On February 8, 2021 Corcept Therapeutics Incorporated (NASDAQ: CORT), a commercial-stage company engaged in the discovery and development of drugs to treat severe metabolic, oncologic and neuropsychiatric disorders by modulating the effects of the stress hormone cortisol, reported preliminary fourth quarter revenue of $85.7 million, compared to $87.9 million in the fourth quarter of 2019 (Press release, Corcept Therapeutics, FEB 8, 2021, https://ir.corcept.com/news-releases/news-release-details/corcept-therapeutics-announces-fourth-quarter-full-year-2020 [SID1234574731]). Preliminary 2020 revenue was $353.9 million compared to $306.5 million in 2019. The company expects 2021 revenue of $375 – 405 million.

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Cash and investments increased by $32.7 million in the fourth quarter to $476.9 million. At December 31, 2019 cash and investments totaled $315.3 million. The company spent $9.7 million in the fourth quarter repurchasing 458,769 shares of common stock pursuant to its stock repurchase program. Under the currently authorized terms of that program, $190.3 million remains available for the repurchase of shares.

These results are prior to completion of the company’s annual independent audit and are subject to adjustment.

"Corcept’s performance during the COVID-19 pandemic demonstrates the durability of our business," said Joseph K. Belanoff, MD, Corcept’s Chief Executive Officer. "Confronted with unprecedented obstacles, we generated significantly more revenue, more income and more cash than we did in 2019. Having won an important legal victory in our dispute with Teva Pharmaceuticals, we look with confidence to the future. As the pandemic is contained, we expect our commercial growth to resume and have provided 2021 revenue guidance of $375 – 405 million.

"The pandemic’s impact on our clinical activities has been variable. Trials in acutely life-threatening indications, such as advanced ovarian and pancreatic cancer, recruited briskly. Studies of illnesses with a slower course of disease, such as Cushing’s syndrome, castration-resistant prostate cancer ("CRPC"), anti-psychotic-induced weight gain ("AIWG") and non-alcoholic steatohepatitus ("NASH") have proceeded more slowly.

"Despite these challenges, our development team made important advances. They maintained our existing trials, although the pandemic significantly slowed enrollment in many of them. They also started new trials that greatly broadened the scope of our clinical program. In 2020, we initiated trials in Cushing’s syndrome of adrenal origin, metastatic pancreatic cancer, advanced adrenocortical cancer, AIWG and NASH. We also laid the groundwork for further expansion by advancing promising compounds from our portfolio of selective cortisol modulators towards the clinic."

Cushing’s Syndrome

Phase 3 GRACE trial of relacorilant as a treatment for patients with any etiology of
Cushing’s syndrome continues at sites in the United States, Canada, Europe and Israel;
pandemic conditions delay expected timing of NDA submission
Enrollment continues in Phase 3 GRADIENT trial of relacorilant as a treatment for patients with Cushing’s syndrome of adrenal origin, with sites planned in the United States, Europe and Israel
"While our Phase 3 GRACE and GRADIENT trials in patients with Cushing’s syndrome continue to accrue patients and generate valuable data, pandemic-related public health measures, which in many places became even more restrictive in the fourth quarter, continue to slow the pace of enrollment," said Andreas Grauer, MD, Corcept’s Chief Medical Officer. "As vaccination campaigns falter – especially in Europe, where many of our most productive clinical sites are located – the retarding effects of the pandemic remain in place. Ultimately, relacorilant’s NDA submission date will depend on the duration and severity of pandemic-related restrictions, which cannot be known with certainty. The delay may be as long as one year, to the second quarter of 2023.

"These delays are especially frustrating because relacorilant’s Phase 2 data were extremely promising. Our team of clinical investigators are enthusiastic. We are confident enrollments will accelerate once conditions improve."

Solid Tumors

Preliminary results in 178-patient, controlled, Phase 2 trial of relacorilant plus nab-paclitaxel
in patients with metastatic ovarian cancer expected in first half 2021
Preliminary results in first 40 patients enrolled in open-label Phase 3 RELIANT trial
of relacorilant plus nab-paclitaxel in patients with metastatic pancreatic cancer expected
in first half 2021
Selection of optimum dose of exicorilant plus enzalutamide in patients with castration-resistant prostate cancer ("CRPC") expected by third quarter 2021
Patient selection underway in 20-patient, open-label, Phase 1b trial of relacorilant plus PD-1 checkpoint inhibitor pembrolizumab in patients with adrenal cancer with cortisol excess
"Our trials in patients with metastatic ovarian and pancreatic cancer are on track to generate preliminary data in the first half of 2021, as planned," said Dr. Grauer. "These trials are evaluating whether relacorilant can enhance the efficacy of nab-paclitaxel by reducing cortisol’s suppression of apoptosis in patients with advanced disease, many of whom have experienced progression on prior rounds of taxane-based therapies. It would be wonderful to be able to offer a therapy that benefits them.

"The dose-finding trial of our selective cortisol modulator exicorilant with enzalutamide as a treatment for CRPC continues to enroll patients," said Dr. Grauer, "although the pandemic has slowed its pace, pushing selection of an optimum dose to the second or third quarter of this year, depending on how quickly pandemic conditions improve. Our hypothesis, which is well-supported by pre-clinical data, is that combining an androgen receptor antagonist like enzalutamide with a cortisol modulator will block an important tumor escape route.

"Last year, we initiated a Phase 1b trial in patients with adrenal cancer with cortisol excess," said Dr. Grauer. "This study will evaluate whether adding relacorilant to pembrolizumab therapy will reduce cortisol-activated immune suppression sufficiently to help pembrolizumab achieve its intended tumor-killing effect, while relacorilant treats the Cushing’s syndrome caused by excess cortisol activity."

Metabolic Diseases

Enrollment underway in double-blind, placebo-controlled Phase 2 trial of miricorilant
in patients with NASH
Enrollment continues in GRATITUDE, a double-blind, placebo-controlled, Phase 2 trial
of miricorilant to reverse recent AIWG
Enrollment continues in GRATITUDE II, a 150-patient, double-blind, placebo-controlled
Phase 2 trial of miricorilant to reverse long-standing AIWG
"In the fourth quarter, we initiated a double-blind, placebo-controlled Phase 2 trial of miricorilant as a potential treatment for NASH, a serious liver disorder that affects millions of people," said Dr. Grauer. "We plan to enroll 120 patients, who will receive either 900 mg miricorilant, 600 mg miricorilant or placebo for twelve weeks. The primary endpoint will be reduction in liver fat content, as measured by MRI. Our pre-clinical data suggest miricorilant may be a potent treatment for NASH. We hope to demonstrate similarly encouraging results in patients.

"Our Phase 2 trials in AIWG – GRATITUDE and GRATITUDE II – continue to enroll patients, although the pandemic has slowed the pace," added Dr. Grauer. "AIWG reduces the quality of life and shortens the life expectancy of millions of patients. Results from the Phase 1b trial we completed last year suggest that miricorilant may benefit them. In that study, healthy volunteers given miricorilant plus olanzapine gained less weight and had lower triglycerides and less sharply elevated liver enzymes than those who received olanzapine plus placebo after only two weeks of dosing. These results build on those we achieved in similar trials using mifepristone (see Gross et al, Advances in Therapy (2009); Gross et al, Obesity (2010). Miricorilant, like mifepristone, modulates cortisol activity. Unlike mifepristone, miricorilant does not affect progesterone activity."

Conference Call

We will hold a conference call on February 8, 2021, at 5:00 p.m. Eastern Time (2:00 p.m. Pacific Time). To participate, click this link (listen-only mode) or dial 1-833-693-0540 (United States) or 1-661-407-1581 (international) approximately ten minutes before the start of the call. The conference ID number is 9289307. A replay will be available on the Investors / Past Events tab of our website.

Hypercortisolism

Hypercortisolism, often referred to as Cushing’s syndrome, is caused by excessive activity of the hormone cortisol. Endogenous Cushing’s syndrome is an orphan disease that most often affects adults aged 20-50. In the United States, an estimated 20,000 patients have Cushing’s syndrome, with about 3,000 new patients diagnosed each year. Symptoms vary, but most patients experience one or more of the following manifestations: high blood sugar, diabetes, high blood pressure, upper-body obesity, rounded face, increased fat around the neck, thinning arms and legs, severe fatigue and weak muscles. Irritability, anxiety, cognitive disturbances and depression are also common. Hypercortisolism can affect every organ system in the body and can be lethal if not treated effectively.

On February 8, 2021 Anticancer Bioscience (ACB), pioneers in synthetic lethal approaches to precision oncology, reported that having successfully closed an additional financing round, raising CNY63m (~USD10m), it has already achieved positive animal data in its small molecule program targeting MYC overexpression (Press release, Anticancer Bioscience, FEB 8, 2021, View Source [SID1234574730]).

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The financing, by a small syndicate of undisclosed, experienced Chinese angel investors adds to the previous seed financing of CNY68.75m (~USD11m) and is being used to support further expansion of ACB’s proprietary screening libraries and discovery platforms, with the goal of progressing two of its programs towards IND enabling studies this year.

ACB is an international private company, commercialising discoveries emerging from China’s world-leading cancer research at the J. Michael Bishop Institute of Cancer Research.

The Company is using its unique screening libraries and discovery platforms in cancer biology to uncover novel mechanisms to induce cancer cell death, without harming healthy cells. Synthetic lethality is possible when the same genetic changes that enable carcinogenesis also make the cancer cell overly dependent on specific pathways and proteins. Attacking these dependencies with drugs can yield dramatic anti-cancer effects, while leaving normal cells healthy. Synthetic lethality enables targeting of drivers of carcinogenesis that are not currently amenable to drug development.

The Company has five distinct synthetic lethality programs in drug development. These include:

Oncogene enabled synthetic lethality (focused on MYC inhibition)

Tumour suppressor synthetic lethality

Polyploid cell synthetic lethality

Centrosome amplification/delustering therapy

Restoration of contact inhibition

ACB has invested in proprietary small molecule and natural product libraries, that comprise novel scaffolds of drug-like molecules and natural medicinal botanicals, with over 20,000 botanical samples already collected and curated. ACB’s small molecule libraries are based on novel scaffolds upon which further diversity can be assembled. These general-utility new scaffold-drug fragment (GUNS-DF) libraries, are being expanded and evolved through iterative screening/optimization processes for multiple phenotypic screening projects.

In the company’s lead MYC inhibition program, a novel chemical series with low nM activity has been identified in model cell lines. Already, functional activity of ACB’s lead ‘HJ’ compound series has been demonstrated in vitro that mimics inhibition of Aurora B kinase. Inhibition of Aurora B kinase is known to elicit synthetic lethality in cells overexpressing MYC. The synthetic lethal phenotype includes the induction of cell cycle arrest early in mitosis followed by accumulation of polyploid cells. ACB is further exploring a second MYC inhibitory compound series.

Founder, President, and CEO of ACB, Dr. Dun Yang, said, "With the additional financing, we are well placed to accelerate our synthetic lethal approach and to maximise the value of our libraries and pipeline. Already a provisional filing covering the novel library of HJ compounds has been completed and this is the first GUNS-DF library for which ACB has filed for PCT patent protection, testifying to the utility of our library technology platform. We expect to follow this with additional composition of matter filings as we progress our MYC and other discovery programs."

ACB’s goal is to generate first-in-class oncology drugs for a broad range of indications (targeting over 30% of cancer patients), with a focus on therapies disabling previously untargeted mitotic regulators. Overexpression of MYC engenders vulnerability in mitosis and many other cellular processes. It is the most commonly deregulated oncoprotein, making targeting it through synthetic lethality an attractive strategy for cancer therapy.

Since its foundation in 2016, ACB has grown to almost 50 employees in Chengdu China, Hyderabad, India, San Francisco, USA, and St Andrews, UK.

On February 8, 2021 Lion TCR reported abstracts presentation at the European Association for the Study of the Liver (EASL) Digital Liver Cancer Summit 2021 on 05-06 February 2021 for the use of its lead T-cell product, LioCyx-M for the treatment of unresectable Hepatitis B virus (HBV)- related hepatocellular carcinoma (HCC) in a Phase 1 study (NCT03899415), with an oral abstract (O07) selected for Highlights in the Best of Liver Cancer Summit (Press release, Lion TCR, FEB 8, 2021, View Source [SID1234574729]).

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We have previously presented clinical data for this study at the 2020 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting, highlighting the use of LioCyx-M as a promising TCR-T immunotherapy for primary HCC. Here, we present an updated clinical data (poster abstract P065), with supporting biomarker analysis data (oral abstract O07).

The median overall survival was 33.57 months with a follow-up period of 47.9 months and an objective response rate of 16.7%. LioCyx-M infusions were well tolerated with no cytokine release syndrome (CRS), neurotoxicity or other systemic immune-related adverse events observed. Two patients had a self-limiting and localized liver inflammation upon infusion of 1x10E05 cells/kg per bodyweight that fully resolved despite the advanced pathological liver condition of the patient.

A total of 3 patients had elevations of serum chemokines and/or activation of the T cell compartment upon receiving the treatment, indicative of treatment induced immunological alterations. These alterations were followed with subsequent tumour destruction (partial response as per modified RECIST) in one patient with a durable tumour response lasting approximately 30 months, or a stable disease in the other 2, implicating the LioCyx-M treatment induced immunological alterations with anti-tumour response.

Overall, the clinical and biomarker data highlight the good safety profile and efficacy of LioCyx-M. Further exploration of efficacy of LioCyx-M treatment for advanced HBV-HCC is warranted in a Phase 2 study. Lion TCR is actively applying for global multi-center Phase II clinical trials, including the US FDA, Singapore HSA and China NMPA.

Details of oral presentation:

Abstract Title Immunological alterations induced by HBV-TCR T cell immunotherapy associates with treatment response of primary HBV related-HCC
Presenter Name Dr Tan Anthony Tanoto
Abstract Number O07 (Click here for oral presentation slides)

Details of poster presentation:

Abstract Title Phase 1 study of autologous hepatitis B virus (HBV)-specific T cell receptor (TCR) T-cells, LioCyx-M in unresectable HBV-related hepatocellular carcinoma (HCC)
Presenter Name Prof Fu-Sheng Wang
Abstract Number P065 (Click here for poster)

The full abstracts are attached in this release and will be published in The Digital Liver Cancer Summit 2021 abstract book on 22 January at 10:00 CET.

Abstract O07 has been chosen to be highlighted in the Best of Liver Cancer Summit.

On February 8, 2021 Bristol Myers Squibb (NYSE: BMY) reported that the European Commission (EC) has granted full Marketing Authorization for Inrebic (fedratinib) for the treatment of disease-related splenomegaly (enlarged spleen) or symptoms in adult patients with primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythaemia myelofibrosis, who are Janus Associated Kinase (JAK) inhibitor naïve or have been treated with ruxolitinib (Press release, Bristol-Myers Squibb, FEB 8, 2021, View Source [SID1234574728]). Inrebic is the first, once-daily oral therapy to significantly reduce spleen volume and symptom burden for patients with myelofibrosis where treatment with ruxolitinib has failed, who are intolerant to ruxolitinib or who are JAK inhibitor naïve. The centralized Marketing Authorization approves use of Inrebic in all European Union (EU) member states, as well as Norway, Iceland and Liechtenstein.* Inrebic was granted orphan drug designation in the United States and is also approved in the United States and Canada. 1,2

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"Myelofibrosis is a serious and often debilitating bone marrow disorder for which there has only been one approved treatment option for nearly a decade," said Claire Harrison, M.D., FRCP, FRCPath, JAKARTA and JAKARTA2 study investigator and professor of hematology at Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom. "Inrebic showed clinically meaningful reductions in spleen volume and symptoms in patients who progressed on ruxolitinib or who are JAK inhibitor naïve. Approximately one out of every 100,000 people in the EU will be diagnosed with myelofibrosis each year, and today’s approval provides an important new option for patients who have remained in urgent need of new therapies."

The EC approval of Inrebic was based on results from the JAKARTA and JAKARTA2 studies, which included patients from 14 countries in the EU. The pivotal JAKARTA study evaluated the efficacy of once-daily oral doses of Inrebic compared with placebo in 289 patients with intermediate-2 or high-risk primary or secondary myelofibrosis with splenomegaly. The JAKARTA2 study evaluated the efficacy of once-daily oral doses of Inrebic in 97 patients with intermediate or high-risk primary or secondary myelofibrosis with splenomegaly previously treated with ruxolitinib.3 In the clinical development program of Inrebic, which included 608 patients, serious and fatal cases of encephalopathy, including Wernicke’s, occurred in Inrebic-treated patients. Serious cases were reported in 1.3% (8/608) of patients treated with Inrebic in clinical trials and 0.16% (1/608) of cases were fatal.1

"With today’s EC approval of Inrebic, patients with myelofibrosis throughout Europe will now have a critical new option for a rare bone marrow disorder that’s seen little progress in several years," said Diane McDowell, M.D., vice president, Hematology Global Medical Affairs, Bristol Myers Squibb. "We’re committed to improving on standards of care for patients living with hard-to-treat blood diseases and are working collaboratively with European member states to make Inrebic available to patients as quickly as possible."

*Centralized Marketing Authorization does not include approval in Great Britain (England, Scotland and Wales).

About JAKARTA and JAKARTA2
The Inrebic development program consisted of multiple studies (including JAKARTA and JAKARTA2) in 608 patients who received more than one dose (ranging from 30 mg to 800 mg), of whom 459 had myelofibrosis, including 97 previously treated with ruxolitinib.3 JAKARTA was a pivotal Phase 3, multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy of once-daily oral doses of Inrebiccompared with placebo in patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with splenomegaly and a platelet count of ≥50 x 109/L who were previously untreated with a JAK inhibitor. The study included 289 patients randomized to receive either Inrebic500 mg (n=97) or 400 mg (n=96) or placebo (n=96) across 94 sites in 24 countries.1 JAKARTA2 was a Phase 2, open-label, single arm study of Inrebic in myelofibrosis patients previously treated with ruxolitinib with a diagnosis of intermediate-1 with symptoms, intermediate-2 or high-risk myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis with splenomegaly and platelet count ≥50 x 109/L. The study included 97 patients who started Inrebic at 400 mg once daily across 10 countries.3

The primary endpoint of JAKARTA and JAKARTA2 was spleen response rate, defined as the proportion of patients achieving greater than or equal to a 35% reduction from baseline in spleen volume at the end of cycle 6 as measured by magnetic resonance imaging (MRI) or computerized tomography (CT) with a follow-up scan 4 weeks later in the JAKARTA study. Secondary endpoints of the studies included symptom response rate, defined as the proportion of patients with a 50% or greater reduction in Total Symptom Score when assessed from baseline to the end of cycle 6 as measured by the modified Myelofibrosis Symptoms Assessment Form (MFSAF) v2.0 diary2 (night sweats, itching, abdominal discomfort, early satiety, pain under ribs on left side, bone or muscle pain).1,3

About Myelofibrosis
Myelofibrosis is a serious and rare bone marrow disorder that disrupts the body’s normal production of blood cells. Bone marrow is gradually replaced with fibrous scar tissue, which limits the ability of the bone marrow to make blood cells. The disorder can lead to anemia, weakness, fatigue and enlargement of the spleen and liver, among other symptoms.4 Myelofibrosis is classified as a myeloproliferative neoplasm, a group of rare blood cancers that are derived from blood-forming stem cells.5 In the EU, approximately 1 of every 100,000 people will be diagnosed with myelofibrosis each year.6 Both men and women are affected, and while the disease can affect people of all ages, the median age at diagnosis ranges from 60 to 67 years.7,8 Median survival after ruxolitinib discontinuation is generally poor, ranging from 6 months to 2 years,representing a significant need for alternative treatment options.9

About Inrebic
Inrebic (fedratinib) is an oral kinase inhibitor with activity against wild type and mutationally activated Janus Associated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). Inrebic is a JAK2-selective inhibitor with higher potency for JAK2 over family members JAK1, JAK3 and TYK2. Abnormal activation of JAK2 is associated with myeloproliferative neoplasms, including myelofibrosis and polycythemia vera. In cell models expressing mutationally active JAK2 or FLT3, Inrebic reduced phosphorylation of signal transducer and activator of transcription (STAT3/5) proteins, inhibited cell proliferation, and induced apoptotic cell death. In mouse models of JAK2V617F-driven myeloproliferative disease, Inrebic blocked phosphorylation of STAT3/5, increased survival and improved disease-associated symptoms, including reduction of white blood cells, hematocrit, splenomegaly and fibrosis.1

U.S. INDICATION
INREBIC (fedratinib) is indicated for the treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF).

U.S. IMPORTANT SAFETY INFORMATION

WARNING: ENCEPHALOPATHY INCLUDING WERNICKE’S

Serious and fatal encephalopathy, including Wernicke’s, has occurred in patients treated with INREBIC. Wernicke’s encephalopathy is a neurologic emergency. Assess thiamine levels in all patients prior to starting INREBIC, periodically during treatment, and as clinically indicated. Do not start INREBIC in patients with thiamine deficiency; replete thiamine prior to treatment initiation. If encephalopathy is suspected, immediately discontinue INREBIC and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize.

WARNINGS AND PRECAUTIONS
Encephalopathy, including Wernicke’s: Serious and fatal encephalopathy, including Wernicke’s encephalopathy, has occurred in INREBIC-treated patients. Serious cases were reported in 1.3% (8/608) of patients treated with INREBIC in clinical trials and 0.16% (1/608) of cases were fatal.

Wernicke’s encephalopathy is a neurologic emergency resulting from thiamine (Vitamin B1) deficiency. Signs and symptoms of Wernicke’s encephalopathy may include ataxia, mental status changes, and ophthalmoplegia (e.g., nystagmus, diplopia). Any change in mental status, confusion, or memory impairment should raise concern for potential encephalopathy, including Wernicke’s, and prompt a full evaluation including a neurologic examination, assessment of thiamine levels, and imaging. Assess thiamine levels in all patients prior to starting INREBIC, periodically during treatment, and as clinically indicated. Do not start INREBIC in patients with thiamine deficiency; replete thiamine prior to treatment initiation. If encephalopathy is suspected, immediately discontinue INREBIC and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize.

Anemia: New or worsening Grade 3 anemia occurred in 34% of INREBIC-treated patients. The median time to onset of the first Grade 3 anemia was approximately 2 months, with 75% of cases occurring within 3 months. Mean hemoglobin levels reached nadir after 12 to 16 weeks with partial recovery and stabilization after 16 weeks. Red blood cell transfusions were received by 51% of INREBIC-treated patients and permanent discontinuation of INREBIC occurred due to anemia in 1% of patients. Consider dose reduction for patients who become red blood cell transfusion dependent.

Thrombocytopenia: New or worsening Grade ≥3 thrombocytopenia during the randomized treatment period occurred in 12% of INREBIC-treated patients. The median time to onset of the first Grade 3 thrombocytopenia was approximately 1 month; with 75% of cases occurring within 4 months. Platelet transfusions were received by 3.1% of INREBIC-treated patients. Permanent discontinuation of treatment due to thrombocytopenia and bleeding that required clinical intervention both occurred in 2.1% of INREBIC-treated patients. Obtain a complete blood count (CBC) at baseline, periodically during treatment, and as clinically indicated. For Grade 3 thrombocytopenia with active bleeding or Grade 4 thrombocytopenia, interrupt INREBIC until resolved to less than or equal to Grade 2 or baseline. Restart dose at 100 mg daily below the last given dose and monitor platelets as clinically indicated.

Gastrointestinal Toxicity: Gastrointestinal toxicities are the most frequent adverse reactions in INREBIC-treated patients. During the randomized treatment period, diarrhea occurred in 66% of patients, nausea in 62% of patients, and vomiting in 39% of patients. Grade 3 diarrhea 5% and vomiting 3.1% occurred. The median time to onset of any grade nausea, vomiting, and diarrhea was 1 day, with 75% of cases occurring within 2 weeks of treatment. Consider providing appropriate prophylactic anti-emetic therapy (e.g., 5-HT3 receptor antagonists) during INREBIC treatment. Treat diarrhea with anti-diarrheal medications promptly at the first onset of symptoms. Grade 3 or higher nausea, vomiting, or diarrhea not responsive to supportive measures within 48 hours, interrupt INREBIC until resolved to Grade 1 or less or baseline. Restart dose at 100 mg daily below the last given dose. Monitor thiamine levels and replete as needed.

Hepatic Toxicity: Elevations of ALT and AST (all grades) during the randomized treatment period occurred in 43% and 40%, respectively, with Grade 3 or 4 in 1% and 0%, respectively, of INREBIC-treated patients. The median time to onset of any grade transaminase elevation was approximately 1 month, with 75% of cases occurring within 3 months. Monitor hepatic function at baseline, periodically during treatment, and as clinically indicated. For Grade 3 or higher ALT and/or AST elevations (greater than 5 × ULN), interrupt INREBIC dose until resolved to Grade 1 or less or to baseline. Restart dose at 100 mg daily below the last given dose. If re-occurrence of a Grade 3 or higher elevation of ALT/AST, discontinue treatment with INREBIC.

Amylase and Lipase Elevation: Grade 3 or higher amylase 2% and/or lipase 10% elevations developed in INREBIC-treated patients. The median time to onset of any grade amylase or lipase elevation was 15 days, with 75% of cases occurring within 1 month of starting treatment. One patient developed pancreatitis in the fedratinib clinical development program (n=608) and pancreatitis resolved with treatment discontinuation. Monitor amylase and lipase at baseline, periodically during treatment, and as clinically indicated. For Grade 3 or higher amylase and/or lipase elevations, interrupt INREBIC until resolved to Grade 1 or less or to baseline. Restart dose at 100 mg daily below the last given dose.

ADVERSE REACTIONS:
The most common adverse reactions for INREBIC treated vs. placebo were diarrhea (66% vs. 16%), nausea (62% vs. 15%), anemia (40% vs. 14%), and vomiting (39% vs. 5%). Dosage interruptions due to an adverse reaction during the randomized treatment period occurred in 21% of patients who received INREBIC. Adverse reactions requiring dosage interruption in >3% of patients who received INREBIC included diarrhea and nausea. Dosage reductions due to an adverse reaction during the randomized treatment period occurred in 19% of patients who received INREBIC. Adverse reactions requiring dosage reduction in >2% of patients who received INREBIC included anemia (6%), diarrhea (3%), vomiting (3%), and thrombocytopenia (2%).

DRUG INTERACTIONS:
Coadministration of INREBIC with a strong CYP3A4 inhibitor increases fedratinib exposure. Increased exposure may increase the risk of adverse reactions. Consider alternative therapies that do not strongly inhibit CYP3A4 activity. Alternatively, reduce the dose of INREBIC when administering with a strong CYP3A4 inhibitor. Avoid INREBIC with strong and moderate CYP3A4 inducers. Avoid INREBIC with dual CYP3A4 and CYP2C19 inhibitor. Coadministration of INREBIC with drugs that are CYP3A4 substrates, CYP2C19 substrates, or CYP2D6 substrates increases the concentrations of these drugs, which may increase the risk of adverse reactions of these drugs. Monitor for adverse reactions and adjust the dose of drugs that are CYP3A4, CYP2C19, or CYP2D6 substrates as necessary when coadministered with INREBIC.

PREGNANCY/LACTATION: Consider the benefits and risks of INREBIC for the mother and possible risks to the fetus when prescribing INREBIC to a pregnant woman. Due to the potential for serious adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with INREBIC, and for at least 1 month after the last dose.

RENAL IMPAIRMENT: Reduce INREBIC dose when administered to patients with severe renal impairment. No modification of the starting dose is recommended for patients with mild to moderate renal impairment. Due to potential increase of exposure, patients with preexisting moderate renal impairment require more intensive safety monitoring, and if necessary, dose modifications based on adverse reactions.

HEPATIC IMPAIRMENT: Avoid use of INREBIC in patients with severe hepatic impairment.

On February 8, 2021 Moleculin Biotech, Inc., (Nasdaq: MBRX) (Moleculin or the Company), a clinical stage pharmaceutical company with a broad portfolio of drug candidates targeting highly resistant tumors and viruses, reported that the Agencja Badań Medycznych (The Medical Research Agency) a Polish state agency responsible for development of scientific research in the field of medical and health sciences, awarded a grant equivalent to $1.5 million USD to the Maria Sklodowska-Curie National Research Institute to fund a Phase 1B/2 clinical trial of Annamycin for the treatment of soft tissue sarcoma (STS) lung metastases (Press release, Moleculin, FEB 8, 2021, View Source [SID1234574727]). The grant-funded clinical trial will be led by Prof. Piotr Rutkowski, MD, PhD, Head of Department of Soft Tissue/Bone Sarcoma and Melanoma at the Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw, Poland.

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Prof. Piotr Rutkowski will be assisted in part, by WPD Pharmaceuticals in Poland, a licensee of Annamycin, who will provide support in preparation for and conduct of the clinical trial, which is expected to begin this year. As a part of the collaboration between Moleculin and Prof. Rutkowski, Moleculin will be supplying the drug product necessary for the clinical trial, but Moleculin will not participate in conducting the clinical trial. This trial is independent from and will be in addition to the US clinical trial Moleculin is planning to conduct with Annamycin in sarcoma lung metastases.

"There is a significant unmet need for improved treatments for patients with sarcoma lung metastases," commented Prof. Piotr Rutkowski of Maria Sklodowska-Curie National Research Institute of Oncology, "so we are excited to begin this trial. Although this is considered a rare disease, there are no other clinical trials of this kind currently active in Poland, so it’s a tremendous opportunity for our patients."

"Prof. Rutkowski’s trial is a key element in a collaboration between teams in the US and Poland," added Walter Klemp, Chairman and CEO of Moleculin. "We are hopeful that data from the US and Poland can be combined to identify the potential for Annamycin to treat lung metastases."

Soft tissue sarcomas are the most common form of sarcoma, accounting for an estimated 130,000 incident cases per year worldwide. While many sarcomas can be addressed through surgical removal, it is estimated that as many 20% to 50% of STS sarcomas will eventually metastasize to the lungs, where treatment can become more challenging.

Once metastasized to the lungs, if tumors cannot be surgically removed, the primary chemotherapy regimen is the anthracycline doxorubicin (also known as Adriamycin). While 10% to 30% of patients with sarcoma lung metastases may initially respond to doxorubicin, most will relapse leaving the majority of these patients without an alternative chemotherapy. Treatment options are further limited because of the inherent cardiotoxicity of currently approved anthracyclines, including doxorubicin, which limits the amount of anthracycline that can be given to patients.

Annamycin is a "next generation" anthracycline that has recently been shown in animal models to accumulate in the lungs at up to 34 times the level of doxorubicin. Importantly, Annamycin has also demonstrated a lack of cardiotoxicity in recently conducted human clinical trials for the treatment of acute myeloid leukemia, so the use of Annamycin may not face the same dose limitations imposed on doxorubicin.