On November 21, 2016 Aeglea BioTherapeutics, Inc. (NASDAQ:AGLE), a biotechnology company committed to developing enzyme-based therapeutics in the field of amino acid metabolism to treat genetic rare diseases and cancer, reported results of preclinical studies demonstrating that its product candidate AEB3103 suppressed the growth of tumors in models of prostate and breast cancer and extended survival in a model of chronic lymphocytic leukemia (CLL) (Press release, Aeglea BioTherapeutics, NOV 21, 2016, View Source [SID1234516727]). The article entitled "Systemic depletion of serum L-Cyst(e)ine with an engineered human enzyme induces production of reactive oxygen species and suppresses tumor growth in mice" was published online today in Nature Medicine.

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In these preclinical models, AEB3103 deprived tumors of a key ingredient for cysteine-dependent anti-oxidant pathways, such as in the production of glutathione, which are involved in protecting tumors from oxidative stress due to reactive oxygen species (ROS). AEB3103 systemically degraded serum L-cysteine and its oxidized form L-cystine resulting in increased oxidative stress and cancer cell death.

"These preclinical results suggest that the use of AEB3103 to deplete the amino acid L-cysteine has the potential to be a well-tolerated approach for treating tumors with high levels of ROS. The idea of targeting cancer with an enzyme that degrades L-cysteine was first proposed in 1961. Since then, the evidence that this is an important and unexploited vulnerability of cancer has been widely described but not effectively applied for therapeutic benefit," said David G. Lowe, Ph.D., president and chief executive officer of Aeglea. "Our results with AEB3103 also provide support for our broader cancer strategy of using well established amino acid biology to target tumor metabolism."

"Preclinical findings showed that AEB3103 had a potent anti-tumor effect in multiple solid tumor models, including prostate and breast cancer, and was well tolerated for more than five months. This suggests AEB3103 could be a safe and effective alternative to experimental drugs targeting oxidative stress that are currently under clinical evaluation," said study co-author George Georgiou, Ph.D., co-founder of Aeglea and Laura Jennings Turner Chair in Engineering at the University of Texas at Austin. "As many other chemotherapeutic agents are also known to oxidatively stress cancer cells, we are looking forward to exploring AEB3103 in combination with ROS-inducing drugs as a potential cancer treatment."

"In these preclinical studies, treatment with AEB3103 demonstrated significantly longer survival in a CLL animal model compared to treatment with the standard of care alone, indicating that AEB3103 has potential as a treatment for hematological malignancies as well as solid tumors," said Peng Huang, M.D., Ph.D., co-author of the published paper and professor, Department of Translational Molecular Pathology at The University of Texas MD Anderson Cancer Center in Houston. "Of particular interest, AEB3103 was effective at treating CLL patient samples with 17p deletions, a mutation associated with more aggressive disease that can be resistant to treatment with standard of care drugs such as fludarabine."

Rationale for Preclinical Studies

Tumors cells experience an abnormally high level of oxidative stress through ROS and, as a result, require elevated levels of anti-oxidant compounds for their survival and growth. Oxidative stress is one of the hallmarks of cancer and occurs in numerous tumor types. It had been suspected for several decades that the levels of ROS stress and the ensuing increased demand for anti-oxidants may represent an opportunity for the development of therapeutics that selectively increase the oxidative stress of cancer cells but do not impact normal tissues. However, earlier efforts to develop therapeutics that block the synthesis of glutathione, one of the major cellular anti-oxidants, or to inhibit other cellular pathways that serve to protect cancer cells from ROS had not been successful.

The defense of tumor cells against ROS is critically dependent on the absorption of L-cysteine and its oxidized form L-cystine from the blood. L-cysteine is used to make glutathione and plays a central role in other cellular anti-oxidant mechanisms. The requirement for extracellular L-cysteine to support cancer cell growth is well established in hematological malignancies such as myeloma, acute myelogenous leukemia and CLL, and solid tumors such as glioblastoma, triple negative breast cancer, esophageal squamous cell carcinoma, small cell lung cancer and prostate carcinoma. AEB3103, an engineered human enzyme that in these preclinical studies efficiently degraded L-cysteine in serum into non-toxic metabolites, was developed to exploit this metabolic vulnerability, killing tumor cells by depriving them of a key anti-oxidant precursor.

Results of Preclinical Studies

Results showed that administration of AEB3103 significantly reduced L-cysteine/cystine in the serum, depleting intracellular glutathione and elevating ROS, resulting in cell cycle arrest/death in cancer cells. When tested in mouse tumor models, AEB3103 suppressed the growth of human prostate cancer cells, and reduced the growth of mouse prostate and breast cancer cells. Additionally, AEB3103 had an improved therapeutic effect over the standard of care drug fludarabine in a mouse genetic model of CLL, doubling the median survival time from 3.5 to 7 months. AEB3103 was also effective in treating CLL patient samples with 17p deletions. This genetic deletion is a hallmark for the loss of the tumor suppressor gene p53, the most commonly mutated gene in human cancers. Patients with these deletions often develop more aggressive disease and are typically resistant to standard of care drugs such as fludarabine.

AEB3103 in CLL Models

The effect of AEB3103 was studied both alone and in combination with fludarabine, a standard of care for CLL, in leukemic cells from an animal model of CLL. Results showed that the leukemic cells were moderately affected by fludarabine but were killed by treatment with AEB3103. A separate long-term survival study conducted in the mouse genetic model of CLL treated with either fludarabine, AEB3103 or the combination showed that the median survival time in untreated animals was 3.5 months compared with a median survival time of 5.3 months for fludarabine treated animals (p<0.001). Those treated with AEB3103 exhibited a significantly longer median survival time of 7 months (p<0.0001). The combination of fludarabine and AEB3103 showed a slight but not statistically significant improvement in median survival (p=0.092, 7.4 months vs. 7 months) compared with AEB3103 alone. AEB3103 was well tolerated with the longest surviving animals treated twice a week for over 5 months.

A separate study evaluated the efficacy of AEB3103, fludarabine or the combination against primary leukemia cells isolated from CLL patients with or without 17p deletions (17p- CLL cells and 17p wt CLL cells, respectively). Treatment for 48 hours with AEB3103 alone or in combination with fludarabine was efficacious in killing both p17 wt CLL cells and 17p- CLL cells. In contrast, fludarabine treatment alone only moderately impacted p17 wt CLL cells in the presence of stromal cells that provide trophic support for the cancer cells, and was even less effective against 17p- CLL samples, consistent with the known chemotherapeutic resistance arising from 17p deletions. Both patient-derived CLL cells and CLL cells from the mouse genetic model showed a marked reduction in glutathione levels following treatment with AEB3103 for 24 hours and a concomitant increase in ROS levels. Collectively, the results suggest that treatment with AEB3103 induces death in cancer cells that depend on an exogenous supply of L-cysteine/cystine for survival.

On November 21, 2016 Teva Pharmaceutical Industries Ltd., (NYSE and TASE:TEVA) reported it has obtained approval from the European Commission for an indication extension of Trisenox (arsenic trioxide) (Press release, Teva, NOV 21, 2016, View Source [SID1234516724]). This marks an important advancement in treatment for Acute Promyelocytic Leukemia (APL) patients in Europe, as it is the first time that a form of acute leukemia can be effectively treated with a regimen that is entirely chemotherapy-free. APL is a rare and aggressive type of acute leukemia that can kill within hours or days if left untreated2. Trisenox, in combination with retinoic acid, has shown a 99% overall survival rate with almost no relapses after more than four years (50 months) of median follow-up1.

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"Teva is committed to providing wider access to high-quality medicines to ensure more people can benefit from the treatments they need. We’re very pleased by this decision of the European Commission, and we look forward to offering a chemotherapy-free treatment option for all newly diagnosed APL patients," said Rob Koremans, MD, President & CEO, Teva Global Specialty Medicines.
The decision by the European Commission, which follows a positive recommendation from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) on October 13, grants marketing authorization for first line use of Trisenox in the 28 countries of the European Union. The indication extension is for newly diagnosed low to intermediate risk Acute Promyelocytic Leukemia (APL) in combination with retinoic acid. Today’s announcement points to a recognition by the European Commission that treating low to intermediate risk APL with a chemo-free regimen of Trisenox plus retinoic acid can increase survival rates, dramatically reduce the risk of relapse, and help avoid chemotherapy-related side effects, such as the risk of life-threatening infections.

Welcoming the approval, Francesco Lo-Coco, Professor of Haematology and Head of the Laboratory of Integrated Diagnosis of Oncohematologic Diseases, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Italy said, "This approval by the European Commission is good news for APL patients as we now have access to a cure for an acute leukemia without using chemotherapy. Moreover, this decision is a very positive endorsement by the European Commission, as it was made based solely on published academic research and studies. From now on, APL patients with non-high risk disease will have access to this chemotherapy-free regimen of Trisenox plus retinoic acid at diagnosis, which has the potential to increase survival rates while minimizing side effects associated with chemotherapy."
In Europe, approximately 1,500 to 2,000 people are diagnosed with APL each year3. APL, a life-threatening form of leukemia, can cause uncontrollable bleeding leading rapidly to death if left untreated2. The rapid progression of APL leading to early mortality is a substantial problem, affecting up to 30% of patients4. Rapid diagnosis and commencement of treatment is essential to avoid early mortality2,5.

About Acute Promyelocytic Leukemia
Acute Promyelocytic Leukemia is a form of acute myeloid leukemia (AML), a cancer of the blood-forming tissue (bone marrow). Approximately 5% to 10% of patients initially diagnosed with AML present with the aggressive sub-type of the condition, APL6.
In normal bone marrow, hematopoietic stem cells produce red blood cells (erythrocytes) that carry oxygen, white blood cells (leukocytes) that protect the body from infection, and platelets (thrombocytes) that are involved in blood clotting. In APL, immature white blood cells called promyelocytes accumulate in the bone marrow. The overgrowth of promyelocytes leads to a shortage of normal white and red blood cells and platelets in the body, which causes many of the signs and symptoms of the condition.

People with APL are especially susceptible to developing bruises, small red dots under the skin (petechiae), nosebleeds, bleeding from the gums, blood in the urine (hematuria), or excessive menstrual bleeding. The most important lethal bleeding sites are pulmonary (35%) and intracranial (65%)7. The abnormal bleeding and bruising occur because leukemic blasts produce anticoagulant factors and substances are released that cause excessive blood clotting, leading as a consequence to a low number of platelets in the blood (thrombocytopenia). The low number of red blood cells (anemia) can cause people with acute promyelocytic leukemia to have pale skin (pallor) or excessive tiredness (fatigue). In addition, affected individuals may heal slowly from injuries or have frequent infections due to the decrease of normal white blood cells that fight infection. Furthermore, the leukemic cells can expand into the bones and joints, which may cause pain in those areas. Other general signs and symptoms may occur as well, such as fever, loss of appetite, and weight loss.

APL is generally diagnosed in much younger patients than in AML (the median age is approximately mid-408,9 for APL patients and 67 for AML patients10), and can be diagnosed in patients of any age.

About Trisenox
On 5 March 2002, the European Commission granted approval for the Marketing Authorization Application (MAA) for Trisenox. The authorization, which was valid throughout the European Union (EU), was granted to treat patients with relapsed or refractory acute promyelocytic leukemia (APL) and characterized by the presence of the t(15;17) translocation and/or the presence of the Pro-Myelocytic Leukaemia/Retinoic-Acid-Receptoralpha (PML/(RARα) gene. Trisenox, a targeted drug, degrades the PML- RARα fusion protein. Trisenox received marketing authorization in 2000 by the U.S. Food and Drug Administration.

The marketing approval for Trisenox was granted based on results from a multicenter study in which 40 relapsed APL patients were treated with Trisenox 0.15 mg/kg until bone marrow remission or a maximum of 60 days. Thirty-four patients (85 percent) achieved complete remission after two cycles. When the results for these 40 patients were combined with those for the 12 patients in a pilot trial, an overall response rate of 87 percent was observed11.

1mL of Trisenox contains 1mg of arsenic trioxide. Trisenox is a concentrate for solution for infusion. It is a sterile, clear, colorless, aqueous solution. Trisenox must be administered under the supervision of a physician who is experienced in the management of acute leukaemias, and special monitoring procedures must be followed.
Study Results
The APL0406 Intergroup GIMEMA-AMLSG-SAL study was a prospective, randomized, multicenter, open-label, phase III non-inferiority study1. Eligible patients were adults between 18 and 71 years of age with newly diagnosed, genetically proven low- or intermediate-risk APL (WBC at diagnosis ≤ 103 x 109/L). Overall, 276 patients were randomly assigned to receive ATRA-ATO or ATRA-CHT between October 2007 and January 2013. Of 263 patients evaluable for response to induction, 127 (100%) of 127 patients and 132 (97%) of 136 patients achieved complete remission (CR) in the ATRA-ATO and ATRA-CHT arms, respectively (P = .12). After a median follow-up of 40.6 months, the event-free survival, cumulative incidence of relapse, and overall survival at 50 months for patients in the ATRA-ATO versus ATRA-CHT arms were 97.3%v 80%, 1.9% v 13.9%, and 99.2% v 92.6%, respectively (P , .001, P = .0013, and P = .0073, respectively).
Post-induction events included two relapses and one death in CR in the ATRA-ATO arm and two instances of molecular resistance after third consolidation, 15 relapses, and five deaths in CR in the ATRA-CHT arm. Two patients in the ATRA-CHT arm developed a therapy-related myeloid neoplasm.
References:
1. Journal of Clinical Oncology, July 11, 2016 as 10.1200/JCO.2016.67.1982.Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non–High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial. Professor Uwe Platzbecker et al. View Source
2. Coombs CC, et al. Blood Cancer J. 2015;5,e304.
3. Sant M, Allemani C, Tereanu C, De Angelis R, Capocaccia R, Visser O, et al. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood 2010;116(19):3724-34.
4. Lehmann S, Ravn A, Carlsson L, et al. Continuing high early death rate in acute promyelocytic leukemia: a population based report from the Swedish Adult Acute Leukemia Registry. Leukemia 2011;25:1128–34
5. Lo-Coco F. Blood. 2011;118:1188-9
6. Cicconi L, Lo-Coco F. Ann Oncol. 2016;27:1847-81
7. De la Serna J, et al. Blood. 2008;111:3395-402
8. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2012, National Cancer Institute. Bethesda, MD. View Source, based on November 2014 SEER data submission, posted to the SEER web site, April 2015. Accessed June 8, 2016.
9. Lo-Coco F, Cicconi L, Breccia M. Current standard treatment of adult acute promyelocytic leukaemia. Br J Haematol. 2015. doi.10.1111.bjh.13890.
10. National Cancer Institute SEER Stat Factsheet Acute Promyelocytic Leukemia View Source accessed 16 Nov 2016
11. Soignet SL, et al. J Clin Oncol. 2001;19:3852-3860.

On November 21, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported the U.S. Food and Drug Administration (FDA) has approved the use of DARZALEX (daratumumab) in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy (Press release, Genmab, NOV 21, 2016, View Source [SID1234516717]). In July 2016, daratumumab was granted a Breakthrough Therapy Designation (BTD) in this patient population. In August 2012, Genmab granted Janssen Biotech, Inc. an exclusive worldwide license to develop, manufacture and commercialize DARZALEX.

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Genmab will receive milestone payments totaling USD 65 million from Janssen associated with the first commercial sale of the daratumumab in combination with lenalidomide and dexamethasone and in combination with bortezomib and dexamethasone in the United States. As this will occur quickly after this approval, Genmab is improving its financial guidance for the year. See the Outlook section of this announcement for more information.

"This is an exciting day for patients with multiple myeloma in the U.S., who will now have the opportunity to receive DARZALEX at an earlier point in treatment of their disease," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab. "We believe daratumumab has the potential to become a backbone therapy for multiple myeloma."

The approval was based on data from two Phase III studies: the CASTOR study of daratumumab in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone alone in patients with relapsed or refractory multiple myeloma, and the POLLUX study of daratumumab in combination with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with relapsed or refractory multiple myeloma.

Data from the Phase I study of daratumumab in combination with pomalidomide and dexamethasone in relapsed or refractory multiple myeloma was also submitted as part of the supplemental Biologics License Application (sBLA) for daratumumab in the newly approved indications in August 2016. The FDA granted a Standard Review for the use of daratumumab in combination with pomalidomide and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received at least two prior therapies, including a proteasome inhibitor and an immunomodulatory agent. The FDA assigned a Prescription Drug User Fee Act (PDUFA) target date of June 17, 2017 for the combination of daratumumab with pomalidomide and dexamethasone.

DARZALEX was initially approved by the FDA in November 2015 for the monotherapy treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and immunomodulatory agent.

OUTLOOK
MDKK Revised Guidance Previous Guidance
Revenue 1,650 — 1,700 1,200 — 1,250
Operating expenses (800) — (850) (800) — (850)
Operating income 825 — 875 375 — 425
Cash position at end of year* 3,650 — 3,750 3,650 — 3,750
*Cash, cash equivalents, and marketable securities

Genmab is improving the 2016 financial guidance it published on November 2, 2016, due to the inclusion of daratumumab milestones totaling USD 65 million. The milestones are associated with the first commercial sale of DARZALEX in combination with lenalidomide and dexamethasone, and bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy in the U.S. following FDA approval in this indication.

Operating Result
We expect our 2016 revenue to be in the range of DKK 1,650 — 1,700 million, an increase of DKK 450 million compared to the previous guidance. We have increased our projected daratumumab milestones to DKK 1,020 million (previously DKK 570 million) due to inclusion of USD 65 million in milestone payments triggered by the first commercial sale of DARZALEX in combination with lenalidomide and dexamethasone, and bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. We expect DARZALEX royalties to remain in the range of DKK 400 — 450 million, based on an estimated USD 500 — 550 million of DARZALEX sales in 2016. The remainder of the revenue mainly consists of Arzerra royalties, DuoBody milestones, and non-cash amortization of deferred revenue.

We anticipate that our 2016 operating expenses will remain in the range of DKK 800 — 850 million.
As a result of the increased revenue, we now expect the operating income for 2016 to be approximately DKK 825 — 875 million, compared to DKK 375 — 425 million in the previous guidance.

Cash Position
There is no change to the projected cash position at the end of 2016 of DKK 3,650 — 3,750 million as we expect to receive payment for the additional milestones shortly after year-end.
Outlook: Risks and Assumptions
In addition to factors already mentioned, the estimates above are subject to change due to numerous reasons, including but not limited to the achievement of certain milestones associated with our collaboration agreements; the timing and variation of development activities (including activities carried out by our collaboration partners) and related income and costs; DARZALEX and Arzerra sales and corresponding royalties to Genmab; fluctuations in the value of our marketable securities; and currency exchange rates. The financial guidance assumes that no significant agreements are entered into during 2016 that could materially affect the results.

About the CASTOR study
The Phase III CASTOR study included 498 patients who had relapsed or refractory multiple myeloma. Patients were randomized to receive either daratumumab combined with subcutaneous bortezomib (a type of chemotherapy, called a proteasome inhibitor) and dexamethasone (a corticosteroid), or bortezomib and dexamethasone alone. The study met the primary endpoint of improving progression free survival (PFS); Hazard Ratio (HR) = 0.39, 95% CI 0.28-0.53, p<0.0001. The median PFS for patients treated with daratumumab has not been reached, compared to median PFS of 7.2 months for patients who did not receive daratumumab.

Daratumumab also significantly increased the overall response rate (ORR) (79% vs. 60%, p<0.0001), including doubling rates of complete response (CR) or better (18% vs. 9%) and rates of very good partial response (VGPR) or better (57% vs. 28%). The most common grade 3 or 4 adverse events in patients treated with daratumumab in combination with bortezomib and dexamethasone compared to those who only received bortezomib and dexamethasone were thrombocytopenia (47% vs 35%), anemia (13% vs 14%) and neutropenia (15% vs 5%). Daratumumab-associated infusion-related reactions were reported in 45% of patients, were mostly grade 1/2, and occurred predominantly during the first infusion. This is consistent with the reported safety profile of daratumumab monotherapy and background bortezomib/dexamethasone therapy.

About the POLLUX study
The Phase III POLLUX study enrolled 569 patients who had relapsed or refractory multiple myeloma. Patients were randomized to receive either daratumumab combined with lenalidomide (an immunomodulatory drug) and dexamethasone (a corticosteroid), or lenalidomide and dexamethasone alone. The study met the primary endpoint of improving progression-free survival (PFS) (Hazard Ratio (HR) = 0.37; 95% CI 0.27-0.52; p<0.0001) for patients treated with daratumumab versus patients who did not receive daratumumab. Patients who received treatment with daratumumab in combination with lenalidomide and dexamethasone had a 63% reduction in risk of their disease progressing, compared to those who did not receive daratumumab. The median PFS for patients treated with daratumumab in combination with lenalidomide and dexamethasone has not been reached, compared to an estimated median PFS of 18.4 months for patients who received lenalidomide and dexamethasone alone. Additionally, daratumumab significantly increased ORR (91% vs. 75%, p<0.0001, including doubling rates of CR or better (42% vs. 19%), as well as rates of VGPR or better (75% vs. 43%). The most common grade 3 or 4 adverse events in patients treated with daratumumab in combination with lenalidomide and dexamethasone versus those who received only lenalidomide and dexamethasone were neutropenia (53% vs 40%), thrombocytopenia (13% vs 15%), and anemia (13% vs 19%). Daratumumab-associated infusion-related reactions occurred in 48% of patients, were mostly grade 1/2, and occurred predominantly during the first infusion. Overall, the safety profile was consistent with known toxicities of daratumumab monotherapy and combination therapy of lenalidomide and dexamethasone.

Both the CASTOR study and the POLLUX study were published in The New England Journal of Medicine in August 2016 and October 2016 respectively.

About multiple myeloma
Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excess proliferation of plasma cells.1 Multiple myeloma is the third most common blood cancer in the U.S., after leukemia and lymphoma.2 Approximately 30,330 new patients are expected to be diagnosed with multiple myeloma and approximately 12,650 people are expected to die from the disease in the U.S. in 2016.3 Globally, it was estimated that 124,225 people would be diagnosed and 87,084 would die from the disease in 2015.4 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation, kidney problems or infections.5 Patients who relapse after treatment with standard therapies, including proteasome inhibitors or immunomodulatory agents, have poor prognoses and few treatment options.6

About DARZALEX (daratumumab)
DARZALEX (daratumumab) injection for intravenous infusion is indicated in the United States for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.7 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. DARZALEX is indicated in Europe for use as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a PI and an immunomodulatory agent and who have demonstrated disease progression on the last therapy. For more information, visit www.DARZALEX.com.

Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through programmed cell death, or apoptosis,7,8 and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity,7,8 antibody-dependent cellular phagocytosis9,10 and antibody-dependent cellular cytotoxicity.7,8 In addition, daratumumab therapy results in a reduction of immune-suppressive myeloid derived suppressor cells (MDSCs) and subsets of regulatory T cells (Tregs) and B cells (Bregs), all of which express CD38. These reductions in MDSCs, Tregs and Bregs were accompanied by increases in CD4+ and CD8+
T cell numbers in both the peripheral blood and bone marrow.7,11

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. Five Phase III clinical studies with daratumumab in relapsed and frontline settings are currently ongoing, and additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma, non-Hodgkin’s lymphoma and solid tumors.

IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS – None
WARNINGS AND PRECAUTIONS
Infusion Reactions — DARZALEX can cause severe infusion reactions. Approximately half of all patients experienced a reaction, most during the first infusion. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing an infusion. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed. Permanently discontinue therapy for life-threatening (Grade 4) reactions. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following DARZALEX infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

Interference with Serological Testing – Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type are not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX. Type and screen patients prior to starting DARZALEX.

Neutropenia – DARZALEX may increase neutropenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. DARZALEX dose delay may be required to allow recovery of neutrophils. No dose reduction of DARZALEX is recommended. Consider supportive care with growth factors.

Thrombocytopenia – DARZALEX may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. DARZALEX dose delay may be required to allow recovery of platelets. No dose reduction of DARZALEX is recommended. Consider supportive care with transfusions.

Interference with Determination of Complete Response – Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both, the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Adverse Reactions — In patients who received DARZALEX in combination with lenalidomide and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: neutropenia (92%), thrombocytopenia (73%), upper respiratory tract infection (65%), infusion reactions (48%), diarrhea (43%), fatigue (35%), cough (30%), muscle spasms (26%), nausea (24%), dyspnea (21%) and pyrexia (20%). The overall incidence of serious adverse events was 49%. Serious adverse reactions were pneumonia (12%), upper respiratory tract infection (7%), influenza (3%) and pyrexia (3%).

In patients who received DARZALEX in combination with bortezomib and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: thrombocytopenia (90%), neutropenia (58%), peripheral sensory neuropathy (47%), infusion reactions (45%), upper respiratory tract infection (44%), diarrhea (32%), cough (27%), peripheral edema (22%), and dyspnea (21%). The overall incidence of serious adverse events was 42%. Serious adverse reactions were upper respiratory tract infection (5%), diarrhea (2%) and atrial fibrillation (2%).

In patients who received DARZALEX as monotherapy, the most frequently reported adverse reactions (incidence ≥20%) were: neutropenia (60%), thrombocytopenia (48%), infusion reactions (48%), fatigue (39%), nausea (27%), back pain (23%), pyrexia (21%), cough (21%), and upper respiratory tract infection (20%). Serious adverse reactions were reported in 51 (33%) patients. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%).

DRUG INTERACTIONS
Effect of Other Drugs on daratumumab: The coadministration of lenalidomide or bortezomib with DARZALEX did not affect the pharmacokinetics of daratumumab.

Effect of Daratumumab on Other Drugs: The coadministration of DARZALEX with bortezomib did not affect the pharmacokinetics of bortezomib.

On November 21, 2016 CTI BioPharma Corp. (CTI) (NASDAQ and MTA: CTIC) reported that data from the randomized Phase 3 PERSIST-2 clinical trial comparing the investigational agent pacritinib, an oral multikinase inhibitor, with physician-specified best available therapy (BAT), including ruxolitinib, for treatment of patients with myelofibrosis whose baseline platelet counts are less than 100,000 per microliter will be presented in a late-breaking oral presentation at the upcoming 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, being held December 3-6 in San Diego, CA (Press release, CTI BioPharma, NOV 21, 2016, View Source [SID1234516716]).

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Myelofibrosis is associated with significantly reduced quality of life and shortened survival. Spleen enlargement (splenomegaly) is a common and debilitating symptom of myelofibrosis. As the disease progresses, the body slows production of important blood cells and within one year of diagnosis the incidence of disease-related thrombocytopenia (very low blood platelet counts), severe anemia and red blood cell transfusion requirements increase significantly.

Details of the PERSIST-2 presentation, two additional poster presentations regarding pacritinib, as well as poster presentations highlighting PIXUVRI (pixantrone) and tosedostat, are below. Full abstracts can be accessed on the ASH (Free ASH Whitepaper) website at www.hematology.org.

PERSIST-2 Oral Presentation

Results of the PERSIST-2 Phase 3 Study of Pacritinib (PAC) Versus Best Available Therapy (BAT), Including Ruxolitinib (RUX), in Patients with Myelofibrosis (MF) and Platelet Counts Less Than 100,000/µL
First Author: John Mascarenhas, M.D., Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
Date/Time: Tuesday, December 6 at 8:30 a.m. PT
Location: Hall AB
Oral Session: Late-Breaking Abstracts
Abstract #LBA-5

Poster Presentations

Pacritinib

Relationship of JAK2V617F Allelic Burden (AB) to Demographics, Disease Characteristics, and Response to Therapy in PERSIST-1, A Randomized Phase 3 Study of Pacritinib (PAC) Versus Best Available Therapy (BAT) in Patients (Pts) with Primary and Secondary Myelofibrosis (MF)First Author: Alessandro M. Vannucchi, M.D., CRIMM, AOU Careggi, University of Florence, Florence, Italy
Date/Time: Sunday, December 4 at 6:00-8:00 p.m. PT
Location: Hall GH
Poster Session: 634. Myeloproliferative Syndromes: Clinical: Poster II
Abstract #3131

Pacritinib Targets IRAK1 and Shows Synergy with HDAC and BET Inhibitors in Acute Myeloid Leukemia
First Author: Anupriva Agarwal, Ph.D., Knight Cancer Institute, Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR
Date/Time: Sunday, December 4 at 6:00-8:00 p.m. PT
Location: Hall GH
Poster Session: 802. Chemical Biology and Experimental Therapeutics: Poster II
Abstract #3514

Pixantrone

The Combination of Pixantrone, Etoposide, Bendamustine and, in CD20+ Tumors, Rituximab (PREBEN) Shows Promising Feasibility/Efficacy in Heavily Pre-Treated Aggressive Lymphomas of B- And T-Cell Phenotype – Results of the Pre-Trial Experience Leading to a Nordic Phase 1/2 Study (the PREBEN Trial)
First Author: Michael R. Clausen, M.D., Hematology, Aarhus University Hospital, Aarhus, Denmark
Date/Time: Saturday, December 3 at 5:30-7:30 pm PT
Location: Hall GH
Poster Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma – Clinical Studies: Poster I
Abstract #1782

Tosedostat

A Phase 1 Dose-Escalation Study of the Class 1 Selective Histone Deacetylase Inhibitor CHR-3996 in Combination with Tosedostat for Patients with Relapsed, Refractory Multiple Myeloma: Results of the MUK Three Trial
First Author: Rakesh Popat, MBBS, Ph.D., University College London Hospitals NHS Foundation Trust, London, UK
Date/Time: Sunday, December 4 at 6:00-8:00 p.m. PT
Location: Hall GH
Poster Session: 653. Myeloma: Therapy, excluding Transplantation: Poster II
Abstract #3321

About the Phase 3 Development Program of Pacritinib

Pacritinib was evaluated in two Phase 3 clinical trials, known as the PERSIST program, for patients with myelofibrosis, with one trial in a broad set of patients without limitations on platelet counts, the PERSIST-1 trial; and the other in patients with low platelet counts, the PERSIST-2 trial. In August 2014, pacritinib was granted Fast Track designation by the FDA for the treatment of intermediate and high risk myelofibrosis including, but not limited to, patients with disease-related thrombocytopenia (low platelet counts); patients experiencing treatment-emergent thrombocytopenia on other JAK2 inhibitor therapy; or patients who are intolerant of, or whose symptoms are not well controlled (sub-optimally managed) on other JAK2 therapy.

Clinical studies under the CTI BioPharma investigational new drug (IND) for pacritinib are currently subject to a full clinical hold issued by the U.S. Food and Drug Administration in February 2016.

About Pacritinib

Pacritinib is an investigational oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R. The JAK family of enzymes is a central component in signal transduction pathways, which are critical to normal blood cell growth and development, as well as inflammatory cytokine expression and immune responses. Mutations in these kinases have been shown to be directly related to the development of a variety of blood-related cancers, including myeloproliferative neoplasms, leukemia and lymphoma. In addition to myelofibrosis, the kinase profile of pacritinib suggests its potential therapeutic utility in conditions such as acute myeloid leukemia, or AML, myelodysplastic syndrome, or MDS, chronic myelomonocytic leukemia, or CMML, and chronic lymphocytic leukemia, or CLL, due to its inhibition of c-fms, IRAK1, JAK2 and FLT3.

About PIXUVRI (pixantrone)

PIXUVRI is a novel aza-anthracenedione with unique structural and physiochemical properties. PIXUVRI was structurally designed so that it cannot bind iron and perpetuate oxygen radical production or form a long-lived hydroxyl metabolite — both of which are the putative mechanisms for anthracycline induced acute and chronic cardiotoxicity.

In May 2012, the European Commission granted conditional marketing authorization for PIXUVRI as a monotherapy for the treatment of adult patients with multiply relapsed or refractory aggressive NHL. The benefit of PIXUVRI treatment has not been established in patients when used as fifth line or greater chemotherapy in patients who are refractory to last therapy. The Summary of Product Characteristics (SmPC) has the full prescribing information, including the safety and efficacy profile of PIXUVRI in the approved indication. The SmPC is available at www.pixuvri.eu. PIXUVRI does not have marketing approval in the United States.

About Tosedostat

Tosedostat is an investigational oral aminopeptidase inhibitor that has demonstrated anti-tumor responses in blood-related cancers and solid tumors in Phase 1-2 clinical trials. Tosedostat is currently being evaluated in multiple Phase 2 clinical trials for the treatment of patients with AML or high-risk MDS. Tosedostat is not approved or commercially available.

On November 21, 2016 Stemline Therapeutics, Inc. (Nasdaq:STML) reported the oral presentation of clinical data from its ongoing Phase 2 trial of SL-701 in patients with second-line glioblastoma (GBM) (Press release, Stemline Therapeutics, NOV 21, 2016, View Source [SID1234516715]). The Phase 2 results were delivered by David A. Reardon, M.D., Clinical Director, Center for Neuro-Oncology, Dana-Farber Cancer Institute and Professor of Medicine, Harvard Medical School, at the Society for Neuro-Oncology (SNO) annual meeting in Scottsdale, AZ this past Friday, November 18, at 6:20 PM ET. SL-701 is a subcutaneously delivered immunotherapy designed to generate a long-term T cell response against GBM.

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David A. Reardon, M.D., the lead investigator of the study, commented, "We are observing encouraging clinical activity, including major responses, some with promising durability, from the combination of SL-701 and bevacizumab." Dr. Reardon continued, "These preliminary findings are consistent with a potential long-term immunotherapeutic benefit of SL-701 as a large majority of treated patients remain alive and the trial has not reached a median overall survival." Dr. Reardon concluded, "We look forward to following our patients and reporting longer-term survival and response data as the trial matures. In parallel, we are evaluating additional combination regimens and the design of a potential pivotal trial."

SL-701 Phase 2 Trial
The SL-701 Phase 2 trial enrolled second-line GBM patients and was comprised of a single-agent stage (Stage 1; n=46) and a combination stage which evaluated SL-701 with bevacizumab (Stage 2; n=28).

SL-701 was found to be safe and well-tolerated, and demonstrated clinical activity, including major responses, in second-line GBM when used alone or in combination with bevacizumab.

Key efficacy outcomes observed to date with the overall program include:

Combination activity in second-line GBM
SL-701 + poly-ICLC + bevacizumab (Phase 2 trial, Stage 2; n=21 evaluable)
Major responses (n=7; 2 complete responses [CR] and 5 partial responses [PR])
4 confirmed with 2nd response assessment
2 with pending 2nd response assessment
1 progressed prior to 2nd response assessment
Response duration encouraging, with several responses of 6 months-plus in duration, all ongoing
Overall survival appears promising; median not reached and data continue to mature
Single agent activity in relapsed/refractory GBM
SL-701 + GM-CSF + Imiquimod (Phase 2 trial, Stage 1; n=42 evaluable)
1 partial response (PR) of 13+ months duration, ongoing
2 stable diseases (SD) of 18+ and 20+ months duration, both ongoing
Earlier versions of SL-701 + poly-ICLC (Phase 1 trial)
Major responses in second- and third-line GBM
Patients continue to be followed for response and survival, and additional clinical data updates are expected next year, as well as immunocorrelative analyses.

The full presentation is now available on the Stemline website, under the "Scientific Presentations" tab (see link: View Source).