On December 16, 2019 Cellectar Biosciences, Inc. (NASDAQ: CLRB), a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of drugs for the treatment of cancer, reported Jarrod Longcor, chief business officer of Cellectar, presented a poster at the AACR (Free AACR Whitepaper) San Antonio Breast Cancer Symposium in San Antonio, TX (Press release, Cellectar Biosciences, DEC 16, 2019, View Source [SID1234552392]).

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The poster, entitled: "Preclinical evaluation of a novel phospholipid drug conjugate, CLR 2000045 with a combretastatin A-4 analogue for improved breast cancer therapy," featured data demonstrating potent in vivo activity in multiple animal models of breast cancer, including a model of triple negative breast cancer. Multiple doses of CLR 2000045 resulted in a statistically significant reduction in tumor volume (p<0.05 and 0.01 respectively) and survival (p<0.05 and 0.001 respectively) in the HCC70, triple negative breast cancer model as compared to vehicle control. In a separate study, the compound displayed comparable activity to paclitaxel in an initial screening model of metastatic breast cancer and the data showed that all doses of CLR 2000045 were well tolerated in both models.

"The data further demonstrate that PDCs are an exciting and novel class of targeted oncology agents with potential in a wide variety of tumor types," said Jarrod Longcor, chief business officer of Cellectar. "We have validated targeted delivery to tumor cells and shown efficacy in multiple cancer types utilizing our phospholipid ether delivery vehicle with four separate classes of molecules. These data demonstrate the unique potential of our novel cancer targeting platform."

About Phospholipid Drug Conjugates

Cellectar’s product candidates are built upon a patented delivery and retention platform that utilizes optimized phospholipid ether-drug conjugates (PDCs) to target cancer cells. The PDC platform selectively delivers diverse oncologic payloads to cancerous cells and cancer stem cells, including hematologic cancers and solid tumors. This selective delivery allows the payloads’ therapeutic window to be modified, which may maintain or enhance drug potency while reducing the number and severity of adverse events. This platform takes advantage of a metabolic pathway utilized by all tumor cell types in all cell cycle stages. Compared with other targeted delivery platforms, the PDC platform’s mechanism of entry does not rely upon specific cell surface epitopes or antigens. In addition, PDCs can be conjugated to molecules in numerous ways, thereby increasing the types of molecules selectively delivered. Cellectar believes the PDC platform holds potential for the discovery and development of the next generation of cancer-targeting agents.

On December 16, 2019 Pfizer Inc. (NYSE: PFE) and Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") reported that the U.S. Food and Drug Administration (FDA) has approved a supplemental New Drug Application (sNDA) for XTANDI (enzalutamide) for the treatment of patients with metastatic castration-sensitive prostate cancer (mCSPC) (Press release, Astellas, DEC 16, 2019, View Source [SID1234552391]). In 2019, it is estimated that just over 40,000 men in the United States are living with mCSPC, a form of prostate cancer that has spread to other parts of the body and still responds to a medical or surgical treatment that lowers testosterone.1,2,3

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With this approval, XTANDI is now the first and only oral treatment approved by the FDA in three distinct types of advanced prostate cancer – non-metastatic and metastatic castration-resistant prostate cancer (CRPC) and mCSPC. The approval is based on results from ARCHES, a randomized Phase 3 study which evaluated 1,150 men with mCSPC and met its primary endpoint of radiographic progression-free survival (rPFS).

"Men with metastatic castration-sensitive prostate cancer face complex treatment decisions and it is critical for physicians and patients to have as much information as possible when deciding on all of the options available," said Andrew Armstrong, M.D., Professor of Medicine, Surgery, Pharmacology and Cancer Biology, Director of Research in the Duke Cancer Institute’s Center for Prostate and Urologic Cancers and lead investigator of ARCHES. "The research supporting the FDA approval and updated treatment guidelines provide physicians and patients with compelling evidence to consider enzalutamide as a treatment option for men with this disease."

Data from the ARCHES trial demonstrated that the use of XTANDI plus androgen deprivation therapy (ADT) significantly reduced the risk of radiographic progression or death by 61 percent compared to placebo plus ADT (n=1,150; hazard ratio [HR]: 0.39 [95% confidence interval (CI): 0.30-0.50]; p<0.0001). Overall survival data were not mature at the time of final rPFS analysis.

The safety analysis of the ARCHES trial is generally consistent with the safety profile of XTANDI in previous clinical trials in CRPC. In ARCHES, common adverse reactions (Grade 1 to 4 ARs; occurring in at least 5% of patients) that were reported more frequently in patients treated with XTANDI plus ADT vs placebo plus ADT included hot flush (27% vs 22%), asthenic conditions (24% vs 20%), hypertension (8.0% vs 5.6%), fractures (6.5% vs 4.2%), and musculoskeletal pain (6.3% vs 4.0%).

"XTANDI has been established as a standard of care for men with castration-resistant prostate cancer and has been prescribed to more than 420,000 patients worldwide since it was first approved in 2012," said Andrew Krivoshik, M.D., Ph.D., Senior Vice President and Oncology Therapeutic Area Head at Astellas. "This approval in metastatic castration-sensitive prostate cancer means physicians can now offer XTANDI to men earlier in their advanced prostate cancer treatment journey."

"Today’s approval adds to over a decade of global clinical research aimed at better understanding the potential benefit of XTANDI for men with advanced prostate cancer," said Andy Schmeltz, Global President, Pfizer Oncology. "The FDA approval marks continued progress to help meet the needs of patients, including men living with metastatic castration-sensitive prostate cancer."

Pfizer and Astellas are committed to helping patients access XTANDI by providing them with access and reimbursement support resources, including information regarding patient healthcare coverage options and financial assistance options that may be available to help patients with financial needs. Patients can visit www.XTANDI.com or call XTANDI Support Solutions at 1-855-898-2634 to learn more.

About Metastatic Castration-Sensitive Prostate Cancer
Prostate cancer is considered metastatic once it has spread outside of the prostate gland to other parts of the body, such as the bones, lymph nodes, bladder, and rectum.2 Men are considered castration- (or hormone-) sensitive if their disease still responds to medical or surgical treatment to lower testosterone levels.1 The prevalence of mCSPC in the U.S. in 2019 is estimated to be just over 40,000.3

ARCHES Trial
The company-sponsored, Phase 3, randomized, double-blind, placebo-controlled, multi-national ARCHES trial (NCT02677896) enrolled 1,150 patients with mCSPC at sites in the U.S., Canada, Europe, South America, and the Asia-Pacific region. Patients in the trial were randomized to receive XTANDI 160 mg daily or placebo and continued on a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist or had a history of bilateral orchiectomy.

The primary endpoint of the trial was rPFS assessed by blinded independent central review. Radiographic progression-free survival was defined as the time from randomization to radiographic disease progression at any time or death within 24 weeks after study drug discontinuation. Radiographic disease progression was defined by identification of two or more new bone lesions on a bone scan with confirmation (Prostate Cancer Working Group 2 criteria) and/or progression in soft tissue disease. Patients were stratified by volume of disease (low vs high) and prior docetaxel therapy for prostate cancer (no prior docetaxel, 1-5 cycles, or 6 prior cycles).

About XTANDI (enzalutamide)
XTANDI (enzalutamide) is an androgen receptor inhibitor indicated for the treatment of patients with castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer (mCSPC).

Important Safety Information for XTANDI

Warnings and Precautions

Seizure occurred in 0.5% of patients receiving XTANDI in seven randomized clinical trials. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Patients in the study had one or more of the following predisposing factors: use of medications that may lower the seizure threshold, history of traumatic brain or head injury, history of cerebrovascular accident or transient ischemic attack, and Alzheimer’s disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, history of seizure, presence of a space occupying lesion of the brain, history of arteriovenous malformation, or history of brain infection. Advise patients of the risk of developing a seizure while taking XTANDI and of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) There have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder that can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.

Hypersensitivity reactions, including edema of the face (0.5%), tongue (0.1%), or lip (0.1%) have been observed with XTANDI in seven randomized clinical trials. Pharyngeal edema has been reported in post-marketing cases. Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue XTANDI and promptly seek medical care. Permanently discontinue XTANDI for serious hypersensitivity reactions.

Ischemic Heart Disease In the combined data of four randomized, placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (2.9% vs 1.3%). Grade 3-4 ischemic events occurred in 1.4% of patients on XTANDI versus 0.7% on placebo. Ischemic events led to death in 0.4% of patients on XTANDI compared to 0.1% on placebo. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue XTANDI for Grade 3-4 ischemic heart disease.

Falls and Fractures occurred in patients receiving XTANDI. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents. In the combined data of four randomized, placebo-controlled clinical studies, falls occurred in 11% of patients treated with XTANDI compared to 4% of patients treated with placebo. Fractures occurred in 10% of patients treated with XTANDI and in 4% of patients treated with placebo.

Embryo-Fetal Toxicity The safety and efficacy of XTANDI have not been established in females. XTANDI can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment with XTANDI and for 3 months after the last dose of XTANDI.

Adverse Reactions (ARs)
In the data from the four randomized placebo-controlled trials, the most common ARs (≥ 10%) that occurred more frequently (≥ 2% over placebo) in XTANDI-treated patients were asthenia/fatigue, back pain, hot flush, constipation, arthralgia, decreased appetite, diarrhea, and hypertension. In the bicalutamide-controlled study, the most common ARs (≥ 10%) reported in XTANDI-treated patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, diarrhea, upper respiratory tract infection, and weight loss.

In AFFIRM, the placebo-controlled study of metastatic CRPC (mCRPC) patients who previously received docetaxel, Grade 3 and higher ARs were reported among 47% of XTANDI-treated patients. Discontinuations due to adverse events (AEs) were reported for 16% of XTANDI-treated patients. In PREVAIL, the placebo-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to AEs were reported for 6% of XTANDI-treated patients. In TERRAIN, the bicalutamide-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 39% of XTANDI patients and 38% of bicalutamide patients. Discontinuations with an AE as the primary reason were reported for 8% of XTANDI patients and 6% of bicalutamide patients.

In PROSPER, the placebo-controlled study of non-metastatic CRPC (nmCRPC) patients, Grade 3 or higher ARs were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an AE as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients.

In ARCHES, the placebo-controlled study of metastatic CSPC (mCSPC) patients, Grade 3 or higher AEs were reported in 24% of XTANDI-treated patients. Permanent discontinuation due to AEs as the primary reason was reported in 5% of XTANDI patients and 4% of placebo patients.

Lab Abnormalities: Lab abnormalities that occurred in ≥ 5% of patients, and more frequently (> 2%) in the XTANDI arm compared to placebo in the pooled, randomized, placebo-controlled studies are neutrophil count decreased, white blood cell decreased, hyperglycemia, hypermagnesemia, hyponatremia, and hypercalcemia.

Hypertension: In the combined data from four randomized placebo-controlled clinical trials, hypertension was reported in 12% of XTANDI patients and 5% of placebo patients. Hypertension led to study discontinuation in < 1% of patients in each arm.

Drug Interactions

Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI.

Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI.

Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Please see Full Prescribing Information for additional safety information.

About the Enzalutamide Development Program
As part of Pfizer and Astellas’ ongoing commitment to the clinical development of enzalutamide, XTANDI is also being evaluated in the EMBARK trial, in men with high-risk non-metastatic CSPC. Details about EMBARK (NCT02319837) are available on www.clinicaltrials.gov.

The European Medicines Agency (EMA) and the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan are currently evaluating XTANDI for men with metastatic hormone-sensitive prostate cancer.

On December 16, 2019 Aptose Biosciences Inc. ("Aptose" or the "Company") (NASDAQ: APTO, TSX: APS), reported that it has commenced an underwritten public offering of its common shares (the "Offering") (Press release, Aptose Biosciences, DEC 16, 2019, View Source [SID1234552390]). In addition, Aptose intends to grant the Underwriters a 30-day option to purchase up to an additional 15% of the common shares offered in the Offering. The Offering is subject to market and other conditions, and there can be no assurance as to whether or when the Offering may be completed, or as to the actual size or terms of the offering. All of the common shares to be sold in the proposed offering will be sold by the Company.

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Aptose intends to use all or a portion of the net proceeds to (i) accelerate and expand clinical trials for CG-806; (ii) accelerate and expand our clinical trials for APTO-253; (iii) acquire and fund (including through partnerships and in-licensing) additional clinical assets; and (iv) for working capital and general corporate purposes relating to (i), (ii) or (iii) above.

Piper Jaffray & Co. is acting as the sole active book-running manager and Canaccord Genuity is acting as passive book-running manager for the Offering.

No common shares will be offered or sold in Canada as part of this Offering. The Offering is subject to the approval of the Toronto Stock Exchange ("TSX") and Nasdaq. For the purposes of TSX approval, the Company is relying on the exemption set forth in Section 602.1 of the TSX Company Manual, which provides that the TSX will not apply its standards to certain transactions involving eligible interlisted issuers on a recognized exchange, such as Nasdaq.

The securities described above are being offered by Aptose pursuant to a shelf registration statement on Form S-3 (File. No. 333-230218), including a base prospectus, that was previously filed by Aptose with the Securities and Exchange Commission ("SEC") and declared effective on April 25, 2019. The offering is being made only by means of a written prospectus and prospectus supplement that form a part of the registration statement. Before you invest, you should read the prospectus supplement and the accompanying prospectus and other documents the Company has filed with the SEC for more complete information about the Company and this offering. You may get these documents for free by visiting EDGAR on the SEC Web site at www.sec.gov. Alternatively, copies of the the prospectus supplement and the accompanying prospectus may be obtained, once available, from Piper Jaffray & Co., Attention: Prospectus Department, 800 Nicollet Mall, J12S03, Minneapolis, MN 55402, by email at [email protected] or by phone: 1-800-747-3924.

This press release does not constitute an offer to sell or the solicitation of offers to buy any securities of Aptose, and shall not constitute an offer, solicitation or sale of any security in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

On December 16, 2019 Anixa Biosciences, Inc. (NASDAQ: ANIX), a biotechnology company focused on harnessing the body’s immune system in the fight against cancer, reported the commercial launch of its Cchek Prostate Cancer Confirmation test (Cchek PCC), the first test developed with the Cchek artificial intelligence driven, flow cytometry based, liquid biopsy technology platform (Press release, Anixa Biosciences, DEC 16, 2019, View Source [SID1234552389]).

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The Cchek PCC test will be offered as a CLIA validated test through Anixa’s partner laboratory, ResearchDx. This test has been independently validated by ResearchDx and is designed to confirm the need for prostate biopsy, as a means to minimize unnecessary invasive procedures and reduce healthcare costs associated with traditional methods of prostate cancer diagnosis and the associated adverse events.

Amit Kumar, Ph.D., Chief Executive Officer of Anixa, stated, "This is a major milestone for Anixa and our partner-based business model. From the start, our goal with Cchek has been to develop an inexpensive blood test that accurately detects the existence of cancer by measuring the body’s immune response."

Data shows that more than 90% of prostate biopsies performed in the U.S. are negative, which indicates that over a million men undergo unnecessary, painful and anxiety-provoking procedures every year. The goal of Cchek PCC is to reduce the number of unnecessary biopsies by between 40% and 50%, while still accurately identifying those patients that require a biopsy to diagnose their prostate cancer.

Dr. Kumar continued, "In the coming months, we expect to conduct a number of activities to support the marketing of Cchek PCC, including the development of marketing materials, education of key opinion leaders in urology, and development of a reimbursement path for the test. We expect Cchek PCC to be broadly available throughout the U.S. by April 2020."

About Cchek
Cchek is an early cancer detection technology, which measures a patient’s immunological response to a malignancy by analyzing immune system cells in peripheral blood. The goal is to utilize the technology to determine a patient’s cancer status from a simple blood draw, eliminating the need for a biopsy, which can be an expensive, painful and invasive procedure. Further, conventional methods using current cancer screening tests often lack accuracy and reliability. Anixa’s orthogonal approach using flow cytometry coupled with artificial intelligence provides an alternative method with greater affordability, efficacy and efficiency. To date, Anixa has successfully used Cchek to detect the presence of 20 different cancers including lung, colon, breast and prostate. The robust cancer detection performance of Cchek makes it a platform from which multiple cancer diagnostic tests may be developed.

On December 16, 2019 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for TIBSOVO (ivosidenib) for the treatment of adult patients with relapsed or refractory myelodysplastic syndrome (MDS) with a susceptible IDH1 mutation as detected by an FDA-approved test (Press release, Agios Pharmaceuticals, DEC 16, 2019, View Source [SID1234552388]). MDS is a group of bone marrow disorders that can cause severe complications, such as infections and uncontrolled bleeding, and can lead to the development of acute myelogenous leukemia (AML).

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"There is a significant need for new targeted therapeutic approaches for individuals with MDS whose disease continues to progress despite treatment with standard of care," said Chris Bowden, M.D., chief medical officer at Agios. "The Breakthrough Therapy designation is based on results from the initial 12 patients in the MDS arm of our Phase 1 study in advanced hematologic malignancies with an IDH1 mutation and recognizes the potential for single-agent treatment with TIBSOVO to make an impact on these patients. We recently re-opened the MDS arm of this study with the goal of generating sufficient data to pursue a regulatory filing in this indication."

The FDA’s Breakthrough Therapy designation is intended to expedite the development and review of a drug candidate that is under investigation to treat a serious or life-threatening disease or condition when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapies on one or more clinically significant endpoints.

Results from the MDS arm of the ongoing TIBSOVO Phase 1 dose-escalation and expansion study in hematologic malignancies were presented at the 7thSociety of Hematologic Oncology Annual Meeting, held September 11-14, 2019, in Houston, Texas. These demonstrate that TIBSOVO administered as a monotherapy was well tolerated and associated with durable remissions as well as the achievement and maintenance of transfusion independence in patients with relapsed or refractory MDS with an IDH1 mutation. Among the 12 patients who received 500 mg of oral TIBSOVO daily, the median treatment duration was 11.4 months. The median age was 72.5 years, and 42% of patients were age 75 or older. As of the November 2, 2018 data cut-off, 75% (9/12) of patients had a response and 42% (5/12) had a complete response (CR). The median duration of CR had not been reached (95% CI, 2.8 months, NE). Of the patients who had a CR, 60% remained relapse-free at 12 months. In addition, 9 (75%) patients were transfusion-independent for 56 days or longer during study treatment. The most common adverse events (AEs) of any grade were back pain, diarrhea, fatigue and rash. Grade 2 IDH differentiation syndrome was observed in 1 of 12 patients. No AEs resulted in permanent discontinuation of treatment.

TIBSOVO Clinical Development in MDS
The MDS arm of the Phase 1 dose-escalation and expansion study evaluating TIBSOVO (ivosidenib) in adults with advanced hematologic malignancies with IDH1 mutations is assessing the clinical activity, safety, tolerability, pharmacokinetics and pharmacodynamics of TIBSOVO in adult patients with relapsed or refractory MDS with a susceptible IDH1 mutation. The arm was re-opened in October 2019 and will enroll up to 25 total patients with the goal of generating sufficient data to pursue a potential regulatory filing in this indication. Study recruitment is ongoing across 22 sites in the U.S. and France.

About Myelodysplastic Syndrome (MDS)
MDS comprises a diverse group of bone marrow disorders in which immature blood cells in the bone marrow do not mature or become healthy blood cells. The National Cancer Institute estimates that more than 10,000 people are diagnosed with MDS in the U.S. each year. Failure of the bone marrow to produce mature healthy cells is a gradual process, and reduced blood cell and/or reduced platelet counts may be accompanied by the loss of the body’s ability to fight infections and control bleeding. For roughly 30 percent of the patients diagnosed with MDS, this bone marrow failure will progress to AML. Chemotherapy, hypomethylating agents and supportive blood products are used to treat MDS.

TIBSOVO is not approved in any country for the treatment of patients with MDS.

About TIBSOVO (ivosidenib)

TIBSOVO (ivosidenib) is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test. For more information, visit TIBSOVO.com.

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME

Patients treated with TIBSOVO have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.

WARNINGS AND PRECAUTIONS

Differentiation Syndrome: See Boxed WARNING. In the clinical trial, 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased. Of the 34 patients who experienced differentiation syndrome, 27 (79%) recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis.

If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. If concomitant noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt TIBSOVO until signs and symptoms are no longer severe.

QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. One patient developed ventricular fibrillation attributed to TIBSOVO. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or in those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary.

Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.

Guillain-Barré Syndrome: Guillain-Barré syndrome occurred in <1% (2/258) of patients treated with TIBSOVO in the clinical study. Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) of any grade were fatigue (39%), leukocytosis (38%), arthralgia (36%), diarrhea (34%), dyspnea (33%), edema (32%), nausea (31%), mucositis (28%), electrocardiogram QT prolonged (26%), rash (26%), pyrexia (23%), cough (22%), and constipation (20%).
The most frequently reported ≥Grade 3 adverse reactions (≥5%) were electrocardiogram QT prolonged (10%), dyspnea (9%), leukocytosis (8%), tumor lysis syndrome (6%), and differentiation syndrome (5%).
Serious adverse reactions (≥5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolonged (7%). There was one case of progressive multifocal leukoencephalopathy (PML).
DRUG INTERACTIONS

Strong or Moderate CYP3A4 Inhibitors: Reduce TIBSOVO dose with strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc interval prolongation.

Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO.

Sensitive CYP3A4 Substrates: Avoid concomitant use with TIBSOVO.

QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-administration is unavoidable, monitor patients for increased risk of QTc interval prolongation.

LACTATION

Many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with TIBSOVO and for at least 1 month after the last dose.