On January 14, 2022, X4 Pharmaceuticals, Inc. (the "Company" and Lincoln Park Capital Fund, LLC ("Lincoln Park") reported that entered into a purchase agreement (the "Purchase Agreement") and a registration rights agreement (the "Registration Rights Agreement"), pursuant to which the Company has the right to sell to Lincoln Park shares of the Company’s common stock, par value $0.001 per share (the "Common Stock"), having an aggregate value of up to $50,000,000 (the "Purchase Shares"), subject to certain limitations and conditions set forth in the Purchase Agreement (Filing, 8-K, X4 Pharmaceuticals, JAN 14, 2022, View Source [SID1234605498]). The Company will control the timing and amount of any sales of Purchase Shares to Lincoln Park pursuant to the Purchase Agreement.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

In consideration for entering into the Purchase Agreement, the Company agreed to issue 230,414 shares of Common Stock (the "Initial Commitment Shares") to Lincoln Park as an initial commitment fee. The Company will not receive any cash proceeds from the issuance of the Commitment Shares.

Upon execution of the Purchase Agreement and the Registration Rights Agreement on January 14, 2022, the Company sold to Lincoln Park, as an initial purchase under the Purchase Agreement, 1,382,488 shares of common stock, at a per share price of $2.17 per share, for aggregate consideration of approximately $3,000,000.

Under the Purchase Agreement, on any business day after January 14, 2022 selected by the Company over the 36-month term of the Purchase Agreement (each, a "Purchase Date"), the Company may direct Lincoln Park to purchase up to 50,000 shares of Common Stock on such Purchase Date (a "Regular Purchase") if the closing sale price per share of the Common Stock on the Nasdaq Capital Market is not below $1.00 on the applicable Purchase Date; provided, however, that (i) a Regular Purchase may be increased to up to 75,000 shares, if the closing sale price per share of the Common Stock on Nasdaq is not below $7.50 on the applicable Purchase Date; and (ii) a Regular Purchase may be increased to up to 100,000 shares, if the closing sale price per share of the Common Stock on Nasdaq is not below $10.00 on the applicable Purchase Date. In any case, Lincoln Park’s maximum obligation under any single Regular Purchase will not exceed $2,000,000, unless the Company and Lincoln Park mutually agree to increase the maximum amount of such Regular Purchase. The above-referenced share amount limitations and closing sale price thresholds are subject to adjustment for any reorganization, recapitalization, non-cash dividend, stock split, reverse stock split or other similar transaction as provided in the Purchase Agreement. The purchase price per share for each such Regular Purchase will be equal to the lesser of:
•the lowest sale price for the Common Stock on the Nasdaq Capital Market on the date of sale; and
•the average of the three lowest closing sale prices for the Common Stock on the Nasdaq Capital Market during the 10 consecutive business days ending on the business day immediately preceding the purchase date.

The Company also has the right to direct Lincoln Park, on any business day on which the Company has properly submitted a Regular Purchase notice for the maximum amount the Company is then permitted to sell to Lincoln Park in such Regular Purchase, to purchase an additional amount of the Common Stock (an "Accelerated Purchase") of up to the lesser of:
•300% of the number of shares to be purchased pursuant to such Regular Purchase; and
•30% of the aggregate shares of the Common Stock traded on the Nasdaq Capital Market during all or, if certain trading volume or market price thresholds specified in the Purchase Agreement are crossed on the applicable Accelerated Purchase date, the portion of the normal trading hours on the applicable Accelerated Purchase date prior to such time that any one of such thresholds is crossed, which period of time on the applicable Accelerated Purchase date is referred to as the Accelerated Purchase Measurement Period.

The parties may mutually agree to increase the number of shares to be purchased by Lincoln Park pursuant to any Accelerated Purchase.

The purchase price per share for each such Accelerated Purchase will be equal to 97% of the lessor of:
•the volume-weighted average price of the Common Stock on the Nasdaq Capital Market during the applicable Accelerated Purchase Measurement Period on the applicable Accelerated Purchase date; and
•the closing sale price of the Common Stock on the Nasdaq Capital Market on the applicable Accelerated Purchase date.

The Company also has the right to direct Lincoln Park on any business day on which an Accelerated Purchase has been completed and all of the shares to be purchased thereunder have been properly delivered to Lincoln Park in accordance with the Purchase Agreement to purchase an additional amount of the Common Stock (an "Additional Accelerated Purchase") of up to the lesser of:
•300% of the number of shares purchased pursuant to the applicable corresponding Regular Purchase; and
•30% of the aggregate shares of the Common Stock traded on the Nasdaq Capital Market during all or, if certain trading volume or market price thresholds specified in the Purchase Agreement are crossed on the applicable Additional Accelerated Purchase date, the portion of the normal trading hours on the applicable Additional Accelerated Purchase date prior to such time that any one of such thresholds is crossed, which period of time on the applicable Additional Accelerated Purchase date is referred to as the Additional Accelerated Purchase Measurement Period.

The parties may mutually agree to increase the number of shares to be purchased by Lincoln Park pursuant to any Additional Accelerated Purchase.

The Company may, in its sole discretion, submit multiple Additional Accelerated Purchase notices to Lincoln Park on a single Accelerated Purchase date, provided that all prior Accelerated Purchases and Additional Accelerated Purchases (including those that have occurred earlier on the same day) have been completed and all of the shares to be purchased thereunder have been properly delivered to Lincoln Park in accordance with the Purchase Agreement.

The purchase price per share for each such Additional Accelerated Purchase will be equal to 97% of the lower of:
•the volume-weighted average price of the Common Stock on the Nasdaq Capital Market during the applicable Additional Accelerated Purchase Measurement Period on the applicable Additional Accelerated Purchase date; and
•the closing sale price of the Common Stock on the Nasdaq Capital Market on the applicable Additional Accelerated Purchase date.

In the case of Regular Purchases, Accelerated Purchases and Additional Accelerated Purchases, the purchase price per share will be equitably adjusted for any reorganization, recapitalization, non-cash dividend, stock split, reverse stock split or other similar transaction occurring during the business days used to compute the purchase price.
Other than as described above, there are no trading volume requirements or restrictions under the Purchase Agreement, and the Company will control the timing and amount of any sales of Common Stock to Lincoln Park.

The Purchase Agreement prohibits the Company from directing Lincoln Park to purchase any shares of Common Stock if those shares, when aggregated with all other shares of Common Stock then beneficially owned by Lincoln Park (as calculated pursuant to Section 13(d) of the Securities Exchange Act of 1934, as amended, and Rule 13d-3 thereunder), would result in Lincoln Park beneficially owning more than 9.99% of the then total outstanding shares of Common Stock.

Under applicable rules of the Nasdaq Capital Market, the Company may not issue or sell to Lincoln Park under the Purchase Agreement more than 19.99% of the shares of the Common Stock outstanding immediately prior to the execution of the Purchase Agreement (the "Exchange Cap") (or 5,622,718 shares, based on 28,127,657 shares outstanding immediately prior to the execution of the Purchase Agreement), unless (i) the Company obtains stockholder approval to issue shares of its common stock in excess of the Exchange Cap to Lincoln Park under the Purchase Agreement in accordance with applicable Nasdaq rules or (ii) the average price of all applicable sales of Common Stock to Lincoln Park under the Purchase Agreement equals or exceeds $2.17 per share, which is the lower of (A) the official closing price of the Common Stock on Nasdaq on the date immediately preceding the execution Purchase Agreement and (B) the average official closing price of the Common Stock on Nasdaq for the five consecutive trading days immediately preceding date of the Purchase Agreement, such that the transactions contemplated by the Purchase Agreement are exempt from the Exchange Cap limitation under applicable Nasdaq rules.

The Purchase Agreement does not limit the Company’s ability to raise capital from other sources at its sole discretion, except that, subject to certain exceptions, for a period set forth in the Purchase Agreement, the Company may not enter into any equity line of credit or similar continuous offering other than with Lincoln Park, excluding an "at the market offering" of Common Stock exclusively through one or more registered broker dealers.

The Purchase Agreement and Registration Rights Agreement each contain customary representations, warranties, and agreements of the Company and Lincoln Park, indemnification rights and other obligations of the parties. The Offering of Common Stock pursuant to the Purchase Agreement will terminate on the date that all shares offered by the Purchase Agreement have been sold or, if earlier, the expiration or termination of the Purchase Agreement. The Company has the right to terminate the Purchase Agreement at any time, without fee, penalty or cost to the Company.

Lincoln Park has covenanted not to cause or engage in any manner whatsoever, any direct or indirect short selling or hedging of the Common Stock.

The aggregate net proceeds under the Purchase Agreement to the Company will depend on the frequency and prices at which shares of Common Stock are sold to Lincoln Park. Actual sales of shares of Common Stock to Lincoln Park under the Purchase Agreement and the amount of such net proceeds will depend on a variety of factors to be determined by the Company from time to time, including (among others) market conditions, the trading price of the Common Stock and determinations by the Company as to other available and appropriate sources of funding for the Company. The Company expects to use any proceeds from the sale of the Purchase Shares to develop its product pipeline, for working capital and for general corporate purposes.

The issuance of the Purchase Shares and Commitment Shares have been registered pursuant to the Company’s effective shelf registration statement on Form S-3 (File No. 333-242372) (the "Registration Statement"), and the related base prospectus included in the Registration Statement, as supplemented by a prospectus supplement filed on January 14, 2022. A copy of the legal opinion as to the legality of the shares of Common Stock subject to the Purchase Agreement is filed as Exhibit 5.1 attached hereto.

The foregoing is a summary description of certain terms of the Purchase Agreement and the Registration Rights Agreement and, by its nature, is incomplete. Copies of the Purchase Agreement and the Registration Rights Agreement are attached hereto as Exhibit 10.1 and Exhibit 10.2, respectively, and are incorporated herein by reference. The foregoing descriptions of the Purchase Agreement and the Registration Rights Agreement are qualified in their entirety by reference to such exhibits.

The Purchase Agreement and Registration Rights Agreement contain customary representations and warranties, covenants and indemnification provisions that the parties made to, and solely for the benefit of, each other in the context of all of the terms and conditions of such agreements and in the context of the specific relationship between the parties thereto. The provisions of the Purchase Agreement and Registration Rights Agreement, including any representations and warranties contained therein, are not for the benefit of any party other than the parties thereto and are not intended as documents for investors and the public to obtain factual information about the current state of affairs of the parties thereto. Rather, investors and the public should look to other disclosures contained in the Company’s annual, quarterly and current reports the Company may file with the Securities and Exchange Commission ("SEC").

The information contained in this Current Report on Form 8-K shall not constitute an offer to sell or the solicitation of an offer to buy the shares of Common Stock discussed herein, nor shall there be any offer, solicitation or sale of the shares in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such jurisdiction.

On January 14, 2022 I-Mab (the "Company") (Nasdaq: IMAB), a clinical-stage biopharmaceutical company committed to the discovery, development, and commercialization of novel biologics, reported that the senior management team of the Company, including Founder, Chairman and Acting CEO Dr. Jingwu Zang, President Dr. Andrew Zhu, Chief Financial Officer John Long, Chief Strategy Officer Jielun Zhu and Chief Business Officer Dr. Weimin Tang, have executed the share purchase plan with the open market purchase of over 70,000 of the Company’s American depositary shares ("ADSs") in an aggregate amount of over US$2.6 million as of 14 Jan, 2022 (Press release, I-Mab Biopharma, JAN 14, 2022, View Source [SID1234605493]). The average price per ADS is approximately US$38. The senior management team plans to continue to purchase the Company’s ADSs on the open market for an minimum US$3 million and up to US$20 million on an accumulative basis.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

On January 14, 2022 Eisai reported the presentation of six abstracts across various gastrointestinal cancers during the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (#GI22), which is taking place in-person in San Francisco and online from January 20-22 (Press release, Eisai, JAN 14, 2022, View Source [SID1234605492]). Notable data include a primary analysis from the Phase 2 TACTICS-L trial evaluating the safety and efficacy of LENVIMA in combination with transcatheter arterial chemoembolization (TACE) in the treatment of patients in Japan with unresectable hepatocellular carcinoma (uHCC) (NCT03838796; Abstract #417).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

Additional presentations will highlight Eisai’s commitment to researching potential treatments for patients across the cancer continuum, including trial-in-progress (TiP) posters from the LEAP (LEnvatinib And Pembrolizumab) clinical program evaluating KEYTRUDA plus LENVIMA in esophageal squamous cell carcinoma (NCT04949256, Abstract #TPS367), gastroesophageal adenocarcinoma (NCT04662710; Abstract #TPS369) and HCC (NCT04246177; Abstract #TPS494). Eisai will also share research updates on the Phase 4 STELLAR study evaluating safety and tolerability of LENVIMA in patients with uHCC (NCT04763408; Poster Abstract #TPS485), as well as a Phase 2 study of KEYTRUDA plus LENVIMA and belzutifan in patients with advanced solid tumors, including HCC, colorectal cancer, pancreatic ductal adenocarcinoma and biliary tract cancer (NCT04976634; Abstract #TPS669).

"Gastrointestinal cancers account for one in four cancer cases and one in three cancer deaths globally, with these malignancies expected to increase over the coming decade. It is with these staggering statistics in mind that we remain dedicated to exploring the potential of LENVIMA alone and in combination as a treatment for advanced cancers," said Richard C. Woodman, MD, Chief Clinical Officer, CCLO, Oncology Business Group at Eisai. "This research is reflective of our human health care (hhc) mission and our unwavering commitment of working to develop innovative and effective treatment options for patients living with difficult-to-treat cancers."

In March 2018, Eisai and Merck (known as MSD outside the United States and Canada), through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of LENVIMA, both as monotherapy and in combination with Merck’s anti-PD-1 therapy KEYTRUDA. To date, more than 20 trials have been initiated under the LEAP (LEnvatinib And Pembrolizumab) clinical program, which is evaluating the combination across more than 10 different tumor types. For more information on the LEAP program, please visit clinicaltrials.gov.

This release discusses investigational compounds and investigational uses for FDA-approved products. It is not intended to convey conclusions about efficacy and safety. There is no guarantee that any investigational compounds or investigational uses of FDA-approved products will successfully complete clinical development or gain FDA approval.

The full list of Eisai presentations is included below. All abstracts will be made available on Tuesday, January 18 at 5:00 PM EDT and will be available on demand via ASCO (Free ASCO Whitepaper)’s website.

Cancer Type(s)

Study/Trial

Abstract Title

Presentation Details

Lenvatinib

Gastrointestinal Cancer

TACTICS-L

Transcatheter arterial chemoembolization therapy in combination strategy with lenvatinib in patients with unresectable hepatocellular carcinoma (TACTICS-L) in Japan: Primary analysis

Abstract: 417

Poster Session B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract

Kazuomi Ueshima, MD

Kindai University Faculty of Medicine

January 21, 2022

3:05 P.M. EST

STELLAR/Study 508

A multicenter, observational, phase 4 study (STELLAR) to evaluate the safety and tolerability of lenvatinib (LEN) in patients with advanced or unresectable hepatocellular carcinoma (uHCC)

Abstract: TPS485

Trials in Progress Poster Session B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract

Markus Peck-Radosavljevic, MD, MBA

Klinikum Klagenfurt

January 21, 2022

3:05 P.M. EST

Lenvatinib Combinations

Gastrointestinal Cancer

LEAP-014

LEAP-014: An open-label, randomized, phase 3 study of first-line lenvatinib plus pembrolizumab plus chemotherapy in esophageal carcinoma squamous cell carcinoma

Abstract: TPS367

Trials in Progress Poster Session A: Cancers of the Esophagus and Stomach and Other GI Cancers

Jong-Mu Sun, MD, PhD

Samsung Medical Center

January 20, 2022

3:00 P.M. EST

LEAP-015

A randomized phase 3 study evaluating the efficacy and safety of first-line pembrolizumab plus lenvatinib plus chemotherapy versus chemotherapy in patients with advanced/metastatic gastroesophageal adenocarcinoma: LEAP-015

Abstract: TPS369

Trials in Progress Poster Session A: Cancers of the Esophagus and Stomach and Other GI Cancers

DJ Cohen, MD

Icahn School of Medicine at Mount Sinai

January 20, 2022

3:00 P.M. EST

LEAP-012

LEAP-012 Trial in progress: Transarterial chemoembolization with or without lenvatinib plus pembrolizumab for intermediate-stage hepatocellular carcinoma not amenable to curative treatment

Abstract: TPS494

Trials in Progress Poster Session B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract

AB El-Khoueiry, MD

Keck School of Medicine of USC

January 21, 2022

3:05 P.M. EST

Solid Tumors

MK-6482-016

Phase 2, open-label study of pembrolizumab plus lenvatinib and belzutifan in patients with advanced solid tumors

Abstract: TPS669

Trials in Progress Poster Session A: Cancers of the Esophagus and Stomach and Other GI Cancers

Robin K. Kelly, MD

University of California San Francisco Department of Medicine

January 20, 2022

3:00 P.M. EST

About LENVIMA (lenvatinib) Capsules

LENVIMA is indicated:

For the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC)
In combination with pembrolizumab, for the first line treatment of adult patients with advanced renal cell carcinoma (RCC)
In combination with everolimus for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy (RCC)
For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC)
In combination with pembrolizumab, for the treatment of patients with advanced endometrial carcinoma (EC) that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
LENVIMA, discovered and developed by Eisai, is a kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4, platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGD-receptor substrate 2α (FRS2α) phosphorylation. The combination of lenvatinib and everolimus showed increased anti-angiogenic and anti-tumor activity as demonstrated by decreases in human endothelial cell proliferation, tube formation, and VEGF signaling in vitro and decreases in tumor volume in mouse xenograft models of human renal cell cancer greater than with either drug alone. In syngeneic mouse tumor models, lenvatinib decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity in combination with an anti-PD-1 monoclonal antibody compared to either treatment alone.

Important Safety Information

Warnings and Precautions

Hypertension. In DTC (differentiated thyroid cancer), hypertension occurred in 73% of patients on LENVIMA (44% grade 3-4). In RCC (renal cell carcinoma), hypertension occurred in 42% of patients on LENVIMA + everolimus (13% grade 3). Systolic blood pressure ≥160 mmHg occurred in 29% of patients, and 21% had diastolic blood pressure ≥100 mmHg. In HCC (hepatocellular carcinoma), hypertension occurred in 45% of LENVIMA-treated patients (24% grade 3). Grade 4 hypertension was not reported in HCC.

Serious complications of poorly controlled hypertension have been reported. Control blood pressure prior to initiation. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at reduced dose when hypertension is controlled or permanently discontinue based on severity.

Cardiac Dysfunction. Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in 799 patients with DTC, RCC, and HCC, grade 3 or higher cardiac dysfunction occurred in 3% of LENVIMA-treated patients. Monitor for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Arterial Thromboembolic Events. Among patients receiving LENVIMA or LENVIMA + everolimus, arterial thromboembolic events of any severity occurred in 2% of patients in RCC and HCC and 5% in DTC. Grade 3-5 arterial thromboembolic events ranged from 2% to 3% across all clinical trials.

Among patients receiving LENVIMA with pembrolizumab, arterial thrombotic events of any severity occurred in 5% of patients in CLEAR, including myocardial infarction (3.4%) and cerebrovascular accident (2.3%).

Permanently discontinue following an arterial thrombotic event. The safety of resuming after an arterial thromboembolic event has not been established, and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

Hepatotoxicity. Across clinical studies enrolling 1327 LENVIMA-treated patients with malignancies other than HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events, including hepatic failure, acute hepatitis, and hepatorenal syndrome, occurred in 0.5% of patients. In HCC, hepatic encephalopathy occurred in 8% of LENVIMA-treated patients (5% grade 3-5). Grade 3-5 hepatic failure occurred in 3% of LENVIMA-treated patients; 2% of patients discontinued LENVIMA due to hepatic encephalopathy, and 1% discontinued due to hepatic failure.

Monitor liver function prior to initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Renal Failure or Impairment. Serious including fatal renal failure or impairment can occur with LENVIMA. Renal impairment was reported in 14% and 7% of LENVIMA-treated patients in DTC and HCC, respectively. Grade 3-5 renal failure or impairment occurred in 3% of patients with DTC and 2% of patients with HCC, including 1 fatal event in each study. In RCC, renal impairment or renal failure was reported in 18% of LENVIMA + everolimus–treated patients (10% grade 3).

Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume at reduced dose upon recovery or permanently discontinue for renal failure or impairment based on severity.

Proteinuria. In DTC and HCC, proteinuria was reported in 34% and 26% of LENVIMA-treated patients, respectively. Grade 3 proteinuria occurred in 11% and 6% in DTC and HCC, respectively. In RCC, proteinuria occurred in 31% of patients receiving LENVIMA + everolimus (8% grade 3). Monitor for proteinuria prior to initiation and periodically during treatment. If urine dipstick proteinuria ≥2+ is detected, obtain a 24-hour urine protein. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Diarrhea. Of the 737 LENVIMA-treated patients in DTC and HCC, diarrhea occurred in 49% (6% grade 3). In RCC, diarrhea occurred in 81% of LENVIMA + everolimus–treated patients (19% grade 3). Diarrhea was the most frequent cause of dose interruption/reduction, and diarrhea recurred despite dose reduction. Promptly initiate management of diarrhea. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Fistula Formation and Gastrointestinal Perforation. Of the 799 patients treated with LENVIMA or LENVIMA + everolimus in DTC, RCC, and HCC, fistula or gastrointestinal perforation occurred in 2%. Permanently discontinue in patients who develop gastrointestinal perforation of any severity or grade 3-4 fistula.

QT Interval Prolongation. In DTC, QT/QTc interval prolongation occurred in 9% of LENVIMA-treated patients and QT interval prolongation of >500 ms occurred in 2%. In RCC, QTc interval increases of >60 ms occurred in 11% of patients receiving LENVIMA + everolimus and QTc interval >500 ms occurred in 6%. In HCC, QTc interval increases of >60 ms occurred in 8% of LENVIMA-treated patients and QTc interval >500 ms occurred in 2%.

Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at reduced dose upon recovery based on severity.

Hypocalcemia. In DTC, grade 3-4 hypocalcemia occurred in 9% of LENVIMA-treated patients. In 65% of cases, hypocalcemia improved or resolved following calcium supplementation with or without dose interruption or dose reduction. In RCC, grade 3-4 hypocalcemia occurred in 6% of LENVIMA + everolimus–treated patients. In HCC, grade 3 hypocalcemia occurred in 0.8% of LENVIMA-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS). Across clinical studies of 1823 patients who received LENVIMA as a single agent, RPLS occurred in 0.3%. Confirm diagnosis of RPLS with MRI. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity and persistence of neurologic symptoms.

Hemorrhagic Events. Serious including fatal hemorrhagic events can occur with LENVIMA. In DTC, RCC, and HCC clinical trials, hemorrhagic events, of any grade, occurred in 29% of the 799 patients treated with LENVIMA as a single agent or in combination with everolimus. The most frequently reported hemorrhagic events (all grades and occurring in at least 5% of patients) were epistaxis and hematuria. In DTC, grade 3-5 hemorrhage occurred in 2% of LENVIMA-treated patients, including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. In RCC, grade 3-5 hemorrhage occurred in 8% of LENVIMA + everolimus–treated patients, including 1 fatal cerebral hemorrhage. In HCC, grade 3-5 hemorrhage occurred in 5% of LENVIMA-treated patients, including 7 fatal hemorrhagic events. Serious tumor-related bleeds, including fatal hemorrhagic events, occurred in LENVIMA-treated patients in clinical trials and in the postmarketing setting. In postmarketing surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than other tumors. Safety and effectiveness of LENVIMA in patients with ATC have not been demonstrated in clinical trials.

Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (eg, carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction. LENVIMA impairs exogenous thyroid suppression. In DTC, 88% of patients had baseline thyroid stimulating hormone (TSH) level ≤0.5 mU/L. In patients with normal TSH at baseline, elevation of TSH level >0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. In RCC and HCC, grade 1 or 2 hypothyroidism occurred in 24% of LENVIMA + everolimus–treated patients and 21% of LENVIMA-treated patients, respectively. In patients with normal or low TSH at baseline, elevation of TSH was observed post baseline in 70% of LENVIMA-treated patients in HCC and 60% of LENVIMA + everolimus–treated patients in RCC.

Monitor thyroid function prior to initiation and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.

Impaired Wound Healing. Impaired wound healing has been reported in patients who received LENVIMA. Withhold LENVIMA for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of LENVIMA after resolution of wound healing complications has not been established.

Osteonecrosis of the Jaw (ONJ). ONJ has been reported in patients receiving LENVIMA. Concomitant exposure to other risk factors, such as bisphosphonates, denosumab, dental disease, or invasive dental procedures, may increase the risk of ONJ.

Perform an oral examination prior to treatment with LENVIMA and periodically during LENVIMA treatment. Advise patients regarding good oral hygiene practices and to consider having preventive dentistry performed prior to treatment with LENVIMA and throughout treatment with LENVIMA.

Avoid invasive dental procedures, if possible, while on LENVIMA treatment, particularly in patients at higher risk. Withhold LENVIMA for at least 1 week prior to scheduled dental surgery or invasive dental procedures, if possible. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk of ONJ.

Withhold LENVIMA if ONJ develops and restart based on clinical judgement of adequate resolution.

Embryo-Fetal Toxicity. Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to pregnant women. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended clinical doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus and advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 30 days after the last dose.

Adverse Reactions
In DTC, the most common adverse reactions (≥30%) observed in LENVIMA-treated patients were hypertension (73%), fatigue (67%), diarrhea (67%), arthralgia/myalgia (62%), decreased appetite (54%), decreased weight (51%), nausea (47%), stomatitis (41%), headache (38%), vomiting (36%), proteinuria (34%), palmar-plantar erythrodysesthesia syndrome (32%), abdominal pain (31%), and dysphonia (31%). The most common serious adverse reactions (≥2%) were pneumonia (4%), hypertension (3%), and dehydration (3%). Adverse reactions led to dose reductions in 68% of LENVIMA-treated patients; 18% discontinued LENVIMA. The most common adverse reactions (≥10%) resulting in dose reductions were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%).

In RCC, the most common adverse reactions (≥20%) observed in LENVIMA + pembrolizumab-treated patients were fatigue (63%), diarrhea (62%), musculoskeletal pain (58%), hypothyroidism (57%), hypertension (56%), stomatitis (43%), decreased appetite (41%), rash (37%), nausea (36%), decreased weight (30%), dysphonia (30%), proteinuria (30%), palmar-plantar erythrodysesthesia syndrome (29%), abdominal pain (27%), hemorrhagic events (27%), vomiting (26%), constipation (25%), hepatotoxicity (25%), headache (23%), and acute kidney injury (21%). The most common serious adverse reactions (≥2%) were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%). Fatal adverse reactions occurred in 4.3% of patients receiving LENVIMA in combination with pembrolizumab, including cardio-respiratory arrest (0.9%), sepsis (0.9%), and one case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm and subarachnoid hemorrhage. Serious adverse reactions occurred in 51% of patients receiving LENVIMA and pembrolizumab. Serious adverse reactions in ≥2% of patients were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%). Permanent discontinuation of LENVIMA, pembrolizumab, or both due to an adverse reaction occurred in 37% of patients; 26% LENVIMA only, 29% pembrolizumab only, and 13% both drugs. The most common adverse reactions (≥2%) leading to permanent discontinuation of LENVIMA, pembrolizumab, or both were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%). Dose interruptions of LENVIMA, pembrolizumab, or both due to an adverse reaction occurred in 78% of patients receiving LENVIMA in combination with pembrolizumab. LENVIMA was interrupted in 73% of patients and both drugs were interrupted in 39% of patients. LENVIMA was dose reduced in 69% of patients. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of LENVIMA were diarrhea (26%), fatigue (18%), hypertension (17%), proteinuria (13%), decreased appetite (12%), palmar-plantar erythrodysesthesia (11%), nausea (9%), stomatitis (9%), musculoskeletal pain (8%), rash (8%), increased lipase (7%), abdominal pain (6%), and vomiting (6%), increased ALT (5%), and increased amylase (5%).

In RCC, the most common adverse reactions (≥30%) observed in LENVIMA + everolimus–treated patients were diarrhea (81%), fatigue (73%), arthralgia/myalgia (55%), decreased appetite (53%), vomiting (48%), nausea (45%), stomatitis (44%), hypertension (42%), peripheral edema (42%), cough (37%), abdominal pain (37%), dyspnea (35%), rash (35%), decreased weight (34%), hemorrhagic events (32%), and proteinuria (31%). The most common serious adverse reactions (≥5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%). Adverse reactions led to dose reductions or interruption in 89% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Treatment discontinuation due to an adverse reaction occurred in 29% of patients.

In HCC, the most common adverse reactions (≥20%) observed in LENVIMA-treated patients were hypertension (45%), fatigue (44%), diarrhea (39%), decreased appetite (34%), arthralgia/myalgia (31%), decreased weight (31%), abdominal pain (30%), palmar-plantar erythrodysesthesia syndrome (27%), proteinuria (26%), dysphonia (24%), hemorrhagic events (23%), hypothyroidism (21%), and nausea (20%). The most common serious adverse reactions (≥2%) were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%), and decreased appetite (2%). Adverse reactions led to dose reductions or interruption in 62% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were fatigue (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%). Treatment discontinuation due to an adverse reaction occurred in 20% of patients. The most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were fatigue (1%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure (1%).

In EC, the most common adverse reactions (≥20%) observed in LENVIMA and pembrolizumab–treated patients were hypothyroidism (67%), hypertension (67%), fatigue (58%), diarrhea (55%), musculoskeletal disorders (53%), nausea (49%), decreased appetite (44%), vomiting (37%), stomatitis (35%), decreased weight (34%), abdominal pain (34%), urinary tract infection (31%), proteinuria (29%), constipation (27%), headache (26%), hemorrhagic events (25%), palmar–plantar erythrodysesthesia (23%), dysphonia (22%), and rash (20%). Fatal adverse reactions occurred in 4.7% of those treated with LENVIMA and pembrolizumab, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction. Serious adverse reactions occurred in 50% of patients receiving LENVIMA and pembrolizumab. Serious adverse reactions with frequency ≥3% were hypertension (4.4%), and urinary tract infection (3.2%). Discontinuation of LENVIMA due to an adverse reaction occurred in 26% of patients. The most common (≥1%) adverse reactions leading to discontinuation of LENVIMA were hypertension (2%), asthenia (1.8%), diarrhea (1.2%), decreased appetite (1.2%), proteinuria (1.2%), and vomiting (1.2%). Dose reductions of LENVIMA due to adverse reactions occurred in 67% of patients. The most common (≥5%) adverse reactions resulting in dose reduction of LENVIMA were hypertension (18%), diarrhea (11%), palmar-plantar erythrodysesthesia syndrome (9%), proteinuria (7%), fatigue (7%), decreased appetite (6%), asthenia (5%), and weight decreased (5%). Dose interruptions of LENVIMA due to an adverse reaction occurred in 58% of these patients. The most common (≥2%) adverse reactions leading to interruption of LENVIMA were hypertension (11%), diarrhea (11%), proteinuria (6%), decreased appetite (5%), vomiting (5%), increased alanine aminotransferase (3.5%), fatigue (3.5%), nausea (3.5%), abdominal pain (2.9%), decreased weight (2.6%), urinary tract infection (2.6%), increased aspartate aminotransferase (2.3%), asthenia (2.3%), and palmar-plantar erythrodysesthesia (2%).

Use in Specific Populations
Because of the potential for serious adverse reactions in breastfed infants, advise women to discontinue breastfeeding during treatment and for at least 1 week after the last dose. LENVIMA may impair fertility in males and females of reproductive potential.

No dose adjustment is recommended for patients with mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. LENVIMA concentrations may increase in patients with DTC, RCC, or EC and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose for patients with DTC, RCC, or EC and severe renal impairment. There is no recommended dose for patients with HCC and severe renal impairment. LENVIMA has not been studied in patients with end-stage renal disease.

No dose adjustment is recommended for patients with HCC and mild hepatic impairment (Child-Pugh A). There is no recommended dose for patients with HCC with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. No dose adjustment is recommended for patients with DTC, RCC, or EC and mild or moderate hepatic impairment. LENVIMA concentrations may increase in patients with DTC, RCC, or EC and severe hepatic impairment. Reduce the dose for patients with DTC, RCC, or EC and severe hepatic impairment.

LENVIMA (lenvatinib) is available as 10 mg and 4 mg capsules.

Please see Prescribing information for LENVIMA (lenvatinib) at View Source

About the Eisai and Merck Strategic Collaboration
In March 2018, Eisai and Merck, known as MSD outside the United States and Canada, through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of LENVIMA. Under the agreement, the companies will jointly develop, manufacture and commercialize LENVIMA, both as monotherapy and in combination with Merck’s anti-PD-1 therapy KEYTRUDA.

In addition to ongoing clinical studies evaluating the KEYTRUDA plus LENVIMA combination across several different tumor types, the companies have jointly initiated new clinical studies through the LEAP (LEnvatinib And Pembrolizumab) clinical program and are evaluating the combination in 13 different tumor types (endometrial carcinoma, hepatocellular carcinoma, melanoma, non-small cell lung cancer, renal cell carcinoma, squamous cell carcinoma of the head and neck, urothelial cancer, biliary tract cancer, colorectal cancer, gastric cancer, glioblastoma, and pancreatic cancer) across more than 20 clinical trials.

On January 14, 2022 Oblique Therapeutics AB reported that key aspects of its AbiProt technology for discovering and developing pharmacologically tailored antibodies against clinically important targets has been granted by the USPTO as US Patent No. 11,161,901 B2 (Press release, Oblique Therapeutics, JAN 14, 2022, View Source [SID1234605491]). The technology uses artificially intelligent molecular probes and mass spectrometry to identify antibody binding sites on clinically relevant targets, many of which have been considered undruggable with antibodies. The AbiProt proteomics technology from Oblique Therapeutics has the potential to bring several novel antibody medicines to large patient populations in multiple disease areas

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

AbiProt was recently presented in detail in a research article in Science Advances, Rational antibody design for undruggable targets using kinetically controlled biomolecular probes (science.org). The grant of this patent provides further recognition of the high quality of the innovation being carried out by Oblique Therapeutics’ team.

Owe Orwar, Ph.D., Professor, Founder and CEO of Oblique Therapeutics says:

"We are absolutely thrilled by the news from USPTO. We are today developing a number of programs out of the AbiProt platform with a focus on pain and aggressive cancer. In particular, we have developed a world-leading portfolio of mutant-selective KRAS mAbs showing efficacy in animal models of G13D-mutated colorectal cancer and highly interesting first-in-class mAbs targeting TRPV1 intended as a replacement for opioids in pain management. The aTRPV1 mAb is R&D-partnered with a license-option with a major pharma company."

Carolina Trkulja, Ph.D., Founder and CSO of Oblique Therapeutics says:

"I’m delighted to receive this news from the USPTO and very excited for what the future holds for the AbiProt platform and what it will mean for the patients. This technology has the potential to transform the treatment landscape for several aggressive diseases and bring new hope to these patient populations."

About AbiProt

AbiProt, is a proprietary methodology to identify epitopes on protein targets that have previously proven difficult to address with antibodies. AbiProt can identify high-affinity antibody binding sites in a given protein with single amino acid resolution while the protein resides in its native environment. It is based on using a tailored molecular reporter system and proteomics. The platform yields detailed sequence and structure information for epitope identification and development. Oblique Therapeutics is applying this technology for discovery of a new generation of selective antibody therapeutics targeting cancer and pain.

Science Advances Publication about AbiProt:

On January 14, 2022 Pieris Pharmaceuticals, Inc. (NASDAQ:PIRS), a clinical-stage biotechnology company advancing novel biotherapeutics through its proprietary Anticalin technology platform for respiratory diseases, cancer, and other indications, reported that the first patient has been dosed in the phase 2 study of cinrebafusp alfa (PRS-343), a 4-1BB/HER2 Anticalin-based bispecific for the treatment of HER2-expressing gastric cancer (Press release, Pieris Pharmaceuticals, JAN 14, 2022, View Source [SID1234605490]). The two-arm, multicenter, open-label phase 2 study is evaluating the efficacy, safety, and tolerability of cinrebafusp alfa in combination with ramucirumab and paclitaxel in patients with HER2-high gastric cancer and in combination with tucatinib in patients with HER2-low gastric cancer.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

Patients in the phase 2 study will receive a loading dose of 18 mg/kg in week one and three, followed by maintenance doses of 8 mg/kg (Q2W) for both arms in the study. The Company is targeting an ORR of at least 40% with meaningful durability in the HER2-low arm, for which it intends to present data later this year. In the HER2-high arm, the Company is targeting an ORR of at least 50% with meaningful durability. Pieris intends to present data for the HER2-high arm in 2023. Collaboration partners Lilly and Seagen will supply ramucirumab and tucatinib, respectively, under previously announced drug supply agreements.

"The dosing of the first patient in this next phase of development of cinrebafusp alfa marks an important milestone for patients afflicted by gastric cancer without adequate treatment options, and we look forward to further evaluating the potential of this drug," said Tim Demuth, M.D., Ph.D., Chief Medical Officer of Pieris. "We believe cinrebafusp alfa can provide differentiated treatment options for patients with gastric cancer via 4-1BB-mediated T-cell engagement, both in terms of efficacy and safety."

About Cinrebafusp Alfa:

Cinrebafusp alfa (PRS-343) is a 4-1BB/HER2 fusion protein comprising 4-1BB-targeting Anticalin proteins and a HER2-targeting antibody. The drug candidate is currently in phase 2 development for the treatment of HER2-expressing solid tumors. In phase 1 studies, cinrebafusp alfa has shown an acceptable safety profile at all doses tested with no dose-limiting toxicities. The bispecific also showed a dose response and a 4-1BB-driven mechanism of action based on clinical benefit and pharmacodynamic correlates.