European Commission Approves LORVIQUA® (lorlatinib) as a First-Line Treatment for ALK-Positive Advanced Lung Cancer

On January 28, 2022 Pfizer Inc. (NYSE: PFE) reported that the European Commission (EC) granted marketing authorization for LORVIQUA (lorlatinib, available in the U.S. under the brand name LORBRENA) as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK)- positive advanced non-small cell lung cancer (NSCLC) previously not treated with an ALK inhibitor (Press release, Pfizer, JAN 28, 2022, View Source [SID1234607488]).

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"For more than a decade, Pfizer has worked tirelessly in its pursuit to help transform the trajectory for people living with advanced, biomarker-driven lung cancers," said Andy Schmeltz, Global President & General Manager, Pfizer Oncology. "The European Commission’s approval of LORVIQUA as a first-line therapy is a significant milestone that we hope will help bring a needed and meaningful difference to those impacted by this deadly disease in Europe."

The approval for the first-line use of LORVIQUA was based on the results of the pivotal Phase 3 CROWN trial, in which LORVIQUA reduced the risk of disease progression or death by 72% compared to XALKORI (crizotinib). As a secondary endpoint, the confirmed objective response rate (ORR) was 76% (95% CI, 68 to 83) with LORVIQUA and 58% (95% CI, 49 to 66) with XALKORI. In patients with measurable brain metastases, 82% of patients in the LORVIQUA arm experienced an intracranial response (71% had an intracranial complete response), compared to 23% of XALKORI patients. The CROWN trial is a randomized, open-label, parallel 2-arm trial in which 296 people with previously untreated advanced ALK-positive NSCLC were randomized 1:1 to receive LORVIQUA monotherapy (n=149) or XALKORI monotherapy (n=147).

"The expanded approval for LORVIQUA in Europe is a considerable advancement – especially for the close to 40 percent of patients with ALK-positive metastatic NSCLC who are faced with brain metastases at diagnosis," said Professor Benjamin Solomon, MBBS, PhD., Department of Medical Oncology at the Peter MacCallum Cancer Centre in Melbourne, Australia. "It is exciting to see the significant data generated from the CROWN trial continuing to support expanded use around the world and providing physicians in Europe with a highly effective option from the onset of their patients’ treatment journey."

The EC approval of LORVIQUA follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in December 2021. LORVIQUA is approved in the U.S. by the Food and Drug Administration (FDA) under the brand name LORBRENA for the treatment of adults with metastatic NSCLC whose tumors are ALK-positive as detected by an FDA-approved test. In 2019, the EC granted conditional marketing authorization for LORVIQUA as a monotherapy for the treatment of adult patients with ALK-positive advanced NSCLC whose disease has progressed after alectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI) therapy, or crizotinib and at least one other ALK TKI.

About the CROWN Trial of LORVIQUA

In the CROWN trial, patients were required to have an ECOG performance status of 0-2 and ALK-positive NSCLC as identified by the VENTANA ALK (D5F3) CDx assay. The primary endpoint of the CROWN trial was progression-free survival (PFS) based on blinded independent central review (BICR). Secondary endpoints included overall survival (OS) and tumor assessment related data by BICR, including ORR, and duration of response (DOR). In patients with measurable central nervous system (CNS) metastases at baseline, additional outcome measures were intracranial (IC)-ORR and IC-DOR by BICR. The trial is continuing in order to further evaluate the secondary endpoint of OS, which was not mature at the time of analysis.

Overall, the safety profile of LORVIQUA was similar to that reported in previous studies. The most frequent adverse events (AEs) in ≥20% of 149 patients treated with LORVIQUA were edema, weight gain, peripheral neuropathy, cognitive effects, diarrhea, dyspnea and hypertriglyceridemia. Serious AEs occurred in 34% of people treated with LORVIQUA; the most frequently reported serious AEs were pneumonia, dyspnea, respiratory failure, cognitive effects and pyrexia. Fatal AEs occurred in 3.4% of people treated with LORVIQUA. Permanent discontinuation of LORVIQUA due to AEs occurred in 6.7% of people. Detailed results from the CROWN study were published in the November 2020 issue of the New England Journal of Medicine.

About Non-Small Cell Lung Cancer (NSCLC)

Lung cancer is the number one cause of cancer-related death around the world.1 NSCLC accounts for approximately 80-85% of lung cancers,2 with ALK-positive tumors occurring in about 3-5% of NSCLC cases.3 Up to 40% of people with ALK-positive metastatic NSCLC present with brain metastases at initial diagnosis.4,5,6

About LORVIQUA (lorlatinib)

LORVIQUA is a TKI that has been shown to be highly active in preclinical lung cancer models harboring chromosomal rearrangements of ALK. LORVIQUA was specifically developed to inhibit tumor mutations that drive resistance to other ALK inhibitors and to penetrate the blood brain barrier.

The full U.S. prescribing information for LORBRENA can be found here.

IMPORTANT LORBRENA (lorlatinib) SAFETY INFORMATION FROM THE U.S. PRESCRIBING INFORMATION

Contraindications: LORBRENA is contraindicated in patients taking strong CYP3A inducers, due to the potential for serious hepatotoxicity.

Risk of Serious Hepatotoxicity with Concomitant Use of Strong CYP3A Inducers: Severe hepatotoxicity occurred in 10 of 12 healthy subjects receiving a single dose of LORBRENA with multiple daily doses of rifampin, a strong CYP3A inducer. Grade 4 ALT or AST elevations occurred in 50% of subjects, Grade 3 in 33% of subjects, and Grade 2 in 8% of subjects. ALT or AST elevations occurred within 3 days and returned to within normal limits after a median of 15 days (7 to 34 days); median time to recovery in subjects with Grade 3 or 4 or Grade 2 ALT or AST elevations was 18 days and 7 days, respectively. LORBRENA is contraindicated in patients taking strong CYP3A inducers. Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to initiating LORBRENA.

Central Nervous System (CNS) Effects: A broad spectrum of CNS effects can occur; overall, CNS effects occurred in 52% of the 476 patients receiving LORBRENA. These included seizures (1.9%, sometimes in conjunction with other neurologic findings), psychotic effects (7%; 0.6% severe [Grade 3 or 4]), and changes in cognitive function (28%; 2.9% severe), mood (including suicidal ideation) (21%; 1.7% severe), speech (11%; 0.6% severe), mental status (1.3%; 1.1% severe), and sleep (12%). Median time to first onset of any CNS effect was 1.4 months (1 day to 3.4 years). Overall, 2.1% and 10% of patients required permanent or temporary discontinuation of LORBRENA, respectively, for a CNS effect; 8% required dose reduction. Withhold and resume at same or reduced dose or permanently discontinue based on severity.

Hyperlipidemia: Increases in serum cholesterol and triglycerides can occur. Grade 3 or 4 elevations in total cholesterol occurred in 18% and Grade 3 or 4 elevations in triglycerides occurred in 19% of the 476 patients who received LORBRENA. Median time to onset was 15 days for both hypercholesterolemia and hypertriglyceridemia. Approximately 4% and 7% of patients required temporary discontinuation and 1% and 3% of patients required dose reduction of LORBRENA for elevations in cholesterol and in triglycerides in Study B7461001 and Study B7461006, respectively. Eighty-three percent of patients required initiation of lipid-lowering medications, with a median time to onset of start of such medications of 17 days. Initiate or increase the dose of lipid-lowering agents in patients with hyperlipidemia. Monitor serum cholesterol and triglycerides before initiating LORBRENA, 1 and 2 months after initiating LORBRENA, and periodically thereafter. Withhold and resume at same dose for the first occurrence; resume at same or reduced dose of LORBRENA for recurrence based on severity.

Atrioventricular (AV) Block: PR interval prolongation and AV block can occur. In 476 patients who received LORBRENA at a dose of 100 mg orally once daily and who had a baseline electrocardiography (ECG), 1.9% experienced AV block and 0.2% experienced Grade 3 AV block and underwent pacemaker placement. Monitor ECG prior to initiating LORBRENA and periodically thereafter. Withhold and resume at reduced or same dose in patients who undergo pacemaker placement. Permanently discontinue for recurrence in patients without a pacemaker.

Interstitial Lung Disease (ILD)/Pneumonitis: Severe or life-threatening pulmonary adverse reactions consistent with ILD/pneumonitis can occur. ILD/pneumonitis occurred in 1.9% of patients, including Grade 3 or 4 ILD/pneumonitis in 0.6% of patients. Four patients (0.8%) discontinued LORBRENA for ILD/pneumonitis. Promptly investigate for ILD/pneumonitis in any patient who presents with worsening of respiratory symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, and fever). Immediately withhold LORBRENA in patients with suspected ILD/pneumonitis. Permanently discontinue LORBRENA for treatment-related ILD/pneumonitis of any severity.

Hypertension: Hypertension can occur. Hypertension occurred in 13% of patients, including Grade 3 or 4 in 6% of patients. Median time to onset of hypertension was 6.4 months (1 day to 2.8 years), and 2.3% of patients temporarily discontinued LORBRENA for hypertension. Control blood pressure prior to initiating LORBRENA. Monitor blood pressure after 2 weeks and at least monthly thereafter. Withhold and resume at reduced dose or permanently discontinue based on severity.

Hyperglycemia: Hyperglycemia can occur. Hyperglycemia occurred in 9% of patients, including Grade 3 or 4 in 3.2% of patients. Median time to onset of hyperglycemia was 4.8 months (1 day to 2.9 years), and 0.8% of patients temporarily discontinued LORBRENA for hyperglycemia. Assess fasting serum glucose prior to initiating LORBRENA and monitor periodically thereafter. Withhold and resume at reduced dose or permanently discontinue based on severity.

Embryo-fetal Toxicity: LORBRENA can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective non-hormonal method of contraception, since LORBRENA can render hormonal contraceptives ineffective, during treatment with LORBRENA and for at least 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with LORBRENA and for 3 months after the final dose.

Adverse Reactions: In the pooled safety population of 476 patients who received 100 mg LORBRENA once daily, the most frequent (≥ 20%) adverse reactions were edema (56%), peripheral neuropathy (44%), weight gain (31%), cognitive effects (28%), fatigue (27%), dyspnea (27%), arthralgia (24%), diarrhea (23%), mood effects (21%), and cough (21%). The most frequent (≥ 20%) Grade 3-4 laboratory abnormalities in patients receiving LORBRENA were hypercholesterolemia (21%) and hypertriglyceridemia (21%).

In previously untreated patients, serious adverse reactions occurred in 34% of the 149 patients treated with LORBRENA; the most frequently reported serious adverse reactions were pneumonia (4.7%), dyspnea (2.7%), respiratory failure (2.7%), cognitive effects (2.0%), and pyrexia (2.0%). Fatal adverse reactions occurred in 3.4% of patients and included pneumonia (0.7%), respiratory failure (0.7%), cardiac failure acute (0.7%), pulmonary embolism (0.7%), and sudden death (0.7%). In the Phase 1/2 study, serious adverse reactions occurred in 32% of the 295 patients; the most frequently reported serious adverse reactions were pneumonia (3.4%), dyspnea (2.7%), pyrexia (2%), mental status changes (1.4%), and respiratory failure (1.4%). Fatal adverse reactions occurred in 2.7% of patients and included pneumonia (0.7%), myocardial infarction (0.7%), acute pulmonary edema (0.3%), embolism (0.3%), peripheral artery occlusion (0.3%), and respiratory distress (0.3%).

Drug Interactions: LORBRENA is contraindicated in patients taking strong CYP3A inducers. Avoid concomitant use with moderate CYP3A inducers, strong CYP3A inhibitors, and fluconazole. If concomitant use of moderate CYP3A inducers cannot be avoided, increase the LORBRENA dose as recommended. If concomitant use with a strong CYP3A inhibitor or fluconazole cannot be avoided, reduce the LORBRENA dose as recommended. Avoid concomitant use of LORBRENA with CYP3A substrates and P-gp substrates, which may reduce the efficacy of these substrates.

Lactation: Because of the potential for serious adverse reactions in breastfed infants, instruct women not to breastfeed during treatment with LORBRENA and for 7 days after the final dose.

Hepatic Impairment: No dose adjustment is recommended for patients with mild hepatic impairment. The recommended dose of LORBRENA has not been established for patients with moderate or severe hepatic impairment.

Renal Impairment: Reduce the dose of LORBRENA for patients with severe renal impairment. No dose adjustment is recommended for patients with mild or moderate renal impairment.

Aixindawei’s small molecule targeted anticancer new drug AST-001 obtained implicit approval from NMPA to enter clinical trials

On January 28, 2022, Shenzhen Aixindawei Pharmaceutical Technology Co., Ltd. (hereinafter referred to as: "Aixindawei" or "the Company") reported that the company’s independently developed small molecule targeted conjugate new drug (project number: AST-001) based on the AKR1C3 enzyme-activated prodrug platform has obtained NMPA’s implicit approval to enter clinical trials (acceptance number CXHL2101680) (Press release, Ascentawits Pharmaceuticals, JAN 28, 2022, View Source [SID1234650302]). The indication is malignant solid tumors. This is another major milestone in the company’s development after the company’s first project AST-3424 obtained NMPA’s implicit approval to enter clinical trials on June 13, 2019.

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Dr. Jianxin Duan, founder and chairman of Aixindawei Pharmaceuticals, said: "We are very pleased that the AST-001 project, another small molecule targeted conjugate new drug independently developed based on the AKR1C3 enzyme-activated prodrug platform, has obtained implicit approval for clinical trials from the NMPA. Multiple preclinical in vitro and in vivo studies have demonstrated that AST-001 has good safety and broad-spectrum anti-tumor activity. In addition, AST-001 has shown encouraging pharmacodynamic effects in multiple in vivo tumor models with high expression of AKR1C3 and KRAS G12D mutations. We are very much looking forward to the clinical performance of AST-001, which will bring more effective and more beneficial treatment options to patients with different tumor types and contribute to a healthy China."

Advaxis Prices Offering of $5,000,000 of Convertible Redeemable Preferred Stock Through a Private Placement

On January 28, 2022 Advaxis, Inc. (OTCQX: ADXS), a clinical-stage biotechnology company focused on the development and commercialization of immunotherapy products, reported that the Company entered into an agreement with certain institutional investors for the private placement of 1,000,000 shares of Series D convertible redeemable preferred stock (Press release, Advaxis, JAN 28, 2022, View Source [SID1234607473]). The shares to be sold will have an aggregate stated value of $5,000,000. Each share of the Series D preferred stock has a purchase price of $4.75, representing an original issue discount ("OID") of 5% of the stated value. The shares of Series D preferred stock are convertible into shares of the Company’s common stock, upon the occurrence of certain events, at a conversion price of $0.25 per share of common stock. The conversion, at the option of the stockholder, may occur at any time following the receipt of the stockholders’ approval for a reverse stock split. The Company will be permitted to compel conversion of the Series D preferred stock after the fulfillment of certain conditions and subject to certain limitations. The Series D preferred stock will also have a liquidation preference over the common stock, and may be redeemed by the investors, in accordance with certain terms, for a redemption price equal to 105% of the stated value, or in certain circumstances, 110% of the stated value. The Company and the holders of the Series D preferred stock will also enter into a registration rights agreement to register the resale of the shares of common stock issuable upon conversion of the Series D preferred stock.

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Total gross proceeds from the offering, before deducting the financial advisor’s fees and other estimated offering expenses, are $4.75 million.

The Series D preferred stock permit the holders thereof to vote together with the holders of the Company’s common stock on a proposal to effectuate a reverse stock split of the Company’s common stock at a special meeting of Company stockholders, with the holders of the Series D preferred stock having the right to cast 30,000 votes per share of Series D preferred stock on such proposal. The holders of the Series D preferred stock agreed to vote their shares in the same proportions as the shares of common stock are voted on that proposal. The Series D preferred stock will not be permitted to vote on any other matter. The holders of the Series D preferred stock agreed not to transfer their shares of preferred stock until after a special meeting of Company stockholders to be held in the first half of 2022.

The closing of the offering is expected to occur on January 31, 2022, subject to the satisfaction of customary closing conditions. Additional information about the offering and the terms of the offering will be included in the Current Report on Form 8-K to be filed with the United States Securities and Exchange Commission ("SEC").

The Series D preferred stock and shares of common stock into which these preferred shares are convertible are being issued in reliance upon the exemption from the securities registration afforded by Section 4(a)(2) of the Securities Act of 1933, as amended (the "1933 Act") and/or Rule 506 of Regulation D as promulgated by SEC under the 1933 Act.

Neither the Series D preferred stock nor the shares of common stock into which these preferred shares are convertible have been, nor will be, registered under the 1933 Act and may not be offered or sold in the United States absent registration under the 1933 Act or an applicable exemption from the registration requirements of the 1933 Act.

The closing of the offering is expected to occur on January 31, 2022, subject to the satisfaction of customary closing conditions. Additional information about the offering above and the terms of the offering will be included in the Current Report on Form 8-K to be filed with the SEC.

Curaleaf Announces Revised Date of Fourth Quarter and Fiscal Year End 2021 Earnings Conference Call

On January 28, 2022 Curaleaf Holdings, Inc. (CSE: CURA /OTCQX: CURLF) ("Curaleaf" or the "Company"), a leading international provider of consumer products in cannabis, reported that it will report its financial and operating results for the fourth quarter and fiscal year ended December 31, 2021 after market close on March 3, 2022 (Press release, Curaleaf Holdings, JAN 28, 2022, View Source [SID1234607489]).

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Management will host a conference call and audio webcast that evening at 5:00 p.m. ET consisting of prepared remarks followed by a question and answer session related to the Company’s operational and financial highlights.

For interested individuals unable to join the conference call, a dial-in replay of the call will be available until March 10, 2022 and can be accessed by dialing +1-877-344-7529 (U.S.), +1-855-669-9658 (Canada) or +1-412-317-0088 (International) and entering replay pin number: 4919700.

I-Mab Announces Partnership Agreement to Localize Manufacturing and Accelerate Commercialization of Innovative Biologics Drugs

On January 28, 2022 I-Mab (the "Company") (Nasdaq: IMAB), a clinical-stage biopharmaceutical company committed to the discovery, development, and commercialization of novel biologics, reported the signing of a partnership agreement with the Hangzhou Qiantang New Area in China to manufacture its innovative drugs locally and accelerate its transition to commercialization (Press release, I-Mab Biopharma, JAN 28, 2022, View Source [SID1234607474]). This strategic partnership will accelerate I-Mab’s commercialization strategy with an execution plan and timeline to commercialize its innovative assets, including felzartamab (TJ202/MOR202), and meet unmet medical needs for patients in China.

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"Today’s announcement demonstrates the Company’s commitment to translating our scientific innovation into clinical and commercial value as soon as possible so that we can provide more high-quality, affordable options for patients through locally-manufactured, innovative drugs," said Yifei Zhu, Chief Commercial Officer, I-Mab. "This brings us one step closer to our new commercial model that integrates manufacturing, distribution and sales."

I-Mab Hangzhou has commenced pilot operation in phase I facility, which is equipped with process development and analytical laboratories and in parallel the construction of phase II facility with an 80,000-square-meter manufacturing floor space was completed in December 2021. The GMP operations and quality systems will be fully compliant with standards and requirements of China’s National Medical Product Administration (NMPA), the U.S. Food and Drug Administration (FDA), and the European Medicines Agency (EMA). It also lays the foundation for I-Mab to meet IND (investigational new drug) supply and future commercial demand.

The first planned I-Mab’s innovative assets to be locally manufactured at I-Mab Hangzhou is felzartamab (TJ202/MOR202), a differentiated antibody drug. I-Mab has completed third line Multiple Myeloma (MM) trial of felzartamab successfully, achieving primary and secondary clinical endpoints which validate the product’s differentiated clinical advantages. In addition, patient enrollment for a randomized, open-label, parallel-controlled phase 3 trial for felzartamab, in combination with lenalidomide, for second-line MM treatment was completed in the second half of 2021. I-Mab owns the exclusive rights for development and commercialization of TJ202/MOR202 in mainland China, Taiwan, Hong Kong and Macao.

About Felzartamab

Felzartamab (TJ202/MOR202) is an investigational human monoclonal antibody derived from MorphoSys’ HuCAL antibody technology. The antibody is directed against CD38 on the surface of multiple myeloma cells, which has been characterized as one of the most strongly and uniformly expressed antigens on the surface of malignant plasma cells. According to its suggested mode of action, the antibody recruits cells of the body’s immune system to kill the tumor through antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). The antibody does not involve complement dependent cytotoxicity, or CDC, an additional immune mechanism involved in tumor cell killing. Scientific research suggests that an anti-CD38 antibody may have therapeutic potential also in other cancers as well as autoimmune diseases. Based on a licensing agreement between MorphoSys and I-Mab signed in November 2017, I-Mab owns the exclusive rights for development and commercialization of TJ202/MOR202 in mainland China, Taiwan, Hong Kong and Macao.

HuCAL is a registered trademark of MorphoSys AG.

About Multiple Myeloma in China

Multiple myeloma (MM) is the second most common hematologic malignancy in China, accounting for approximately 1 percent of all cancers and 13 percent of all blood malignancies. Being primarily a disease of the elderly, the incidence of MM in China, which was about 1.6 per 100,000 in 2020, is expected to grow exponentially with the country’s aging population.1 The prognosis of patients with relapsed or refractory MM remains poor, with a huge unmet need for expanding the progression-free survival and overall survival of MM patients.