On July 2, 2019 TRACON Pharmaceuticals (NASDAQ:TCON), a clinical stage biopharmaceutical company focused on the development and commercialization of novel targeted therapeutics for cancer, wet age-related macular degeneration through our license to Santen Pharmaceutical Co. Ltd., and utilizing our product development platform to partner with ex-U.S. companies to develop and commercialize innovative products in the U.S., reported an update on its TRC253 program for the treatment of metastatic castrate resistant prostate cancer, which was licensed from Janssen Pharmaceutica N.V. in 2016 (Press release, Tracon Pharmaceuticals, JUL 2, 2019, View Source [SID1234537366]).

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Phase 1 data from the ongoing Phase 1/2 clinical trial published in the 2019 ASCO (Free ASCO Whitepaper) Proceedings

21 patients with metastatic castrate resistant prostate cancer who had progressed on prior Xtandi (enzalutamide) or Erleada (apalutamide) treatment were enrolled into one of six cohorts of escalating doses of TRC253.

Target PK exposures were achieved consistently with the 280 mg daily oral dose, which was selected as the recommended Phase 2 dose.

The single patient with a F877L androgen receptor (AR) point mutation at baseline remained on treatment for 49 weeks with a partial response by RECIST.

The remaining 20 patients did not have a F877L AR point mutation at baseline, and 48% (10) remained on study for at least 6 months and one patient had a greater than 50% decrease in prostate specific antigen (PSA).

TRC253 was well-tolerated and no drug-related serious adverse events were reported. Drug-related adverse events included QTcF prolongation, elevated lipase, fatigue, arthralgia, diarrhea, and platelet count decrease.

Additional data are available on the ASCO (Free ASCO Whitepaper) website: View Source
Phase 2 portion of the ongoing Phase 1/2 trial amended to add an additional cohort of patients

Based on evidence of potential efficacy in the data from the completed Phase 1 portion of the study, an additional cohort of patients was added to the ongoing Phase 2 study. This cohort will test the hypothesis of whether TRC253 has efficacy in mCRPC patients with a defined point mutation other than F877L AR.

Enrollment is ongoing in the new cohort with a defined point mutation, as well as the two existing cohorts, the first including patients with a F877L AR mutation and the second consisting of patients with another basis for resistance to Xtandi or Erleada.
"We are pleased to have successfully completed the Phase 1 portion of the first-in-human study of TRC253 and look forward to the availability of Phase 2 data, which we expect in the second half of 2020," said Charles Theuer, M.D., Ph.D., President and CEO of TRACON. "Following delivery of the Phase 2 data, Janssen will have the right to reacquire the TRC253 program in return for an opt-in fee of $45 million and further success-based milestone and royalty payments."

About TRC253 (formerly JNJ-63576253)

TRC253 is a novel, orally bioavailable small molecule discovered and developed by Janssen that is a potent, high affinity competitive inhibitor of the AR. TRC253 is also a pan-inhibitor of multiple AR mutations, including the F877L mutation, and is under development for the treatment of men with prostate cancer in a Phase 1/2 clinical trial (NCT02987829). The AR F877L mutation results in an alteration in the ligand binding domain that confers resistance to current AR inhibitors.

Activation of the AR is crucial for the growth of prostate cancer at all stages of the disease. Therapies targeting the AR have demonstrated clinical efficacy by extending time to disease progression, and in some cases, the survival of patients with metastatic castration-resistant prostate cancer. However, resistance to these agents is often observed and several molecular mechanisms of resistance have been identified, including amplification, overexpression or mutation of the AR.

TRC253 is intended to address resistance mechanisms to current AR inhibitors by specifically targeting mutations in the AR ligand binding domain. TRC253 also potently inhibits signalling through the wild type AR. These susceptible AR mutations have been identified using circulating tumor DNA assays, potentially allowing for selected patient biomarker-directed therapy.

Following completion of the initial Phase 1/2 clinical trial, Janssen will have an exclusive option to reacquire full rights to TRC253 for an upfront payment of $45 million to TRACON, and obligations to pay regulatory and commercialization milestones totaling up to $137.5 million upon achievement of specified events and a low single-digit royalty. If Janssen does not exercise its exclusive option to reacquire the program, TRACON would then retain worldwide development and commercialization rights to the program and would be obligated to pay Janssen a total of up to $45 million in development and regulatory milestones upon achievement of specified events, in addition to a low single digit royalty.

On July 2, 2019 BioInvent International AB (BINV) reported it has received authorization from the U.S. Food and Drug Administration (FDA) to proceed with an Investigational New Drug (IND) application for a Phase I/IIa clinical trial of an immune-modulatory anti-FcγRllB antibody in combination with an anti-PD1 antibody in solid tumors (Press release, BioInvent, JUL 2, 2019, View Source [SID1234537365]).

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The anti-FcγRllB antibody is part of BioInvent’s FcγRIIB-targeting program, which has emerged from its F.I.R.S.T platform technology, which simultaneously identifies both targets and high-quality antibodies that bind to them, generating potentially promising new drug candidates. The Phase I/IIa trial is planned to be carried out in the U.S. and the EU.

"This antibody may improve the therapeutic efficacy of anti-PD1 targeting antibodies, and this study will explore the potential to improve responses observed in the treatment of solid cancers. Progressing this first in class monoclonal antibody into clinical development further reinforces the productivity of BioInvent’s platform, which continues to produce novel cancer therapies which not only broaden our own pipeline, but also add further licensing and partnering opportunities," says BioInvent’s CEO Martin Welschof.

The Phase I/IIa study is one of four new clinical programs in solid cancers that the Company intends to initiate. These also include BI-1607 (an anti-FcγRllB antibody) in combination with a checkpoint inhibitor; BI-1808 (an anti-TNFR2 antibody); and the collaboration with Transgene to develop oncolytic viruses encoding a validated anti-CTLA-4 antibody.

On July 2, 2019 Monopar Therapeutics Inc., an oncology-focused biopharmaceutical company, and the Spanish Sarcoma Group (Grupo Español de Investigación en Sarcomas, or GEIS) reported that they have entered into a clinical collaboration agreement to conduct a Phase 2 clinical trial to evaluate Monopar’s investigational drug Camsirubicin in patients with advanced soft tissue sarcoma (ASTS) (Press release, Monopar Therapeutics, JUL 2, 2019, View Source [SID1234537364]).

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Soft tissue sarcomas are a diverse and aggressive class of cancers with generally poor survival outcomes. They usually develop in the connective tissue of the body, which include cartilage, muscles, nerves, bones, deep skin tissues, fat and blood vessels. Currently, there are limited therapeutic options for advanced sarcoma patients, with median overall survival of 12-16 months. The most effective first-line drug for ASTS is doxorubicin, a drug which, while effective, has to be stopped after six to eight cycles of treatment due to the heart damage it causes at higher cumulative doses.

Camsirubicin is being developed to replace doxorubicin as first-line therapy for ASTS. "The cumulative dose limitation of doxorubicin often results in advanced sarcoma patients receiving suboptimal dosing for the treatment of their cancer. Even if they are responding, they have to stop doxorubicin treatment permanently," said Andrew Mazar, Ph.D., Monopar’s chief scientific officer. "Camsirubicin has been specifically designed to avoid the irreversible heart toxicity while retaining the anticancer activity of doxorubicin, thus removing the limitations on cumulative dose."

Under the collaboration with Monopar, GEIS will lead a multi-country, randomized, open-label Phase 2 clinical trial to evaluate Camsirubicin head to head against doxorubicin in patients with ASTS. "The favorable safety profile and efficacy observed in previous clinical studies of Camsirubicin suggest that it could be dosed higher and longer than doxorubicin, which may improve the outcomes for ASTS patients," said Dr. Claudia Valverde, president of GEIS. "Patients with ASTS have few treatments available that improve overall survival, and our network of sarcoma referral centers in Spain and across Europe are eager to evaluate Camsirubicin’s ability to improve patient outcomes."

Enrollment of the trial is expected to begin in early 2020 and will include approximately 170 ASTS patients. The primary endpoint of the trial will be progression-free survival, with secondary endpoints including overall survival and incidence of treatment-emergent adverse events. GEIS will be the study sponsor with support from Monopar.

"We are very excited to be entering into this clinical collaboration with GEIS. They have an impressive track record of working on sarcoma studies with many of the leading biotech and global pharma companies, and with working on many of the drugs that have been tested for the treatment of ASTS," said Chandler Robinson, MD, chief executive officer of Monopar.

ON July 2, 2019 Celyad (Euronext Brussels and Paris, and Nasdaq: CYAD), a clinical-stage biopharmaceutical company focused on the development of CAR-T cell-based therapies, reported several strategic updates to its relapse/refractory (r/r) acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) program, including its lead autologous NKG2D-based CAR-T therapy, CYAD-01, as well as the next-generation NKG2D-based CAR-T candidate, CYAD-02 (Press release, Celyad, JUL 2, 2019, View Source [SID1234537363]). The Company’s management team will host a conference call tomorrow, July 2nd, at 2 p.m. CEDT / 8 a.m. EDT, to discuss each of the updates and future milestones for the program.

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Filippo Petti, CEO of Celyad noted "Over the past few years Celyad has made great strides in evaluating our NKG2D-based CAR-T therapy for the treatment of relapsed/refractory acute myeloid leukemia and myelodysplastic syndrome. We have observed that targeting NKG2D ligands with our lead CAR-T candidate CYAD-01 drives anti-leukemic activity and is well tolerated. Today marks a milestone event as we announce that the FDA has accepted our Investigational New Drug application to commence clinical trials for our next-generation, CAR-T candidate, CYAD-02, and that the FDA and FAMHP have accepted our proposal to utilize our new, proprietary ‘OptimAb’ manufacturing process for both CYAD-01 and CYAD-02. Given the recent updates to our relapsed/refractory AML program, we believe we are well-positioned to improve upon the initial signals we’ve observed to date for CYAD-01 in this difficult to treat and rapidly progressing patient population."

Overview of CYAD-01 r/r AML and MDS Clinical Program

To date, results from the Phase 1 THINK trial evaluating CYAD-01 without prior preconditioning chemotherapy for the treatment of r/r AML and MDS have shown the NKG2D-based CAR-T to be well tolerated with encouraging preliminary anti-leukemic activity in six of thirteen patients (46%) evaluable per protocol.

The company is currently evaluating the potential for CYAD-01 in the treatment of r/r AML and MDS in multiple clinical trials including the Schedule Optimization cohorts of the THINK trial, which is assessing a more frequent dosing schedule of CYAD-01, and in the Phase 1, dose-escalation DEPLETHINK trial, which is assessing CYAD-01 following the preconditioning chemotherapy cyclophosphamide and fludarabine, or CyFlu. CyFlu is the preconditioning therapy typically used with other hematological malignancies evaluating CAR-T cell therapies.

In June 2019, preliminary data presented at the European Hematology Association (EHA) (Free EHA Whitepaper) meeting demonstrated that a denser schedule of infusions of CYAD-01 without preconditioning in Cohort 10 (Schedule Optimization) of the THINK trial and a single infusion of low dose (1×108 cells) CYAD-01 following preconditioning chemotherapy in the DEPLETHINK trial was well tolerated and led to better time-averaged engraftment of the CAR-T cells.

Strategic Drivers Aimed to Enhance NKG2D-based CAR-T for r/r AML and MDS

Based on the initial clinical data and tolerability profile for CYAD-01 from the r/r AML and MDS clinical program, Celyad aims to increase the potency of the NKG2D-based CAR-T therapy to potentially deepen the breadth, frequency and duration of clinical responses in this patient population. In particular, Celyad is focused on: 1) the optimization of treatment conditions, including denser dosing schedule or exploiting preconditioning chemotherapy; 2) optimization of the manufacturing process, including enrichment of T cells with memory-like phenotype; and 3) improving the persistence of CAR-T cell therapies through RNA interference using short hairpin RNA (shRNA) technology.

Recent Developments for r/r AML and MDS Program

CYAD-01 – Enriching Early Memory T cells in our First-in-Class, NKG2D-based CAR-T Candidate by Leveraging the OptimAb Manufacturing Process

Celyad recently submitted Chemistry, Manufacturing, and Control ("CMC") amendments to the U.S. Food and Drug Administration (FDA) and Belgium’s Federal Agency for Medicines and Health Products (FAMHP) related to "OptimAb", a modified manufacturing process for CYAD-01.

OptimAb, is designed as an iterative improvement of Celyad’s first two manufacturing processes for CYAD-01 (the LY and mAb processes) and builds upon key characteristics of both. OptimAb utilizes a shortened eight-day cell culture and incorporates a selective PI3K inhibitor. Combined with the manufacturing optimizations previously developed by the company, the OptimAb process results in a product that is enriched for T cells with a memory-like phenotype while maintaining the high level of manufacturing reliability required to support clinical development. The amendment filed with the regulatory agencies is based upon our in-house research focused on the development of a manufacturing process to enrich for T cells with memory-like phenotype.

Preclinical data based on conditions where the dose of CYAD-01 produced with the mAb manufacturing process is reduced to have minimal activity indicate that cells produced using the OptimAb manufacturing process drive improved anti-tumor activity in an aggressive AML model.

Following feedback from the FDA and FAMHP, the CMC amendments were accepted and now in effect with regulators under the current Investigational New Drug (IND) application for CYAD-01. Celyad expects to treat the first patient using the recently accepted OptimAb manufacturing process for CYAD-01 in cohort 4 (1×109 cells) of the Phase 1 DEPLETHINK trial in August 2019. Based on regulatory feedback, Celyad expects to stagger treatment of the first three subjects treated with CYAD-01 cells manufactured by OptimAb.

CYAD-02 – Next-Generation, NKG2D-based CAR-T Candidate

At the company’s R&D Day held in March 2019, management unveiled its novel shRNA platform to develop next-generation autologous and allogeneic CAR-T cell therapies, including CYAD-02, a next-generation, autologous NKG2D-based CAR-T candidate that incorporates shRNA technology to target the NKG2D ligands MICA and MICB. The single shRNA modulates the expression of both ligands which translates to encouraging increases in in vitro proliferation, in vivo engraftment and anti-tumor activity. CYAD-02 also incorporates the OptimAb manufacturing process thereby enriching for T cells with memory-like phenotype.

In late June 2019, the FDA accepted the IND application for CYAD-02 and permitted it to go into effect. The company plans to begin enrollment of a Phase 1 dose-escalation trial evaluating the safety and clinical activity of CYAD-02 with the preconditioning chemotherapy CyFlu for the treatment of r/r AML and MDS in early 2020.

The CYAD-02 Phase 1 trial will be the first CAR-T cell therapy clinical trial employing the optimized shRNA SMARTvector technology licensed from Horizon Discovery and represents the output of a strong collaboration with the company’s partner.

Upcoming Milestones for r/r AML and MDS Program based on OptimAb Manufacturing Process

Initial clinical data from cohort 4 of the Phase 1 DEPLETHINK trial for CYAD-01 using the OptimAb manufacturing process are expected by year-end 2019. Full results from cohort 4 of the DEPLETHINK trial are anticipated in first quarter 2020.
Initiate the Phase 1 dose-escalation trial evaluating CYAD-02, following preconditioning chemotherapy for the treatment of r/r AML and MDS in early 2020. Preliminary data from the Phase 1 trial are expected by mid-2020.

Conference Call and Webcast Details

Celyad will host a conference call to discuss the update to the r/r AML and MDS program on Tuesday, July 2nd, 2019 at 2 p.m. CEDT / 8 a.m. EDT. The conference call can be accessed through the following numbers:

United States: +1 877 407 9208

International: +1 201 493 6784

Conference ID: 13692100

The conference call will be webcast live and can be accessed here. The event will also be archived and available on the "Events & Webcasts" section of the Company’s website. Please visit the website several minutes prior to the start of the broadcast to ensure adequate time for registration to the webcast.

Background on Acute myeloid leukemia (AML) and Myelodysplastic syndromes (MDS)

Acute myeloid leukemia (AML) is an aggressive (fast-growing) form of leukemia characterized by the abnormal growth of myeloid cells, that spread in the bone marrow, blood stream and occasionally to other organs. AML is most commonly diagnosed in males aged 65-74 years old.

With about 40,000 new cases diagnosed each year in aggregate in the United States and Europe, AML is the most common type of aggressive leukemia in adults. The five-year survival rate for people 20 and older with AML is approximately 24%. For people younger than 20 diagnosed with AML, the survival rate is 67%. It has one of the lowest survival rates of all types of leukemia.

AML can develop either de novo in a healthy individual or in patients with a predisposing disease called myelodysplastic syndrome (MDS). Myelodysplastic syndrome (MDS) can be considered a premalignant disease that affects myeloid cells. Approximately 1,400 individuals in the United States are diagnosed each year with MDS.

Standard therapies for AML include chemotherapy (cytarabine) or hypomethylating agents (azacytidine or decitabine). If these therapies fail patients will receive a blood stem cell transplant. In addition, some patients are not eligible for transplant due to a poor general health condition. Despite these treatments, most patients relapse. As such, new or improved therapies for the treatment of AML are urgently needed.

On July 2, 2019 Unum Therapeutics Inc. (NASDAQ: UMRX), a clinical-stage biopharmaceutical company focused on the development of cellular immunotherapies to treat cancer based on its novel T cell technology platforms, reported that the U.S. Food and Drug Administration (FDA) has placed a clinical hold on the Phase 1 trial (ATTCK-20-2) evaluating Unum’s ACTR087 in combination with rituximab following lymphodepleting chemotherapy with fludarabine and cyclophosphamide in patients with relapsed/refractory CD20+ B cell non-Hodgkin lymphoma (r/r NHL) (Press release, Unum Therapeutics, JUL 2, 2019, View Source [SID1234537362]). The clinical hold was initiated following the submission of a safety report by Unum to the FDA regarding one patient in the safety expansion cohort of the trial (Cohort 3) who recently experienced serious adverse events that included Grade 3 neurotoxicity and cytomegalovirus (CMV) infection, and Grade 4 respiratory distress.

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In November 2018, Unum announced it was deprioritizing ACTR087 as its lead product candidate in combination with rituximab to treat patients with r/r NHL in order to advance its new ACTR construct, ACTR707, in this setting. As a result of this decision, in May 2019, Unum announced its completion of enrollment in the Phase 1 ATTCK-20-2 trial with ACTR087. FDA has agreed that patients who previously received ACTR087 and have ongoing clinical responses may continue to receive rituximab infusions, with continued monitoring for adverse events. Unum will continue to work closely with the FDA to further review these events and continues to plan to report data from the ATTCK-20-2 trial at the end of 2019.