Inflammation-related changes in the concentrations of inflammatory mediators such as c-reactive protein (CRP), interleukin 1β (IL-1), and IL-6 as well as kynurenine metabolites are associated with major depressive disorder (MDD) and affect depressive behavior, cognition, and hippocampal plasticity in animal models. We previously reported that the ratios of kynurenic acid (KynA) to the neurotoxic metabolites, 3-hydroxykynurenine (3HK) and quinolinic acid (QA), were positively correlated with hippocampal volume in depression. The hippocampus is critical for autobiographical memory (AM) recall which is impaired in MDD. Here we tested whether the ratios, KynA/3HK and KynA/QA were associated with AM recall performance as well as hippocampal activity during AM recall. Thirty-five unmedicated depressed participants and 25 healthy controls (HCs) underwent fMRI scanning while recalling emotionally-valenced AMs and provided serum samples for the quantification of kynurenine metabolites, CRP, and cytokines (IL-1 receptor antagonist – IL-1RA; IL-6, tumor necrosis factor alpha – TNF, interferon gamma -IFN-γ, IL-10). KynA/3HK and KynA/QA were lower in the MDD group relative to the HCs. The concentrations of the CRP and the cytokines did not differ significantly between the HCs and the MDD group. Depressed individuals recalled fewer specific AMs and displayed increased left hippocampal activity during the recall of positive and negative memories. KynA/3HK was inversely associated with left hippocampal activity during specific AM recall in the MDD group. Further, KynA/QA was positively correlated with percent negative specific memories recalled in the MDD group and showed a non-significant trend toward a positive correlation with percent positive specific memories recalled in HCs. In contrast, neither CRP nor the cytokines were significantly associated with AM recall or activity of the hippocampus during AM recall. Conceivably, an imbalance in levels of KynA versus QA-pathway metabolites may adversely impact the function of the hippocampus and AM recall, raising the possibility that kynurenine pathway may affect emotion-dependent memory within the context of depression.
Copyright © 2016. Published by Elsevier Inc.

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On April 20, 2016 Spectrum Pharmaceuticals (NasdaqGS: SPPI), a biotechnology company with fully integrated commercial and drug development operations with a primary focus in Hematology and Oncology, reported that the U.S. Food and Drug Administration (FDA) Office of Orphan Products Development (OOPD) has granted 7 years of Orphan Drug Exclusivity for EVOMELA for use as a high-dose conditioning treatment prior to hematopoietic progenitor (stem) cell transplantation in patients with multiple myeloma (Press release, Spectrum Pharmaceuticals, APR 20, 2016, View Source [SID:1234511152]). EVOMELA has also been recently listed in the Orange Book, including two composition of matter patents that do not expire until March 2029.

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"We are pleased to receive FDA Orphan Drug Exclusivity for EVOMELA, another important regulatory milestone for Spectrum," said Rajesh C. Shrotriya, MD, Chairman and Chief Executive Officer of Spectrum Pharmaceuticals. "EVOMELA is reconstituted with normal saline and does not contain propylene glycol. EVOMELA’s formulation is based on Captisol technology and is stable at room temperature for 1 hour following reconstitution and for an additional 4 hours after further dilution. We believe EVOMELA has the potential to become an important therapy for multiple myeloma patients undergoing high-dose conditioning treatment prior to hematopoietic stem cell transplantation and fits very well with our existing Hematology/Oncology infrastructure. Revenues from our niche products like EVOMELA help us develop our late-stage drugs that target blockbuster markets."

The FDA Orphan Drug Designation program provides a special status to drugs and biologics intended to treat, diagnose or prevent so-called orphan diseases and disorders that affect fewer than 200,000 people in the U.S. Orphan Drug Designation provides the sponsor certain benefits and incentives, including a period of marketing exclusivity if regulatory approval is ultimately received for the designated indication, potential tax credits for certain activities, eligibility for orphan drug grants, and the waiver of certain administrative fees.

Spectrum Pharmaceuticals gained global development and commercialization rights to EVOMELA from Ligand Pharmaceuticals Incorporated (NASDAQ: LGND) in March 2013. Spectrum assumed responsibility for completing the pivotal Phase 2 clinical trial, and was responsible for filing the NDA. Under the license agreement, Ligand received a license fee, and NDA approval milestone, and is eligible to receive further potential milestones and royalties in connection with commercialization.

About Multiple Myeloma

Multiple Myeloma is a systemic malignancy of plasma cells that accumulate in the bone marrow, usually associated with monoclonal antibody secretion, and results in bone marrow failure and bone destruction. It is the second most common hematologic disease with nearly 30,000 new cases projected in the US in 2016 and over 11,000 deaths annually (American Cancer Society Stats, 2016). The rate of autologous stem cell transplantation (ASCT) for patients with MM is growing by approximately 3.3% annually.

Melphalan is the most commonly used IV agent for high-dose conditioning for patients undergoing ASCT for MM. The current IV melphalan market is approximately $100 million annually, with predominant use in ASCT; EVOMELA is the only intravenous melphalan product that is approved for use in the high-dose conditioning indication.

About EVOMELA

EVOMELA was approved by FDA based on its bioequivalence to the standard melphalan formulation (Alkeran) in a Phase 2 clinical study (Aljitawi et al, Bone Marrow Transplant, 2014) via the 505(b)(2) regulatory pathway. EVOMELA has been granted Orphan Drug Designation by the FDA for its use as a high-dose conditioning regimen for patients with MM undergoing ASCT.

EVOMELA’s melphalan formulation does not contain propylene glycol. The use of the Captisol technology to reformulate also contributes to the 4-hour admixture stability of EVOMELA at room temperature. This is in addition to the 1 hour stability of reconstituted EVOMELA drug product at room temperature and 24 hour stability at refrigerated temperature (5°C).

Please see the Important Safety Information below and the full prescribing information, including BOXED WARNINGS, for EVOMELA at www.evomela.com.

Important Safety Information

WARNING: SEVERE BONE MARROW SUPPRESSION,
HYPERSENSITIVITY, and LEUKEMOGENICITY

Severe bone marrow suppression with resulting infection or bleeding may occur. Controlled trials comparing intravenous (IV) melphalan to oral melphalan have shown more myelosuppression with the IV formulation. Monitor hematologic laboratory parameters.

Hypersensitivity reactions, including anaphylaxis, have occurred in approximately 2% of patients who received the IV formulation of melphalan. Discontinue treatment with EVOMELA for serious hypersensitivity reactions.

Melphalan produces chromosomal aberrations in vitro and in vivo. EVOMELA should be considered potentially leukemogenic in humans.

Contraindications

History of serious allergic reaction to melphalan.
Warnings and Precautions

Nausea, vomiting, diarrhea or oral mucositis may occur. Provide supportive care using antiemetic and antidiarrheal medications as needed.

Hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice have been reported after treatment with melphalan. Hepatic veno-occlusive disease has also been reported. Monitor liver chemistries.
EVOMELA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid pregnancy during and after treatment with EVOMELA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, advise the patient of potential risk to the fetus.

Melphalan-based chemotherapy regimens have been reported to cause suppression of ovarian function in premenopausal women, resulting in persistent amenorrhea in approximately 9% of patients. Reversible or irreversible testicular suppression has also been reported.

Adverse Reactions

The most common adverse reactions observed in at least 50% of patients with multiple myeloma treated with EVOMELA were neutrophil count decreased (100%), white blood cell count decreased (100%), lymphocyte count decreased (98%), platelet count decreased (98%), diarrhea (93%), nausea (90%), fatigue (77%), hypokalemia (74%), anemia (66%), and vomiting (64%).
In a single-arm clinical study, twelve (20%) patients with multiple myeloma who received EVOMELA conditioning for ASCT experienced a treatment emergent serious adverse reaction. The most common serious adverse reactions ( > 1 patient, 1.6%) were pyrexia, hematochezia, febrile neutropenia, and renal failure.

In a randomized clinical trial studying the palliative treatment of patients with multiple myeloma, severe myelotoxicity (WBC ≤1,000 and/or platelets ≤25,000) was more common in the IV melphalan arm (28%) than in the oral melphalan arm (11%).
Drug Interactions

No formal drug interaction studies have been conducted. When nalidixic acid and IV melphalan are given simultaneously, the incidence of severe hemorrhagic necrotic enterocolitis has been reported to increase in pediatric patients.
Use in Specific Populations

It is not known whether melphalan is present in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from melphalan, breastfeeding is not recommended during treatment with EVOMELA.

Advise females of reproductive potential to avoid pregnancy, which may include the use of effective contraception methods, during and after treatment with EVOMELA.

For Palliative Treatment, consider dose reduction for patients with renal impairment receiving EVOMELA.
About Captisol

Captisol is a patent-protected, chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs. Captisol was invented and initially developed by scientists in the laboratories of Dr. Valentino Stella at the University of Kansas’ Higuchi Biosciences Center for specific use in drug development and formulation. This unique technology has enabled six FDA-approved products, including Onyx Pharmaceuticals’ Kyprolis, Baxter International’s Nexterone and Merck’s NOXAFIL IV. There are also more than 30 Captisol-enabled products currently in clinical development.

Mogamulizumab (Mog), a humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody (mAb) that mediates antibody-dependent cellular cytotoxicity (ADCC) using FcγR IIIa (CD16)-expressing effector cells, has recently been approved for treatment of CCR4-positive adult T-cell leukemia (ATL) in Japan. However, Mog failure has sometimes been observed in patients who have accompanying chemotherapy-associated lymphocytopenia. In this study, we examined whether adoptive transfer of artificial ADCC effector cells combined with Mog would overcome this drawback.
We lentivirally gene-modified peripheral blood T cells from healthy volunteers and ATL patients expressing the affinity-increased chimeric CD16-CD3ζ receptor (cCD16ζ-T cells). Subsequently we examined the ADCC effect mediated by those cCD16ζ-T cells in the presence of Mog against ATL tumor cells both in vitro and in vivo.
cCD16ζ-T cells derived from healthy donors killed in vitro Mog-opsonized ATL cell line cells (n=7) and primary ATL cells (n=4) depending on both the number of effector cells and the dose of the antibody. cCD16ζ-T cells generated from ATL patients (n=3) also exerted cytocidal activity in vitro against Mog-opsonized autologous ATL cells. Using both intravenously disseminated model (n=5) and subcutaneously inoculated model (n=4), co-administration of Mog and human cCD16ζ-T cells successfully suppressed tumor growth in xenografted immunodeficient mice, and significantly prolonged their survival (p<0.01 and p=0.02, respectively).
These data strongly suggest clinical feasibility of the novel combined adoptive immunotherapy using cCD16ζ-T cells and Mog for treatment of aggressive ATL, particularly in patients who are ineligible for allo-HSCT.
Copyright ©2016, American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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On April 20, 2016 Checkmate Pharmaceuticals , a clinical-stage biopharmaceutical company focused on developing novel approaches for cancer immunotherapy, reported the appointment of David Mauro, M.D., Ph.D . to the newly created position of Chief Medical Officer. Checkmate also announced the dosing of the first patient in a Phase 1b trial with CMP-001 in combination with pembrolizumab in melanoma patients who have either progressed on or failed to respond to at least 12 weeks of anti -‐ PD1 therapy. CMP -‐ 001 is a first -‐ in -‐ class CpG -‐ A oligonucleotide that activates the innate immune system via Toll -‐ like receptor 9 (TLR9) (Press release, Checkmate Pharmaceuticals, APR 20, 2016, View Source [SID1234516800]). The combination therapy has the potential to increase the proportion of cancer patients who respond to checkpoint inhibitor therapies and to increase the magnitude and duration of the anti -‐ tumor responses , providing added clinical benefit . Industry Veteran with Immun o -‐ Oncology Clinical Development and Leadership Expertise Dr. Mauro brings to Checkmate more than 15 years of experience in early and late stage oncology drug development, clinical and translational research , and medical affairs. Previously he served as Exe cu tive Vice President and Chief Medical Officer at Advaxis , where he was responsible for the strategy and oversight of the company’s clinical programs, including several combination drug programs with checkpoint inhibitor s . "We welcome David to the Checkmate team at this pivotal time ," said Art Krieg, M.D., Chief E xecutive Officer of Checkmate. " His deep knowledge and experience in immuno -‐ oncology , and specifically in the development of checkpoint inhibitor combinations, will be invaluable to Checkmate in the clinical development of CMP -‐ 001 for patients with advanced cancer ." Dr. Mauro has held senior level positions at Merck & Co. and Bristol Myers Squibb Company, where he was involved in the clinical development, trans la tional science , and life cycle management for multiple programs , including Keytruda ( pembrolizumab ), Erbitux (cetuximab), Sprycel (dasatinib), and Sylatron (peginterferon alfa -‐ 2b). He received his Bachelor of Science in Bioch emistry from Cornell University, his medical degree and his doctorate in pharmacology from Temple Univ ersity School of Medicine , and completed his residency training at the National Cancer Institute. A s Chief Medical Officer at Checkmate, Dr. Mauro will oversee the development of the Company’s current and future clinical programs, based on the TLR9 mechani sm of immune activation. " I am excited to be joining Checkmate as it progress es CMP -‐ 001 into the clinic in itially in melanoma patients ," said Dr. Mauro. "I look forward to working with the team to further expand the development of this compound in other indications and checkpoint inhibitor combinations . The immun o -‐ oncology field is evolving rapidly , and I believe that CMP -‐ 001 has the potential to increase the response rates to current checkpoint therapies a nd have a broad impact in the development of new standards of care f or oncology treatment." Initiation of Phase 1b Trial in Advanced Melanoma with a TLR9 Immune Activator Checkmate has dosed the first patient in its Phase 1b clinical study of CMP -‐ 001 . Th e trial is designed as a multi -‐ center, open -‐ label study of CMP -‐ 001 in combination with pembrolizumab for patients with advanced melanoma who have either progressed on an anti -‐ PD1 , or have failed to respond to at least 12 weeks of therapy . Patients will c ontinue on the approved dose and schedule of pembrolizumab, with the addition of intratumoral CMP -‐ 001 therapy. The trial will include a dose escalation study and will enroll patients in an expansion phase , as well as undertake correlative studies to characterize the immune effects of treatment in the blood and tumor. P atients will be monitored for safety and tolerability as well as possible clinical response . " We are excited to begin our clinical development of this new appr oac h of a ltering the tumor microenvironment with intratumoral CMP -‐ 001," said Dr. Krieg. " We believe this treatment should convert "cold" tumors , which lack immune activation and are not likely to respond to checkpoint inhibitors , in to immunologically "hot" tumors which are much more likely to respond to checkpoint inhibition . This has the potential to induce a powerful anti -‐ tumor CD8 + T cell immune response resulting in significantly increased response rates to checkpoint inhibitor therapy in multiple cancer indications ." About CMP -‐ 001 CMP -‐ 001 comprises a CpG -‐ A oligonucleotide packaged within a virus -‐ like particle . It is designed to activate the innate immune system via Toll -‐ like receptor 9 (TLR9) and mediate tumor control by the subsequent induction of both innate and adaptive anti -‐ tumor immune responses . CMP -‐ 001 is the only CpG -‐ A oligonucleotide in clinical development . It differs from the other major classes of TLR9 agonists in development , CpG -‐ B, and CpG -‐ C , by it s induction of much higher levels of type I interferons, without inducing immune suppressive IL -‐ 10. In addition, the virus -‐ like particle nature of CMP -‐ 001 will promote formation of immune complexes within tumors, providing an additional mechanism driving anti -‐ tumor i mmunity. In preclinical models , CMP -‐ 001 shows single agent activity in controlling growth of both local and distant tumors, with increased anti -‐ tumor ac tivity seen in combination with systemic anti -‐ PD -‐ 1 therapy. CMP -‐ 001 was licensed from Kuros Biosciences AG and was formerly known as CYT003. It has previously demonstrated a good safety profile and evidence of immune activity in over 700 patients who participated in clinical trials for non -‐ oncology indications.
About Checkmate
Checkmate Pharmaceuticals is a clinical stage company pursuing a novel approach to specifically activating the innate arm of the immune system to recognize and ultimately destroy tumor cells. The company is leveraging its expertise and the vast body of knowledge in the field of CpG oligonucleotides and is validating a n approach that will combine the ability of CpG DNA to activate an anti -‐ tumor T cell response with checkpoint inhibition to overcome a tumor’s ability to mute the immune response .
Checkmate’s founder and CEO, Dr. Art Krieg, discovered immune stimulatory CpG DNA in 1994 . S ince then , CpG containing DNA therapies have been administered to thousands of patients showing potent immune activation and a n acceptable safety profile. Checkmate is a privately held company headquartered in Cambridge, M A , whose Series A investors include Sofinnova Ventures and venBio

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In this proof-of-concept, open-label, phase 2 study, patients with relapsed/refractory multiple myeloma (RRMM) received elotuzumab with bortezomib and dexamethasone (EBd) or bortezomib and dexamethasone (Bd) until disease progression/unacceptable toxicity. Primary endpoint was progression-free survival (PFS); secondary/exploratory endpoints included overall response rate (ORR) and overall survival (OS). Two-sided 0.30 significance level was specified (80% power, 103 events) to detect hazard ratio (HR) of 0.69. Efficacy and safety analyses were performed on all randomized patients and all treated patients, respectively. Of 152 randomized patients (77 EBd, 75 Bd), 150 were treated (75 EBd, 75 Bd). PFS was greater with EBd versus Bd (HR, 0.72; 70% confidence interval [CI], 0.59-0.88; stratified log-rank P=.09); median PFS was longer with EBd (9.7 months) versus Bd (6.9 months). In an updated analysis, EBd-treated patients homozygous for the high-affinity FcγRIIIa allele had median PFS of 22.3 months versus 9.8 in EBd-treated patients homozygous for the low-affinity allele. ORR was 66% (EBd) versus 63% (Bd). Very good partial response or better occurred in 36% of patients (EBd) versus 27% (Bd). Early OS results, based on 40 deaths, revealed an HR of 0.61 (70% CI, 0.43-0.85). To date, 60 deaths have occurred (28 EBd, 32 Bd). No additional clinically significant adverse events occurred with EBd versus Bd. Grade 1/2 infusion reaction rate was low (5% EBd) and mitigated with premedication. In patients with RRMM, elotuzumab, an immunostimulatory antibody, appears to provide clinical benefit without added clinically significant toxicity when combined with Bd versus Bd alone. ClinicalTrials.govNCT01478048 .
Copyright © 2016 American Society of Hematology (ASH) (Free ASH Whitepaper).

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