On September 28, 2021 Aptevo Therapeutics Inc. ("Aptevo") (NASDAQ:APVO), a clinical-stage biotechnology company focused on developing novel immuno-oncology therapeutics based on its proprietary ADAPTIR and ADAPTIR-FLEX platform technologies, reported that the prestigious medical journal Frontiers in Aging, published a peer-reviewed article by Fatih Uckun, M.D., Ph.D., Chief Clinical Advisor at Aptevo who is coordinating the APVO436 clinical development program (Press release, Aptevo Therapeutics, SEP 28, 2021, View Source [SID1234590404]).

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The article discusses the clinical impact potential of bispecific antibodies (BiAB) capable of redirecting host T-cell cytotoxicity to malignant clones as well as immunosuppressive myeloid-derived suppressor cells (MDSC) as a new class of anti-MDS drug candidates.

The article, "CD123-Directed Bispecific Antibodies for Targeting MDS Clones and Immunosuppressive Myeloid-Derived Suppressor Cells (MDSC) in High-Risk MDS Patients," has been published in Frontiers in Aging, section "Neoplastic Pathologies of Aging,"

and it is available online. To view the online publication, click here:
http://journal.frontiersin.org/article/10.3389/fragi.2021.757276/full?&utm_source=Email_to_authors_&utm_medium=Email&utm_content=T1_11.5e1_author&utm_campaign=Email_publication&field=&journalName=Frontiers_in_Aging&id=757276.

Citation Reference: Uckun FM and Watts J (2021) CD123-Directed Bispecific Antibodies for Targeting MDS Clones and Immunosuppressive Myeloid-Derived Suppressor Cells (MDSC) in High-Risk Adult MDS Patients. Front. Aging 2:757276. doi: 10.3389/fragi.2021.757276

Adult myelodysplastic syndrome (MDS), a heterogeneous group of clonal malignant hematologic disorders with an incidence rate of 4.5 per 100,000 persons per year, is characterized by an enhanced risk of transformation to acute myeloid leukemia (AML). There is no effective standard treatment that will prevent the leukemic transformation or result in sustained deep remissions in high-risk adult MDS patients.

The immunosuppressive bone marrow microenvironment (BMME) in adult MDS has been implicated in clonal evolution and disease progression. Expanded populations of myeloid-derived suppressor cells (MDSC) contribute to the immunosuppressive tumor microenvironment (TME) by inhibiting both memory and cytotoxic effector T-cell populations as well as natural killer (NK) cells, thereby promoting the immune evasion of MDS clones. The abundance of MDSC is associated with a higher risk of rapidly progressive disease and poor survival outcomes in adult MDS.

The expression of CD123 on MDSC as well as MDS clones provides a compelling rationale for targeting CD123 antigen on the malignant clones as well as the MDSC in the immunosuppressive BMME of adult MDS patients in an effort to delay disease progression and transformation to AML.

In a recently completed APTEVO study the results of which have been published in the respected oncology journal, Cancers, APVO436 induced bone marrow complete remissions in 3 of 6 evaluable high-risk MDS patients, providing the first proof of concept that APVO436 is a new candidate anti-MDS drug.

"There is an urgent need to identify effective strategies to prevent leukemic transformation and induce sustained deep remissions in adult high-risk myelodysplastic syndrome (MDS) patients," explained Fatih Uckun, M.D. Ph.D., the study’s lead author. "T-cell engaging bispecific antibodies targeting the CD123 antigen like our lead drug candidate APVO436 may help delay disease progression in high-risk adult MDS and potentially reduce the risk of transformation to secondary AML."

"Emerging data that show APVO436 can sufficiently empower dysfunctional and exhausted T-cells to induce remissions in relapsed AML and MDS patients is the driving motivation behind our current clinical development plan for our lead clinical candidate," said Marvin White, CEO of Aptevo.

About APVO436

Overexpression of CD123 is the hallmark of many forms of leukemia. Aptevo’s lead proprietary drug candidate, APVO436 is a bispecific ADAPTIR that targets CD123 x CD3 and is designed to redirect the immune system of the patient to destroy leukemia cells expressing the target CD123 molecule on their surface. This antibody-like recombinant protein therapeutic is designed to engage both leukemia cells and T-cells of the immune system and bring them closely together to trigger a rapid and complete destruction of leukemia cells. APVO436 has been engineered using Aptevo’s proprietary and enabling bioengineering methods and is designed to reduce the likelihood and severity of an unintended and potentially harmful activation of the immune system. APVO436 has been engineered to stay in the blood circulation long enough to locate, bind with and destroy target leukemia cells. APVO436 has received orphan drug designation ("orphan status") for AML according to the Orphan Drug Act.

On September 28, 2021 Arrowhead Pharmaceuticals Inc. (NASDAQ: ARWR) reported that it earned a $10 million milestone payment from Janssen Pharmaceuticals, Inc., (Janssen) part of the Janssen Pharmaceutical Companies of Johnson & Johnson (Press release, Arrowhead Pharmaceuticals, SEP 28, 2021, View Source [SID1234590403]). The milestone payment was earned after Janssen dosed the fifth patient in a Phase 1 clinical study of ARO-JNJ1, an investigational RNAi therapeutic candidate which utilizes Arrowhead’s proprietary Targeted RNAi Molecule (TRiM) platform.

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Arrowhead entered into a license and collaboration agreement, and into a research collaboration and option agreement, with Janssen in October 2018. Arrowhead is eligible for additional payments when future milestones are met and is also eligible for royalties on commercial sales of ARO-JNJ1.

On September 28, 2021 Cartesian Therapeutics, a fully integrated, clinical-stage biopharmaceutical company pioneering RNA cell therapy in and beyond oncology, reported the hire of Miloš Miljković, M.D., as Vice President and Chief Medical Officer (Press release, Cartesian Therapeutics, SEP 28, 2021, View Source [SID1234590401]). Dr. Miljković will oversee the strategy and execution of the Company’s growing clinical pipeline of RNA cell therapies. In addition, the Cartesian appointed co-founder Metin Kurtoglu, M.D., Ph.D., as the Company’s first Chief Operating Officer, responsible for bridging clinical operations with the cGMP manufacturing and translational medicine groups. Cartesian also announced that it has expanded its cGMP manufacturing facility in Gaithersburg, MD to support its growing clinical pipeline.

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"We are delighted to have Miloš join our leadership team at Cartesian," said Murat Kalayoglu, M.D., Ph.D., President and Chief Executive Officer at Cartesian Therapeutics. "His experience in developing and executing clinical programs will be a valuable addition to our team as we accelerate development of our three clinical-stage RNA cell therapies and matriculate new therapies into clinical trials."

Dr. Miljković added, "I am eager to lead Cartesian’s engagement with the medical community and regulators throughout clinical development. I am impressed by the pace of progress at Cartesian to date, highlighted by recent positive clinical data from the ongoing Phase 1/2a clinical trial of Descartes-08 in generalized Myasthenia Gravis (gMG). Cartesian’s focus on using the cell as both a factory for producing, as well as a vehicle for delivering, RNA therapeutics is a novel, highly differentiated strategy, one that has the potential to change the treatment paradigm for a spectrum of indications."

Dr. Miljković is board-certified in hematology, medical oncology, and internal medicine. Prior to joining Cartesian, he was a Staff Clinician at the National Cancer Institute for over seven years, where he specialized in early-stage trials in immuno-oncology. Dr. Miljković has served as Principal Investigator on 6 clinical trials of immunotherapy and targeted agents and as Associate Investigator on more than 20 others. He completed residency at the Johns Hopkins University and Sinai Hospital of Baltimore program in internal medicine, followed by clinical and research fellowships in the joint NCI/NHLBI program at the NIH, where he also served as Chief Fellow.

Meanwhile, Cartesian is nearly doubling its footprint in Gaithersburg to accommodate the Company’s growing need for GMP manufacturing and clinical operations space. As part of this expansion, Cartesian expects to double its headcount in 2022.

Dr. Kurtoglu stated, "Our in-house cGMP manufacturing capabilities are essential to our long-term strategy: to pioneer RNA cell therapy as a new therapeutic modality. As COO, I look forward to working closely with Miloš to create an optimal environment for cross-functional development of our RNA cell therapies."

On September 28, 2021 CRISPR Therapeutics (Nasdaq: CRSP), a biopharmaceutical company focused on creating transformative gene-based medicines for serious diseases, reported that members of its senior management team are scheduled to participate in the Chardan’s 5th Annual Genetic Medicines Conference on Monday, October 4, 2021 at 2:00 p.m. ET (Press release, CRISPR Therapeutics, SEP 28, 2021, View Source [SID1234590399]).

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A live webcast of the event will be available on the "Events & Presentations" page in the Investors section of the Company’s website at View Source A replay of the webcast will be archived on the Company’s website for 14 days following each presentation.

On September 28, 2021 Seagen Inc. (Nasdaq: SGEN) reported it completed patient enrollment in the phase 2 open-label MOUNTAINEER clinical trial, evaluating TUKYSA (tucatinib) in combination with trastuzumab (Herceptin) and as a single agent in patients with HER2-positive (HER2+) metastatic colorectal cancer (mCRC) following previous treatment with first- and second-line standard-of-care therapies (Press release, Seagen, SEP 28, 2021, View Source [SID1234590398]).

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"Completing enrollment in the MOUNTAINEER trial is an important step toward potentially bringing this therapy to patients with HER2-positive metastatic colorectal cancer," said Roger D. Dansey, M.D., Chief Medical Officer, Seagen. "We previously expanded the size of this trial, with the intention of supporting registration under accelerated approval regulations in the United States. We look forward to receiving the trial results to potentially address a significant unmet medical need for patients."

Early results from the MOUNTAINEER trial were presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2019 Congress and showed encouraging anti-tumor activity with a well-tolerated safety profile.1

TUKYSA is an oral, small molecule tyrosine kinase inhibitor that is highly selective for HER2. HER2 amplification or overexpression occurs in approximately three-to-five percent of all patients with mCRC.2,3

About MOUNTAINEER

MOUNTAINEER is a U.S. and European multi-center, open label, phase 2 clinical trial of TUKYSA in combination with trastuzumab and as a single agent in 117 patients with previously treated HER2-positive metastatic or unresectable colorectal cancer. The primary endpoint of the trial is objective response rate by RECIST (Response Evaluation Criteria in Solid Tumors) v1.1 criteria. Duration of response, progression-free survival, overall survival and safety and tolerability of the combination regimen are secondary objectives.

About Colorectal Cancer

Colorectal cancer is the second leading cause of cancer death in the United States (U.S.).4 In 2021, it is estimated there will be 149,500 new cases and 52,980 deaths in the U.S.4 Approximately 22 percent of U.S. patients with colorectal cancer are diagnosed at the advanced stage. 4 According to the U.S. Centers for Disease Control and Prevention, the most effective way to reduce the risk of colorectal cancer is routine screening beginning at age 50. In colorectal cancer, human epidermal growth factor receptor 2 (HER2) is overexpressed in three-to-five percent of patients.2,3 There are currently no therapies approved that specifically target HER2 in colorectal cancer.

About TUKYSA (tucatinib)

TUKYSA is an oral medicine that is a tyrosine kinase inhibitor of the HER2 protein. In vitro (in lab studies), TUKYSA inhibited phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell growth (proliferation), and showed anti-tumor activity in HER2-expressing tumor cells. In vivo (in living organisms), TUKYSA inhibited the growth of HER2-expressing tumors. The combination of TUKYSA and the anti-HER2 antibody trastuzumab showed increased anti-tumor activity in vitro and in vivo compared to either medicine alone.

TUKYSA in combination with trastuzumab and capecitabine was approved by the U.S. Food and Drug Administration (FDA) in April 2020 for adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. In February 2021, the European Medicines Agency (EMA) and U.K. Medicines and Healthcare products Regulatory Agency (MHRA) each approved TUKYSA in combination with trastuzumab and capecitabine for the treatment of adult patients with HER2-positive locally advanced or metastatic breast cancer who have received at least two prior anti-HER2 treatment regimens. TUKYSA is also approved in Canada, Switzerland, Singapore and Australia.

In September 2020, Seagen granted Merck, known as MSD outside the U.S. and Canada, exclusive rights to commercialize TUKYSA in Asia, the Middle East and Latin America and other regions outside of the U.S., Canada and Europe.

U.S. Important Safety Information

Warnings and Precautions

Diarrhea – TUKYSA can cause severe diarrhea including dehydration, hypotension, acute kidney injury, and death. In HER2CLIMB, 81% of patients who received TUKYSA experienced diarrhea, including 12% with Grade 3 diarrhea and 0.5% with Grade 4 diarrhea. Both patients who developed Grade 4 diarrhea subsequently died, with diarrhea as a contributor to death. The median time to onset of the first episode of diarrhea was 12 days and the median time to resolution was 8 days. Diarrhea led to dose reductions of TUKYSA in 6% of patients and discontinuation of TUKYSA in 1% of patients. Prophylactic use of antidiarrheal treatment was not required on HER2CLIMB.

If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Based on the severity of the diarrhea, interrupt dose, then dose reduce or permanently discontinue TUKYSA.
Hepatotoxicity – TUKYSA can cause severe hepatotoxicity. In HER2CLIMB, 8% of patients who received TUKYSA had an ALT increase >5 × ULN, 6% had an AST increase >5 × ULN, and 1.5% had a bilirubin increase >3 × ULN (Grade ≥3). Hepatotoxicity led to dose reduction of TUKYSA in 8% of patients and discontinuation of TUKYSA in 1.5% of patients.

Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every 3 weeks during treatment, and as clinically indicated. Based on the severity of hepatotoxicity, interrupt dose, then dose reduce or permanently discontinue TUKYSA.
Embryo-Fetal Toxicity – TUKYSA can cause fetal harm. Advise pregnant women and females of reproductive potential risk to a fetus. Advise females of reproductive potential, and male patients with female partners of reproductive potential, to use effective contraception during TUKYSA treatment and for at least 1 week after the last dose.
Adverse Reactions

Serious adverse reactions occurred in 26% of patients who received TUKYSA. Serious adverse reactions in ≥2% of patients who received TUKYSA were diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). Fatal adverse reactions occurred in 2% of patients who received TUKYSA including sudden death, sepsis, dehydration, and cardiogenic shock.

Adverse reactions led to treatment discontinuation in 6% of patients who received TUKYSA; those occurring in ≥1% of patients were hepatotoxicity (1.5%) and diarrhea (1%). Adverse reactions led to dose reduction in 21% of patients who received TUKYSA; those occurring in ≥2% of patients were hepatotoxicity (8%) and diarrhea (6%).

The most common adverse reactions in patients who received TUKYSA (≥20%) were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.

Lab Abnormalities

In HER2CLIMB, Grade ≥3 laboratory abnormalities reported in ≥5% of patients who received TUKYSA were: decreased phosphate, increased ALT, decreased potassium, and increased AST. The mean increase in serum creatinine was 32% within the first 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.

Drug Interactions

Strong CYP3A or Moderate CYP2C8 Inducers: Concomitant use may decrease TUKYSA activity. Avoid concomitant use of TUKYSA.
Strong or Moderate CYP2C8 Inhibitors: Concomitant use of TUKYSA with a strong CYP2C8 inhibitor may increase the risk of TUKYSA toxicity; avoid concomitant use. Increase monitoring for TUKYSA toxicity with moderate CYP2C8 inhibitors.
CYP3A Substrates: Concomitant use may increase the toxicity associated with a CYP3A substrate. Avoid concomitant use of TUKYSA where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP3A substrate dosage.
P-gp Substrates: Concomitant use may increase the toxicity associated with a P-gp substrate. Consider reducing the dosage of P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicity.
Use in Specific Populations

Lactation: Advise women not to breastfeed while taking TUKYSA and for at least 1 week after the last dose.
Renal Impairment: Use of TUKYSA in combination with capecitabine and trastuzumab is not recommended in patients with severe renal impairment (CLcr < 30 mL/min), because capecitabine is contraindicated in patients with severe renal impairment.
Hepatic Impairment: Reduce the dose of TUKYSA for patients with severe (Child-Pugh C) hepatic impairment.