (6×106 cells/kg).

The temporary pause in ATA2271 study enrollment does not impact the IND-enabling work currently underway to advance ATA3271, a separate, off-the-shelf, allogeneic CAR-T therapy targeting mesothelin using next-generation PD1DNR and 1XX CAR technologies for patients with advanced mesothelioma. ATA3271, ATA3219, tab-cel, and ATA188 all utilize Atara’s allogeneic EBV T-cell platform, the safety and tolerability of which has been validated by clinical studies and experience in approximately 400 patients in various disease areas with no observed cytokine release syndrome (CRS) to date.

MSK Disclosure: MSK has intellectual property rights and associated interests by virtue of licensing agreements between MSK and Atara.

On February 18, 2022 Merck, a leading science and technology company, reported the results of an exploratory analysis from the Phase III JAVELIN Bladder 100 trial with 19 additional months of follow-up data from the initial primary analysis (Press release, Merck & Co, FEB 18, 2022, View Source [SID1234608330]). This analysis reinforced the original results and showed that BAVENCIO (avelumab) plus best supportive care (BSC) in the first-line maintenance setting prolonged median overall survival (OS) by 8.8 months versus BSC alone for patients with locally advanced or metastatic urothelial carcinoma (UC) whose tumors had not progressed on a platinum-based chemotherapy. These results were presented at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s annual Genitourinary Cancers Symposium taking place February 17-19, 2022.

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"Since the introduction of the first-line maintenance regimen of BAVENCIO plus best supportive care, it has been recommended with the highest level of evidence in the NCCN, ESMO (Free ESMO Whitepaper), EAU and JUA guidelines, and BAVENCIO first-line maintenance has become a standard of care in the locally advanced and metastatic UC treatment setting. The results from this analysis further reinforce the benefit of first-line maintenance therapy, and of BAVENCIO as the only immunotherapy in the maintenance setting shown to improve survival in this disease," said Thomas Powles, MBBS, MRCP, MD, Professor of Genitourinary Oncology, Lead for Solid Tumor Research at Barts Cancer Institute, Queen Mary University of London, and Director of Barts Cancer Centre, London, UK.

At 38 months median follow-up, patients who received first-line maintenance BAVENCIO plus BSC showed consistent overall survival benefit over patients on BSC alone.

Median OS was 23.8 months (95% CI, 19.9 to 28.8) vs 15.0 months (95% CI, 13.5 to 18.2) (HR 0.76; 95% CI, 0.631 to 0.915).1
43.7% of patients (95% CI, 38.2% to 49.0%) in the BAVENCIO arm were alive at 30 months vs 33.5% (95% CI, 28.4% to 38.7%) of patients who received BSC alone.1
In the population of patients with PD-L1+ tumors (n=358):

Median OS was 30.9 months (95% CI, 24.0-39.8) vs 18.5 months (95% CI, 14.1-24.2) (HR 0.69; 95% CI, 0.521 to 0.901).1
More than half (51.3%; 95% CI, 43.7% to 58.4%) of patients who received BAVENCIO were alive at 30 months vs 38.5% (95% CI, 30.9% to 46.1%) in the BSC arm.1
Median overall survival was measured from the time of randomization, after completion of four to six cycles of platinum-based chemotherapy.

The safety profile for BAVENCIO was consistent with the overall JAVELIN monotherapy clinical development program, with no new safety signals. Patients continued treatment until disease progression, unacceptable toxicity or any other criteria for withdrawal occurred. In the primary population of all randomized patients, 19.5% of patients received ≥2 years of treatment, with 10.2% of patients discontinuing due to treatment-related adverse event with onset after ≥12 months of treatment.

"Locally advanced and metastatic urothelial carcinoma has a low five-year survival rate and high recurrence rate, requiring additional medicines to maintain the benefits of chemotherapy and improve survival rates. The continued improvement in survival in the JAVELIN Bladder 100 trial further supports the use of BAVENCIO as maintenance therapy in patients whose disease has not progressed on first-line platinum-containing chemotherapy and reinforces our commitment to further evaluation of BAVENCIO in advanced bladder cancer," said Victoria Zazulina, MD, Head of Development Unit Oncology, Merck.

About JAVELIN Bladder 100
JAVELIN Bladder 100 (NCT02603432) is a Phase III, multicenter, multinational, randomized, open-label, parallel-arm study investigating first-line maintenance treatment with BAVENCIO plus BSC versus BSC alone in patients with locally advanced or metastatic UC. The primary endpoint was OS in the two primary populations of all patients and patients with PD-L1+ tumors defined by the Ventana SP263 assay. Secondary endpoints included progression-free survival, anti-tumor activity, safety, pharmacokinetics, immunogenicity, predictive biomarkers and patient-reported outcomes in the co-primary populations. All primary and secondary endpoints are measured from the time of randomization.

About Urothelial Carcinoma
Bladder cancer is the tenth most common cancer worldwide.2 In 2020, there were over half a million new cases of bladder cancer diagnosed, with around 200,000 deaths from the disease globally.2 In the US, an estimated 83,730 cases of bladder cancer were diagnosed in 2021, with around 10,000 locally advanced or metastatic cases presented annually.3 UC, which accounts for about 90% of all bladder cancers,4 becomes harder to treat as it advances, spreading through the layers of the bladder wall.5 Only 25% to 55% of patients receive any second-line therapy after first-line chemotherapy.6 In the US and EU5 markets, approximately 40% to 50% of patients receive an immune checkpoint inhibitor in second-line therapy.3 For patients with advanced UC, the five-year survival rate is 6.4%.3

About BAVENCIO (avelumab)
BAVENCIO is a human anti-programmed death ligand-1 (PD-L1) antibody. BAVENCIO has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, BAVENCIO has been shown to release the suppression of the T cell-mediated antitumor immune response in preclinical models.7-9 In November 2014, Merck and Pfizer announced a strategic alliance to co-develop and co-commercialize BAVENCIO.

BAVENCIO Approved Indications
The European Commission (EC) has authorized the use of BAVENCIO as monotherapy for the first-line maintenance treatment of adult patients with locally advanced or metastatic urothelial carcinoma (UC) who are progression-free following platinum-based chemotherapy. BAVENCIO in combination with axitinib is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). BAVENCIO is also authorized by the EC for use as a monotherapy for the treatment of adult patients with metastatic Merkel cell carcinoma (MCC).

In the US, BAVENCIO is indicated for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy. BAVENCIO is also indicated for the treatment of patients with locally advanced or metastatic UC who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

BAVENCIO in combination with axitinib is indicated in the US for the first-line treatment of patients with advanced RCC. Additionally, the US Food and Drug Administration (FDA) granted accelerated approval for BAVENCIO for the treatment of adults and pediatric patients 12 years and older with metastatic MCC. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

BAVENCIO is currently approved for at least one indication for patients in more than 50 countries.

BAVENCIO Safety Profile from the EU Summary of Product Characteristics (SmPC)
The special warnings and precautions for use for BAVENCIO monotherapy include infusion-related reactions, as well as immune-related adverse reactions that include pneumonitis and hepatitis (including fatal cases), colitis, pancreatitis (including fatal cases), myocarditis (including fatal cases), endocrinopathies, nephritis and renal dysfunction, and other immune-related adverse reactions. The special warnings and precautions for use for BAVENCIO in combination with axitinib include hepatotoxicity.

The SmPC list of the most common adverse reactions with BAVENCIO monotherapy in patients with solid tumors includes fatigue, nausea, diarrhea, decreased appetite, constipation, infusion-related reactions, weight decreased and vomiting. The list of most common adverse reactions with BAVENCIO in combination with axitinib includes diarrhea, hypertension, fatigue, nausea, dysphonia, decreased appetite, hypothyroidism, cough, headache, dyspnea, and arthralgia.

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On February 18, 2022 Cellectis (Euronext Growth: ALCLS – Nasdaq: CLLS), a clinical-stage biotechnology company using its pioneering gene-editing platform to develop life-saving cell and gene therapies, and Calyxt, Inc. ("Calyxt"), a majority-owned (61.8% as of December 31, 2021) subsidiary of Cellectis S.A., reported the placement to an institutional investor in an underwritten offering of (i) 3,880,000 shares of Calyxt common stock, (ii) pre-funded warrants to purchase up to 3,880,000 shares of its common stock, and (iii) common warrants to purchase up to 7,760,000 shares of its common stock (the "Offering") (Press release, Cellectis, FEB 18, 2022, View Source [SID1234608315]).

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The shares of common stock and the pre-funded warrants were each sold in combination with corresponding common warrants, with one common warrant to purchase one share of common stock for each share of common stock or each pre-funded warrant sold. The pre-funded warrants will have an exercise price of $0.0001 per share of Calyxt common stock and the common warrants will have an exercise price of $1.41 per share of Calyxt common stock. The pre-funded warrants will be immediately exercisable and remain exercisable until exercised, while the common warrants will be exercisable six months after the date of issuance and will have a term of five years from the date of exercisability. The aggregate public offering price for each share of common stock or each pre-funded warrant and, in each case, an accompanying common warrant was $1.41. All securities sold in the Offering were sold by Calyxt.

In connection with the Offering, Calyxt disclosed certain preliminary estimated financial information as of December 31, 2021: Calyxt’s cash and cash equivalents was $13.7 million, restricted cash was $0.6 million, total current liabilities were $4.1 million, and financing lease obligations, including current portion, were $17.9 million.

This preliminary financial information, which has not been audited, is based on information currently available to Calyxt and is subject to the completion of Calyxt’s year-end financial closing procedures. It is possible that Calyxt’s independent registered public accounting firm may identify items that require Calyxt to make adjustments to the preliminary estimates set forth above and those changes could be material.

In connection with the Offering, Calyxt also provided an updated description of certain aspects of its business (the "Updated Calyxt Business Disclosure") and updated the risk factor disclosure (the "Updated Calyxt Risk Factor Disclosure") from Calyxt’s prior filings with the U.S. Securities and Exchange Commission.

On February 18, 2022 Dizal Pharmaceutical Co., Ltd. (SHEX:688192) ("Dizal"), reported that the U.S. Food and Drug Administration ("FDA") has granted Fast Track Designation to DZD4205 (Golidocitinib) for the treatment of patients with Refractory or Relapsed Peripheral T-Cell Lymphoma (r/r PTCL) (Press release, Dizal Pharma, FEB 18, 2022, View Source [SID1234608331]).

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"Relapsed or refractory peripheral T-cell lymphoma is an aggressive and rare type of non-Hodgkin lymphoma. Patients with r/r PTCL are often associated with poor prognosis. Couple years ago, our translational science team first identified JAK1 as a potential target for PTCL treatment. Based on the finding, we launched clinical studies to test the hypothesis. Now, we have patient data which validated our translational science finding. This is a great example of translational science-driven drug development." said Dr. Xiaolin Zhang, Chief Executive Officer at Dizal. "The FDA Fast Track Designation for DZD4205 is an important milestone and we look forward to working closely with the U.S. FDA to potentially bring this treatment to our patients."

Fast track is a process designed by U.S. FDA to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. The purpose is to get important new drugs to the patient earlier [1].

About DZD4205 (Golidocitinib)

DZD4205 (Golidocitinib) is an orally available, potent, and JAK1-specific inhibitor. The preliminary data from an ongoing phase I/II study in r/r PTCL shows that 21 (42.9%) out of the 49 patients have achieved tumor response.

Dizal is conducting Phase II pivotal clinical trials in the U.S., China, Australia, South Korea and other countries and regions.

On February 18, 2022 TransThera Sciences (Nanjing), Inc. ("TransThera") reported that the U.S. Food and Drug Administration ("FDA") approved the Investigational New Drug ("IND") application of TT-01488, a non-covalent reversible Bruton’s Tyrosine Kinase ("BTK") inhibitor, for the treatment of B-cell lymphomas on January 24, 2022, and TransThera will initiate the Phase I clinical trials in the U.S. soon (Press release, TransThera Biosciences, FEB 18, 2022, View Source [SID1234608317]). TransThera also announced that China National Medical Products Administration ("NMPA") officially accepted the IND application of TT-01488 for the treatment of B-cell lymphomas on February 14, 2022.

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According to Frost & Sullivan, the global and China BTK inhibitor market reached USD7.2 billion and RMB1.3 billion in 2020 respectively. The market is expected to continue to expand in the next 5 years, with the CAGR of 22.7% globally and 58.6% in China from 2020 to 2025. As of 2021, there were 5 BTK inhibitors approved in different markets, all being covalent irreversible BTK inhibitors. The mechanism of action for covalent irreversible BTK inhibitors is to form covalent bond with the C481 site of BTK. However, when C481S mutation occurs, they will not be able to maintain the covalent bond, which eventually leads to drug resistance. Long-term follow-up results for the use of irreversible BTK inhibitors, according to Frost & Sullivan, demonstrate cumulative discontinuation rates as high as 40%, which show the large unmet medical needs.

"Non-covalent BTK inhibitors are not affected by the C481S mutation and are expected to overcome acquired resistance developed from marketed covalent BTK inhibitors. In a head-to-head kinase panel screening, TT-01488 demonstrated higher potency and better kinase selectivity on EGFR and TEC than peer non-covalent reversible BTK inhibitor under clinical investigation, indicating a potentially better safety profile. Moreover, in the DLBCL CDX model, TT-01488 showed a superior antitumor effect compared to peer non-covalent reversible BTK inhibitor." Said Dr. Peng Peng, vice president of project management and head of oncology portfolio at TransThera, "The approval by FDA and the acceptance from NMPA for its IND applications are two important milestones in the development of TT-01488. We will actively cooperate with the regulatory authorities to initiate the clinical trials of TT-01488 globally as soon as possible. "

About TT-01488：

TT-01488 is a non-covalent, reversible BTK inhibitor for overcoming acquired resistance mutation developed from marketed covalent BTK inhibitors in various types of B-Cell lymphomas. In preclinical trials, TT-01488 showed potential advantages such as overcoming drug resistance, improved target selectivity, antitumor efficacy and favorable safety.