On May 27, 2015 MacroGenics reported the publication of a nonclinical research paper on MGD006 in Science Translational Medicine (Press release, MacroGenics, MAY 27, 2015, View Source [SID:1234504851]). MGD006 is a humanized, Dual-Affinity Re-Targeting (DART) molecule that recognizes both CD123 and CD3. CD123, the Interleukin-3 receptor alpha chain, is expressed on malignant cells, including leukemic stem cells (LSC), in acute myeloid leukemia (AML) and other hematological diseases. The primary mechanism of action of MGD006 is its ability to redirect T lymphocytes to kill CD123-expressing cells. To achieve this, the DART combines a portion of an antibody recognizing CD3, an activating molecule expressed by T cells, with an arm that recognizes CD123 on the target cells. The recently published research shows anticancer activity in vitro and in mouse models together with favorable pharmacodynamic and safety profile in nonhuman primates.

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The prognosis of patients with AML remains poor overall despite existing therapy, and substantial unmet need exists for these individuals. AML patients may benefit from targeted immunotherapy approaches. The paper titled "A CD3xCD123 bispecific DART for redirecting host T cells to myelogenous leukemia: Preclinical activity and safety in nonhuman primates," describes how MacroGenics’ scientists engineered the MGD006 DART and demonstrated in vitro that the molecule can arm T cells from AML patients to reduce blast counts and is effective in eliminating AML cells implanted in mice. Furthermore, MGD006 administered to cynomolgus monkeys demonstrated potent pharmacodynamic activity in the form of near complete elimination of circulating CD123-positive cells at doses that were safe and well tolerated.

"This research paved the way for our initiation of a Phase 1 clinical study of MGD006 in 2014," said Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics. "This was a significant milestone for our DART platform and I am pleased to say that the study is progressing well. MGD006 has demonstrated great promise as a T-cell re-directed cancer immunotherapy in pre-clinical studies. We are hopeful that these studies will translate into clinical trial results indicative of clinical improvement for patients with AML, myelodysplastic syndrome and several other forms of leukemia and lymphoma."

About the Phase 1 Study of MGD006

MacroGenics continues to enroll patients in the dose escalation portion of a Phase 1 study of MGD006 for the treatment of AML. The Phase 1 dose-escalation study is designed to assess the safety and tolerability of MGD006 in patients with relapsed or refractory AML. In addition to the primary safety endpoint, secondary endpoints of pharmacokinetics and pharmacodynamic activity will be evaluated, as will a number of biomarkers examining the immunobiology of MGD006. The Phase 1 study was initiated at Washington University School of Medicine in St. Louis. In addition, Emory University and Providence Portland Medical Center are now recruiting patients and a fourth site is expected to commence patient recruitment in June.

About MGD006

MGD006 is a humanized DART molecule that can simultaneously bind CD123 and CD3. CD123 has been reported to be overexpressed on malignant cells in a wide range of hematological malignancies including AML and myelodysplastic syndrome (MDS). AML and MDS are thought to arise in, and be perpetuated by, a small population of LSCs that generally resist conventional chemotherapeutic agents. LSCs are characterized by comparably high levels of CD123 expression in contrast to the limited or absent CD123 expression in the corresponding hematopoietic stem cell population in normal human bone marrow.

MacroGenics has retained development and commercialization rights to MGD006 in the U.S., Canada, Mexico, Japan, South Korea and India. MacroGenics’ partner, Servier, has rights to MGD006 in all other countries.

About the DART Platform

MacroGenics’ DART platform enables the targeting of multiple antigens or cells by using a single molecule with dual antibody-like binding regions. The Company has created over 100 DART molecules, which have been designed for evaluation in the potential treatment of cancer, autoimmune disorders and infectious disease. These DART molecules can be tailored for either short or prolonged pharmacokinetics and have demonstrated good stability and manufacturability. MacroGenics and its partners expect to have a total of five DART molecules in clinical development by the end of 2015.

Cellectar Biosciences has filed a 10-Q – Quarterly report [Sections 13 or 15(d)] with the U.S. Securities and Exchange Commission (Filing, 10-Q, Cellectar Biosciences, MAY 20, 2015, View Source [SID1234504606]).

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On May 19, 2015 SignalRx Pharmaceuticals Inc., focused on developing more effective oncology drugs though molecular design imparting selective multiple target inhibition, reported that it has received non-dilutive funding to advance the preclinical development of unique small molecule inhibitors designed to inhibit multiple critical cancer targets (Press release, SignalRx, MAY 19, 2015, http://www.ireachcontent.com/news-releases/signalrx-pharmaceuticals-inc-awarded-sttr-grant-from-the-national-institutes-of-health-for-development-of-dual-pi3-kinasebromodomain-inhibitors-as-anticancer-agents-504347611.html [SID1234527329]).

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SignalRx was awarded a Phase 1 Small Business Technology Transfer Research (STTR) grant from the National Cancer Institute (NCI), a division of the National Institutes of Health (NIH), in support of the preclinical development of novel small molecules that simultaneously inhibit two key cancer targets: PI3kinase (PI3K) and the bromodomain protein BRD4. The principal investigator on the STTR grant is SignalRx’s scientific advisor Dr. Donald Durden, MD, PhD who also serves as the academic collaborator for the grant while in his capacity as the Associate Director for Pediatric Oncology at the Moores UCSD Cancer Center at the University of California, San Diego.

Inhibiting the key cancer promoting transcription factor MYC (both cMYC and MYCN) is vigorously pursued since this inactivates many genes that drive cancer cell growth and proliferation. To date, small molecule inhibitors of MYC have been elusive. SignalRx’s innovative approach is to indirectly orthogonally diminish the activity of MYC by enhancing its degradation using PI3K inhibition combined with simultaneous blocking the transcription of the gene producing MYC via inhibition of the bromodomain protein BRD4—all resulting from a single molecule. Combination treatments are necessary in cancer, and there is an ever increasing need for more complex combinations to inhibit multiple targets to maximize efficacy. However, combining single-action drugs becomes unfeasible due to prohibitive costs when combining expensive targeted therapies in addition to being a barrier to early clinical evaluation of such complex combinations of drugs. SignalRx provides proprietary single molecules designed to inhibit multiple specific key cancer targets and thus strive for more cost-effective efficacy-improved therapeutics.

SignalRx has discovered and patented a novel molecular scaffold whose members are potent PI3K inhibitors designed to simultaneously inhibit the bromodomain protein BRD4. These dual PI3K/BRD4 inhibitors are the subject of the awarded grant along with the development of molecular modeling tools to help facilitate the structure activity relationships now under study. Preliminary results of these dual PI3K/BRD4 inhibitors have demonstrated in vivo efficacy without toxicity in several mouse cancer models, confirming the advantage of circumventing potential safety concerns arising from the use of multiple drugs. Moreover, successful proof of concept by showing knockdown of both the PI3K pathway and MYC levels was confirmed from the examination of excised mouse tumors 4 hours after administration of a dual PI3K/BRD4 inhibitor.

"The STTR grant award by the NCI to develop a single molecule that inhibits both PI3K and BRD4 represents a major step forward in translating new findings in cancer biology to maximize the activity and durability of effect in new anticancer agents" said Donald L. Durden, MD, PhD. "This approach, in addition to challenging the current dogma of single-targeted oncology drugs, has promise to maximally block the tumor suppressor gene MYC which drives many cancers including CLL, medulloblastoma, multiple myeloma, and high-grade epithelial ovarian cancers exhibiting elevated MYCN expression."

On May 18, 2015 Agios Pharmaceuticals reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to AG-120 for the treatment of patients with acute myelogenous leukemia (AML) who harbor an isocitrate dehydrogenase-1 (IDH1) mutation (Press release, Agios Pharmaceuticals, MAY 18, 2015, View Source [SID1234504501]).

AG-120 is a first-in-class, oral, selective, potent inhibitor of the mutated IDH1 protein being evaluated in two Phase 1 clinical trials, one in hematologic malignancies that recently initiated three expansion cohorts, and one in advanced solid tumors, including glioma.

"We are pleased that now both AG-120 and AG-221 have been granted Fast Track designation, demonstrating the FDA’s commitment to facilitate the development and expedite the review of our lead IDH programs as important new therapies for people with AML who carry these mutations," said Chris Bowden, M.D., chief medical officer of Agios. "We look forward to presenting new data from the ongoing Phase 1 study at the EHA (Free EHA Whitepaper) Annual Congress next month and remain on track to initiate a global, registration-enabling Phase 3 study in collaboration with Celgene in AML patients who harbor an IDH1 mutation in the first half of 2016."

The FDA’s Fast Track Drug Development Program is designed to expedite clinical development and submission of New Drug Applications (NDA) for medicines with the potential to treat serious or life-threatening conditions and address unmet medical needs. Specifically, Fast Track designation facilitates frequent interactions with the FDA review team, including meetings to discuss all aspects of development to support approval, and also provides the opportunity to submit sections of an NDA on a rolling basis as data become available.

On May 18, 2015 Cancer Research Technology (CRT) reported that Teva Pharmaceutical Industries Ltd has returned a portfolio of DNA Damage Response (DDR) projects to CRT (Press release, Cancer Research Technology, MAY 18, 2015, View Source [SID1234523205]). The move, which follows a strategic decision by Teva to focus on market-ready or close-to-market assets in oncology, presents new partnership opportunities including a leading PolQ project.

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The alliance, which bought together world-leading Cancer Research UK scientists in the field of DDR research, CRT’s drug discovery team (CRT’s Discovery Laboratories) and Teva, has successfully established an early DDR portfolio that will continue to be developed by CRT’s Discovery Laboratories whilst a new partner is sought.

The portfolio includes a drug discovery programme targeting PolQ. PolQ is implicated in a wide range of roles including double strand break repair. It is anticipated that Inhibitors of PolQ will induce radiosensitisation in a range of cancers, and potentially exhibit stand alone activity in Homologous Recombination (HR) deficient tumours**.

The DNA damage response pathways can activate cell cycle checkpoints to stop cells dividing, or they can activate specific DNA repair pathways in response to certain types of DNA damage. Some of the proteins in these pathways are mutated, or non-functional in human tumours. This can cause cancer cells to be more reliant on an intact DNA repair pathway for survival providing a therapeutic window. Developing new drugs that target DDR is a promising new avenue of research to tackle this problem.

Dr Phil L’Huillier, said: "Together with Teva, CRT has created an exciting portfolio, backed by a world-class hub of expertise in DDR-related basic, translational, and clinical research, that we will continue to develop through our in-house drug discovery laboratories.

"This restructure represents a unique new partnership opportunity to research and develop first-in-class cancer drugs that exploit DNA damage and repair response processes to fight cancer."

. The move, which follows a strategic decision by Teva to focus on market-ready or close-to-market assets in oncology, presents new partnership opportunities including a leading PolQ project.

The alliance, which bought together world-leading Cancer Research UK scientists in the field of DDR research, CRT’s drug discovery team (CRT’s Discovery Laboratories) and Teva, has successfully established an early DDR portfolio that will continue to be developed by CRT’s Discovery Laboratories whilst a new partner is sought.

The portfolio includes a drug discovery programme targeting PolQ. PolQ is implicated in a wide range of roles including double strand break repair. It is anticipated that Inhibitors of PolQ will induce radiosensitisation in a range of cancers, and potentially exhibit stand alone activity in Homologous Recombination (HR) deficient tumours**.

The DNA damage response pathways can activate cell cycle checkpoints to stop cells dividing, or they can activate specific DNA repair pathways in response to certain types of DNA damage. Some of the proteins in these pathways are mutated, or non-functional in human tumours. This can cause cancer cells to be more reliant on an intact DNA repair pathway for survival providing a therapeutic window. Developing new drugs that target DDR is a promising new avenue of research to tackle this problem.

Dr Phil L’Huillier, said: "Together with Teva, CRT has created an exciting portfolio, backed by a world-class hub of expertise in DDR-related basic, translational, and clinical research, that we will continue to develop through our in-house drug discovery laboratories.

"This restructure represents a unique new partnership opportunity to research and develop first-in-class cancer drugs that exploit DNA damage and repair response processes to fight cancer."