On February 28, 2022 Atara Biotherapeutics, Inc. (Nasdaq: ATRA), a leader in T-cell immunotherapy, leveraging its novel allogeneic EBV T-cell platform to develop transformative therapies for patients with cancer and autoimmune diseases, reported financial results for the fourth quarter and full year 2021, recent business highlights and key upcoming catalysts for 2022 (Press release, Atara Biotherapeutics, FEB 28, 2022, View Source [SID1234609107]).

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"With our EMA filing for tab-cel and a strategic commercial collaboration with Pierre Fabre, ATA188’s FDA Fast Track designations and new data reinforcing its potential to reverse or halt disability in progressive multiple sclerosis, 2021 provided strong validation for Atara and our industry-leading allogeneic T-cell pipeline," said Pascal Touchon, President and Chief Executive Officer of Atara.

"2022, which has already delivered two landmark publications confirming EBV as the leading cause of MS in advance of our interim analysis from our ATA188 Phase 2 study, and a long-term strategic manufacturing partnership with Fujifilm, will be a critical year as we progress our strategic priorities. Although further engagement and alignment is required with FDA to determine the path forward for a BLA submission in the U.S., we anticipate a groundbreaking EU approval this year that will position tab-cel as the first ever allogeneic off-the-shelf T-cell therapy available for patients."

Tabelecleucel (tab-cel) for Post-Transplant Lymphoproliferative Disease (PTLD)

Atara has performed extensive studies demonstrating analytical comparability between the tab-cel manufacturing process versions used for the pivotal study and that intended for commercialization

Comprehensive comparability analyses included all 74 available product lots manufactured by Atara and covered 21 key attributes associated with potency, purity, and alloreactivity. Atara believes analytic comparability between tab-cel process versions has been demonstrated based on well-established statistical methodology and application of ICH1 guidelines and is further supported by significant and consistent clinical experience

These comparability data analyses were submitted to the European Medicines Agency (EMA) through our MAA filing in November 2021 and the review, under Accelerated Assessment, is progressing as planned following receipt of EMA day 80 Critical Assessment report, with anticipated approval in Q4 2022

A Type B CMC meeting was conducted in late February 2022 with the U.S. Food & Drug Administration (FDA) review team to discuss and potentially align on comparability between commercial and pivotal clinical trial products

The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use

Preliminary meeting responses and discussion did not result in alignment on comparability and the FDA has initially recommended Atara conduct a clinical study with commercial product as they do not agree that comparability has been demonstrated

Atara has responded with additional questions to clarify the FDA’s view and has suggested several alternative approaches to progress to a BLA submission given tab-cel is a BTD product that addresses an urgent medical need and has the potential to save the lives of patients with an ultra-rare, often fatal disease with no approved therapeutic options

Additional interactions with the Agency are expected, including receipt of final Type B CMC meeting minutes. However, based on the preliminary feedback received from the FDA, Atara does not currently expect to file a BLA in Q2 2022.

Atara expects further engagement with FDA on potential pathways to a BLA submission for tab-cel and plans to provide a further update during its next quarterly call

After entering an exclusive commercialization collaboration in Q4 2021, Atara is working with Pierre Fabre to prepare for the launch of tab-cel in Europe while adapting its U.S. commercialization preparation to account for possible delays in submission and potential approval of a BLA in the U.S.

Tab-cel for Potential Additional Indications

The multi-cohort Phase 2 study evaluating tab-cel in six additional patient populations for EBV+ immunodeficiency-associated lymphoproliferative diseases (IA-LPDs) and other EBV-driven diseases is currently enrolling in the U.S. and EU

First data from the multi-cohort study is on track for presentation in 2023

ATA188 for Progressive Multiple Sclerosis (MS)

Recent landmark studies further validate Atara’s approach and EBV-targeted platform. Publications in Science and Nature provide compelling new epidemiological evidence that EBV is the leading cause of MS and mechanistic evidence showing how EBV infection can initiate and propagate the autoimmune attack on the brain in MS

The FDA granted Fast Track designation to ATA188 for non-active primary progressive multiple sclerosis (PPMS) and non-active secondary progressive multiple sclerosis (SPMS), two populations with high unmet medical need and limited treatment options

Encouraging data presented at ECTRIMS 2021 from the ongoing Phase 1 open-label extension study of ATA188 with up to 39 months follow-up demonstrated that 20 out of 24 patients had sustained disability improvement or stabilization of disease on expanded disability status scale (EDSS)

Patients who achieved sustained EDSS improvement at any time showed significant increase in Magnetization Transfer Ratio (MTR) in non-enhancing T2 lesions at 12 months compared to baseline, suggestive of remyelination

Atara continues to advance enrollment in the Phase 2 EMBOLD study, with target enrollment of 80 patients expected soon after a planned formal interim analysis (IA) in Q2 2022

The IA will include efficacy, safety, and biomarker data to inform adjustments to sample size, if needed, to optimize likelihood of Phase 2 success, and confirm the Company’s current development strategy moving forward

A key data point at the time of the IA will be EDSS improvement at six months for applicable patients. In the Phase 1 study, EDSS improvement at six months was >85 percent predictive of achieving sustained EDSS improvement at 12 months, the primary endpoint of EMBOLD

Following the IA, Atara plans to communicate next steps for the program, including rationale, while still maintaining the integrity of the study. Atara also plans to interact with the FDA following the IA to discuss potential development pathways for ATA188

Prior to conducting the IA in Q2 2022, the Company will host a public webcast, Atara MS Day, for the investor community on March 22nd to review the key drivers generating excitement around our potentially transformative ATA188 MS program. The Company will also communicate new areas of development, including exploratory work on a differentiated EBV vaccine with encouraging pre-clinical data

CAR T Programs

Atara is building an innovative next-generation CAR T platform, which includes key features needed for efficacy and persistence, such as the use of PD-1 dominant negative receptor (DNR) and 1XX CAR co-stimulatory signaling domain technologies

The CAR T platform retains the endogenous T-cell receptor (TCR), shown to be essential for T cell persistence and survival

ATA2271/ATA3271 (Solid Tumors Over-Expressing Mesothelin)

The global strategic collaboration for autologous ATA2271 and allogeneic ATA3271 with Bayer continues to progress

Encouraging early safety and persistence of ATA2271 from lower dose cohorts of the ongoing Phase 1 dose-escalation trial in patients with advanced mesothelioma was presented at the ESMO (Free ESMO Whitepaper) Immuno-Oncology Congress in December 2021

Memorial Sloan Kettering Cancer Center (MSK) notified the FDA of a fatal serious adverse event (SAE) associated with a patient treated in the third, higher dose cohort in the ongoing Phase 1, MSK-conducted dose-escalation clinical study of autologous mesothelin CAR T, ATA2271

MSK has voluntarily paused enrollment of new patients in the ATA2271 study on a temporary basis while additional information regarding the case is gathered and reviewed. The FDA notified MSK of its agreement with this approach

Subject to the outcome of this review and resumption of enrollment of new patients in this study we expect to provide a data update from this Phase 1 study in 2022

The single case involved a patient with a history of multiple malignancies and other comorbidities undergoing treatment for advanced recurrent mesothelioma

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 PD-1 DNR and 1XX CAR technologies for patients with advanced mesothelioma, with an expected IND filing in Q4 2022

Atara’s pipeline programs, including ATA3271, ATA3219, tab-cel, and ATA188 all utilize the Company’s allogeneic EBV T-cell platform, the safety and tolerability of which has been demonstrated by clinical studies and experience in approximately 400 patients in various disease areas with no SAEs, including cytokine release syndrome (CRS), observed to date

ATA3219 (B-cell Malignancies)

Atara is progressing ATA3219, our potential best-in-class, allogeneic CAR T for B cell malignancies expressing CD19, and expects to submit an IND in Q4 2022

ATA3219 is an optimized approach to address high unmet medical need, leveraging our next-generation 1XX CAR co-stimulatory signaling domain and allogeneic EBV T-cell platform and does not require TCR or human leukocyte antigen (HLA) gene editing

Allogeneic T-Cell Platform Development and Operations

Atara entered a strategic manufacturing partnership in January 2022 with FUJIFILM Diosynth Biotechnologies (FDB), a subsidiary of FUJIFILM Corporation (Fujifilm), under which Fujifilm will acquire Atara’s T-cell Operations and Manufacturing (ATOM) facility for USD 100 million upfront, retaining current manufacturing and quality staff at the site. Closing of the transaction is expected to occur in April

As part of the long-term supply agreement, which could extend to 10 years following anticipated completion of the transaction, FDB will also provide Atara with flexible capacity and specific capability needed to manufacture and support the Company’s maturing and promising pipeline

Atara continues to leverage its recently established and now fully operational Thousand Oaks-based Atara Research Center (ARC), which houses the Company’s Pre-Clinical, Translational Sciences, Manufacturing Process Sciences, and Analytical Development Teams to further drive innovation

Fourth Quarter and Full Year 2021 Financial Results

Cash, cash equivalents and short-term investments as of December 31, 2021 totaled $371.1 million, as compared to $500.7 million as of December 31, 2020

The December 31, 2021 cash balance includes $47.7 million of net proceeds from the sale of 2,836,062 shares of common stock through the Company’s ATM facilities in the fourth quarter, and a $45.0 million upfront payment received under the Pierre Fabre Commercialization Agreement, partially offset by operating cash outflows

Atara believes that its cash as of December 31, 2021, together with the anticipated $100.0 million payable to Atara upon closing of the strategic transaction with FDB, will be sufficient to fund the Company’s planned operations into the fourth quarter of 2023

Net cash used in operating activities was $34.3 million and $220.5 million for the fourth quarter and fiscal year 2021, respectively, as compared to $4.1 million and $180.8 million for the same periods in 2020; the increase in operating cash usage in 2021 was primarily due to a $33.5 million increase in net loss and increased usage of net working capital, partially offset by $45.0 million received under the Pierre Fabre Commercialization Agreement

Atara reported net losses of $93.3 million, or $0.96 per share, and $340.1 million, or $3.63 per share, for the fourth quarter and fiscal year 2021, respectively, as compared to $81.3 million, or $0.95 per share, and $306.6 million, or $4.15 per share, for the same periods in 2020

Total operating expenses include non-cash expenses of $16.5 million and $63.0 million for the fourth quarter and fiscal year 2021, respectively, as compared to $13.6 million and $59.4 million for the same periods in 2020

Research and development expenses were $79.1 million and $282.0 million for the fourth quarter and fiscal year 2021, respectively, as compared to $65.6 million and $244.7 million for the same periods in 2020

The increases in the fourth quarter and fiscal year 2021 were primarily due to higher employee-related and overhead costs from increased headcount, higher facility-related costs in support of continuing expansion of research and development activities and increased spending on research, development and clinical trial costs to further advance ATA188 and CAR T programs

Research and development expenses include $8.4 million and $32.1 million of non-cash stock-based compensation expenses for the fourth quarter and fiscal year 2021, respectively, as compared to $7.2 million and $31.5 million for the same periods in 2020

General and administrative expenses were $21.8 million and $78.8 million for the fourth quarter and fiscal year 2021, respectively, as compared to $16.1 million and $64.4 million for the same periods in 2020

The increases in the fourth quarter and fiscal year 2021 were primarily due to higher compensation-related costs from increased headcount and activities to support an anticipated tab-cel launch

General and administrative expenses include $5.6 million and $21.8 million of non-cash stock-based compensation expenses for the fourth quarter and fiscal year 2021, respectively, as compared to $4.3 million and $19.8 million for the same periods in 2020

Conference Call and Webcast Details

Atara will host a live conference call and webcast today, Monday, February 28, 2022, at 4:30 p.m. EST to discuss the Company’s financial results and recent operational highlights. Analysts and investors can participate in the conference call by dialing 877-407-8291 for domestic callers and 201-689-8345 for international callers, using the conference ID 13725930. A live audio webcast can be accessed by visiting the Investors & Media – News & Events section of atarabio.com. An archived replay will be available on the Company’s website for 30 days following the live webcast.

On February 28, 2022 Arvinas, Inc. (Nasdaq: ARVN), a clinical-stage biotechnology company creating a new class of drugs based on targeted protein degradation, reported financial results for the fourth quarter and full year ended December 31, 2021 and provided a corporate update (Press release, Arvinas, FEB 28, 2022, View Source [SID1234609106]).

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"It has been an exciting time for Arvinas over the past 12 months, including the beginning of a transformational collaboration with Pfizer, and compelling clinical updates supporting our two lead clinical programs, ARV-471 and bavdegalutamide, or ARV-110," said John Houston, Ph.D., chief executive officer and president at Arvinas. "We believe ARV-471 has the potential for a best-in-class profile for the treatment of ER+/HER2- breast cancer and, looking ahead, we have a number of important clinical milestones upcoming with ARV-471, including the initiation of two planned Phase 3 trials in metastatic breast cancer as a monotherapy and in combination."

"To follow up our strong finish to 2021, we began 2022 by presenting new data at ASCO (Free ASCO Whitepaper) GU that showed bavdegalutamide demonstrated a clinical profile that we believe supports its potential as a precision medicine for men with prostate cancer and tumors harboring AR T878/H875 point mutations," continued Dr. Houston. "We anticipate starting a pivotal trial with bavdegalutamide by year-end 2022, which will be our third pivotal trial planned for the year – one with bavdegalutamide, and two with ARV-471. We are making significant progress across our pipeline, bringing us one step closer to potentially delivering life-saving new therapies to patients."

Business Highlights and Recent Developments

In December 2021, presented ARV-471 Phase 1 dose escalation trial data at the San Antonio Breast Cancer Symposium, continuing to demonstrate an encouraging clinical benefit rate (CBR) in patients with locally advanced or metastatic ER+/HER2- breast cancer
ARV-471 demonstrated antitumor activity in patients previously treated with cyclin-dependent kinase (CDK) 4/6 inhibitors, with a CBR of 40% in 47 evaluable patients
Three patients exhibited confirmed RECIST (Response Evaluation Criteria in Solid Tumors) partial responses (among 38 patients with measurable disease at baseline who had ≥1 on-treatment scan)
ARV-471 continued to demonstrate a favorable tolerability profile
In February 2022, presented completed Phase 1 dose escalation and ongoing Phase 2 ARDENT expansion cohort data from bavdegalutamide in metastatic castration-resistant prostate cancer (mCRPC) at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary Cancers Symposium (ASCO GU), that showed:
A PSA50 rate (reduced prostate-specific antigen (PSA) levels greater than or equal to 50%) of 46% in patients with AR T878X/H875Y (T878X = T878A or T878S) tumor mutations (n=28)
Two durable confirmed RECIST partial responses (out of seven RECIST-evaluable patients with AR T878X/H875Y tumor mutations)
Bavdegalutamide had a manageable tolerability profile at the recommended Phase 2 dose (RP2D) of 420 mg oral, once daily
PSA reductions and evidence of anti-tumor activity as measured by RECIST were observed across all subgroups regardless of mutation status, including in patients with tumors not harboring AR T878X/875Y mutations
Anticipated 2022 Milestones and Expectations

ARV-471

Present data from the VERITAC Phase 2 expansion trial (200 mg and 500 mg) (2H 2022)
Present safety data from the Phase 1b combination trial with palbociclib (2H 2022)
Initiate two Phase 3 trials in patients with metastatic breast cancer (as monotherapy and in combination)
Initiate a Phase 1b combination trial with CDK inhibitors or other targeted therapies
Initiate a Phase 1b combination trial with everolimus
Initiate a Phase 2 neoadjuvant trial in patients with early breast cancer
Bavdegalutamide (ARV-110)

Discuss the potential accelerated approval path with the Food and Drug Administration (FDA) (1H 2022)
Finalize partnership for a companion diagnostic (1H 2022)
Initiate a pivotal trial in mCRPC for patients with AR T878/H875 tumor mutations (2H 2022)
ARV-766

Share Phase 1 dose escalation data in mCRPC (2H 2022)
Initiate Phase 2 expansion trial in mCRPC (2H 2022)
Full Year and Fourth Quarter Financial Results
Cash, Cash Equivalents and Marketable Securities Position: As of December 31, 2021, cash, cash equivalents, restricted cash and marketable securities were $1,507.1 million, as compared with $688.6 million as of December 31, 2020. The increase in cash, cash equivalents, restricted cash and marketable securities of $818.5 million for the year was primarily related to cash received from the global Pfizer collaboration agreement to develop and commercialize ARV-471 (ARV-471 Collaboration Agreement) of $650.0 million, the equity investment by Pfizer of $350.0 million and proceeds from the exercise of stock options of $18.6 million, partially offset by cash used in operating activities of $172.7 million (net of $4.2 million received from two collaborators), professional fees associated with the ARV-471 Collaboration Agreement and equity investment of $17.5 million, the purchase of lab equipment and leasehold improvements of $4.7 million and unrealized loss on marketable securities of $5.2 million.

Research and Development Expenses: Research and development expenses were $180.4 million and $61.8 million for the year and quarter ended December 31, 2021, respectively as compared with $108.4 million and $33.2 million for the year and quarter ended December 31, 2020, respectively. The increase in research and development expenses of $72.0 million for the year ended December 31, 2021, was primarily due to an increase in expenses associated with our platform and exploratory programs of $41.2 million, our AR program (which includes bavdegalutamide and ARV-766) of $17.4 million and our ER program of $13.4 million. The increase in research and development expenses of $28.6 million for the quarter ended December 31, 2021, was primarily due to an increase in expenses associated with our platform and exploratory programs of $15.0 million, our AR program of $3.2 million and our ER program of $10.4 million.

General and Administrative Expenses: General and administrative expenses were $61.6 million and $18.9 million for the year and quarter ended December 31, 2021, respectively, as compared with $38.3 million and $12.2 million for the year and quarter ended December 31, 2020, respectively. The increase in general and administrative expenses of $23.3 million for the year ended December 31, 2021, was primarily due to an increase of personnel and facility related costs of $19.2 million and insurance, taxes and professional fees of $4.2 million. The increase in general and administrative expenses of $6.7 million for the quarter ended December 31, 2021was primarily due to an increase of personnel and facility related costs of $6.0 million and insurance, taxes and professional fees of $0.6 million.

Revenues: Revenue was $46.7 million and $26.3 million for the year and quarter ended December 31, 2021, respectively, as compared with $21.8 million and $2.2 million for the year and quarter ended December 31, 2020, respectively. Revenue is related to the ARV-471 Collaboration Agreement with Pfizer that was initiated in July 2021, the license and rights to technology fees and research and development activities related to the collaboration and license agreement with Bayer that was initiated in July 2019, the collaboration and license agreement with Pfizer that was initiated in January 2018 and the amended and restated option, license and collaboration agreement with Genentech that was initiated in November 2017. The increase in revenue of $24.9 million and $24.1 million for the year and quarter ended December 31, 2021, respectively was primarily due to revenue from the ARV-471 Collaboration Agreement with Pfizer.

Net Loss: Net loss was $191.0 million and $53.0 million for the year and quarter ended December 31, 2021, respectively as compared with $119.3 million and $41.5 million for the year and quarter ended December 31, 2020, respectively. The increase in net loss for the year and quarter ended December 31, 2021, was primarily due to increased research and development expenses and increased general and administrative expenses, partially offset by increased revenue.

About bavdegalutamide (ARV-110)
Bavdegalutamide (ARV-110) is an investigational orally bioavailable PROTAC protein degrader designed to selectively target and degrade the androgen receptor (AR). Bavdegalutamide is being developed as a potential treatment for men with metastatic castration-resistant prostate cancer.

Bavdegalutamide has demonstrated activity in preclinical models of AR mutation or overexpression, both common mechanisms of resistance to currently available AR-targeted therapies.

About ARV-471
ARV-471 is an investigational orally bioavailable PROTAC protein degrader designed to specifically target and degrade the estrogen receptor (ER) for the treatment of patients with locally advanced or metastatic ER+/HER2- breast cancer.

In preclinical studies, ARV-471 demonstrated near-complete ER degradation in tumor cells, induced robust tumor shrinkage when dosed as a single agent in multiple ER-driven xenograft models, and showed superior anti-tumor activity when compared to a standard of care agent, fulvestrant, both as a single agent and in combination with a CDK4/6 inhibitor. In July 2021, Arvinas announced a global collaboration with Pfizer for the co-development and co-commercialization of ARV-471; Arvinas and Pfizer will equally share worldwide development costs, commercialization expenses, and profits.

About ARV-766
ARV-766 is an investigational orally bioavailable PROTAC protein degrader designed to selectively target and degrade AR. In preclinical studies, ARV-766 degraded all resistance-driving point mutations of AR, including L702H, a mutation associated with treatment with abiraterone and other AR-pathway therapies.

ARV-766 is being developed as a potential treatment for men with metastatic castration-resistant prostate cancer, and ARV-766 may also have applicability in other AR-driven diseases both in and outside oncology. ARV-766 has demonstrated activity in preclinical models of resistance to currently available AR-targeted therapies.

On February 28, 2022 Agios Pharmaceuticals, Inc. (NASDAQ: AGIO), a leader in the field of cellular metabolism pioneering therapies for genetically defined diseases, reported the company is scheduled to present at the following March investor conferences (Press release, Agios Pharmaceuticals, FEB 28, 2022, View Source [SID1234609105]):

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Cowen 42nd Annual Virtual Healthcare Conference on Monday, March 7, 2022, at 9:10 a.m. ET; and
Oppenheimer 32nd Annual Virtual Healthcare Conference on Wednesday, March 16, 2021 at 1:20 p.m. ET.
Live webcasts of the presentations can be accessed under "Events & Presentations" in the Investors section of the company’s website at www.agios.com. Replays of the webcasts will be archived on the Agios website for at least two weeks following each presentation.

On February 28, 2022 Semmelweis University and pharmaceutical group Sanofi reported that they have signed a cooperation agreement to increase the number of clinical trials they participate in jointly (Press release, Semmelweis University, FEB 28, 2022, View Source [SID1234609094]). Under the agreement, the university will become one of the company’s partner institutions and a member of its global network of partner sites. The agreement will enable the university to provide patients with innovative therapeutic options and its researchers and physicians to be among the first to gain experience with new treatments.

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"The strategic objectives of Semmelweis University include increasing clinical research activities and further developing strategic partnerships with the pharmaceutical industry. Participation in clinical trials and the intensification of cooperation in this area will not only enable our patients to gain access to innovative therapeutic options as soon as possible, but will also enable our researchers and doctors to be among the first to gain experience with new treatment methods," said Rector Dr. Béla Merkely on the occasion of the signing of the cooperation agreement. In 2021, around 150 new trials were launched at the university, and in the last month around 700 patients participated in trials at the university’s departments. The leading therapeutic areas are oncology, neurology, cardiology, pediatrics and dermatology, he said.

The rector noted that Sanofi is one of the world’s largest pharmaceutical groups, with a centuries-old tradition in Hungary. He pointed out that under the partnership agreement on clinical trials, Semmelweis University will become one of Sanofi’s key partner institutions and a member of its global network of partner trial sites.

Working together, we can create innovations that help people live healthier lives and improve their quality of life,"

– he said. Dr. Béla Merkely pointed out that this also plays a significant role in the research performance of the institution, which has a major impact on its position in international rankings. "Recognizing this, we have strengthened our system of support for research, development and innovation, including the establishment of the Clinical Research Coordination Center. We have developed a new set of procedures to reduce and simplify the administration of clinical research start-ups," he underlined. "The agreement is another step towards the strategic goal of making the university one of the top 100 higher education institutions in the world and one of the top 5 medical universities in Europe," said the rector.

Dr. Tamás Rónay, CEO of Sanofi Hungary, emphasized in his speech that today cooperation, joint thinking and knowledge sharing have become particularly important, which is much needed in all fields of science and society as a whole. However, the pharmaceutical industry and medicine have gone hand in hand since the very beginning. "The pharmaceutical industry is working to bring newer, more innovative, more effective and more personalized medicines to patients. Clinical trials are a key part of this process. But this clinical trial can only be successful if the patient, the doctor and the drug developer work closely together," he said. But clinical trials are not just about therapeutic benefits: trials conducted in Hungary strengthen Hungary’s role in the pharmaceutical industry, improve doctors and therapeutic protocols, and give patients access to innovative therapies not available elsewhere.

Rónay pointed out that Sanofi is currently conducting more than 30 clinical trials in Hungary at nearly 100 sites, with the participation of 1,200 patients and healthy volunteers, in all key therapeutic areas of the group, and Semmelweis University is involved in all of them.

"Through our collaborations, our group is playing an increasingly important role not only in the pharmaceutical industry itself, but also in the development of health care research and the innovation ecosystem, which is of key importance to the national economy," he said. He added that the company and the university share common goals, as both are working to safeguard the health of the Hungarian people.

The cooperation agreement was signed by Rector Dr. Béla Merkely and Chancellor Dr. Lívia Pavlik on behalf of the university, and by CEO Dr. Tamás Rónay and Director of Clinical Research Dr. Mária Letanóczki on behalf of Sanofi.

In his closing remarks, Vice-Rector for Science and Innovation Dr. Péter Ferdinandy thanked the Semmelweis Citizens who helped to conclude the agreement, with special mention to Dr. János Filakovszky, director of the Clinical Research Coordination Center. He also expressed the hope that the collaboration will generate preclinical research and early phase development in addition to clinical research, which may even lead to joint intellectual properties.

On February 28, 2022 Astellas Pharma Inc. (TSE:4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") and Seagen Inc. (Nasdaq:SGEN) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has confirmed its previously adopted positive opinion, recommending approval of PADCEV (enfortumab vedotin) as monotherapy for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received platinum-containing chemotherapy and a PD-1/L1 inhibitor (Press release, Seagen, FEB 28, 2022, View Source [SID1234609093]).

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The CHMP initially adopted a positive opinion of enfortumab vedotin on December 16, 2021, providing its recommendation to the European Commission (EC) for a final decision. During the EC’s decision-making process, further safety information was brought to the attention of the CHMP. Following a request from the EC and taking into account the latest information, the CHMP re-adopted its positive opinion.1 If approved by the EC, enfortumab vedotin will be the first antibody-drug conjugate authorized in the European Union for people living with advanced urothelial cancer.

The positive opinion from the CHMP will now be reviewed by the EC. EC decisions are valid in the European Union Member States, as well as Iceland, Norway and Liechtenstein.2

About Urothelial Cancer

Urothelial cancer is the most common type of bladder cancer (90 percent of cases) and can also be found in the renal pelvis (where urine collects inside the kidney), ureter (tube that connects the kidneys to the bladder) and urethra.3 Globally, approximately 573,000 new cases of bladder cancer and 212,000 deaths are reported annually.4

About Enfortumab Vedotin

Enfortumab vedotin is an antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.5,6 Nonclinical data suggest the anticancer activity of enfortumab vedotin is due to its binding to Nectin-4 expressing cells followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).6

PADCEV (enfortumab vedotin-ejfv) U.S. Indication & Important Safety Information

BOXED WARNING: SERIOUS SKIN REACTIONS

PADCEV can cause severe and fatal cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which occurred predominantly during the first cycle of treatment, but may occur later.
Closely monitor patients for skin reactions.
Immediately withhold PADCEV and consider referral for specialized care for suspected SJS or TEN or severe skin reactions.
Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions.
U.S. Indication

PADCEV is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC) who:

have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy, or
are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.5
Important Safety Information

Warnings and Precautions

Skin reactions Severe cutaneous adverse reactions, including fatal cases of SJS or TEN, occurred in patients treated with PADCEV. SJS and TEN occurred predominantly during the first cycle of treatment but may occur later. Skin reactions occurred in 55% of the 680 patients treated with PADCEV in clinical trials. Twenty-three percent (23%) of patients had maculo-papular rash and 33% had pruritus. Grade 3-4 skin reactions occurred in 13% of patients, including maculo-papular rash, rash erythematous, rash or drug eruption, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), dermatitis bullous, dermatitis exfoliative, and palmar-plantar erythrodysesthesia. In clinical trials, the median time to onset of severe skin reactions was 0.6 months (range: 0.1 to 6.4). Among patients experiencing a skin reaction leading to dose interruption who then restarted PADCEV (n=59), 24% of patients restarting at the same dose and 16% of patients restarting at a reduced dose experienced recurrent severe skin reactions. Skin reactions led to discontinuation of PADCEV in 2.6% of patients. Monitor patients closely throughout treatment for skin reactions. Consider topical corticosteroids and antihistamines, as clinically indicated. Withhold PADCEV and refer for specialized care for suspected SJS or TEN or for severe (Grade 3) skin reactions. Permanently discontinue PADCEV in patients with confirmed SJS or TEN, or for Grade 4 or recurrent Grade 3 skin reactions.

Hyperglycemia and diabetic ketoacidosis (DKA), including fatal events, occurred in patients with and without pre-existing diabetes mellitus, treated with PADCEV. Patients with baseline hemoglobin A1C ≥8% were excluded from clinical trials. In clinical trials, 14% of the 680 patients treated with PADCEV developed hyperglycemia; 7% of patients developed Grade 3-4 hyperglycemia. The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. Five percent (5%) of patients required initiation of insulin therapy for treatment of hyperglycemia. The median time to onset of hyperglycemia was 0.6 months (range: 0.1 to 20.3). Hyperglycemia led to discontinuation of PADCEV in 0.6% of patients. Closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia. If blood glucose is elevated (>250 mg/dL), withhold PADCEV.

Pneumonitis Severe, life-threatening or fatal pneumonitis occurred in patients treated with PADCEV. In clinical trials, 3.1% of the 680 patients treated with PADCEV had pneumonitis of any grade and 0.7% had Grade 3-4. In clinical trials, the median time to onset of pneumonitis was 2.9 months (range: 0.6 to 6). Monitor patients for signs and symptoms indicative of pneumonitis, such as hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams. Evaluate and exclude infectious, neoplastic and other causes for such signs and symptoms through appropriate investigations. Withhold PADCEV for patients who develop persistent or recurrent Grade 2 pneumonitis and consider dose reduction. Permanently discontinue PADCEV in all patients with Grade 3 or 4 pneumonitis.

Peripheral neuropathy (PN) occurred in 52% of the 680 patients treated with PADCEV in clinical trials, including 39% with sensory neuropathy, 7% with muscular weakness and 6% with motor neuropathy; 4% experienced Grade 3-4 reactions. PN occurred in patients treated with PADCEV with or without preexisting PN. The median time to onset of Grade ≥2 PN was 4.6 months (range: 0.1 to 15.8 months). Neuropathy led to treatment discontinuation in 5% of patients. Monitor patients for symptoms of new or worsening peripheral neuropathy and consider dose interruption or dose reduction of PADCEV when PN occurs. Permanently discontinue PADCEV in patients who develop Grade ≥3 PN.

Ocular disorders were reported in 40% of the 384 patients treated with PADCEV in clinical trials in which ophthalmologic exams were scheduled. The majority of these events involved the cornea and included events associated with dry eye such as keratitis, blurred vision, increased lacrimation, conjunctivitis, limbal stem cell deficiency, and keratopathy. Dry eye symptoms occurred in 34% of patients, and blurred vision occurred in 13% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.6 months (range: 0 to 19.1 months). Monitor patients for ocular disorders. Consider artificial tears for prophylaxis of dry eyes and ophthalmologic evaluation if ocular symptoms occur or do not resolve. Consider treatment with ophthalmic topical steroids, if indicated after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV for symptomatic ocular disorders.

Infusion site extravasation Skin and soft tissue reactions secondary to extravasation have been observed after administration of PADCEV. Of the 680 patients, 1.6% of patients experienced skin and soft tissue reactions, including 0.3% who experienced Grade 3-4 reactions. Reactions may be delayed. Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation and resolved within 1-4 weeks of peak. Two patients (0.3%) developed extravasation reactions with secondary cellulitis, bullae, or exfoliation. Ensure adequate venous access prior to starting PADCEV and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.

Embryo-fetal toxicity PADCEV can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during PADCEV treatment and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for 4 months after the last dose.

Adverse Reactions

Most Common Adverse Reactions, Including Laboratory Abnormalities (≥20%)

Rash, aspartate aminotransferase (AST) increased, glucose increased, creatinine increased, fatigue, PN, lymphocytes decreased, alopecia, decreased appetite, hemoglobin decreased, diarrhea, sodium decreased, nausea, pruritus, phosphate decreased, dysgeusia, alanine aminotransferase (ALT) increased, anemia, albumin decreased, neutrophils decreased, urate increased, lipase increased, platelets decreased, weight decreased and dry skin.

EV-301 Study: 296 patients previously treated with a PD-1/L1 inhibitor and platinum-based chemotherapy.

Serious adverse reactions occurred in 47% of patients treated with PADCEV; the most common (≥2%) were urinary tract infection, acute kidney injury (7% each) and pneumonia (5%). Fatal adverse reactions occurred in 3% of patients, including multiorgan dysfunction (1.0%), hepatic dysfunction, septic shock, hyperglycemia, pneumonitis and pelvic abscess (0.3% each). Adverse reactions leading to discontinuation occurred in 17% of patients; the most common (≥2%) were PN (5%) and rash (4%). Adverse reactions leading to dose interruption occurred in 61% of patients; the most common (≥4%) were PN (23%), rash (11%) and fatigue (9%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common (≥2%) were PN (10%), rash (8%), decreased appetite and fatigue (3% each). Clinically relevant adverse reactions (<15%) include vomiting (14%), AST increased (12%), hyperglycemia (10%), ALT increased (9%), pneumonitis (3%) and infusion site extravasation (0.7%).

EV-201, Cohort 2 Study: 89 patients previously treated with a PD-1/L1 inhibitor and not eligible for platinum-based chemotherapy.

Serious adverse reactions occurred in 39% of patients treated with PADCEV; the most common (≥3%) were pneumonia, sepsis and diarrhea (5% each). Fatal adverse reactions occurred in 8% of patients, including acute kidney injury (2.2%), metabolic acidosis, sepsis, multiorgan dysfunction, pneumonia and pneumonitis (1.1% each). Adverse reactions leading to discontinuation occurred in 20% of patients; the most common (≥2%) was PN (7%). Adverse reactions leading to dose interruption occurred in 60% of patients; the most common (≥3%) were PN (19%), rash (9%), fatigue (8%), diarrhea (5%), AST increased and hyperglycemia (3% each). Adverse reactions leading to dose reduction occurred in 49% of patients; the most common (≥3%) were PN (19%), rash (11%) and fatigue (7%). Clinically relevant adverse reactions (<15%) include vomiting (13%), AST increased (12%), lipase increased (11%), ALT increased (10%), pneumonitis (4%) and infusion site extravasation (1%).

Drug Interactions

Effects of other drugs on PADCEV (Dual P-gp and Strong CYP3A4 Inhibitors)

Concomitant use with a dual P-gp and strong CYP3A4 inhibitors may increase unconjugated monomethyl auristatin E exposure, which may increase the incidence or severity of PADCEV toxicities. Closely monitor patients for signs of toxicity when PADCEV is given concomitantly with dual P-gp and strong CYP3A4 inhibitors.

Specific Populations

Lactation Advise lactating women not to breastfeed during treatment with PADCEV and for at least 3 weeks after the last dose.

Hepatic impairment Avoid the use of PADCEV in patients with moderate or severe hepatic impairment.