On September 23, 2020 Ligand Pharmaceuticals Incorporated (NASDAQ: LGND) reported that recent new contracting with partners and investments in manufacturing capacity have contributed to its Captisol business operating at the highest levels in the history of the technology and position Captisol for major growth (Press release, Ligand, SEP 23, 2020, View Source [SID1234565518]). Significant new clinical and regulatory developments with Evomela and Kyprolis, among other drugs, are reinforcing the role the proprietary technology serves in enabling important medicines. During 2020, Ligand has facilitated the successful installation of equipment to allow production at significantly higher levels to support anticipated demand. In addition to manufacturing at partner Hovione’s facilities in Ireland and Portugal, Ligand has now added final step processing capacity for Captisol in both the United States and England. Ligand also introduces guidance for 2021 Captisol material sales of approximately $200 million.

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"The global medical need for Captisol-enabled drugs has never been higher," said John Higgins, Chief Executive Officer of Ligand. "Our recently expanded operating team has successfully positioned our Captisol technology for the substantial growth we now expect in 2021 and beyond. There is significant ongoing investment by our partners for over 30 Captisol-enabled medicines in clinical development. We have entered into more contracts this year than any other year and are proud to be working closely with Gilead under our recently extended 10-year supply contract. We continue to be pleased with the momentum relating to Captisol, as it is a critical component in multiple life-saving medicines."

Recent Captisol technology business highlights include the following:

To date in 2020 Ligand has entered into more than 120 Captisol research use agreements and eight clinical and/or commercial license agreements. This is the highest number of use agreements to be signed in a single year since the invention of Captisol.
Captisol is utilized in the formulation of Gilead Sciences’ Veklury (remdesivir), which has received emergency use authorizations or regulatory approvals for the treatment of moderate or severe COVID-19 in over 50 countries and is included in more than 30 ongoing clinical trials. Ligand is supplying Captisol to Gilead and the company’s voluntary licensing partners who are supplying generic remdesivir to 127 low- and middle-income countries. Ligand expects Captisol orders into 2021 and beyond to Gilead and its partners to help countries around the world manage the pandemic.
Ligand recently extended its Captisol supply agreement with Gilead until September 2030. The contract defines terms and conditions for forecasting, supply, order commitments and price.
Ligand’s manufacturing partner Hovione announced today that to meet Captisol demand associated with Veklury, Hovione will soon be producing more Captisol per month than it usually produces per year. "This spike in demand has required unique mobilization efforts across the Hovione network to secure additional raw material supply, execute major capital expenditure projects at oursites, maximize operational efficiency, hire additional talent and identify external partners to expand our overall capacity. The pharmaceutical supply chain is working together in an unprecedented fashion to treat patients and save lives. Hovione is privileged to be part of this truly global rapid response," said Jean-Luc Herbeaux, Chief Operating Officer of Hovione.
Recent clinical data have been announced including publication of a study from the Medical College of Wisconsin that compared safety parameters for Captisol-enabled Evomela versus Alkeran in patients undergoing autologous stem cell transplantation for the treatment of multiple myeloma. The study of 294 patients demonstrated a statistically significant reduction in 30-day re-hospitalization rates for patients treated with Evomela (6.8% for Evomela vs. 17.9% for Alkeran, p=0.04)a with a similar safety profile to Alkeran. Evomela is marketed by Acrotech Biopharma in the U.S. and by CASI Pharmaceuticals in China.
Partner Marinus was recently awarded a BARDA contract by the U.S. government to develop Captisol-enabled IV ganaxolone for the treatment of refractory status epilepticus caused by nerve agent exposure.
Ligand’s pivotal trial for Captisol-enabled Iohexol (CE-Iohexol) is planned to initiate in December 2020. CE-Iohexol is an iodine-based contrast agent for hospital-based imaging procedures. The market for iodinated contrast agents is substantial with approximately 20 million imaging procedures per year in the U.S., representing an estimated $1.5 billion in sales. The objective of the clinical trial will be to demonstrate a reduction in the incidence of contrast-induced acute kidney injury and an equivalent image quality compared to GE’s Omnipaque. The trial is expected to enroll approximately 500 patients and results are expected within two years.
Ligand’s forecast for 2021 Captisol material sales of approximately $200 million is based on information it has on anticipated demand from its major partners given growth in existing and new markets, clinical requirements for Captisol-enabled development programs and binding orders from certain commercial or pre-commercial partners. The 2021 Captisol outlook compares with the Company’s guidance for 2020 Captisol material sales of approximately $90 million.

About Captisol

Captisol is a patent-protected, chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs. Captisol was invented and initially developed by scientists in the laboratories of Dr. Valentino Stella, University Distinguished Professor at the University of Kansas’ Higuchi Biosciences Center for specific use in drug development and formulation. This unique technology has enabled several FDA-approved products, including Gilead’s VEKLURY, Amgen’s KYPROLIS, Baxter International’s NEXTERONE, Acrotech Biopharma L.L.C.’s and CASI Pharmaceuticals’ EVOMELA, Melinta Therapeutics’ BAXDELA and Sage Therapeutics’ ZULRESSO. There are many Captisol-enabled products currently in various stages of development. Ligand maintains a broad global patent portfolio for Captisol with more than 400 issued patents worldwide relating to the technology (including 37 in the U.S.) and with the latest expiration date in 2033. Other patent applications covering methods of making Captisol, if issued, extend to 2040.

On September 23, 2020 Pfizer Inc. (NYSE:PFE) reported that the U.S. Food and Drug Administration (FDA) has accepted and granted priority review to the Company’s supplemental New Drug Application(sNDA)for XALKORI (crizotinib) for the treatment of pediatric patients with relapsed or refractory systemic anaplastic large cell lymphoma (ALCL) that is anaplastic lymphoma kinase (ALK)-positive (Press release, Pfizer, SEP 23, 2020, View Source [SID1234565528]). XALKORI received Breakthrough Therapy designation (BTD) for the ALK-positive ALCL indication in May 2018 and if approved, would be the first biomarker-driven therapy for this type of pediatric lymphoma. The Prescription Drug User Fee Act (PDUFA) goal date for a decision by the FDA is January 2020.

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"Despite high survival rates for children with ALK-positive anaplastic large cell lymphoma, many will relapse, requiring novel treatment approaches," said Chris Boshoff, M.D., Ph.D., Chief Development Officer, Oncology, Pfizer Global Product Development. "Today’s FDA filing exemplifies Pfizer’s commitment to broadening the use of biomarker-driven therapies in areas with significant needs, such as rare, pediatric cancers. Given XALKORI’s proven efficacy in ALK-positive lung cancer and activity seen in clinical trials investigating relapsed or refractory ALK- and ROS-1 positive anaplastic large cell lymphoma, if approved, XALKORI could represent an important step toward improving outcomes for children with this type of cancer."

Anaplastic large cell lymphoma is a rare type of non-Hodgkin lymphoma (NHL), divided into ALK-positive or ALK-negative disease.1,2 Though the five-year survival rate for children with cancer in the U.S. is now the highest it’s ever been at 80%, children with cancer continue to face challenges in treating their disease, including rare tumor types, variations in medicine response and prolonged risk of side effects. 3

"Children with cancer and their families have been desperate for new and innovative medicines. We applaud Pfizer’s commitment to drug discovery and development to help address childhood cancers, and continue to work together on behalf of patients with these cancers," said George Dahlman, Chief Executive Officer, Children’s Cancer Cause. "We look forward to potentially having a new biomarker-driven therapy for children with relapsed or refractory ALK-positive ALCL that may help improve these children’s lives."

The FDA submission is supported by the results from Study ADVL0912 (NCT00939770) and Study A8081013 (NCT01121588). Study ADVL0912 is a Phase 1/2 study conducted in collaboration with the Children’s Oncology Group (COG), evaluating the maximum dose that is safe and tolerable, and assessing clinical activity in pediatric patients with relapsed or refractory solid tumors and ALCL. Pfizer provided funding and support to COG for this trial. Study A8081013 evaluated XALKORI in pediatric and adult patients with advanced malignancies known to be ALK-positive other than non-small cell lung cancer (NSCLC) and included patients with relapsed or refractory ALCL. These two studies showed compelling antitumor activity in pediatric and adult patients who received XALKORI.4,5 Please visit clinicaltrials.gov for more information on these studies.

This FDA submission is in addition to the European Medicines Agency’s agreement on a Pediatric Investigational Plan (PIP) for XALKORI including the treatment of pediatric patients with relapsed or refractory systemic ALK-positive ALCL. This decision represents a step forward for potential regulatory submission for XALKORI in pediatric patients with relapsed or refractory ALK-positive ALCL in the European Union.

About XALKORI (crizotinib)

XALKORI is a tyrosine kinase inhibitor (TKI) indicated for the treatment of patients with metastatic NSCLC whose tumors are ALK-positive or ROS1-positive as detected by an FDA-approved test. XALKORI has received approval for patients with ALK-positive NSCLC in more than 90 countries worldwide including Australia, Canada, China, Japan, South Korea and the European Union. XALKORI is also approved for ROS1-positive NSCLC in more than 70 countries.

The full prescribing information for XALKORI can be found here.

IMPORTANT XALKORI (crizotinib) SAFETY INFORMATION FROM THE U.S. PRESCRIBING INFORMATION

Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome occurred in 0.1% of patients treated with XALKORI across clinical trials (n=1719). Increased transaminases generally occurred within the first 2 months. Monitor liver function tests, including ALT, AST, and total bilirubin, every 2 weeks during the first 2 months of treatment, then once a month, and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop increased transaminases. Permanently discontinue for ALT/AST elevation >3 times ULN with concurrent total bilirubin elevation >1.5 times ULN (in the absence of cholestasis or hemolysis); otherwise, temporarily suspend and dose-reduce XALKORI as indicated.

Interstitial Lung Disease/Pneumonitis: Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur. Across clinical trials (n=1719), 2.9% of XALKORI-treated patients had any grade ILD, 1.0% had Grade 3/4, and 0.5% had fatal ILD. ILD generally occurred within 3 months after initiation of treatment. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes and permanently discontinue XALKORI in patients with drug-related ILD/pneumonitis.

QT Interval Prolongation: QTc prolongation can occur. Across clinical trials (n=1616), 2.1% of patients had QTcF (corrected QT by the Fridericia method) ≥500 ms and 5% of 1582 patients had an increase from baseline QTcF ≥60 ms by automated machine-read evaluation of ECGs. Avoid use in patients with congenital long QT syndrome. Monitor ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that prolong the QT interval. Permanently discontinue XALKORI in patients who develop QTc >500 ms or ≥60 ms change from baseline with Torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmia. Withhold XALKORI in patients who develop QTc >500 ms on at least 2 separate ECGs until recovery to a QTc ≤480 ms, then resume at next lower dosage.

Bradycardia: Symptomatic bradycardia can occur. Across clinical trials, bradycardia occurred in 13% of patients treated with XALKORI (n=1719). Avoid use in combination with other medications known to cause bradycardia. Monitor heart rate and blood pressure regularly. If bradycardia occurs, re-evaluate for the use of concomitant medications known to cause bradycardia. Permanently discontinue for life-threatening bradycardia due to XALKORI; however, if associated with concomitant medications known to cause bradycardia or hypotension, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of ≥60 bpm. If concomitant medications can be adjusted or discontinued, restart XALKORI at 250 mg once daily with frequent monitoring.

Severe Visual Loss: Across clinical trials, the incidence of Grade 4 visual field defect with vision loss was 0.2% of 1719 patients. Discontinue XALKORI in patients with new onset of severe visual loss (best corrected vision less than 20/200 in one or both eyes). Perform an ophthalmological evaluation. There is insufficient information to characterize the risks of resumption of XALKORI in patients with a severe visual loss; a decision to resume should consider the potential benefits to the patient.

Vision Disorders: Most commonly visual impairment, photopsia, blurred vision or vitreous floaters, occurred in 63% of 1719 patients. The majority (95%) of these patients had Grade 1 visual adverse reactions. 0.8% of patients had Grade 3 and 0.2% had Grade 4 visual impairment. The majority of patients on the XALKORI arms in Studies 1 and 2 (>50%) reported visual disturbances which occurred at a frequency of 4-7 days each week, lasted up to 1 minute, and had mild or no impact on daily activities.

Embryo-Fetal Toxicity: XALKORI can cause fetal harm when administered to a pregnant woman. Advise of the potential risk to the fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least 45 days (females) or 90 days (males) respectively, following the final dose of XALKORI.

ROS1-positive Metastatic NSCLC: Safety was evaluated in 50 patients with ROS1-positive metastatic NSCLC from a single-arm study, and was generally consistent with the safety profile of XALKORI evaluated in patients with ALK-positive metastatic NSCLC. Vision disorders occurred in 92% of patients in the ROS1 study; 90% of patients had Grade 1 vision disorders and 2% had Grade 2.

Adverse Reactions: Safety was evaluated in a phase 3 study in previously untreated patients with ALK-positive metastatic NSCLC randomized to XALKORI (n=171) or chemotherapy (n=169). Serious adverse events were reported in 34% of patients treated with XALKORI, the most frequent were dyspnea (4.1%) and pulmonary embolism (2.9%). Fatal adverse events in XALKORI-treated patients occurred in 2.3% of patients, consisting of septic shock, acute respiratory failure, and diabetic ketoacidosis. Common adverse reactions (all grades) occurring in ≥25% and more commonly (≥5%) in patients treated with XALKORI vs chemotherapy were vision disorder (71% vs 10%), diarrhea (61% vs 13%), edema (49% vs 12%), vomiting (46% vs 36%), constipation (43% vs 30%), upper respiratory infection (32% vs 12%), dysgeusia (26% vs 5%), and abdominal pain (26% vs 12%). Grade 3/4 reactions occurring at a ≥2% higher incidence with XALKORI vs chemotherapy were QT prolongation (2% vs 0%), esophagitis (2% vs 0%), and constipation (2% vs 0%). In patients treated with XALKORI vs chemotherapy, the following occurred: elevation of ALT (any grade [79% vs 33%] or Grade 3/4 [15% vs 2%]); elevation of AST (any grade [66% vs 28%] or Grade 3/4 [8% vs 1%]); neutropenia (any grade [52% vs 59%] or Grade 3/4 [11% vs 16%]); lymphopenia (any grade [48% vs 53%] or Grade 3/4 [7% vs 13%]); hypophosphatemia (any grade [32% vs 21%] or Grade 3/4 [10% vs 6%]). In patients treated with XALKORI vs chemotherapy, renal cysts occurred (5% vs 1%). Nausea (56%), decreased appetite (30%), fatigue (29%), and neuropathy (21%) also occurred in patients taking XALKORI.

Drug Interactions: Use caution with concomitant use of moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice which may increase plasma concentrations of crizotinib. Avoid concomitant use of strong CYP3A inducers and inhibitors. Avoid concomitant use of CYP3A substrates where minimal concentration changes may lead to serious adverse reactions. If concomitant use of XALKORI is unavoidable, decrease the CYP3A substrate dosage in accordance with approved product labeling.

Lactation: Because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with XALKORI and for 45 days after the final dose.

Hepatic Impairment: Crizotinib concentrations increased in patients with pre-existing moderate (any AST and total bilirubin >1.5x ULN and ≤3x ULN) or severe (any AST and total bilirubin >3x ULN) hepatic impairment. Reduce XALKORI dosage in patients with moderate or severe hepatic impairment. The recommended dose of XALKORI in patients with pre-existing moderate hepatic impairment is 200 mg orally twice daily or with pre-existing severe hepatic impairment is 250 mg orally once daily.

Renal Impairment: Decreases in estimated glomerular filtration rate occurred in patients treated with XALKORI. Administer XALKORI at a starting dose of 250 mg taken orally once daily in patients with severe renal impairment (CLcr <30 mL/min) not requiring dialysis.

On September 23, 2020 Oasmia Pharmaceutical’s CEO, Dr Francois Martelet reported that it will present at Erik Penser Bank’s Bolagsdag September 24 at 10:05 (Press release, Oasmia, SEP 23, 2020, View Source [SID1234565519]). The presentation will be live streamed via Erik Penser Bank’s Youtube-channel, Penser Play: View Source

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On September 23, 2020 Athenex, Inc. (NASDAQ: ATNX), a global biopharmaceutical company dedicated to the discovery, development and commercialization of novel therapies for the treatment of cancer and related conditions, reported that the U.S. Food and Drug Administration (FDA) has allowed its Investigational New Drug (IND) application for TCRT-ESO-A2, an autologous T cell receptor (TCR)-T cell therapy targeting solid tumors that are NY-ESO-1 positive in HLA-A*02:01 positive patients (Press release, Athenex, SEP 23, 2020, View Source [SID1234573871]).

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TCRT-ESO-A2 is being developed by Axis Therapeutics Limited, a joint venture between Athenex and Xiangxue Life Sciences Limited ("XLifeSc"), a subsidiary of Xiangxue Pharmaceutical Co., Ltd. (Shenzhen Exchange: 300147). TCRT-ESO-A2 is similar to TAEST16001, an autologous cell-based therapy being developed simultaneously by XLifeSc for clinical application in China in that both therapies express the same affinity-enhanced TCR.

"The FDA’s allowance of this IND application for TCRT-ESO-A2 represents another important milestone for Athenex, as we further expand our oncology-focused pipeline in the field of T cell based cancer immunotherapy," stated Dr. Johnson Lau, Chairman and Chief Executive Officer of Athenex, and Chief Executive Officer of Axis Therapeutics. "We are extremely pleased by the allowance of this IND application, which represents the 10th IND allowed by the FDA for Athenex. We were also excited by the observed preliminary, positive clinical signals in pilot studies in China using TAEST16001 conducted by our partner, XLifeSc."

Mr. YongHui Wang, Chairman and Chief Executive Officer of Xiangxue Pharmaceutical, and Chief Executive Officer of XLifeSc, said, "This achievement with TCRT-ESO-A2 follows the IND allowance of TAEST16001 in China by the National Medical Products Association and represents the successful collaboration of our joint development team at Axis Therapeutics. XLifeSc has initiated a Phase I trial of TAEST16001 in China and we are excited to continue working with the team at Athenex to potentially bring a differentiated and valuable immunotherapy technology to cancer patients around the world."

Dr. Daniel Lang, President of Axis Therapeutics, added, "Our TCR-T cell therapy is based on the proprietary TAEST (T cell receptor Affinity Enhancing Specific T cell therapy) technology platform that provides high binding affinity of TCRs while reducing their off-target toxicity. We are encouraged by the preclinical and early clinical findings that indicate this TCR-T cell therapy technology could potentially be an effective treatment for multiple tumor types. We look forward to rapidly advancing the therapy into clinical development in the U.S."

On September 23, 2020 Immetas Therapeutics reported it has raised a Series A financing of $11 million to advance research on inflammation pathways in aging and the development of novel, immune modulating treatments for cancer and inflammatory disease (Press release, Immetas Therapeutics, SEP 23, 2020, View Source [SID1234565529]). Morningside Ventures was the sole investor in the financing round.

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"Morningside’s investment is a significant endorsement of our approach to targeting inflammation pathways in aging and our clinical evidence-based discovery strategy," said J. Gene Wang, MD, PhD, co-founder and CEO. "Emerging research that molecular pathways driving both aging and age-related diseases converge around chronic, low grade inflammation is creating a new set of opportunities to treat cancer and other serious diseases. Immetas is well positioned to capitalize on these new advances."

Dr. Wang added, "Our approach prioritizes clinical evidence and a deep interrogation of disease mechanisms to guide drug discovery. This strategy is designed to reduce development risk resulting from the ‘translational’ gap between laboratory findings and patients and ensure the development of superior and well-differentiated drugs."

Dr. Wang co-founded Immetas after a 20-year career at large pharmaceutical companies, including Merck, Abbott, GSK and Novartis, where he played integral roles in the successful development of major drugs, including Humira (adalimumab), Varubi (rolapitant), Zolinza (vorinostat) and Gardasil (human papilloma virus vaccine), and led multiple programs from discovery to clinical proof-of-concept. Dr. Wang received his M.D. from Peking University Medical Center and Ph.D. in Immunobiology from Yale University, followed by medical residency training at Yale New Haven Hospital.

Immetas other co-founder, Dr. David Sinclair, is an internationally recognized scientist known for his research on genes and small molecules that delay aging, including Sirtuin genes, resveratrol and NAD precursors. He was among TIME magazine’s "50 Most Influential People in Healthcare" in 2018. Dr. Sinclair is Professor of Genetics at Harvard Medical School and co-Director of the Paul F. Glenn Center for Biology of Aging Research at Harvard and he serves as a science advisor to the Company.

"We have a shared vision that inflammation is the fundamental and ultimate process driving aging and age-related cancers and inflammatory diseases," said Dr. Sinclair. "Our approach is distinct from others that have targeted conventional age-related pathways and to date have proved challenging."

The Company is building a pipeline of biologic and small molecule drugs internally and through collaborations. Immetas’ lead program is aimed at designing a series of bi-specific antibodies to regulate inflammation in the tumor microenvironment and overcome resistance to conventional immune checkpoint therapies.

In connection with the financing, Dr. Lu Huang, MD, MBA, Managing Director at Morningside Ventures, joined the Immetas board of directors. Since joining Morningside in 2003, Dr. Huang has led nearly three dozen healthcare / life science investments in China and the United States.