On December 13, 2021 Harpoon Therapeutics, Inc. (NASDAQ: HARP), a clinical-stage immunotherapy company developing novel T cell engagers, reported a pipeline update on its programs, including the interim data presented from the ongoing dose-escalation portion of the Phase 1/2 trial for HPN217 in patients with relapsed/refractory multiple myeloma (R/R MM) at the 63rd American Society for Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, Harpoon Therapeutics, DEC 13, 2021, View Source [SID1234597098]). Harpoon has four product candidates in clinical trials that are based on its proprietary Tri-specific T cell Activating Construct (TriTAC) platform designed to recruit a patient’s own immune cells to kill tumor cells.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We are focused on advancing our clinical programs in 2022 and are pleased to see the HPN217 and HPN328 programs showing clinical activity at well tolerated dose levels, indicating a threshold effect," stated Julie Eastland, President and CEO, Harpoon Therapeutics. "We look forward to the initiation of expansion cohorts to learn more about these promising TriTAC programs while building our future clinical pipeline with our first ProTriTAC candidate, HPN601 targeting EpCAM, currently in IND-enabling studies."

"The interim clinical data from the escalation portion of the HPN217 trial shows robust anti-myeloma activity that is encouraging," said Natalie Sacks, M.D., Chief Medical Officer of Harpoon. "In addition, we are observing tumor shrinkage in small lung cancer patients in the HPN328 trial, and we are excited to see validation of the TriTAC platform in both solid tumors and hematologic malignancies. We continue to investigate the performance of our novel technology in multiple indications and are encouraged by the signs of clinical activity and manageable tolerability profiles."

Dose escalation for HPN217 (BCMA TriTAC) Phase 1/2 clinical trial Ongoing
Relapsed/refractory multiple myeloma patients (N=37) have been treated across 9 fixed dose cohorts of 5 to 2860 µg/week, and 1 step dose cohort of 1620 (priming) and 3240 (target) µg/week reflecting rapid dose expansion since the trial began. HPN217 has been well tolerated, with one DLT, Grade 4 AST which resolved, as of the November 10, 2021 data cutoff date.

The ASH (Free ASH Whitepaper) poster presentation, included the following observations:

Encouraging clinical activity in higher dose cohorts including a 63% ORR and 88% DCR reported in the 2150 µg/week cohort with 8 disease evaluable patients with R/R MM, including one minimal residual disease (MRD) negative, stringent CR.
HPN217 shows tolerable safety profile with cytokine release syndrome (all Grade 1 or 2) observed in 9 of 37 patients (24%)
Patient enrollment and dose escalation is ongoing to define the RP2D and MTD
Introduction of step dose regimens has allowed for the administration of higher target doses.
Dose escalation for HPN328 (DLL3 TriTAC) Phase 1/2 clinical trial making rapid progress. Fifteen patients have been enrolled in dose cohorts ranging from 15 µg to 7200 µg per week in both fixed and step dose cohorts administered once weekly by intravenous infusion. Fifteen patients with a median of 2 lines (range 1 to 5) of prior therapy have been enrolled and eligible patients include small cell lung cancer patients who have relapsed after platinum chemotherapy and patients with other malignancies with high grade neuroendocrine tumors associated with DLL3 expression. HPN328 has been well tolerated with Grade 1-2 CRS reported in 33% of patients, no DLTs observed and MTD has not been reached. Among four patients with small cell lung cancer receiving the two highest doses tested to date, 1215 µg fixed dose and 3600-7200 µg step dose, three had target lesion reduction, including 1 confirmed RECIST partial response. The patient with a cPR experienced a target lesion reduction of 53% at week 10. Presentation of initial interim clinical data is planned for 2022.

IND-enabling studies for HPN601 (EpCAM ProTriTAC) are progressing as planned. HPN601 is the first conditionally active T cell engager based on the ProTriTAC platform. EpCAM is expressed in a broad range of solid tumors, including gastrointestinal cancers, potentially enabling HPN601 to address multiple indications with high unmet medical need. By the end of 2022, an IND submission for HPN601 is expected as well as identification of a second IND candidate from the ProTriTAC platform.

Harpoon’s T cell engager platforms, TriTAC, ProTriTAC, and TriTAC XR, are designed to mitigate different target toxicities across a range of disease indications, including solid and hematologic malignancies.

Next generation T cell engager platforms advancing. Harpoon continues to discover new technologies to improve the therapeutic application of T cell engagers. We recently introduced the TriTAC XR platform, which is designed to minimize on-target cytokine release syndrome. Nomination of an IND candidate from the TriTAC XR platform is also expected by the end of 2022.

Conference Call and Webcast Today

Harpoon’s management will host a webcast and conference call at 4:30 p.m. ET / 1:30 p.m. PT on Monday, December 13, 2021 to review the data presented at ASH (Free ASH Whitepaper) and provide an update on its other pipeline programs. The live call may be accessed by dialing 866-951-6894 for domestic callers or 409-216-0624 for international callers and using conference ID # 2760075.

A live webcast of the call will be available from the Events and Presentations section of the company’s website at View Source and will be archived there shortly after the live event.

On December 13, 2021 KemPharm, Inc. (NASDAQ: KMPH), a specialty pharmaceutical company focused on the discovery and development of proprietary prodrugs, reported its common stock has been added to the Nasdaq Biotechnology Index (Nasdaq: NBI) in accordance with an annual reconstitution of the index (Press release, KemPharm, DEC 13, 2021, View Source [SID1234597096]). KemPharm’s inclusion in the Nasdaq Biotechnology Index will become effective prior to market open on Monday, December 20, 2021.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We are pleased that KemPharm has been added to the Nasdaq Biotechnology Index, which further raises our profile in the investment community given the importance of the index to funds and portfolio managers focused on the biotechnology sector," said Travis C. Mickle, Ph.D., President and Chief Executive Officer of KemPharm. "Our inclusion in the Nasdaq Biotechnology Index follows the recent uplisting of our stock to The Nasdaq Global Select Market in October and continues what has been a transformative year for our listing and our company as a whole."

The Nasdaq Biotechnology Index is designed to track the performance of a set of securities listed on The Nasdaq Stock Market (Nasdaq) that are classified as either biotechnology or pharmaceutical according to the Industry Classification Benchmark (ICB). The Nasdaq Biotechnology Index is calculated under a modified capitalization-weighted methodology. Companies in the Nasdaq Biotechnology Index must meet eligibility requirements, including minimum market capitalization, average daily trading volume and seasoning as a public company, among other criteria. Nasdaq selects constituents once annually in December.

For more information about the Nasdaq Biotechnology Index, please visit View Source

On December 13, 2021 Rottapharm Biotech reported that dosing the first patient in the Phase 1/2 study of CR6086 in combination with Agenus’ balstilimab (anti-PD-1) in advanced colorectal cancer at the National Cancer Institute (Istituto Nazionale dei Tumori) – Milan (Italy) (Press release, Rottapharm Biotech, DEC 13, 2021, View Source [SID1234597093]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Patients with colorectal cancers have limited treatment options, as most do not respond to PD-1 therapy or other immunotherapy regimens studied to date. Colorectal cancers represent one of the three most common cancers diagnosed, and the second leading cause of deaths across all cancer types globally. More than 80% of colorectal cancers are classified as mismatch repair-proficient (pMMR) and microsatellite stable (MSS) colorectal cancer (CRC), which correlates with low tumor mutation burden and poor immune cell infiltration within the tumor microenvironment ("cold tumors"). These patients generally do not benefit from PD-1 therapy alone and combination strategies with other immune-modulating therapies are necessary to address immune suppression in the tumor microenvironment and improve sensitivity to PD-1 therapy.

The involvement of prostaglandin E2 (PGE2) in cancerogenesis has been known for decades. There is now growing evidence about the role of PGE2, via its EP4 receptor on different immune cells, as a key effector for the impaired immune response within the tumor microenvironment and the potential for an EP4 receptor antagonist to turn the tumor microenvironment into an immune-responsive ("hot") tissue.

Rottapharm Biotech is developing CR6086, a potent and selective small molecule antagonist of EP4. EP4 signaling broadly suppresses immune activity in the tumor microenvironment, contributing to treatment resistance and tumor progression. CR6086 is designed to increase the activity and infiltration of several different immune cell types – including T cells, natural killer cells, and dendritic cells – while blocking the immune suppressive role of PGE2 in the tumor microenvironment. Preclinical evidence suggests that CR6086 may work in combination with PD-1 therapy to promote durable, anti-tumor immune responses. CR6086 is a potential best-in-class EP4 receptor antagonist, based on its pharmacokinetics and pharmacodynamic profile, and has demonstrated a strong safety profile in >250 subjects treated to date.

Balstilimab is a monoclonal antibody developed by Agenus Inc., belonging to the immune checkpoint inhibitor class, and is an inhibitor of programmed cell death 1 (PD-1) protein. It has been evaluated in >400 patients to date and has demonstrated strong clinical activity and an excellent safety profile in several tumor types, including cervical cancer (results published in Gynecologic Oncology this year).

The Phase 1/2 clinical study aims at evaluating the safety and efficacy of CR6086 combined with balstilimab in patients with advanced pMMR/MSS metastatic CRC (mCRC). The primary endpoints are safety, tolerability, and preliminary efficacy, as determined by disease control rate. The secondary endpoints include objective response rate, duration of response, progression-free survival, and overall survival.

Rottapharm Biotech’s clinical collaboration with Agenus offers a promising new combination therapy for patients with advanced pMMR/MSS mCRC where there is a high unmet need, and for a further range of potential applications in other immunotherapy-resistant tumors.

On December 13, 2021 Adagene Inc. ("Adagene") (Nasdaq: ADAG), a biopharmaceutical company committed to transforming the discovery and development of novel antibody-based immunotherapies, reported preclinical data demonstrating the compelling differentiation of ADG153, an anti-CD47 monoclonal antibody (mAb), and ADG152, a CD20xCD3 bispecific T-cell engager (TCE) (Press release, Adagene, DEC 13, 2021, View Source [SID1234597081]). The data were presented in two poster presentations at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition taking place December 11-14, 2021, which are available in the Publications section of the company’s website at www.adagene.com.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Our novel anti-CD47 antibody and CD20xCD3 bispecific TCE programs successfully leverage SAFEbody technology for precision masking to decouple efficacy from the toxicities that are often associated with therapeutic modalities for these two important targets on the forefront of clinical development for hematologic malignancies," said Peter Luo, Ph.D., Co-founder, Chief Executive Officer and Chairman of Adagene. "Our preclinical evaluation shows the desirable target product profiles of these two transformative programs emerging from our deep, broad and differentiated pipeline. In particular, we are very excited about our highly differentiated anti-CD47 SAFEbody in IgG1 format, which introduces IgG1-mediated effects for potent tumor killing with a compelling safety profile and 8-fold prolonged half-life. Our first POWERbody CD20xCD3 bispecific TCE with precision masking on our tailor-made anti-CD3 arm is highly differentiated, engineered for potent and sustained tumor killing with more than 100-fold cytokine release control and 2-3-fold prolonged half-life in comparison with a benchmarked antibody in clinical development. Together, these two programs highlight the strength of our AI-powered antibody platform, paving the way for explosive growth of our pipeline."

ADG153 (Anti-CD47 SAFEbody)

Key findings from the poster (#3342) titled "ADG153, an Anti-CD-47 Monoclonal Antibody Prodrug, Has Strong In Vivo Anti-Tumor Activity, Minimal RBC-Related and Antigen Sink Liabilities, and Extended Half Life in Comparison with Benchmark Clinical Antibodies of the Same IgG Subclass" include:

Given the dose-limiting hematologic toxicity and antigen sink liability associated with current anti-CD47 antibodies in clinical development, Adagene has developed an anti-CD47 SAFEbody with precision masking for preferential binding on CD47 overexpressed on tumor versus normal cells. To realize the full potential of anti-CD47 therapy for both hematologic and solid malignancies, the SAFEbody technology enables IgG1-mediated strong effector functions for potent tumor killing, while minimizing antigen sink and red blood cell (RBC) depletion with an approximately 8-fold prolonged half-life for convenient drug dosing and administration.
An anti-CD47 ADG153-G4 SAFEbody was designed for benchmarking and evaluated in preclinical studies in comparison with its parental antibody, and analogs of magrolimab (Hu5F9) and lemzoparlimab (TJC4) in IgG4 format with the following findings:

ADG153-G4 parental antibody and its activated SAFEbody can block the CD47 signal by targeting a unique epitope of CD47 with high affinity and minimal RBC hemagglutination.
In preclinical studies in monkeys, ADG153-G4 showed a significantly less decrease in RBCs and hemoglobin at the 10, 30 and 60 mg/kg dose levels compared to Hu5F9 at 10 mg/kg, addressing the hematologic toxicities inherent in current anti-CD47 therapies in development.
ADG153-G4 SAFEbody also showed its 8-fold prolonged half-life by overcoming the antigen sink observed with other anti-CD47 therapies in development.
Only antibody-dependent cellular phagocytosis (ADCP) effector function was detected for anti-CD47 antibodies in IgG4 isotype via CD47-mediated phagocytosis by macrophage.
An anti-CD47 ADG153-G1 SAFEbody was designed to maximize tumor killing via IgG1-mediated effector functions unlike many other anti-CD47 therapies in development:

ADG153-G1 induced potent antibody-dependent cellular cytotoxicity (ADCC); as expected, none was observed for the IgG4 benchmark antibodies.
ADG153-G1 induced stronger ADCP activity than the IgG4 benchmark antibodies.
Preclinical results concluded that the ADG153-G1 can achieve potent anti-CD47 efficacy with a well-tolerated safety profile, providing a strong rationale to advance this candidate into clinic. Currently, no other known anti-CD47 antibodies using the IgG1 isotype are in clinical development.

Notably, ADG153-G1 was well tolerated at 10 mg/kg, with only an 8 percent decrease in RBCs, compared to a 49 percent decrease with Hu5F9 in IgG4 format. For reference, it has been reported in the literature that another IgG1 anti-CD47 antibody can cause more than a 40 percent decrease in RBCs at 1 mg/kg.
After a single intravenous dose, ADG153-G1 demonstrated an approximately 8-fold longer apparent half-life and 5-fold higher area under the curve (AUC) at 10mg/kg than Hu5F9.
Taken together, these preclinical findings suggest that the ADG153-G1 SAFEbody integrates safety (by precision masking) and efficacy (by IgG1-mediated ADCC and ADCP) into one single modality for a best-in-class product profile, presenting the exciting opportunity to maximize potential of anti-CD47 therapy – ultimately aimed for solid malignancies.
ADG152 (CD20xCD3 POWERbody)

Key findings from the poster (#1204) titled "ADG152, a Novel CD20xCD3 T-Cell Engager Prodrug with Enhanced Therapeutic Index, Demonstrates Strong Anti-Tumor Activity with Improved Safety" include:

ADG152 is a bispecific CD20xCD3 T-cell engager POWERbody that integrates SAFEbody precision masking technology to minimize cytokine release syndrome (CRS) and on-target/off-tumor toxicities for an increased therapeutic index.
The anti-CD20 arm of ADG152 has enhanced the binding to CD20, while its anti-CD3 arm has tailor made affinity for CD3 using SAFEbody technology.
At a 100-fold higher dose, ADG152 at 30 mg/kg resulted in significantly less cytokine induction (as measured by IFN-γ and IL-2 levels) than an analog of plamotamab at 0.3 mg/kg.

In preclinical models, ADG152 resulted in dose-dependent anti-tumor activity with almost complete tumor growth inhibition when dosed at 1.5 mg/kg.

ADG152 induced strong and sustained B-cell depletion across different dose levels.

ADG152 also demonstrated improved pharmacokinetics in monkeys versus the plamotamab analog, with approximately a 2-fold longer half-life (7-13 days at 0.3 – 30mg/kg) and approximately an 8-fold higher AUC after a single intravenous injection.
"CRS has been a longstanding challenge of T-cell engagers and has limited the ability to safely provide high levels of activity during initial dosing," said Stanley Frankel, M.D., a clinical advisor who contributed to development and approval of blinatumomab (Blincyto) while working at Micromet and Amgen. "I am encouraged that the preclinical profile of ADG152 offers potential to provide a way to simplify treatment by avoiding step dosing and pretreatment with steroids, while also enhancing efficacy of this POWERbody to engage T-cells to attack tumor targets."

Both ADG153 and ADG152 are potential Investigational New Drug candidates from Adagene’s growing portfolio of preclinical discovery programs, five of which are in IND-enabling studies. The preclinical data presented at ASH (Free ASH Whitepaper) provide a strong rationale for advancing these potentially best-in-class candidates into clinical development.

On December 13, 2021 Celyad Oncology SA (Euronext & Nasdaq: CYAD), a clinical-stage biotechnology company focused on the discovery and development of chimeric antigen receptor T cell (CAR T) therapies for cancer, reported that data from the Phase 1 CYCLE-1 trial of CYAD-02 for the treatment of relapsed or refractory (r/r) acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) and the Phase 1 IMMUNICY-1 trial of CYAD-211 for the treatment of r/r multiple myeloma were presented at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, Celyad, DEC 13, 2021, View Source [SID1234597050]). The data support the potential and versatility of non-gene edited short hairpin RNA (shRNA) technology for the development of next-generation CAR T therapies.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Our presentations at this year’s ASH (Free ASH Whitepaper) conference continue to support the potential of our shRNA technology platform to have an impact in the CAR T space without the potential risks recently associated with gene-editing technologies," said Dr. David Gilham, Chief Scientific Officer of Celyad Oncology. "Data from our CYAD-02 program indicate that a single shRNA can target two independent genes to optimize CAR T cell phenotype, a utility that we believe is unique among currently available gene-expression control technologies. Additionally, the initial observations of cell engraftment, lack of GvHD, and initial signs of clinical activity in the early stages of our first-in-human allogeneic CYAD-211 clinical study underpin the broad potential applicability of shRNA as a platform technology. As we continue to explore these individual product candidates and now focus upon evaluating clinical activity, this clinical proof of principle gives us high confidence to develop further novel clinical candidates based upon our novel shRNA platform."

Filippo Petti, Chief Executive Officer of Celyad Oncology, added, "This is an exciting time for our company as we continue to validate the multifaceted approach of our shRNA technology. Continued progress with the CYAD-02 program demonstrates the power of shRNA in an autologous setting and serves as a strong foundation for any potential partnership with the program. We also have clear direction for our CYAD-211 program, where we plan to initiate enhanced lymphodepleting regimens to increase cell persistence to potentially maximize clinical benefit from the therapy. As we continue to build on our solid foundation in the allogeneic CAR T space, we remain committed to developing a new paradigm of therapy for these patients."

Key Highlights from the ASH (Free ASH Whitepaper) Annual Meeting

CYAD-02 and CYCLE-1 Phase 1 Trial Update

Data from autologous NKG2D receptor CAR T candidate CYAD-02 using shRNA shows a single shRNA can target two independent genes to enhance the phenotype of the CAR T cells

A favorable tolerability profile for CYAD-02 with a low rate of Grade ³ 3 cytokine release syndrome in patients with relapsed or refractory acute myeloid leukemia or myelodysplastic syndrome (r/r AML / MDS)

The dual knockdown of genes MICA/MICB with a single shRNA has a positive contribution to the initial clinical activity of CYAD-02 as compared to the first-generation, autologous NKG2D receptor CAR T, CYAD-01

Two MDS patients achieved a marrow complete response at dose level 3

Of the eight patients with stable disease, four had anti-leukemic activity

Comparison of cellular kinetics for CYAD-02 and CYAD-01 trend towards increased engraftment and persistence of CYAD-02 versus CYAD-01, potentially associated with the knockdown of MICA/MICB and reduced fratricide in vivo

CYAD-211 and IMMUNICY-1 Phase 1 Trial Update

Trial observations from allogeneic shRNA-based anti-BCMA CAR T candidate CYAD-211 support the continued development of shRNA-based allogeneic CAR T therapies as a feasible approach to overcome potential drawbacks and risks associated with autologous and gene-edited allogeneic CAR T therapies

CYAD-211 demonstrated a good tolerability profile and evidence of clinical activity in the dose-escalation segment with three out of 12 total patients with relapsed or refractory multiple myeloma (r/r MM) evaluated for activity achieving partial response, one in each dose-level, while eight patients had stable disease

All patients had detectable CYAD-211 cells in the peripheral blood; preconditioning chemotherapy led to earlier-than-expected recovery of host lymphocytes limiting persistence of CAR T cells

The next segment of the IMMUNICY-1 trial will evaluate enhanced lymphodepleting regimens with the aim to improve persistence. In addition, the protocol also allows for CYAD-211 redosing in certain patients

Enrollment in the cohorts evaluating enhanced lymphodepletion is ongoing. Additional data from the CYAD-211 IMMUNICY-1 trial are expected in mid-2022

Conference Call and Webcast Details

Celyad Oncology will host a conference call to discuss the update from ASH (Free ASH Whitepaper) on Monday, December 13, 2021 at 2:30 p.m. CET / 8:30 a.m. EST. The conference call can be accessed through the following numbers:

United States: #1 877-407-9208

International: #1 201-493-6784

The conference call will be webcast live and can be accessed here. The event will also be archived and available on the "Events" 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.