On November 16, 2018 ArQule, Inc. (Nasdaq: ARQL) reported the presentation of clinical and preclinical data on ARQ 751 in three poster presentations at the 30th EORTC/AACR/NCI Symposium held from November 13 to 16, 2018 in Dublin, Ireland (Press release, ArQule, NOV 16, 2018, View Source [SID1234531401]). The data presented highlight clinical data from ARQ 751-101, a Phase 1 study in adult patients with refractory and/or metastatic tumors that harbor AKT, PI3K or PTEN genetic alterations, and preclinical data on ARQ 751 in combination with other agents.

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Clinical data highlights and key conclusions include:

1. A Phase 1 Dose Escalation Study of ARQ 751 in Adult Patients with Advanced Solid Tumors with AKT1, 2, 3 Genetic Alterations, Activating PI3K Mutations, PTEN-null, or Other Known Actionable PTEN Mutations

ARQ 751 demonstrated manageable toxicity at doses from 5 mg QD to 75 mg QD, and the recommended Phase 2 dose was determined to be 75 mg QD
Evidence of clinical activity was observed with two partial responses in ER+/PR+/HER2- stage IV breast cancer patients, one with PTEN C296fs*2 mutation, one with PIK3CA H1047R mutation, 11 patients had stable disease
The data support continued development of ARQ 751 as a monotherapy or in combination with other anti-cancer agents due to its manageable safety profile and preliminary evidence of biological activity
"ARQ 751, as a highly specific allosteric AKT inhibitor, holds great potential in treating patients with solid tumors harboring mutations in the AKT/PI3K/PTEN pathways," said Brian Schwartz, M.D., Chief Medical Officer of ArQule. "The presented data are very encouraging and demonstrate both preliminary signs of clinical activity and a favorable safety profile while also determining the recommended Phase 2 dose. At ArQule, we are committed to developing genetically targeted cancer treatments to provide effective new treatment options for patients, particularly those with advanced or relapsed disease, and look forward to advancing the ARQ 751 clinical program."

Preclinical data highlights include:

2. Combination of the AKT inhibitor ARQ 751 with Immune Checkpoint Inhibitor and Other Therapeutic Agents

In preclinical cellular models, ARQ 751 exerted greater anti-proliferative and biochemical effects when in combination with multiple therapeutic agents including an ER antagonist, aromatase inhibitor, androgen receptor antagonist and a BTK inhibitor
In an in vivo colon cancer animal model, ARQ 751 in combination with an anti-PD-1 antibody exhibited superior anti-tumor activity compared to single agents
3. Miransertib and ARQ 751 exhibit superior cell-death-inducing properties compared to other AKT inhibitors and can overcome resistance to other allosteric AKT inhibitors

ArQule’s AKT inhibitors, miransertib and ARQ 751 showed superior activity in comparison to other allosteric and ATP-competitive AKT inhibitors currently in clinical development
Miransertib and ARQ 751 have the potential to overcome some mechanisms of resistance to AKT inhibitors
Miransertib and ARQ 751 in combination with ATM inhibition demonstrated synergistic effects
Dr. Shubham Pant, MD, Associate Professor in the Department of Investigational Cancer Therapeutics at MD Anderson Cancer Center, said "AKT inhibitors have significant potential to treat a broad range of solid tumors in molecularly defined patient populations. The presented data show that ARQ 751 exhibits unique properties that differentiate it from other AKT inhibitors. It is our hope that by combining ARQ 751 with a broad spectrum of therapeutic agents, including hormonal agents, we could provide new opportunities for combinatorial interventions in oncology."

All posters presented by ArQule at the EORTC/AACR/NCI Symposium are available on the company’s website at View Source

About ARQ 751
ARQ 751 is an orally bioavailable, selective small molecule inhibitor of the AKT serine/threonine kinase. The AKT pathway when abnormally activated is implicated in multiple oncogenic processes such as cell proliferation and apoptosis. This pathway has emerged as a target of potential therapeutic relevance for compounds that inhibit its activity, which has been linked to a variety of cancers as well as to select non-oncology indications. ARQ 751 is currently in a Phase 1 study in adult patients with refractory and/or metastatic tumors that harbor genetic alterations along the AKT pathway.

About Miransertib
Miransertib (ARQ 092) is an orally bioavailable, selective, pan-AKT (protein kinase B) inhibitor that potently inhibits AKT1, 2 and 3 isoforms. Dysregulation of AKT has been implicated in a variety of rare overgrowth diseases and cancers; however, there are currently no approved inhibitors of AKT. AKT inhibitors, either as single agent or combination therapy, show significant promise in molecularly defined patient populations. Miransertib is currently in a Phase 1/2 company-sponsored study for PIK3CA-Related Overgrowth Spectrum (PROS), a Phase 1 study for ultra-rare Proteus syndrome conducted by the National Institutes of Health (NIH/NHGRI), and a Phase 1b study in combination with the hormonal therapy, anastrozole, in patients with advanced endometrial cancer with AKT and PI3K mutations. Miransertib has been granted Rare Pediatric Disease Designation and Fast Track Designation by the U.S. Food and Drug Administration (FDA), as well as Orphan Designation by the FDA and European Medicines Agency in the rare overgrowth disease, Proteus syndrome.

On November 15, 2018 Neovia Oncology reported that Substantial limitations in the response rates for cancer immunotherapy and increasing drug-resistance in cancer patients in general have led to a search for rational drug combination therapy (Press release, Neovia Oncology, NOV 15, 2018, View Source [SID1234531343]). It has been reported that Topoismerase types I (Topo I) and II (Topo II), already well recognized as important targets for inhibiting cellular DNA replication, are highly expressed in many cancers and also ‘cross-talk’ with Epidermal Growth Factor Receptor, which is the target of several recently approved cancer drugs. Moreover Topo I inhibitors have recently been shown to augment T-cell mediated antitumor immune response and enhance the efficacy of immunotherapy. Currently approved Topo inhibitor drugs, however, are single agents and known to be highly toxic even at low doses.

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Neovia’s NEV-801 investigational product is the result of structure-based drug design to create a covalently conjugating camptothecin and podophyllotoxin derivative multi-inhibitor (simultaneously inhibiting topo I and II) with potent anti-cancer efficacy through a synergistic immune response but with minimal toxicity. For example, when used as a single agent in preclinical studies of Chronic Myelogenous Leukemia models, NEV-801 causes tumor sizes to diminish, with 38% of tumors disappearing completely and a 98% tumor growth inhibition rate compared to 0% and 33%, respectively, for leading marketed drug Imatinib (Gleevec). Weight loss was effectively overcome within a week of continued administration. Additionally in an ovarian cancer model NEV-801 was shown to be synergistic with immune checkpoint inhibitors PD-1 and CTLA-4.

Neovia is currently studying NEV-801 in a Phase 1 dose-escalation, dose-confirmation trial, in which anti-tumor effects are also being evaluated to determine the tumor types to be targeted in Phase 2. Through cohort 3 (80 mg), NEV-801 has been well tolerated with no reported serious adverse events. Importantly, NEV-801 can also be used as an oral anticancer drug, which is strongly recommended for cancer therapy of patients, since PK data analysis demonstrates that it can pass the Caco-2 cell membrane with a high permeability of 9.2. This also explains the lower GI-related toxicity.

Neovia has a strong patent portfolio with protection into 2035, with plans to file for Orphan Drug designation that will extend exclusivity for 7 years in the US and 10 years in Europe after approvals.

On November 15, 2018 Seattle Genetics, Inc. (Nasdaq:SGEN) reported that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to ADCETRIS (brentuximab vedotin) for previously untreated systemic anaplastic large cell lymphoma or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with CHP (cyclophosphamide, doxorubicin, and prednisone) (Press release, Seattle Genetics, NOV 15, 2018, View Source [SID1234531359]). The positive topline results of the phase 3 ECHELON-2 clinical trial were announced in October 2018, followed by the submission of a supplemental Biologics License Application (BLA) to the FDA in November 2018. Additional data will be presented at the upcoming American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, December 1-4, 2018 in San Diego, Calif. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, which is expressed on the surface of several types of PTCL. ADCETRIS is currently not approved for the frontline treatment of PTCL.

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The FDA’s Breakthrough Therapy Designation is intended to expedite the development and review of promising drug candidates for serious or life-threatening conditions. It is based upon clinical evidence of substantial improvement over existing therapies on one or more clinically significant endpoints.

"Data from the ECHELON-2 phase 3 trial of ADCETRIS in combination with chemotherapy showed superior progression-free survival and overall survival versus the standard of care chemotherapy regimen, CHOP, in the treatment of frontline CD30-expressing peripheral T-cell lymphomas," said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. "This is the third Breakthrough Therapy Designation for ADCETRIS and supports our goal to make this therapy available to patients with newly diagnosed peripheral T-cell lymphomas as soon as possible. We look forward to presenting the data from our phase 3 ECHELON-2 trial at the upcoming ASH (Free ASH Whitepaper) Annual Meeting."

This Breakthrough Therapy Designation was based on data from the phase 3 ECHELON-2 clinical trial evaluating the combination of ADCETRIS plus CHP versus the control arm, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), in previously untreated CD30-expressing PTCL. The ECHELON-2 study met its primary endpoint demonstrating a statistically significant improvement in progression-free survival (PFS) of ADCETRIS in combination with CHP versus CHOP as assessed by an Independent Review Facility (IRF; hazard ratio=0.71; p-value=0.0110). The ADCETRIS plus CHP arm also demonstrated superior overall survival (OS), a key secondary endpoint, compared to CHOP (hazard ratio=0.66; p-value=0.0244). All other key secondary endpoints, including PFS in patients with systemic anaplastic large cell lymphoma (sALCL), complete remission rate and objective response rate were statistically significant in favor of the ADCETRIS plus CHP arm. The safety profile of ADCETRIS plus CHP in the ECHELON-2 trial was comparable to CHOP and consistent with the established safety profile of ADCETRIS in combination with chemotherapy.

ECHELON-2 Phase 3 Clinical Trial Design

The randomized, double-blind, placebo-controlled phase 3 trial is investigating ADCETRIS plus CHP (cyclophosphamide, doxorubicin, prednisone) versus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) as frontline therapy in patients with CD30-expressing peripheral T-cell lymphoma, also known as mature T-cell lymphoma. The primary endpoint is progression-free survival (PFS) per Independent Review Facility assessment, with events defined as progression, death, or receipt of chemotherapy for residual or progressive disease. Secondary endpoints include PFS in patients with systemic anaplastic large cell lymphoma (sALCL), complete remission rate, overall survival and objective response rate, in addition to safety. The multi-center trial was conducted at sites across North America, Europe and Asia and was designed to enroll 450 patients, approximately 75 percent of whom were to be diagnosed with sALCL. The ECHELON-2 trial is being conducted under a Special Protocol Assessment (SPA) agreement from the U.S. Food and Drug Administration (FDA) and the trial also received European Medicines Agency (EMA) scientific advice.

Please see Important Safety Information, including Boxed Warning, at the end of this press release.

About T-Cell Lymphomas

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. There are more than 60 subtypes of non-Hodgkin lymphomas which are broadly divided into two major groups: B-cell lymphomas, which develop from abnormal B-lymphocytes, and T-cell lymphomas, which develop from abnormal T-lymphocytes. There are many different forms of T-cell lymphomas, some of which are extremely rare. T-cell lymphomas can be aggressive (fast-growing) or indolent (slow-growing). PTCL accounts for approximately 10 percent of non-Hodgkin lymphoma cases in the U.S. and Europe and may be as high as 24 percent in parts of Asia.

About ADCETRIS (brentuximab vedotin)

ADCETRIS is being evaluated broadly in more than 70 clinical trials in CD30-expressing lymphomas. These include the recently completed phase 3 ECHELON-2 trial in frontline peripheral T-cell lymphomas (also known as mature T-cell lymphoma), the completed phase 3 ECHELON-1 trial in previously untreated Hodgkin lymphoma, the completed phase 3 ALCANZA trial in cutaneous T-cell lymphoma, and the ongoing CHECKMATE 812 trial of ADCETRIS in combination with Opdivo (nivolumab) for relapsed/refractory Hodgkin lymphoma.

ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

ADCETRIS injection for intravenous infusion has received FDA approval for five indications in adult patients with: (1) previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with chemotherapy, (2) cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation, (3) cHL after failure of auto-HSCT or failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (4) sALCL after failure of at least one prior multi-agent chemotherapy regimen, and (5) primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.

Health Canada granted ADCETRIS approval with conditions for relapsed or refractory Hodgkin lymphoma and sALCL in 2013, and non-conditional approval for post-autologous stem cell transplantation (ASCT) consolidation treatment of Hodgkin lymphoma patients at increased risk of relapse or progression.

ADCETRIS received conditional marketing authorization from the European Commission in October 2012. The approved indications in Europe are: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, (2) the treatment of adult patients with relapsed or refractory sALCL, (3) for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT, and (4) for the treatment of adult patients with CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy.

ADCETRIS has received marketing authorization by regulatory authorities in 72 countries for relapsed or refractory Hodgkin lymphoma and sALCL. See select important safety information, including Boxed Warning, below.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

On November 15, 2018 PsiOxus Therapeutics, Ltd. (PsiOxus) and the Parker Institute for Cancer Immunotherapy (Parker Institute) reported a research project to investigate the use of PsiOxus’ virus-based gene therapy for treating solid tumors that have been historically resistant to immunotherapy (Press release, PsiOxus Therapeutics, NOV 15, 2018, View Source [SID1234531403]).

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This pre-clinical immuno-oncology research will utilize PsiOxus’ proprietary T-SIGn platform. The platform uses the enadenotucirev oncolytic virus as a vector to deliver combinations of therapeutic transgenes to carcinomas to fight cancer.

In effect, the T-SIGn viruses work by turning tumor cells into "drug factories" to express gene therapy products, such as cytokines or antibodies, designed to engage the immune system to attack cancer cells.

The viruses first selectively infect and replicate only in tumor cells. The tumor cells then express the encoded genes, producing biologic therapies to alter the tumor microenvironment. Changing the tumor microenvironment is believed to enhance the activation of cancer-fighting immune cells so they can eradicate the tumor.

Working together, PsiOxus and the Parker Institute aim to build and test viruses carrying different combinations of genes.

"One of the challenges in treating solid tumors with immunotherapy is the tumor microenvironment, which is very suppressive and effectively prevents the immune system from attacking the tumor," said Fred Ramsdell, Ph.D., vice president of research at the Parker Institute. "What is promising about the PsiOxus approach is its potential to overcome this suppression using a novel virus platform to deliver gene therapy."

Unlike other oncolytic viruses that require direct injections to the tumor, which can be costly and complicated to administer, PsiOxus’ platform can be delivered to patients intravenously.

"Given the potential of PsiOxus’ IV-delivered cancer gene therapy platform, establishing strategic relationships with world leaders in immuno-oncology will accelerate our ability to bring gene therapy treatment to cancer patients," said Brian Champion, Ph.D., Chief Scientific Officer of PsiOxus. "The Parker Institute is a leader in building strategic relationships between leading immuno-oncology academic and industry partners. We are thrilled to collaborate with the Parker Institute to jointly accelerate research on innovative cancer immuno-oncology therapy."

On November 15, 2018 Akari Therapeutics, Plc (NASDAQ:AKTX), a biopharmaceutical company focused on innovative therapeutics to treat orphan autoimmune and inflammatory diseases where complement and or leukotriene systems are implicated, reported its financial results for the third quarter ended September 30, 2018 (Press release, Akari Therapeutics, NOV 15, 2018, View Source [SID1234531344]).

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"We are focused on moving our four priority clinical programs forward and expect initial data from our trials in patients with bullous pemphigoid (BP) and atopic keratoconjunctivitis (AKC) in the first quarter of 2019," commented Clive Richardson, Interim Chief Executive Officer of Akari Therapeutics.

Clinical development highlights and upcoming milestones

Coversin clinical trials focused on orphan diseases mediated by both the complement and leukotriene pathways with initial data readouts expected in the first quarter 2019:
Phase II trial in patients with BP, a severe blistering skin disease
Phase I/II trial in patients with AKC, a sight-threatening surface of the eye condition
Coversin clinical trials in orphan diseases in which complement dysregulation is the primary disease driver:
Two trials open in PNH: a Phase III trial in naïve patients and a Phase II trial in patients who are resistant to eculizumab
An open Phase II trial in atypical hemolytic syndrome (aHUS), a severe thrombotic microangiopathy
Ongoing named patient program in pediatric patients with thrombotic microangiopathy (TMA) post bone marrow transplant
Long-term safety study for Coversin
Total cumulative number of patient-years on Coversin treatment approximately 15 years
All patients in the long term study have now been treated for more than 15 months and the first patient has now been treated for 34 months
No drug related serious adverse events and no neutralizing antibodies reported to date
Six PNH patients were transfusion dependent prior to treatment with Coversin, of which four in the long-term study are now transfusion independent; two remain on transfusion.
Third Quarter 2018 Financial Results

Research and development (R&D) expenses in the third quarter of 2018 were $3.3 million, as compared to $6.4 million in the same quarter the prior year. The decrease was due primarily to lower manufacturing costs for Coversin as the Company had previously manufactured clinical trial material for supply through 2019, partially offset by higher clinical trial activity.
General and administrative (G&A) expenses in the third quarter of 2018 were $2.4 million, as compared to $2.2 million in the same quarter last year. This increase was due primarily to higher professional fees.
Operating expenses were $3.0 million in the third quarter of 2018. Excluding a $2.7 million one-time litigation settlement gain, operating expenses were $5.7 million in the third quarter of 2018, as compared to $8.5 million in the same quarter the prior year. This decrease is primarily due to lower R&D expenses.
Total other expense for the third quarter of 2018 was $0.6 million, as compared to $1.8 million in the same quarter the prior year. This change was primarily attributed to a $0.7 million loss in fair value of the stock option liabilities in the third quarter of 2018, compared to a $1.7 million loss in the third quarter of 2017.
Net loss for the third quarter of 2018 was $3.6 million, compared to a net loss of $10.4 million for the same period in 2017. This year over year decrease in net loss was due primarily to the aforementioned $2.7 million litigation settlement gain, lower R&D expenses and change in fair value of the stock option and warrant liabilities, which were lower in the third quarter of 2018 compared to the prior year period.
As of September 30, 2018, the Company had cash of $10.1 million, as compared to cash of $28.1 million as of December 31, 2017.
In addition, on September 26, 2018, the Company entered into a securities purchase agreement (the "Purchase Agreement") with Aspire Capital Fund, LLC ("Aspire Capital"), which provides that, upon the terms, Aspire Capital is committed to purchase up to an aggregate of $20.0 million of the Company’s ADSs over the 30-month term of the Purchase Agreement. In consideration for entering into the Purchase Agreement, concurrently with the execution of the Purchase Agreement, the Company issued 30,000,000 ordinary shares to Aspire Capital and sold to Aspire Capital 25,000,000 ordinary shares for $0.02 per share (equivalent to $2.00 per ADS and $500,000).