On January 18, 2017 Telix Pharmaceuticals Limited ("Telix") reported a product development partnership with Therapeia GmbH & Co KG ("Therapeia") (Press release, Telix Pharmaceuticals, JAN 18, 2017, View Source [SID1234626270]). Telix will add Therapeia’s ACD-101 theranostic program for glioblastoma to its pipeline of advanced theranostic radiopharmaceutical products. Telix also has secured the option to acquire Therapeia under pre-agreed terms. The financial terms of the transaction are not disclosed.

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ACD-101 is a synthetic amino acid that targets the L-type amino acid transporter 1 (LAT1), which is strongly over-expressed in many aggressive malignancies, including glioblastoma, multiple myeloma, melanoma, gastric, breast, prostate and primary hepatocellular carcinoma (HCC). ACD-101 has been studied clinically with both diagnostic radiolabels (for imaging with Positron Emission Tomography – PET) and therapeutic radionuclides. ACD-101 demonstrates favourable therapeutic biodistribution and kinetics, and is actively transported across the intact blood-brain-barrier into tumour cells. ACD-101 potentially offers therapeutic benefit as a monotherapy, and in conjunction with other therapeutic agents, including radiotherapies (external beam therapy, microspheres, brachytherapy, etc.), due to its radiosensitization effect.

CEO Chris Behrenbruch stated, "ACD-101 is a unique multi-action agent that has the potential to deliver something really new to the management of several very challenging malignancies, particularly glioblastoma. Early patient experience in Germany has demonstrated promising therapeutic results and we are excited to be working with the Therapeia team to take this program forward to Phase II and beyond."

Therapeia Managing Director, Dr. Andreas Kluge added, "We are delighted become part of the Telix team and to add this program to Telix’s stable of theranostic radiopharmaceuticals. The radiopharmaceutical space has lacked commercial critical mass for decades, and has only just started to gain the clinical and product development momentum it truly deserves. Only by building a portfolio of best-in-class products and financing them appropriately, can we expect to see the field deliver on its enormous clinical potential." Dr. Kluge joins Telix as a Co-Founder and Chief Medical Officer.1

About ACD-101

ACD-101 is a synthetic amino acid that targets the L-type amino acid transporter 1 (LAT1), which is over-expressed in many malignancies, including glioblastoma, multiple myeloma and primary hepatocellular carcinoma (HCC). LAT1 forms part of the tumour metabolome, harnessed by tumour cells to grow at the expense of surrounding healthy cells. LAT1 has been recently identified as promising drug target in oncology. Over a hundred patients have been successfully imaged with ACD-101 to study biodistribution and kinetics, including in patients with inoperable brain tumours. Clinical pilot studies for the therapeutic forms of ACD-101 have commenced in Europe.

In glioma, ACD-101 is actively transported over the intact blood-brain-barrier into tumour cells overexpressing LAT1, conveying a unique triple mode of action consisting of 1) a targeted radiation toxicity, when administering radiolabeled forms of ACD-101 (131I, 211At), 2) a direct cytostatic effect combined with 3) an intrinsic radiosensitizer effect, enhancing the activity of both, internal and external radiation therapy. The fact, that pathologically increased amino acid uptake is central function in any tumour disease, suggests that ACD-101 may have very broad clinical applicability.

On January 18, 2017 Immunomedics reported new data for sacituzumab govitecan (IMMU-132) during the Company’s Investor R&D Day (Filing, 8-K, Immunomedics, JAN 18, 2017, View Source [SID1234517458]). The entire presentation is available on the Company’s website, www.immunomedics.com.

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IMMU-132 is Immunomedics’ proprietary solid tumor therapy candidate that is advancing through development in four indications: metastatic triple-negative breast cancer (TNBC), the lead indication and for which the Food and Drug Administration (FDA) has awarded Breakthrough Therapy Designation; urothelial cancer (UC); small-cell lung cancer (SCLC); and non-small-cell lung cancer (NSCLC). Immunomedics expects to submit a Biological License Application (BLA) to the FDA for accelerated approval of IMMU-132 in TNBC patients in mid-2017.

Cynthia L. Sullivan, President and Chief Executive Officer, said, "The data to support our BLA filing for accelerated approval for IMMU-132 in TNBC continues to improve as more confirmed results become available for the patients enrolled into our TNBC clinical trial. Additionally, with the assistance of our outside financial and strategic advisor, Greenhill & Co., LLC, we are making significant progress with multiple partnership and strategic opportunities for IMMU-132, and we are very encouraged with the interest thus far. We believe there is a limited and diminishing number of compelling oncology assets available, and we are focused on bringing IMMU-132 to late-stage cancer patients as expeditiously as possible. Furthermore, now is the right time to deliver on the potential value of IMMU-132 on behalf of our stockholders."

New IMMU-132 Results Highlight Progress Toward Potential Accelerated Approval
Ms. Sullivan reported that IMMU-132 has been studied in over 410 diverse cancer patients, with the dose of 10 mg/kg given on days 1 and 8 of repeated 21-day cycles being the established dose regimen. According to Ms. Sullivan, some patients have been treated for more than a year.

The Company has engaged an independent third-party to review pertinent radiological scan results from the TNBC and its NSCLC indications, in a blinded fashion, as per FDA requirements.

Immunomedics disclosed results in 85 assessable TNBC patients. These results will be part of the BLA submission for the accelerated approval of IMMU-132. The Company announced last month that it had achieved the goal of enrolling 100 TNBC patients, as requested by FDA for this BLA filing. The Company reported that the objective response rate and median progression-free survival (PFS, intention-to-treat, or ITT, basis) have been maintained with these additional patient results, while the median overall survival (OS also on ITT basis) has been extended to almost 19 months. These patients experienced two complete and 23 partial responses, while an additional three patients with initial partial responses are awaiting confirmation. Overall, 81% of patients treated with IMMU-132 showed tumor shrinkage from baseline measurements. The clinical benefit rate (complete and partial remissions, and patients with stable disease) at six months or later computed to 44%. The median duration of response for those with objective responses was almost 11 months. It was emphasized that these are interim results, since 20 patients are continuing treatment; a final outcome must await analysis of all patients enrolled.

The major toxicity (grade >3) has been neutropenia (39%) in this and most cancer patient cohorts, which has been manageable by dose reduction, dose delays, or giving a hematopoietic cytokine. Diarrhea, which is the major side effect with irinotecan, the parent drug from which SN-38 is derived, has been much less, such as a grade >3 of 13%.

Dr. Linda T. Vahdat, Professor of Medicine at Weill Cornell Medical College, and Co-Leader of the Breast Cancer Program at Meyer Cancer Center, New York, who is one of the senior investigators in the IMMU-132 trial and presenter of these results, said: "These are excellent results in this very advanced and heavily-pretreated group of patients who have exhausted virtually all therapeutic options, and come with a relatively good safety profile. As the first investigator to recognize the potential role of IMMU-132 in TNBC, I am delighted with this outcome and look forward to its future use in these critical patients."

"Further, with encouraging preclinical results of the combination of IMMU-132 with PARP inhibitors in TNBC models, we are interested in the prospect of this combination in an earlier therapy setting for these patients," Dr. Vahdat added.

In addition to TNBC, Immunomedics is making progress with IMMU-132 across the other three advanced indications. In patients with urothelial cancer, especially metastatic urinary bladder cancer, Dr. Scott T. Tagawa, Associate Professor of Medicine and Urology, Weill Cornell Medical College, and Attending Physician, New York-Presbyterian Hospital, New York, reported on 27 assessable patients from more than 40 patients enrolled. The objective response rate was 33%, including one complete and eight partial remissions. The duration of objective response was a median of 7.5 months, with one patient with a partial response approaching 17 months. The clinical benefit rate at six months or later was 59%, but 10 patients are still under therapy. Overall, 70% of the patients showed tumor shrinkage from baseline with IMMU-132 therapy. The median PFS and OS on an ITT basis were seven and almost 16 months, respectively. The safety profile was similar to the findings in patients with TNBC.

"These patients had a median of two prior therapies and had extensive metastatic disease. While patients with metastatic urothelial cancer respond well to initial therapy with a platinum-containing regimen, few options are available after they become refractive. The recent approval of an immune checkpoint inhibitor has been an important advance, but only a fraction of patients respond. In our trial, we had two such patients who were unresponsive to this therapy but showed tumor shrinkage with IMMU-132," Dr. Tagawa said: "I am impressed with the results we have seen in this difficult-to-treat population and we continue to enroll these advanced patients in order to better position this new agent in the management of this disease, either as a second line therapy or perhaps someday in combination with chemotherapy or an immune checkpoint inhibitor."

Interim results in patients with lung cancers also were presented. Dr. Ronald J. Scheff, Assistant Professor of Clinical Medicine at Weill Cornell Medical College, New York, reported on over 50 patients with metastatic NSCLC being enrolled, showing about one-fifth of evaluable patients had a partial response. Overall, 64% of patients had tumor shrinkage from baseline measurements when given IMMU-132. These patients had a median of three prior therapies. Importantly, patients with either nonsquamous or squamous pathology responded, as well as patients who failed a prior immune checkpoint inhibitor treatment. The clinical benefit rate at four months or later was 43%. The median duration of response was eight months, but two patients remain under therapy and responsive for over 20 months. Median PFS and OS on an ITT basis were five and over nine months, respectively.

In patients with metastatic SCLC who had a median of two prior therapies, 16% experienced a confirmed partial response, with an additional nine patients showing tumor shrinkage >20%. Overall, 60% of patients showed tumor shrinkage from baseline. The clinical benefit rate at 4 months or later was 40%. The median duration of partial responses and stable disease was about five months (two patients extending out to 21 months), while the median PFS and OS on an ITT basis were almost four months and seven months, respectively.

"These results in advanced metastatic NSCLC and SCLC patients are very impressive. Durable responses were seen even in patients refractory to multiple prior therapeutic regimens, including immune checkpoint inhibitors," Dr. Scheff said. "NSCLC is the most common cause of cancer death in the Western World, with very poor 5-year survival statistics. The demonstration of a median survival of over 9 months after patients had already progressed after a range of one to seven prior therapies represents a significant advance."

Dr. Scheff added, "Although advanced metastatic SCLC commonly responds favorably to first-line chemotherapy, the disease typically subsequently recurs and is associated with a poor prognosis. An agent such as IMMU-132 that can control disease in some patients for up to almost two years is most encouraging."

Ms. Sullivan concluded, "These updated data on our lead indications continue to be impressive, particularly because the results from the additional patients enrolled in these trials did not adversely affect the efficacy and safety outcomes. As a monotherapy in late-stage patients with these solid tumor types, it is very rewarding to have developed a product candidate that could make a positive impact and fill the high unmet medical need of such patients. Our trials continue to evaluate IMMU-132 in other cancer types, such as other metastatic breast cancers, as well as metastatic endometrial and prostate cancers. The positive results we have achieved thus far are a testament to the strength of our clinical investigators and our talented team, and we remain confident in the near-and long-term potential of IMMU-132, which could drive significant value for our stockholders."

In his concluding remarks, Dr. Goldenberg said that the Company’s scientists are conducting studies to enhance the good clinical results with IMMU-132 even further, such as overcoming drug resistance and devising more effective drug combinations. In addition, he emphasized that clinical trials are now expanding in patients with other forms of metastatic breast cancer, as well as metastatic endometrial and prostate cancers, since they have high expression of Trop-2.

Value Realization Process for IMMU-132
In addition to the new clinical data, Immunomedics announced a series of updates related to other aspects of the IMMU-132 program.

Commercial
Immunomedics unveiled a summary of the commercial assessment conducted by Health Advances LLC, an independent third-party consulting firm focused exclusively on the healthcare industry, retained to conduct a full commercial assessment of the U.S. and European market opportunities for IMMU-132. The Health Advances study determined that if the current IMMU-132 clinical data are supported by confirmatory/pivotal studies, the U.S. and European market opportunity for IMMU-132 as a third-line monotherapy in TNBC, UC, NSCLC, and SCLC could exceed $3 billion by 2025. Combination and early-line approaches may increase the opportunity to over $7 billion. "IMMU-132’s initial clinical data are very exciting to top oncology key opinion leaders, who see it as a compelling agent with significant potential to address major unmet needs," said Andrew Funderburk, Partner, Health Advances.

Regulatory
Regulatory developments for the IMMU-132 program in TNBC also were presented. The development timeline includes commencement of the Phase 3 confirmatory trial having a Special Protocol Assessment (SPA) in with FDA, in the next few months. Immunomedics plans to file the results with the 100-patient study required by FDA in the accelerated approval application in mid-2017.

Chemistry, Manufacturing, and Controls (CMC)
The Company has added significant value to the IMMU-132 program in preparation of the BLA filing for accelerated approval in TNBC, including the scaled-up manufacturing of the ADC for Phase 3/commercial launch materials, extensive comparability testing of Phase 2 vs. Phase 3/commercial product, stability assessments of Phase 3/commercial lots, and full characterization and other analyses required in the CMC portion of the BLA. Additionally, an independent audit of commercial manufacturing facilities, processes, and other relevant CMC matters is underway, all in preparation for the timely BLA filing.

Intellectual Property
IMMU-132 has an exceptionally strong patent portfolio. Including the proprietary linker and the use of this ADC in patient therapy, IMMU-132 has been patented in the United States and abroad. IMMU-132, as a biotechnology product, could gain regulatory exclusivity in the United States for 12 years and for 10 years in Europe. Currently, 32 patents on IMMU-132 have been issued in the United States alone, with a patent life extending to 2033; 16 foreign patents also exist.

On January 18, 2017 Immunomedics reported additional value-creation inflection points in its robust pipeline in connection with the Company’s Investor R&D Day held at The Roosevelt Hotel in New York City (Filing, 8-K, Immunomedics, JAN 18, 2017, View Source [SID1234517459]). In addition to announcing new data for sacituzumab govitecan (IMMU-132), Immunomedics detailed the preclinical and clinical progress it has achieved in advancing IMMU-114, IMMU130, IMMU-140 and its immune-oncology program, which the Company believes will result in near- and long-term value creation for stockholders.

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"While IMMU-132 is the key near-term driver of value creation for Immunomedics stockholders, we are making significant progress in advancing the rest of our robust pipeline with the goal of sustained value creation," said Cynthia L. Sullivan, President and Chief Executive Officer. "We are on track to achieve numerous other milestones to position these assets for future monetization in parallel with our efforts to achieve the value potential of IMMU-132."

To date, the Company has:

● Advanced IMMU-114 in clinical trials and presented results at peer-reviewed clinical meetings (2015 Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) and 2016 Pan Pacific Lymphoma Conference);

● Completed the Phase 2 trial of its solid cancer ADC, labetuzumab govitecan (IMMU-130), in patients with advanced, metastatic, colorectal cancer;
● Consulted with the FDA on the Phase 3 registration trial for IMMU-130 in patients with advanced, refractory, colorectal cancer;

● Advanced the Company’s development of IMMU-140, an antibody-drug conjugate (ADC) using the Company’s proprietary SN-38 conjugation technology together with the IMMU-114 humanized antibody, presenting first preclinical results at the 2016 Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper); and

● Continued to establish, expand and explore our robust pipeline of potential treatments, including a novel, proprietary methodology to harness the patient’s own immune system to treat cancer with bispecific antibodies retargeting T cells (immuno-oncology program).
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CLINICAL PROGRAMS:
IMMU-130
This ADC contains the exact same linker + drug as IMMU-132, but employs a different antibody, labetuzumab. The antibody recognizes carcinoembryonic antigen (CEA, or CEACAM5), which is elevated in over 85% of patients with metastatic colorectal cancer (mCRC). Enrollment into a Phase 2, single-arm study in about 91 patients with mCRC has been completed. Promising activity in heavily-pretreated patients (median five prior therapies and all treated with irinotecan) were reported. In patients receiving the 10 mg/kg dose on days 1 and 8 of 21-day cycles, the median progression-free survival (PFS) was 4.6 months, and the median overall survival (OS) was 9.2 months. This compares favorably to results with regorafenib, which had a 3rd line median PFS of 1.9 months and an OS of 6.4 months. Although there were no partial responses (PRs) with IMMU-130 at this dose level/schedule, 87% of these patients had stable disease (SD). Immunomedics states that it will continue to follow patients in this Phase 2 study and will continue discussions with the regulatory authorities on the design of a future Phase 3 clinical trial.

Epratuzumab
To date, epratuzumab (humanized anti-CD22 antibody) has been administered to more than 2,000 patients with non-Hodgkin lymphoma (NHL), acute lymphoblastic lymphoma (ALL), and lupus. Clinical studies showed that it could be combined with rituximab, an anti-CD20 antibody, resulting in improved efficacy, which is the rationale leading to the Company developing bispecific antibodies against both CD22 and CD20 (discussed below). Currently, epratuzumab is being evaluated in a Phase 3 clinical trial in pediatric patients with ALL. This long-term, randomized study will enroll 612 patients, with the primary endpoint of PFS at four years. The IntReALL consortium, based in Berlin, Germany, is sponsoring this study, supported by a program grant from the European Union. The Company provides epratuzumab under a reimbursement program for the manufacturing costs.

Veltuzumab
The Company’s 2nd generation (humanized) anti-CD20 antibody, veltuzumab, was constructed with one amino acid difference in the binding site compared to rituximab, and has different framework regions due to humanization. Because of this structural change, functional difference compared to rituximab were observed during development, including veltuzumab’s binding to CD20 3-times longer, increased complement-dependent cytotoxicity (CDC), and improved survival in lymphoma xenograft models when compared to rituximab. This CD20 antibody has been formulated in subcutaneous (sc) dosing and has been evaluated in patients with NHL and immune thrombocytopenia (ITP), and has been administered under compassionate use in patients with lupus and pemphigus. Promising clinical results in over 200 patients receiving active and convenient sc dosing positions this program for advancement into controlled trials, alone and in combination with other agents. The indications would be patients with hematological malignancies and autoimmune diseases. The Company’s unique sc formulation has been patented.

Milatuzumab
Milatuzumab is a humanized anti-CD74 antibody targeting CD74 present on antigen-presenting cells, including B cells and dendritic cells. The Company is studying milatuzumab (sc formulation) in patients with lupus, under a U.S. Department of Defense grant. Previously, milatuzumab was studied as a monotherapy and in combination with veltuzumab, in patients with relapsed, refractory NHL, as well as a monotherapy in patients with advanced and refractory multiple myeloma; it showed activity in both disease settings. In a Phase 1b open-label study, patients with lupus received a dose per week for four weeks of milatuzumab, and were then assessed for disease activity using BILAG and SELENA-SLEDAI scoring systems. Results presented at EULAR in 2016 included all 10 patients enrolled showed a decrease in disease activity in at least one body system. Suppression of disease activity extended for 24 weeks in most patients. Injection reactions were mild-moderate. This has now moved into a double-blind, placebo-controlled, expansion phase, to confirm the activity of sc milatuzumab in this population, and continues to be supported by the U.S. Department of Defense.

IMMU-114
This 2nd generation anti-HLA-DR humanized antibody is an IgG4 immunoglobulin, administered by sc injection, and designed to reduce toxicities (severe infusion reactions) seen with prior IgG1 antibodies administered intravenously. Initial clinical studies in NHL and chronic lymphocytic leukemia (CLL) patients are continuing, with activity reported after patients had failed therapy with rituximab. Treatment cycles are now given repeatedly in a dose-determining clinical trial.

PRECLINICAL PROGRAMS:
IMMU-132 Preclinical Development (PARP Inhibitors/Chemotherapy Combinations)
Based on a preclinical study, the encouraging efficacy observed with IMMU-132 in animal models were presented, demonstrating the potential for improved therapeutic results when combined with agents that inhibit DNA repair pathways, both in mutated and wild-type BRCA1/2. Results from this preclinical study were published online in Clinical Cancer Research, a major peer-reviewed journal in cancer research and one of the official publications of the American Association for Cancer Research (AACR) (Free AACR Whitepaper). Company scientists are also studying why cancer cells that express Trop-2 respond differentially to IMMU-132, in an effort to enhance the therapeutic effects clinically. Results suggest that different degrees of tumor resistance may be overcome, which could have a major impact on future clinical results.

IMMU-140 Preclinical Development
IMMU-140 is an ADC comprising SN-38 conjugated to IMMU-114 (anti-HLA-DR humanized antibody). It has been shown that the ADC possesses both the functional activities of the unconjugated antibody, IMMU-114, and the toxic effects of selective delivery of SN-38 to tumors, thus having a dual function. At the recent 2016 annual meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper), the Company’s scientists showed that this dual activity resulted in more potent antitumor effects compared to IMMU-114, and that IMMU-140 had potent activity against five hematological neoplasms grown in cell culture and in suitable mice: NHL, CLL, ALL, multiple myeloma, and acute myeloid leukemia. IMMU-140 also targets some solid cancers not under investigation by the Company’s other two ADCs; namely, malignant melanoma and glioblastoma multiforme. This ADC is completing studies necessary to transfer it to clinical trials.

Bispecific Antibody Technology
The Company reported on the Dock-N-Lock (DNL) technology for making multi-valent antibody constructs, including CD22-CD20 bispecific antibodies, and the potential therapeutic indications in NHL, CLL, ALL, and multiple autoimmune diseases. By targeting two different receptors on circulating malignant B cells or B cells implicated in autoimmunity, the Company has shown enhanced potency compared to the parental antibodies targeting either CD22 or CD20. Moreover, these new constructs appear to have less destruction of normal B cells needed for immunity than the parental anti-CD20 antibody or other anti-CD20 antibodies currently available.

T-cell Retargeting
The Company presented preclinical data on a DNL-derived bispecific antibody for T-cell redirected killing of various hematological and solid tumors. This construct comprises the bivalent binding of CD19 or Trop-2 and monovalent CD3 recruitment of T cells on many different types of hematological and epithelial cancers, respectively.