On January 31, 2024 Vas Narasimhan, CEO of Novartis, reported: "Novartis completed its strategic transformation into a pure-play innovative medicines company and continued its relentless pursuit of sustainable shareholder value creation (Press release, Novartis, JAN 31, 2024, View Source [SID1234639746]). Our robust operational performance continues, with strong double-digit top and bottom-line growth, for the quarter and full year. We delivered ten positive Ph3 readouts on assets with significant sales potential, over the past year. The very strong performance of our key growth drivers and pipeline underscores the confidence in our growth (5% cc CAGR 2023-2028) and margin (40%+ by 2027) mid-term guidance."

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Key figures1
Continuing operations
Q4 2023 Q4 2022 % change FY 2023 FY 2022 % change
USD m USD m USD cc USD m USD m USD cc
Net sales 11 423 10 576 8 10 45 440 42 206 8 10
Operating income 2 582 1 755 47 68 9 769 7 946 23 39
Net income 2 638 1 315 101 130 8 572 6 049 42 62
EPS (USD) 1.29 0.62 108 140 4.13 2.77 49 70
Free cash flow 2 141 3 462 -38 13 160 12 123 9
Core operating income 3 821 3 645 5 13 16 372 14 794 11 18
Core net income 3 126 2 963 6 11 13 446 11 946 13 19
Core EPS (USD) 1.53 1.39 10 16 6.47 5.48 18 25
Strategy Update
Our focus
During 2023, Novartis completed our transformation into a "pure-play" innovative medicines business. We have a clear focus on four core therapeutic areas (cardiovascular-renal-metabolic, immunology, neuroscience and oncology), with multiple significant in-market and pipeline assets in each of these areas, that address high disease burden and have substantial growth potential. In addition to two established technology platforms (chemistry and biotherapeutics), three emerging platforms (gene & cell therapy, radioligand therapy and xRNA) are being prioritized for continued investment into new R&D capabilities and manufacturing scale. Geographically, we are focused on growing in our priority geographies – the US, China, Germany and Japan.

Our priorities
Accelerate growth: Renewed attention to deliver high-value medicines (NMEs) and focus on launch excellence, with a rich pipeline across our core therapeutic areas.
Deliver returns: Continuing to embed operational excellence and deliver improved financials. Novartis remains disciplined and shareholder-focused in our approach to capital allocation, with substantial cash generation and a strong capital structure supporting continued flexibility.
Strengthening foundations: Unleashing the power of our people, scaling data science and technology and continuing to build trust with society.
Financials
Following the September 15, 2023, shareholders’ approval of the spin-off of the Sandoz business the Company reported its consolidated financial statements for the current and prior years as "continuing operations" and "discontinued operations."

Continuing operations include the retained business activities of Novartis, comprising the innovative medicines business and the continuing corporate activities. Discontinued operations include the Sandoz Division and selected portions of corporate activities attributable to Sandoz’s business, as well as certain expenses related to the spin-off.

Following the spin-off of the Sandoz business, Novartis operates as a single global operating segment focused innovative medicines company.

The commentary below focuses on continuing operations. We also provide information on discontinued operations, which mainly includes Sandoz and allocated corporate activities.

Continuing operations
Fourth quarter

Net sales were USD 11.4 billion (+8%, +10% cc) in the fourth quarter driven by volume growth of 13 percentage points. Generic competition had a negative impact of 3 percentage points and pricing had no impact.

Operating income was USD 2.6 billion (+47%, +68% cc), mainly driven by higher net sales and lower restructuring charges, partly offset by higher SG&A and R&D investments.

Net income was USD 2.6 billion (+101%, +130% cc), mainly driven by higher operating income and non-recurring favorable tax impacts. EPS was USD 1.29 (+108%, +140% cc), benefiting from lower weighted average number of shares outstanding.

Core operating income was USD 3.8 billion (+5%, +13% cc), mainly driven by higher net sales, partly offset by higher SG&A and R&D investments. Core operating income growth in USD was impacted by negative 2 percentage points from the effect of mid-December currency devaluation in Argentina1. Core operating income margin was 33.5% of net sales, decreasing 1.0 percentage point (+1.0 percentage point cc).

Core net income was USD 3.1 billion (+6%, +11% cc), mainly due to higher core operating income. Core EPS was USD 1.53 (+10%, +16% cc), benefiting from lower weighted average number of shares outstanding.

Free cash flow from continuing operations amounted to USD 2.1 billion (-38% USD), compared with USD 3.5 billion in the prior year quarter driven by lower net cash flows from operating activities.

1 IFRS Accounting Standards requires for our Argentina subsidiary, as it operates in a hyperinflation economy, to translate for consolidation purposes their full year income statement to our USD presentation currency using the ARS closing rate, and not using the average exchange rate for the period. This results in the 9-months and the Q4 devaluation impact being recognized in Q4.

Full year

Net sales were USD 45.4 billion (+8%, +10% cc) in the full year, driven by volume growth of 16 percentage points, partly offset by price erosion of 2 percentage points and the negative impact from generic competition of 4 percentage points.

Operating income was USD 9.8 billion (+23%, +39% cc), mainly driven by higher net sales, lower restructuring charges, and income from legal matters, partly offset by higher impairments and higher SG&A and R&D investments.

Net income was USD 8.6 billion (+42%, +62% cc), mainly driven by higher operating income and non-recurring favorable tax impacts. EPS was USD 4.13 (+49%, +70% cc).

Core operating income was USD 16.4 billion (11%, +18% cc), mainly driven by higher net sales, partly offset by higher SG&A and R&D investments. Core operating income margin was 36.0% of net sales, increasing 0.9 percentage points (+2.4 percentage points cc).

Core net income was USD 13.4 billion (+13%, +19% cc), mainly due to higher core operating income. Core EPS was USD 6.47 (+18%, +25% cc), benefiting from lower weighted average number of shares outstanding.

Free cash flow from continuing operations amounted to USD 13.2 billion (+9% USD), compared with USD 12.1 billion in 2022 driven by higher net cash flows from operating activities.

Discontinued operations
Discontinued operations include the Sandoz generic pharmaceuticals and biosimilars division, certain corporate activities attributable to Sandoz prior to the spin-off up to the distribution date of October 3, 2023, and certain other expenses related to the spin-off. Included in 2023 is also the IFRS Accounting Standards non-cash, non-taxable net gain on the distribution of Sandoz Group AG to Novartis AG shareholders of USD 5.9 billion, representing mainly the excess amount of the IFRS Accounting Standards distribution liability, which is the estimated fair value of the Sandoz business distributed to Novartis AG shareholders, over the then carrying value of Sandoz business net assets. There were no operating results for the fourth quarter 2023 following the distribution date. The prior year includes the results for the full period.

Fourth quarter

Net income from discontinued operations amounted to USD 5.8 billion, driven by the IFRS Accounting Standards non-cash, non-taxable, net gain on distribution of Sandoz Group AG to Novartis AG shareholders of USD 5.9 billion, compared to USD 151 million in prior year.

Full year

Discontinued operations net sales in 2023 were USD 7.4 billion, compared to USD 9.4 billion in 2022 and operating income amounted to USD 265 million compared to USD 1.3 billion in 2022.

Net income from discontinued operations in 2023 amounted to USD 6.3 billion, compared to USD 906 million in 2022, driven by the IFRS Accounting Standards non-cash, non-taxable, net gain on distribution of Sandoz Group AG to Novartis AG shareholders, which amounted to USD 5.9 billion.

Total Company
Fourth quarter

Total Company net income was USD 8.5 billion in 2023, compared to USD 1.5 billion in 2022 and basic EPS was USD 4.14 compared to USD 0.69 in prior year, driven by the IFRS Accounting Standards non-cash, non-taxable, net gain on distribution of Sandoz Group AG to Novartis AG shareholders of USD 5.9 billion. Net cash flows from operating activities for total Company amounted to USD 2.5 billion and free cash flow amounted to USD 2.1 billion.

Full year

Total Company, net income amounted to USD 14.9 billion in 2023, compared to USD 7.0 billion in 2022, and basic earnings per share was USD 7.15 compared to USD 3.19 in prior year, driven by the IFRS Accounting Standards non-cash, non-taxable, net gain on distribution of Sandoz Group AG to Novartis AG shareholders of USD 5.9 billion. Net cash flows from operating activities for the total company amounted to USD 14.5 billion, and free cash flow amounted to USD 13.2 billion.

Q4 key growth drivers
Underpinning our financial results in the quarter is a continued focus on key growth drivers (ranked in order of contribution to Q4 growth) including:

Entresto (USD 1 635 million, +26% cc) sustained robust demand-led growth, with increased patient share across all geographies
Kisqali (USD 610 million, +76% cc) sales grew strongly across all regions, based on increasing recognition of consistently reported overall survival in HR+/HER2- advanced breast cancer
Kesimpta (USD 641 million, +73% cc) sales grew across all regions driven by increased demand and strong access
Cosentyx (USD 1 303 million, +21% cc) US sales grew (+17%) and ex-US sales (+26% cc), benefitting from lower prior year base (including revenue deduction adjustments in the US)
Pluvicto (USD 273 million, +53% cc) continued sales growth in the US. Supply now unconstrained, focusing on initiating new patients
Ilaris (USD 376 million, +29% cc) sales grew across all regions
Leqvio (USD 123 million, +190% cc) launch is ongoing, with focus on patient on-boarding, removing access hurdles and enhancing medical education
Scemblix (USD 125 million, +143% cc) continued its strong launch uptake demonstrating the high unmet need in CML
Jakavi (USD 444 million, +14% cc) sales grew in emerging growth markets, Europe and Japan, driven by strong demand in both myelofibrosis and polycythemia vera indications
Xolair (USD 378 million, +16% cc) sales grew across all regions
Tafinlar + Mekinist (USD 486 million, +7% cc) sales grew mainly in the US and emerging growth markets, partly offset by decline in Europe
Promacta/Revolade (USD 563 million, +4% cc) sales grew mainly in the US driven by increased use in chronic ITP and severe aplastic anemia
Piqray (USD 131 million, +18% cc) sales grew mainly in the US
Lutathera (USD 147 million, +13% cc) sales grew across all regions due to increased demand
Emerging Growth Markets* Grew +18% (cc) overall. China grew (+38% cc) to USD 0.8 billion, due to lower prior year base. For the full year, China grew +17% (cc)
*All markets except the US, Canada, Western Europe, Japan, Australia, and New Zealand
Net sales of the top 20 brands in 2023
Q4 2023 % change FY 2023 % change
USD m USD cc USD m USD cc
Entresto 1 635 27 26 6 035 30 31
Cosentyx 1 303 21 21 4 980 4 5
Promacta/Revolade 563 4 4 2 269 9 10
Kesimpta 641 74 73 2 171 99 99
Kisqali 610 71 76 2 080 69 75
Tafinlar + Mekinist 486 5 7 1 922 9 11
Tasigna 446 -6 - 6 1 848 -4 -3
Jakavi 444 14 14 1 720 10 12
Lucentis 301 -24 - 25 1 475 -21 -20
Xolair 378 17 16 1 463 7 9
Ilaris 376 25 29 1 355 20 22
Sandostatin 316 4 5 1 314 6 8
Zolgensma 286 -7 - 4 1 214 -11 -9
Pluvicto 273 53 53 980 262 261
Gilenya 154 -55 - 55 925 -54 -54
Exforge Group 156 -2 - 1 713 -4 -1
Galvus Group 153 -27 - 17 692 -19 -11
Diovan Group 147 4 6 613 -6 -1
Lutathera 147 15 13 605 28 28
Gleevec/Glivec 128 -27 - 25 561 -25 -22
Top 20 brands total 8 943 13 14 34 935 10 12
R&D update – key developments from the fourth quarter
New approvals
Fabhalta
(iptacopan) Approved in the US as the first oral monotherapy for the treatment of adults (both previously treated and treatment-naïve patients) with paroxysmal nocturnal hemoglobinuria (PNH)
Cosentyx Approved in the US as the first new biologic therapy for the treatment of moderate to severe hidradenitis suppurativa (HS) in adults in nearly a decade

Approved in the US as an intravenous formulation in three indications: psoriatic arthritis, ankylosing spondylitis, and non-radiographic axial SpA
Results from ongoing trials and other highlights
Scemblix
(asciminib) Ph3 ASC4FIRST study met both primary endpoints (major molecular response rate vs. imatinib or investigator-selected tyrosine kinase inhibitors) with clinically meaningful and statistically significant results in newly diagnosed patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP). Additionally, Scemblix showed a favorable safety and tolerability profile. Data will be presented at an upcoming medical conference and submitted to regulatory authorities in 2024

Ph3 ASCEMBL study, median follow-up of almost 4 years, in patients with Ph+ CML-CP continue to support the efficacy, safety and tolerability profile compared with bosutinib in 3L+ setting. Data presented at ASH (Free ASH Whitepaper) 2023
Fabhalta
(iptacopan) Ph3 APPLAUSE-IgAN study interim analysis demonstrated clinically meaningful and highly statistically significant proteinuria reduction in patients with IgA nephropathy. The trial met its pre-specified interim analysis (9 months) primary endpoint, demonstrating superiority vs. placebo in proteinuria reduction, with safety consistent with previously reported data. Novartis plans to review interim data with regulatory authorities for accelerated approval; study continues with final readout at 24 months

Ph3 APPEAR-C3G study met its primary endpoint, demonstrating superiority of iptacopan vs placebo in proteinuria reduction at six-month analysis and provided clinically meaningful and statistically significant proteinuria reduction in patients with C3G on top of background therapy. Iptacopan’s safety profile was consistent with previously reported data. Data to be presented at an upcoming medical meeting. Study continues with all patients receiving active therapy for six-months

Ph3 APPLY-PNH extension data showed sustained efficacy and long-term safety of Fabhalta in adults with paroxysmal nocturnal hemoglobinuria (PNH). Data showed sustained clinically meaningful hemoglobin-level increases to near-normal (≥12 g/dL), blood transfusion avoidance, and improved patient-reported fatigue in the majority of patients. Comparable benefits were seen in those patients switching from anti-C5 therapy to Fabhalta. Safety profile at 48 weeks was similar to 24 week data. Data presented at ASH (Free ASH Whitepaper) 2023
atrasentan

Ph3 ALIGN study met its primary endpoint, demonstrating superiority of atrasentan vs placebo in proteinuria reduction at 36-week interim analysis with clinically meaningful and highly statistically significant reduction in proteinuria in IgAN patients receiving supportive care. Safety profile of atrasentan was consistent with previously reported data. Data to be presented at an upcoming medical meeting. Study continues with final readout expected in 2026
remibrutinib Ph3 REMIX-1 and REMIX-2 trials showed clinically meaningful and statistically significant reduction in weekly urticaria activity (UAS7), itch (ISS7) and hives (HSS7) at Week 12 vs placebo in patients with CSU. Significant improvement in symptom control was seen as early as Week 2 and sustained up to Week 12. Remibrutinib was well-tolerated and demonstrated a favorable safety profile with rates of overall adverse events comparable to placebo and balanced liver function tests across both studies. Studies are ongoing with final (52-week) readout and regulatory submissions in 2024. Data presented at AAAI 2023
Kisqali

(ribociclib) Final protocol-specified iDFS analysis of Ph3 NATALEE trial (with a median follow-up of 33.3 months and 78.3% of patients having completed ribociclib) reinforces 25% reduction in risk of recurrence across broad population of patients with HR+/HER2- early breast cancer and continues to support regulatory submissions. iDFS benefit remains consistent across key patient subgroups, with stability in secondary endpoints including overall survival (OS). Among patients with stage II and stage III tumors, ribociclib lowered risk of disease recurrence by 30% and 24.5%, respectively. Safety profile was in line with previously reported results. Data presented at SABCS 2023. NATALEE data submitted to the FDA in December 2023
Early-stage business development in core therapeutic areas and technologies Cardiovascular-Renal-Metabolic:

Chong Kun Dang (LMW, lead asset CKD-510 for diseases in which the enzyme HDAC6 is thought to play a role, including some cardiovascular diseases)
SanReno (LMW and mAb, securing worldwide rights for Atrasentan/Zigakibart)
Argo Biopharma (xRNA, undisclosed targets)
Neuroscience:

Voyager Therapeutics (Gene therapy, strategic collaboration and capsid license agreement for potential Huntington’s Disease and spinal muscular atrophy therapies)
Immunology:

Calypso (Biotherapeutics, lead asset CALY-002 a promising anti-IL-15 mAB, to be investigated in a range of autoimmune indications)
Oncology:

Legend Biotech (Cell Therapy, targeting DLL3, a ligand highly expressed in several cancers)
Isomorphic Labs – Leveraging AI including next generation AlphaFold model, to discover novel small molecule therapeutics against undisclosed targets
Capital structure and net debt
Retaining a good balance between investment in the business, a strong capital structure and attractive shareholder returns remains a priority.

In 2023, Novartis repurchased a total of 87.5 million shares for USD 8.4 billion on the SIX Swiss Exchange second trading line. These repurchases included 52.8 million shares (USD 4.9 billion) under the USD 15 billion share buyback (announced in December 2021 and completed in June 2023) and 23.0 million shares (USD 2.3 billion) under the new up-to USD 15 billion share buyback announced in July 2023 (which is continuing as planned, with up-to USD 12.7 billion remaining). In addition, 11.7 million shares (USD 1.2 billion) were repurchased to mitigate dilution related to participation plans of associates. Furthermore, 1.6 million shares (for an equity value of USD 0.1 billion) were repurchased from associates. In the same period, 13.5 million shares (for an equity value of USD 1.1 billion) were delivered as a result of options exercised and share deliveries related to participation plans of associates. Consequently, the total number of shares outstanding decreased by 75.6 million versus December 31, 2022. These treasury share transactions resulted in an equity decrease of USD 7.4 billion and a net cash outflow of USD 8.6 billion.

As of December 31, 2023, net debt increased to USD 10.2 billion compared to USD 7.2 billion at December 31, 2022. The increase was mainly due to the USD 7.3 billion annual dividend payment, net cash outflow for treasury share transactions of USD 8.6 billion and net cash outflow for M&A / intangible assets transactions of USD 3.3 billion. This increase in net debt was partially offset by USD 13.2 billion free cash flow and a USD 3.0 billion reduction in the net debt position of Novartis related to the Sandoz spin-off.

As of Q4 2023, the long-term credit rating for the Company is A1 with Moody’s Investors Service and AA- with S&P Global Ratings.

2024 outlook
Barring unforeseen events; growth vs prior year in cc

Net sales Expected to grow mid single digit
Core operating income Expected to grow high single digit
Key assumptions:

Our guidance assumes that no Entresto generics launch in the US in 2024
Foreign exchange impact
If late-January exchange rates prevail for the remainder of 2024, the foreign exchange impact for the year would be negative 1 percentage point on net sales and negative 3 percentage points on core operating income. The estimated impact of exchange rates on our results is provided monthly on our website.

Annual General Meeting
Dividend proposal
The Novartis Board of Directors proposes a dividend payment of CHF 3.30 per share for 2023, up 3.1% from CHF 3.20 per share in the prior year, representing the 27th consecutive dividend increase since the creation of Novartis in December 1996. Shareholders will vote on this proposal at the Annual General Meeting on March 5, 2024.

Reduction of share Capital
The Novartis Board of Directors proposes to cancel 87 547 255 shares (repurchased under the authorization of March 4, 2022) and to reduce the share capital accordingly by CHF 42.9 million, from CHF 1 115 964 098.48 to CHF 1 073 065 943.53.

Elections of the Board Chair and the members of the Board of Directors
The Board of Directors proposes the re-election of all current members of the Board of Directors (including the Board Chair).

Key figures1

Continuing operations2 Q4 2023 Q4 2022 % change FY 2023 FY 2022 % change
USD m USD m USD cc USD m USD m USD cc
Net sales 11 423 10 576 8 10 Net sales 45 440 42 206 8 10
Operating income 2 582 1 755 47 68 Operating income 9 769 7 946 23 39
As a % of sales 22.6 16.6 As a % of sales 21.5 18.8
Net income 2 638 1 315 101 130 Net income 8 572 6 049 42 62
EPS (USD) 1.29 0.62 108 140 EPS (USD) 4.13 2.77 49 70
Cash flows from
operating activities 2 547 3 768 -32 Cash flows from
operating activities 14 220 13 039 9
Non-IFRS measures Non-IFRS measures
Free cash flow 2 141 3 462 -38 Free cash flow 13 160 12 123 9
Core operating income 3 821 3 645 5 13 Core operating income 16 372 14 794 11 18
As a % of sales 33.5 34.5 As a % of sales 36.0 35.1
Core net income 3 126 2 963 6 11 Core net income 13 446 11 946 13 19
Core EPS (USD) 1.53 1.39 10 16 Core EPS (USD) 6.47 5.48 18 25


Discontinued operations2 Q4 2023 Q4 2022 % change FY 2023 FY 2022 % change
USD m USD m USD cc USD m USD m USD cc
Net sales 2 374 nm nm Net sales 7 428 9 372 nm nm
Operating income 194 nm nm Operating income 265 1 251 nm nm
As a % of sales 8.2 As a % of sales 3.6 13.3
Net income 5 842 151 nm nm Net income 6 282 906 nm nm
Non-IFRS measures Non-IFRS measures
Core operating income 385 nm nm Core operating income 1 185 1 871 nm nm
As a % of sales 16.2 As a % of sales 16.0 20.0




Total Company Q4 2023 Q4 2022 % change FY 2023 FY 2022 % change
USD m USD m USD cc USD m USD m USD cc
Net income 8 480 1 466 nm nm Net income 14 854 6 955 nm nm
EPS (USD) 4.14 0.69 nm nm EPS (USD) 7.15 3.19 nm nm
Cash flows from
operating activities 2 547 4 111 nm nm Cash flows from
operating activities 14 458 14 236 nm nm
Non-IFRS measures Non-IFRS measures
Free cash flow 2 141 3 713 nm nm Free cash flow 13 179 13 038 nm nm
Core net income 3 127 3 251 nm nm Core net income 14 336 13 352 nm nm
Core EPS (USD) 1.53 1.52 nm nm Core EPS (USD) 6.90 6.12 nm nm

nm= not meaningful
1Constant currencies (cc), core results and free cash flow are non-IFRS measures. An explanation of non-IFRS measures can be found on page 49 of the Condensed Financial Report. Unless otherwise noted, all growth rates in this Release refer to same period in prior year.
2As defined on page 37 of the Condensed Financial Report, Continuing operations include the retained business activities of Novartis, comprising the innovative medicines business and the continuing Corporate activities and Discontinued operations include operational results from the Sandoz business.

On January 31, 2024 Halia Therapeutics, a clinical-stage biopharmaceutical company pioneering a novel class of small molecule medications designed to combat inflammation, reported the completion of a $30 million Series C financing (Press release, Halia Therapeutics, JAN 31, 2024, View Source [SID1234639744]). The financing was led by Todd Pedersen, with continued participation from existing investors.

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Proceeds from the financing will be used to support the advancement of Halia’s lead asset, HT-6184, a selective and orally bioavailable first-in-class inhibitor of NLRP3/NEK7 inflammasome in Phase II clinical trials. Halia Therapeutics recently initiated a Phase IIa trial in India to treat patients with lower-risk myelodysplastic syndromes (LR-MDS). LR-MDS are a group of cancers in which the bone marrow produces underdeveloped cells that are abnormal in size, shape, or appearance and are therefore "dysplastic." The company also plans to evaluate HT-6184 in Phase II trials in the U.S. for the treatment of post-procedure inflammatory pain response, as well as begin a Phase I trial in Alzheimer’s patients. Funding will also support IND-enabling studies for Halia’s alternative programs that are developing Leucine-rich repeat kinase 2 (LRRK2) inhibitors to treat neurological diseases such as Parkinson’s and Alzheimer’s disease, in addition to building out clinical and regulatory teams further to support the global development of the company’s pipeline.

"We are grateful for the trust investors have in our therapeutic approach. Their confidence is the driving force behind our efforts in developing innovative therapies targeting chronic inflammation," said Dr. David Bearss, CEO of Halia Therapeutics. "This financing will help us to advance significantly our lead drug candidate, HT-6184, in ongoing global Phase II trials and will support the trajectory of our additional programs targeting neuroinflammation into the clinic, bringing us even closer to breakthrough treatments for inflammatory-related diseases."

"We believe that Halia’s unique approach of targeting the NLP3 inflammasome holds significant potential for addressing a wide range of inflammatory diseases, along with hematologic conditions and other malignancies," said Todd Pedersen. "The company’s expertise and patient-focused mindset will be invaluable for advancing these anti-inflammatory therapeutics and revolutionizing the approach for targeting chronic inflammation in patients."

About NLRP3

NLRP3, an innate immune sensor, is activated in response to various pathogenic and sterile stimuli. Activation of NLRP3 triggers the release of the pro-inflammatory cytokines IL-1β and IL-18 and induces a lytic cell death process called pyroptosis. These processes lead to systemic chronic inflammation. Halia’s therapeutic inhibition of NLRP3 prevents the formation of the NLRP3 inflammasome and promotes its disassembly once formed, thereby inhibiting the production and release of IL-1β and IL-18. Persistent activation of the NLRP3 inflammasome is thought to drive the onset and progression of many conditions, including fibrotic, dermatological, and auto-inflammatory diseases. Significant neurological disorders such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis are also driven by NLRP3 activation.

About HT-6184

HT-6184 represents an innovative approach as it is the first drug candidate to target the protein NEK7 through an allosteric mechanism. NEK7 is an essential component of the NLRP3 inflammasome and is critical for its assembly and the maintenance of NLRP3 activity. In preclinical models, Halia has shown that inhibiting the ability of NEK7 to bind to NLRP3 leads to a disruption in the formation of the NLRP3 inflammasome complex, thereby inhibiting the signaling from the inflammasome and reducing the inflammatory response. Preclinical models also showed that in addition to disrupting the formation of the NLRP3 inflammasome, HT-6184 promotes the disassembly of the inflammasome once activated.

On January 31, 2024 CymaBay Therapeutics, Inc. (NASDAQ: CBAY), a biopharmaceutical company focused on innovative therapies for patients with liver and other chronic diseases, reported that members of its management team will participate in the Guggenheim Healthcare Talks 6th Annual Biotechnology Conference, February 7-8, in New York, NY, Raymond James & Associates’ 45th Annual Institutional Investors Conference, March 4-6, in Orlando, Florida, and Leerink Partners Global Biopharma Conference, March 11-13, in Miami, Florida (Press release, CymaBay Therapeutics, JAN 31, 2024, View Source [SID1234639743]).

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Guggenheim Healthcare Talks 6th Annual Biotechnology Conference
Date: Wednesday, February 7th, 2024
Time: 1:00pm Eastern Time, Fireside Chat
Webcast: View Source

Raymond James & Associates’ 45th Annual Institutional Investors Conference
Date: Tuesday, March 5th, 2024
Time: 2:50pm Eastern Time, Fireside Chat
Webcast: View Source

Leerink Partners Global Biopharma Conference
Date: Tuesday, March 12th, 2024
Time: 11:20am Eastern Time, Fireside Chat
Webcast: View Source

On January 31, 2024 BioNTech SE (Nasdaq: BNTX, "BioNTech") and Duality Biologics (Suzhou) Co., Ltd. ("DualityBio") reported that the U.S. Food and Drug Administration ("FDA") granted Fast Track designation for BNT325/DB-1305 for the treatment of patients with platinum-resistant ovarian epithelial cancer, fallopian tube cancer, or primary peritoneal cancer who have received one to three prior systemic treatment regimens (Press release, BioNTech, JAN 31, 2024, View Source [SID1234639742]). BNT325/DB-1305 is a next-generation antibody-drug conjugate ("ADC") candidate targeting the trophoblast cell-surface antigen 2 ("TROP2"), a protein which is overexpressed on a range of tumor types. The candidate is currently being evaluated in an ongoing Phase 1/2 study (NCT05438329) in patients with TROP2-expressing advanced solid tumors.

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Ovarian cancer is the fourth most common gynecological tumor type, with over 300,000 cases diagnosed globally each year.3 Over 90% of ovarian tumors arise from epithelial cells including the epithelial tissue of the ovary, the lining of a fallopian tube or the peritoneum.4 Ovarian epithelial cancer is often diagnosed at advanced disease stages, leading to a poor prognosis for patients. This makes it one of the most frequent causes of cancer death in women.3 The 5-year survival rate ranges from 26% to 42%, depending on the initial disease stage.3

"The FDA’s decision is an important recognition of the potential of our TROP2-targeting ADC candidate. Platinum-based chemotherapy is the backbone of treatment for ovarian epithelial cancer and related subtypes that form in the epithelial tissue. Patients with platinum resistance who relapse within under six months have a poor prognosis, and effective and well-tolerated treatment options remain a substantial unmet medical need," said Prof. Özlem Türeci, M.D., Chief Medical Officer and Co-Founder at BioNTech. "Recent studies have indicated the role of TROP2 in aggressive tumor growth and progression in patients with chemotherapy-resistant ovarian tumors. We are committed to further advancing BNT325/DB-1305 and believe that a TROP2-targeted treatment approach has the potential to overcome current limitations in the treatment of advanced ovarian cancers."

"BNT325/DB-1305 is the second investigational asset in our strategic collaboration which has received FDA Fast Track designation highlighting the potential of the candidate to fill an unmet medical need," said Vivian Gu, M.D., Chief Medical Officer at DualityBio. "Data from the Phase 1/2 clinical trial with BNT325/DB-1305 have demonstrated encouraging anti-tumor signals in heavily pretreated patients with TROP2-expressing solid tumors who had failed standard therapy with an objective response rate of 30.4% and a disease control rate of 87.0%.5 We look forward to progressing the further development of BNT325/DB-1305 within the fast track framework, and hope to be one step closer to potentially improving outcomes for a range of patients."

Fast Track is a process designed to facilitate the development and expedite the review, of new drugs and vaccines that are intended to treat or prevent serious conditions that have the potential to address an unmet medical need. The designation is based on preliminary data from an ongoing Phase 1/2 study with BNT325/DB-1305 in patients with platinum-resistant ovarian epithelial cancer, fallopian tube, or primary peritoneal cancer patients.1 With the Fast Track designation, the development of BNT325/DB-1305 can benefit from more frequent engagement with the FDA, to support the development and expedite the review of BNT325/DB-1305.

About BNT325/DB-1305
BNT325/DB-1305 is a third-generation topoisomerase-1 inhibitor-based ADC targeting TROP2 which was built from DualityBio’s proprietary Duality Immune Toxin Antibody Conjugates ("DITAC") platform. TROP2 is a cell surface protein which is expressed in many normal tissues but is overexpressed in a variety of tumors. TROP2 plays an important role in tumor cell proliferation, apoptosis, and invasion, thereby impacting the prognosis and treatment of cancer patients.6,7 BNT325/DB-1305 has exhibited antitumor activity in tumor models as well as in several advanced solid tumor indications, including non-small cell lung cancer ("NSCLC") and ovarian epithelial cancer.8 Preclinical data and preliminary clinical data for BNT325/DB-1305 indicate its potential to target TROP2 receptors on solid tumors irrespective of expression level with a manageable safety profile and a potentially expanded therapeutic window.

On January 31, 2024 Astellas Pharma Inc. (TSE:4503, President and CEO: Naoki Okamura, "Astellas") reported the submission of a Supplemental New Drug Application (sNDA) on January 31 to Japan’s Ministry of Health, Labour and Welfare (MHLW) for PADCEV (enfortumab vedotin (genetical recombination)) with KEYTRUDA (pembrolizumab (genetical recombination)) as a combination therapy for the first-line treatment of adult patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC) (Press release, Astellas, JAN 31, 2024, View Source [SID1234639741]). If approved, PADCEV with KEYTRUDA has the potential to change the treatment paradigm, becoming the first combination treatment to offer an alternative to platinum-containing chemotherapy, the current standard of care in first-line la/mUC.

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Globally, approximately 573,000 new cases of bladder cancer and 212,000 deaths are reported annually.ⅰ It is estimated that approximately 25,000 people in Japan are diagnosed with bladder cancer each year and approximately 10,000 deaths were reported in 2022.ⅱ

Ahsan Arozullah, M.D., M.P.H., Senior Vice President, Head of Oncology Development, Astellas
"The initiation of MHLW’s review of our application for enfortumab vedotin and pembrolizumab is encouraging, as we are working to improve upon current treatment options for patients in Japan with advanced stage urothelial cancer, who face poor outcomes at the advanced stage. This submission brings us one step closer to the possibility of offering these patients a treatment that demonstrated improved survival and slowed disease progression compared to platinum-containing chemotherapy."

The sNDA for the first-line use of this combination is based on results from the Phase 3 EV-302 clinical trial (also known as KEYNOTE-A39). The study found the combination improved overall survival (OS) and progression-free survival (PFS) with statistically significant and clinically meaningful results in patients with previously untreated la/mUC compared to platinum-containing chemotherapy. The safety results were consistent with those previously reported with this combination, and no new safety issues were identified.

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency is also reviewing the combination therapy. The U.S. Food and Drug Administration approved the combination therapy in December 2023.

About EV-302
The EV-302 trial is an open-label, randomized, controlled Phase 3 study, evaluating enfortumab vedotin in combination with pembrolizumab versus platinum-containing chemotherapy in patients with previously untreated la/mUC. The study enrolled 886 patients with previously untreated la/mUC who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status. Patients were randomized to receive either enfortumab vedotin in combination with pembrolizumab or platinum-containing chemotherapy. The dual primary endpoints of this trial are OS and PFS per RECIST v1.1 by blinded independent central review (BICR). Select secondary endpoints include ORR per RECIST v1.1 by BICR, DOR per RECIST v1.1 by BICR, and safety.

The EV-302 trial is part of an extensive clinical program evaluating this combination in multiple stages of urothelial cancer and other solid tumors. Findings from EV-302 were presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2023 in October 2023.

About Bladder and Urothelial Cancer
Urothelial cancer, or bladder cancer, begins in the urothelial cells, which line the urethra, bladder, ureters, renal pelvis, and some other organs.ⅲ
If bladder cancer has spread to surrounding organs or muscles, it is called locally advanced disease. If the cancer has spread to other parts of the body, it is called metastatic disease.ⅳ
Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter, and urethra.iii
Approximately 12% of cases are locally advanced or metastatic urothelial cancer at diagnosis.ⅴ
Ongoing Investigational Trials
The EV-302 trial (NCT04223856) is an open-label, randomized, controlled Phase 3 study, evaluating enfortumab vedotin in combination with pembrolizumab versus chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC) who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status.

The EV-103 trial (NCT03288545) is an ongoing, multi-cohort, open-label, multicenter Phase 1b/2 study investigating enfortumab vedotin alone or in combination with pembrolizumab and/or chemotherapy in first- or second-line settings in patients with la/mUC and in patients with muscle-invasive bladder cancer (MIBC).

Enfortumab vedotin in combination with pembrolizumab is being investigated in an extensive program in multiple stages of urothelial cancer, including two Phase 3 clinical trials in MIBC in EV-304 (NCT04700124, also known as KEYNOTE-B15) and EV-303 (NCT03924895, also known as KEYNOTE-905). The use of enfortumab vedotin in combination with pembrolizumab in second-line urothelial cancer and in MIBC has not been proven safe or effective.

The EV-202 trial (NCT04225117) is an ongoing, multi-cohort, open-label, multicenter Phase 2 study investigating enfortumab vedotin alone in patients with previously treated advanced solid tumors. This study also has a cohort that is investigating enfortumab vedotin in combination with pembrolizumab in patients with previously untreated recurrent/ metastatic head and neck squamous cell carcinoma.

About PADCEV (enfortumab vedotin (genetical recombination))
PADCEV (enfortumab vedotin (genetical recombination)) is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.ⅵ Nonclinical data suggest the anticancer activity of PADCEV 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).ⅶ

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.
Indication
PADCEV, in combination with pembrolizumab, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC).
PADCEV, as a single agent, is indicated for the treatment of adult patients with locally advanced or 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.
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 70% (all grades) of the 564 patients treated with PADCEV in combination with pembrolizumab in clinical trials. When PADCEV was given in combination with pembrolizumab, the incidence of skin reactions, including severe events, occurred at a higher rate compared to PADCEV as a single agent. The majority of the skin reactions that occurred with combination therapy included maculo-papular rash, macular rash and papular rash. Grade 3-4 skin reactions occurred in 17% of patients (Grade 3: 16%, Grade 4: 1%), including maculo-papular rash, bullous dermatitis, dermatitis, exfoliative dermatitis, pemphigoid, rash, erythematous rash, macular rash, and papular rash. A fatal reaction of bullous dermatitis occurred in one patient (0.2%). The median time to onset of severe skin reactions was 1.7 months (range: 0.1 to 17.2 months). Skin reactions led to discontinuation of PADCEV in 6% of patients.

Skin reactions occurred in 58% (all grades) of the 720 patients treated with PADCEV as a single agent in clinical trials. Twenty-three percent (23%) of patients had maculo-papular rash and 34% had pruritus. Grade 3-4 skin reactions occurred in 14% of patients, including maculo-papular rash, erythematous rash, rash or drug eruption, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia. The median time to onset of severe skin reactions was 0.6 months (range: 0.1 to 8 months). Among patients experiencing a skin reaction leading to dose interruption who then restarted PADCEV (n=75), 24% of patients restarting at the same dose and 24% of patients restarting at a reduced dose experienced recurrent severe skin reactions. Skin reactions led to discontinuation of PADCEV in 3.1% of patients.

Monitor patients closely throughout treatment for skin reactions. Consider topical corticosteroids and antihistamines, as clinically indicated. For persistent or recurrent Grade 2 skin reactions, consider withholding PADCEV until Grade ≤1. Withhold PADCEV and refer for specialized care for suspected SJS, TEN or for Grade 3 skin reactions. Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or 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 of PADCEV as a single agent, 17% of the 720 patients treated with PADCEV developed hyperglycemia of any grade; 7% of patients developed Grade 3-4 hyperglycemia (Grade 3: 6.5%, Grade 4: 0.6%). Fatal events of hyperglycemia and DKA occurred in one patient each (0.1%). The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. The median time to onset of hyperglycemia was 0.5 months (range: 0 to 20 months). Hyperglycemia led to discontinuation of PADCEV in 0.7% of patients. Five percent (5%) of patients required initiation of insulin therapy for treatment of hyperglycemia. Of the patients who initiated insulin therapy for treatment of hyperglycemia, 66% (23/35) discontinued insulin at the time of last evaluation. 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/Interstitial Lung Disease (ILD) Severe, life-threatening or fatal pneumonitis/ILD occurred in patients treated with PADCEV. When PADCEV was given in combination with pembrolizumab, 10% of the 564 patients treated with combination therapy had pneumonitis/ILD of any grade and 4% had Grade 3-4. A fatal event of pneumonitis/ILD occurred in two patients (0.4%). The incidence of pneumonitis/ILD, including severe events, occurred at a higher rate when PADCEV was given in combination with pembrolizumab compared to PADCEV as a single agent. The median time to onset of any grade pneumonitis/ILD was 4 months (range: 0.3 to 26 months).

In clinical trials of PADCEV as a single agent, 3% of the 720 patients treated with PADCEV had pneumonitis/ILD of any grade and 0.8% had Grade 3-4. The median time to onset of any grade pneumonitis/ILD was 2.9 months (range: 0.6 to 6 months).

Monitor patients for signs and symptoms indicative of pneumonitis/ILD 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 Grade 2 pneumonitis/ILD and consider dose reduction. Permanently discontinue PADCEV in all patients with Grade 3 or 4 pneumonitis/ILD.

Peripheral neuropathy (PN) When PADCEV was given in combination with pembrolizumab, 67% of the 564 patients treated with combination therapy had PN of any grade, 36% had Grade 2 neuropathy, and 7% had Grade 3 neuropathy. The incidence of PN occurred at a higher rate when PADCEV was given in combination with pembrolizumab compared to PADCEV as a single agent. The median time to onset of Grade ≥2 PN was 6 months (range: 0.3 to 25 months).

PN occurred in 53% of the 720 patients treated with PADCEV as a single agent in clinical trials including 38% with sensory neuropathy, 8% with muscular weakness and 7% with motor neuropathy. Thirty percent of patients experienced Grade 2 reactions and 5% 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 4.9 months (range: 0.1 to 20 months). Neuropathy led to treatment discontinuation in 6% of patients.

Monitor patients for symptoms of new or worsening PN 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 as a single agent 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 30% of patients, and blurred vision occurred in 10% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.7 months (range: 0 to 30.6 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 720 patients treated with PADCEV as a single agent in clinical trials, 1% 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%) (PADCEV in combination with pembrolizumab) Increased aspartate aminotransferase (AST), increased creatinine, rash, increased glucose, PN, increased lipase, decreased lymphocytes, increased alanine aminotransferase (ALT), decreased hemoglobin, fatigue, decreased sodium, decreased phosphate, decreased albumin, pruritus, diarrhea, alopecia, decreased weight, decreased appetite, increased urate, decreased neutrophils, decreased potassium, dry eye, nausea, constipation, increased potassium, dysgeusia, urinary tract infection and decreased platelets.

Most common adverse reactions, including laboratory abnormalities (≥20%) (PADCEV monotherapy) Increased glucose, increased AST, decreased lymphocytes, increased creatinine, rash, fatigue, PN, decreased albumin, decreased hemoglobin, alopecia, decreased appetite, decreased neutrophils, decreased sodium, increased ALT, decreased phosphate, diarrhea, nausea, pruritus, increased urate, dry eye, dysgeusia, constipation, increased lipase, decreased weight, decreased platelets, abdominal pain, dry skin.

EV-302 Study: 440 patients with previously untreated la/mUC (PADCEV in combination with pembrolizumab)

Serious adverse reactions occurred in 50% of patients treated with PADCEV in combination with pembrolizumab. The most common serious adverse reactions (≥2%) were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%). Fatal adverse reactions occurred in 3.9% of patients treated with PADCEV in combination with pembrolizumab including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%).

Adverse reactions leading to discontinuation of PADCEV occurred in 35% of patients. The most common adverse reactions (≥2%) leading to discontinuation of PADCEV were PN (15%), rash (4.1%) and pneumonitis/ILD (2.3%). Adverse reactions leading to dose interruption of PADCEV occurred in 73% of patients. The most common adverse reactions (≥2%) leading to dose interruption of PADCEV were PN (22%), rash (16%), COVID-19 (10%), diarrhea (5%), pneumonitis/ILD (4.8%), fatigue (3.9%), hyperglycemia (3.6%), increased ALT (3%) and pruritus (2.5%). Adverse reactions leading to dose reduction of PADCEV occurred in 42% of patients. The most common adverse reactions (≥2%) leading to dose reduction of PADCEV were rash (16%), PN (13%) and fatigue (2.7%).

EV-103 Study: 121 patients with previously untreated la/mUC who were not eligible for cisplatin-containing chemotherapy (PADCEV in combination with pembrolizumab)
Serious adverse reactions occurred in 50% of patients treated with PADCEV in combination with pembrolizumab; the most common (≥2%) were acute kidney injury (7%), urinary tract infection (7%), urosepsis (5%), sepsis (3.3%), pneumonia (3.3%), hematuria (3.3%), pneumonitis/ILD (3.3%), urinary retention (2.5%), diarrhea (2.5%), myasthenia gravis (2.5%), myositis (2.5%), anemia (2.5%), and hypotension (2.5%). Fatal adverse reactions occurred in 5% of patients treated with PADCEV in combination with pembrolizumab, including sepsis (1.6%), bullous dermatitis (0.8%), myasthenia gravis (0.8%), and pneumonitis/ILD (0.8%). Adverse reactions leading to discontinuation of PADCEV occurred in 36% of patients; the most common (≥2%) were PN (20%) and rash (6%). Adverse reactions leading to dose interruption of PADCEV occurred in 69% of patients; the most common (≥2%) were PN (18%), rash (12%), increased lipase (6%), pneumonitis/ILD (6%), diarrhea (4.1%), acute kidney injury (3.3%), increased ALT (3.3%), fatigue (3.3%), neutropenia (3.3%), urinary tract infection (3.3%), increased amylase (2.5%), anemia (2.5%), COVID-19 (2.5%), hyperglycemia (2.5%), and hypotension (2.5%). Adverse reactions leading to dose reduction of PADCEV occurred in 45% of patients; the most common (≥2%) were PN (17%), rash (12%), fatigue (5%), neutropenia (5%), and diarrhea (4.1%).

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

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%), hepatic dysfunction, septic shock, hyperglycemia, pneumonitis/ILD, 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).

EV-201, Cohort 2 Study: 89 patients previously treated with a PD-1/L1 inhibitor and not eligible for cisplatin-based chemotherapy (PADCEV monotherapy)

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/ILD (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%), increased AST, 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%).

DRUG INTERACTIONS

Effects of other drugs on PADCEV (Dual P-gp and Strong CYP3A4 Inhibitors)
Concomitant use with 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 3 weeks after the last dose.

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

For more information, please see the U.S. full Prescribing Information including BOXED WARNING for PADCEV here.