SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): May 29, 2020
Harpoon Therapeutics, Inc.
(Exact name of Registrant as Specified in Its Charter)
(State or Other Jurisdiction
131 Oyster Point Blvd, Suite 300
South San Francisco, California
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|Common stock, par value $0.0001 per share||HARP||Nasdaq Global Select Market|
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|Item 8.01|| |
On May 29, 2020, Harpoon Therapeutics, Inc. (the Company) issued a press release announcing its presentation of interim Phase 1 data from its ongoing dose escalation trail for its PSMA-targeting TriTAC, HPN424, at the American Society of Clinical Oncology (ASCO) 2020 Virtual Scientific Program. On May 29, 2020, the Company also posted a presentation (the Presentation) regarding this data as well as updates on its other pipeline programs. Copies of the press release and the Presentation are attached hereto as Exhibits 99.1 and 99.2, respectively, and are incorporated herein by reference.
|Item 9.01|| |
Financial Statements and Exhibits.
|99.1||Press Release, dated May 29, 2020.|
|99.2||Phase 1 HPN424 Interim Data Presentation and Pipeline Update, dated May 29, 2020.|
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
|HARPOON THERAPEUTICS, INC.|
Gerald McMahon, Ph.D.
President and Chief Executive Officer
Dated: May 29, 2020
FOR IMMEDIATE RELEASE
Harpoon Therapeutics Presents Interim Phase 1 Data from an Ongoing Dose
Escalation Trial for the PSMA-targeting TriTAC ® HPN424 at the ASCO20 Virtual
The on-going dose escalation Phase 1 study has enrolled 44 patients with progressive, metastatic castration-resistant prostate cancer in 11 cohorts.
Initial safety data showed that HPN424 is generally well-tolerated, and cytokine-related adverse events have been transient and manageable.
Pharmacokinetic data supports weekly dosing and pharmacodynamic data supports T cell activation and target engagement consistent with the expected mechanism of action.
Signals of clinical activity include multiple patients remaining on study for more than 24 weeks, and serum PSA declines.
Management to host webcast and conference call to review the interim Phase 1 data and provide a pipeline update today at 4 p.m. ET /1 p.m. PT
SOUTH SAN FRANCISCO, Calif., May 29, 2020 - Harpoon Therapeutics, Inc. (NASDAQ: HARP), a clinical-stage immunotherapy company developing a novel class of T cell engagers, today presented interim data from the ongoing dose-escalation portion of a Phase 1 trial for HPN424 in patients with metastatic castration-resistant prostate cancer (mCRPC) at the American Society of Clinical Oncology (ASCO) 2020 Virtual Scientific Program. HPN424 targets prostate-specific membrane antigen (PSMA) and is based on Harpoons proprietary Tri-specific T cell Activating Construct (TriTAC®) platform designed to recruit a patients own immune cells to kill tumor cells.
The presentation highlights interim results in 44 patients across 11 dosing cohorts treated with HPN424 from the ongoing dose escalation portion of a Phase 1 clinical trial. As of the May 11, 2020 cut-off date, initial data demonstrate:
HPN424 is generally well-tolerated and support long-term treatment, and cytokine-related adverse events have been transient and manageable.
Pharmacokinetic data support weekly dosing and pharmacodynamic data supports T cell activation as measured by reduction in circulating tumor cells, increased serum cytokine levels and T cell margination after HPN424 administration.
Early signals of clinical activity include eight patients who remained on study treatment for greater than 24 weeks. In addition, eight patients exhibited decreases in PSA levels compared to baseline, including two who showed PSA (prostate-specific antigen) reductions of at least 50%.
We are particularly encouraged by data supporting the predicted mechanism of action of HPN424, and the early signs of clinical activity in this heavily pretreated population, stated Gerald McMahon, Ph.D., President and CEO, Harpoon Therapeutics. These initial data from our lead program represent the first of four product candidates in our TriTAC clinical portfolio that can provide multiple opportunities to accelerate our pipeline into more advanced clinical studies.
We are excited to share the first clinical data from our HPN424 clinical program. Early data suggest that this novel, half-life extended T cell engager can be administered safely. Several patients remained on treatment for 24 weeks or more, which is notable in this late-stage cancer population, said Natalie Sacks, M.D., Chief Medical Officer of Harpoon. We will continue dose escalation, and plan to open an expansion cohort later in 2020. Our goal is to develop an effective immunotherapy treatment option for patients with prostate cancer.
Trial Design and Interim Results from the HPN424 Phase 1 Clinical Trial
This Phase 1 trial is a multicenter, open-label study designed to evaluate the safety, tolerability, pharmacokinetics and activity of HPN424 in patients with mCRPC who are progressing at the time of enrollment and have had at least two prior systemic treatments for metastatic disease. The initial ongoing phase of the trial is dose escalation, with the goal of determining a recommended dose for the expansion phase. The escalation phase began with single patient cohorts and transitioned to a 3x3 design when Grade 2 toxicity was observed. HPN424 is being administered to patients once weekly by intravenous infusion. The primary outcome measures are an assessment of safety and tolerability, pharmacokinetics, and pharmacodynamics. Secondary endpoints include duration of response, progression free and overall survival. Tumor assessments include PSA, CT and bone scans performed every 9 weeks.
As of the May 11, 2020 cut-off date, 44 patients have been treated in 11 cohorts with doses ranging from 1.3 to 120 ng/kg. Enrolled patients had a median of 7 prior therapies, including 73% with prior chemotherapy, and a median of two prior novel hormonal agents. Median PSA level was 244, with a range of 0.1-5000 ng/ml. The most frequent adverse events were chills ((all grade n= 32 (73%), grade >3 n=0 (0%)), pyrexia (all grade n=21 (48%), grade > 3 n=0 (0%)), and cytokine release syndrome (CRS) (all grade n=14 (32%), grade >3 n=3 (7%)). Cytokine-related adverse events were transient, and all patients with these adverse events were retreated successfully with HPN424. Dexamethasone premedication was instituted in cohort 4 (24 ng/kg) and has been successfully administered to mitigate cytokine-related symptoms in patients treated with higher doses in subsequent cohorts. One DLT of asymptomatic Grade 3 serum lipase elevation was observed which resolved and the patient was retreated successfully as scheduled. The most common reasons for study discontinuation were due to progressive disease (72%) and unrelated adverse events (9%).
HPN424 demonstrated dose proportional increase in Cmax and AUC with a current estimate of median T1/2 of 24.9 hours (range: 9.0 312 hours). Dose-dependent, transient increases in peripheral cytokine and chemokine levels were observed, including increases in interleukin 6, peaking at 5 hours post infusion and returning to baseline 24 hours post-administration. Maximal cytokine/chemokine levels attenuated with each successive dose within six weeks. Baseline circulating tumor cells (CTC) ranged from 0-160 cells/ml of whole blood. Reduction in CTC was seen in 12 of 27 patients with evaluable CTC compared to baseline.
Eight of 26 patients (31%) with at least 24 weeks in follow-up remained on study beyond 24 weeks. Eight patients showed a PSA decline from baseline ranging from -4 to -76%, including patients with initial rises in PSA after study entry. Two patients had confirmed PSA partial responses with declines of 50% or greater.
Patients continue to be enrolled in the escalation phase of the trial, with a goal to identify a dose for an expansion phase planned for the second half of 2020. The expansion phase of the trial will further evaluate the safety and activity of HPN424 in patients with mCRPC. The trial is titled, A Phase 1 Open-label, Multicenter, Dose Escalation and Dose Expansion Study of the Safety, Tolerability, and Pharmacokinetics of HPN424 in Patients with Advanced Prostate Cancer Refractory to Androgen Therapy. For additional information about the trial, please visit www.clinicaltrials.gov using the identifier NCT03577028.
Conference Call and Webcast Today
Harpoons management team will host a webcast and conference call today at 4 p.m. ET / 1 p.m. PT to review the ASCO data and provide an update on other pipeline programs. The live call may be accessed by dialing:
877-407-9716 for domestic callers
201-493-6779 for international callers
A live webcast of the call will be available from the Events and Presentations section of the companys website at https://ir.harpoontx.com/events-and-presentations and will be archived there shortly after the live event.
About Harpoon Therapeutics
Harpoon Therapeutics is a clinical-stage immunotherapy company developing a novel class of T cell engagers that harness the power of the bodys immune system to treat patients suffering from cancer and other diseases. T cell engagers are engineered proteins that direct a patients own T cells to kill target cells that express specific proteins, or antigens, carried by the target cells. Using its proprietary Tri-specific T cell Activating Construct (TriTAC®) platform, Harpoon is developing a pipeline of novel TriTACs initially focused on the treatment of solid tumors and hematologic malignancies. HPN424 targets PSMA and is in a Phase 1 trial for metastatic castration-resistant prostate cancer. HPN536 targets mesothelin and is in a Phase 1/2a trial for cancers expressing mesothelin, initially focused on ovarian and pancreatic cancers. HPN217 targets BCMA and is in a Phase 1/2 trial for relapsed, refractory multiple myeloma. HPN328 targets DLL3 and Harpoon plans to initiate a Phase 1/2a trial in the second half of 2020. For additional information about Harpoon Therapeutics, please visit www.harpoontx.com.
Cautionary Note on Forward-looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as may, will, expect, plan, anticipate, target, estimate, intend and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. These forward-looking statements are based on Harpoon Therapeutics expectations and assumptions as of the date of this press release. Each of these forward-looking statements involves risks and uncertainties that could cause Harpoon Therapeutics clinical development programs, future results or performance to differ significantly from those expressed or implied by the forward-looking statements. Forward-looking statements contained in this press release include, but are not limited to, statements about the progress, timing, scope and anticipated results of clinical trials, the timing of the presentation of data, the association of data with potential treatment outcomes, the development and advancement of product candidates, and the timing of development milestones for product candidates. Many factors may cause differences between current expectations and actual results, including unexpected safety or efficacy data observed during clinical studies, clinical trial site activation or enrollment rates that are lower than expected, unanticipated or greater than anticipated impacts or delays due to COVID-19, changes in expected or existing competition, changes in the regulatory environment, the uncertainties and timing of the regulatory approval process, and unexpected litigation or other disputes. Other factors that may cause Harpoon Therapeutics actual results to differ from those expressed or implied in the forward-looking statements in this press release are discussed in Harpoon Therapeutics filings with the U.S. Securities and Exchange Commission, including the Risk Factors sections contained therein. Except as required by law, Harpoon Therapeutics assumes no obligation to update any forward-looking statements contained herein to reflect any change in expectations, even as new information becomes available.
Harpoon Therapeutics, Inc.
Chief Financial Officer
Robert H. Uhl
Spearheading Immunotherapies Phase 1 HPN424 Interim Data Presentation and Pipeline Update May 29, 2020 Exhibit 99.2
Forward-looking Statements This presentation contains forward-looking statements about Harpoon Therapeutics, Inc.. All statements other than statements of historical facts contained in this presentation are forward-looking statements, including statements about our financial position, strategy, expectations regarding the timing and achievement of our product candidate development activities, research and development activities and ongoing and planned preclinical studies and clinical trials, and plans and expectations for future operations. These forward-looking statements are subject to a number of risks, uncertainties and assumptions, including, but not limited to: our limited operating history; net losses; our expectation that we will incur net losses for the foreseeable future, and that we may never be profitable; our need for additional funding and related risks for our business, product development programs and future commercialization activities; the timing and success of preclinical and clinical trials we conduct; the ability to obtain and maintain regulatory approval of our product candidates; the ability to commercialize our product candidates; our ability to compete in the marketplace; risks regarding our license agreements; our ability to obtain and maintain intellectual property protection for our product candidates; and our ability to manage our growth. We operate in a very competitive and rapidly changing environment. New risks emerge from time to time. It is not possible for our management to predict all risks, nor can we assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward-looking statements we may make. In light of these risks, uncertainties and assumptions, the forward-looking events and circumstances discussed in this presentation may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements. For a discussion of many of these and other risks and uncertainties, see our filings with the Securities and Exchange Commission, including the “Risk Factors” section in our Annual Report on Form 10-K and subsequent Quarterly Reports on Form 10-Q, which are available on the SEC’s website at www.sec.gov. Except as required by law, neither we nor any other person assumes responsibility for the accuracy and completeness of the forward-looking statements. We undertake no obligation to update publicly any forward-looking statements for any reason after the date of this presentation to conform these statements to actual results or to changes in our expectations. Certain information contained in this presentation and statements made orally during this presentation relate to or are based on studies, publications, surveys and other data obtained from third-party sources and our own internal estimates and research. While we believe these third-party studies, publications, surveys and other data to be reliable as of the date of this presentation, we have not independently verified, and make no representations as to the adequacy, fairness, accuracy or completeness of, any information obtained from third-party sources. In addition, no independent source has evaluated the reasonableness or accuracy of our internal estimates or research and no reliance should be made on any information or statements made in this presentation relating to or based on such internal estimates and research.
Therapeutic Focus Clinical-stage immunotherapy company Platform Technologies T cell engager technology, “off-the-shelf” therapies for solid tumors -TriTAC: Tri-specific T cell Activating Construct platform -ProTriTAC: Pro-drug form of TriTAC Multiple Product Candidates HPN424 (PSMA TriTAC) Phase 1 in prostate cancer HPN536 (mesothelin TriTAC) Phase 1/2a in ovarian cancer and other solid tumors HPN217 (BCMA TriTAC) in Phase 1/2 in multiple myeloma HPN328 (DLL3 TriTAC) expected to enter clinic in H2 2020 Multiple Anticipated Clinical Catalysts in 2020 HPN424 – presented interim data at ASCO; initiate expansion study in 2020 HPN536 – present interim data in H2 2020 Strong Financial Position Cash balance of $188.21 million expected to fund operations into 2022 Nov 2019 - AbbVie HPN217 license and expanded discovery agreements; achieved $50M first-patient-in milestone in April 2020 Harpoon Therapeutics – Investment Overview 1- As of March 31, 2020, pro forma for the $50M milestone earned from AbbVie in April 2020.
Product Candidate Target / Indication Stage of Development Anticipated Milestones Preclinical Phase 1 Phase 2 HPN424 PSMA / Prostate cancer Interim data presented at ASCO; anticipate expansion study in 2020 HPN536 MSLN / Ovarian, pancreatic and other solid tumors April 2019: Initiated Phase 1/2a clinical trial; 2020: Interim data HPN217 BCMA / Multiple myeloma April 2020: Initiated Phase 1/2 AbbVie licensing and option agreement HPN328 DLL3 / Small cell lung cancer 2020: Submit IND and Initiate Phase 1 ProTriTAC Undisclosed ProTriTAC IND candidate Phase 3 TriTAC Broad Pipeline of Immuno-Oncology Programs Four Clinical Stage TriTAC Programs in 2020 PSMA – Prostate Specific Membrane Antigen, MSLN – Mesothelin, BCMA – B-Cell Maturation Antigen, DLL3 – Delta-Like 3 Pro
BiTE ~50kD TriTAC ~50kD Bispecific Antibody ~150kD Molecular Weight TriTAC: Small Size and Flexibility, Albumin Domain Confers Extended Half Life Molecular Structure HSA – human serum albumin, BiTE – bispecific T cell engager
Target Cell T Cell Does not require MHC expression for recognition by T cell Does not require a T cell clone with specific T cell receptor Any T cell can recognize a surface antigen TCR Complex TriTAC® X X MHC MHC downregulation and mutations are a major tumor evasion mechanism TriTACs Overcome Immune Escape Mechanisms and Induce Killing Independent of MHC Expression MHC – major histocompatibility complex, TCR – T cell receptor
Interim Analysis: Phase 1 Study of HPN424 in Patients with mCRPC Natalie Sacks, M.D., Chief Medical Officer
Metastatic Prostate Cancer: >$5B Global Market Opportunity* Source: SEER, ACS, 2019 estimates ~ 174K new cases of prostate cancer annually in the U.S. >31K U.S. deaths per year (2nd leading cause of cancer death in men) Mean survival time for mCRPC = 13 months 5-year survival rate is ~30% in more aggressive forms ~ 23% initially diagnosed with advanced disease Significant unmet need for patients with incurable mCRPC Continued high mortality rates of advanced disease Potential “fast to market” strategy for high-risk patient subgroups mCRPC – metastatic castration resistant prostate cancer * Based on combined sales in 2017 of later-generation anti-androgen drugs such as Zytiga and Xtandi.
HPN424 Targets PSMA - A Highly Expressed and Validated Target for Prostate Cancer Designed to bind to human PSMA, CD3, and albumin Redirects T cells to kill PSMA-expressing target cells Target overexpressed in malignant cells, with limited expression in normal tissue Clinically validated by encouraging response data from Amgen’s BiTE targeting PSMA in mCRPC patients Phase 1 trial initiated in patients with mCRPC cancer in August 2018 Cancer cell killing Cytolytic synapse Prostate cancer cell T cell PSMA CD3 anti-PSMA anti-albumin anti-CD3ε HPN424 is a tri-specific single chain molecule of ~50 kDa
Authors Johanna Bendell, MD1, Lawrence Fong, MD2, Mark Stein, MD3, Tomasz M. Beer, MD4, Ashley Ross, MD, PhD5, Xin Gao, MD6, Aaron Weitzman, MD, FACP7, Richard Austin, PhD8, Vaishnavi Ganti, PhD8, Che-Leung Law, PhD8, Bryan Lemon, PhD8, Holger Wesche, PhD8, Johann de Bono, MD9 1Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA 2University of California, San Francisco, CA, USA 3Columbia University, New York, NY, USA 4Oregon Health and Science University, Portland, OR, USA 5Mary Crowley Cancer Research Center/Texas Oncology, Dallas, TX, USA 6Massachusetts General Hospital, Boston, MA, USA 7Weitzman Consulting Group, Los Altos Hills, CA, USA 8Harpoon Therapeutics, South San Francisco, CA, USA 9Royal Marsden Hospital and The Institute of Cancer Research, Sutton, UK
Target Population Metastatic castration-resistant prostate cancer (mCRPC) Disease progression on the prior systemic regimen At least two prior systemic therapies approved for mCRPC Prior chemotherapy allowed, but not required Trial Design Key objectives include characterization of safety, tolerability, pharmacokinetics, and identification of dose for expansion phase Additional assessments including pharmacodynamic markers such as cytokines, CTC Tumor assessments performed every 9 weeks and include conventional CT and bone scans and PSA Dosing, Administration & Exposure HPN424 administered once weekly, one-hour IV infusion One cycle is 3 weeks Starting dose of 1.3ng/kg established by minimally anticipated biological effect level As of May 11, 2020, 44 patients have been dosed across 11 cohorts (range 1.3 to 120ng/kg) Phase 1 Study Design Dose escalation: single patient Dose escalation: 3 + 3 (3 – 6 pts per dose level) MTD or recommended Phase 2 dose Part 1 – Dose escalation Part 2 – Expansion ~20 pts treated at recommended Phase 2 dose determined in Part 1 ³ Gr 2 study drug related toxicity
Table 1. Baseline Characteristics and Demographics (n=44) Age (Years) Median 71 Range 44 - 91 Race White 34 (77%) Black or African American 5 (11%) Asian 1 (2%) Other / Not reported 4 (9%) ECOG Performance Status 0 26 (59%) 1 18 (41%) PSA (ng/mL) Mean 649 Median 244 Range 0.1 - 5000 LDH (U/L) Mean 402 Median 277 Range 126 - 1303 Location of Metastases Bone 42 (96%) Lymph Node 20 (46%) Liver 6 (14%) Lung 6 (14%) Other Visceral 7 (16%) Time Since Diagnosis (Years) Mean 9.1 Median 7.8 Range 0.9 – 25.6 Reason for Entering Study PSA Progression 13 (30%) 13 (30%) PSA & Clinical Progression 1 (2%) 1 (2%) PSA & Radiographic Progression 3 (7%) 3 (7%) Radiographic Progression 13 (30%) 13 (30%) Unknown 14 (32%) 14 (32%) # of Prior Therapies Median (Range) 7 (2 – 16) # of Prior Novel Hormonal Therapies Median (Range) 2 (1 – 3) Prior Chemotherapy (in mCRPC setting) N 32 (73%) Median (Range) 1 (0 – 3) Median of 7 prior systemic therapies, median of 2 prior novel hormonal therapies 73% of patients had prior chemotherapy in metastatic castrate-resistant setting Additional prior therapies include sipuleucel-T, radium-223, A2AR inhibitor, olaparib, rucaparib, pembrolizumab, nivolumab, durvalumab, ipilimumab, listeria vaccine, Lu177/Ac225-PSMA-617, other investigational agents
Table 2. Adverse Events (CTCAE* v5.0) in >10% of Patients by Grade, Regardless of Relationship All CRS events resolved and patients were successfully re-treated High-grade transaminitis was observed primarily in the setting of CRS; abnormalities were transient, no clinical sequelae Short-term premedication with steroids was effective in limiting CRS and allowing long-term treatment 1 DLT observed at 96ng/kg, Grade 3 lipase increase Treatment related SAEs: CRS (n=4) AST increase (n=3), ALT increase (n=2), IRR (n=2), myalgia (n=1), pneumonitis (n=1), seizure (n=1), syncope (n=1) * Common Terminology Criteria for Adverse Events a Includes AEs that were reported as concurrent symptoms of the CRS events Event, n (%) All Grades Grade 3+ Cytokine-Related Adverse Eventsa Chills 32 (73%) 0 (0%) Pyrexia 21 (48%) 0 (0%) Cytokine release syndrome 14 (32%) 3 (7%) Flushing 10 (23%) 0 (0%) Hypotension 8 (18%) 1 (2%) Infusion related reaction 6 (14%) 0 (0%) All Other Adverse Events Fatigue 16 (36%) 2 (5%) Anemia 14 (32%) 4 (9%) Constipation 12 (27%) 0 (0%) Nausea 11 (25%) 0 (0%) Vomiting 8 (18%) 0 (0%) Decreased appetite 8 (18%) 0 (0%) Back Pain 8 (18%) 2 (5%) Insomnia 7 (16%) 0 (0%) Diarrhea 6 (14%) 0 (0%) ALT increase 6 (14%) 2 (5%) Arthralgia 6 (14%) 0 (0%) Tachycardia 5 (11%) 0 (0%) Asthenia 5 (11%) 0 (0%) Blood creatinine increase 5 (11%) 1 (2%) Pain in extremity 5 (11%) 0 (0%) Hypertension 5 (11%) 2 (5%)
Kinetics of Serum Cytokine/Chemokine Levels N = 4 patients dosed at 12 ng/kg (no dex pretreatment) 16 cytokines evaluated Post treatment transient increase in IL-6, IL-8 , as well as IL-5, IL-10, MCP, IFNγ, TNFα, MIP-1α, MIP-1β (not shown) at 12 ng/kg doses Spikes are transient and attenuate after first dose Magnitude decreased with successive doses for most cytokines
Dose-dependent, transient increases in peripheral cytokine and chemokine levels were observed, in the absence of dexamethasone premedication Transient cytokine increases can be effectively managed with short-term dexamethasone premedication Cytokine Spikes Managed with Dexamethasone Figure 8. Cytokine Levels 5-hours Post-1st HPN424 Exposure
HPN424 was initiated at 1.3ng/kg with no dexamethasone (dex) premedication Dose-dependent, transient increases in serum cytokine and chemokines were observed in early cohorts 2 patients who received 24ng/kg with no dex premed experienced Grade 3 CRS; patients were subsequently administered dex premedication weekly Dex taper was implemented at Cohort 5 based on the observation that peripheral cytokines attenuated with each successive dose 6-Week Taper: Administered once weekly prior to HPN424 infusion for 2 cycles 3-Week Taper: Administered once weekly prior to HPN424 infusion for 1 cycle Cohort Dose (ng/kg) N Dex Premed (mg ) Gr 3+ CRS, n 1 1.3 1 -- 0 2 4 1 -- 0 3 12 4 -- 0 4a 24 3 -- 2 Cohort Dose (ng/kg) N Dex Premed (mg) Gr 3+ CRS, n 4b 24 4 10 mg weekly 1 5 30 3 10-10-4-4-2-2 0 6 40 3 10-10-4-4-2-2 0 6a 40 2 10-4-2 0 7 54 3 10-10-4-4-2-2 0 7a 54 1 10-4-2 0 8 72 6 10-10-4-4-2-2 0 8a 72 1 20-10-5 0 9 96 6 10-10-4-4-2-2 0 10 120 1 20-10-4-4-2-2 0 Dexamethasone Premedication
Figure 3. Patient Time on Treatment 11 of 28 patients (39%) with > 18 weeks follow-up remained on study beyond week 18 8 of 26 (31%) patients remained on study > 24 weeks Of the 8 patients on study > 24 weeks, 7 patients (88%) continued on HPN424 treatment longer than the time on their most recent prior systemic regimen (data not shown) 11 patients remain active, patients discontinued study due to: PD (63%), Death due to PD (9%), Death due to Unrelated AE (6%), Unrelated AE (3%), Other (18%) Figure 3. Patient Time on Treatment Starting Dose (ng/kg) – Pt # Dose Increase Dose Decrease Ongoing * Study entry due to radiographic progression 40ng/kg 30ng/kg 54ng/kg 24ng/kg 12ng/kg 12ng/kg Prior chemo in mCRPC setting 12ng/kg 12ng/kg 72ng/kg No prior chemo in mCRPC setting
HPN424-1001 Phase 1 Dose Escalation Figure 4. Patient PSA Values on Treatment Patients with PSA declines during course of treatment Eight patients had PSA decreases from baseline ranging from -3.8% to -76%, including 2 patients with PSA decline >50% from baseline PSA declines observed in patients across dose cohorts * One patient had baseline and subsequent PSA values of 5000ng/mL (not shown)
Patients with PSA Reductions Post-Baseline * * Remain On Study ↑12ng/kg ↑40ng/kg ↑72ng/kg ↑ Dose increase
Patient 003, a 69-year old male, diagnosed March 2013 Patient initiated HPN424 at 12ng/kg and escalated twice to 40 then 72 ng/kg Patient demonstrated early rise in PSA followed by a steady decline starting Week 12, currently -9% PSA decline from baseline Drop in LDH from 2361 to 241 U/L observed, coinciding with PSA decline Patient remains on study after 84 weeks of treatment Baseline Characteristics ECOG 0 Reason for Study Entry Radiographic Progression PSA (ng/mL) 251 Location of Metastases Bone LDH (U/L) 530 Prior Therapies ADT, sipuleucel-T, enzalutamide Patient Profile – Patient 003 - Ongoing
Patient Profile – Patient 024 - Ongoing Patient 024, a 76-year old male, diagnosed December 2009 Patient initiated HPN424 at 54ng/kg with a 6-week dexamethasone taper Patient demonstrated early rise in PSA followed by a slight decline starting Week 15 Patient remains on study after 38 weeks of treatment Baseline Characteristics ECOG 1 Reason for Study Entry PSA Progression PSA (ng/mL) 1294 Location of Metastases Bone LDH (U/L) 187 Prior Therapies ADT, docetaxel, sipuleucel-T, abiraterone, enzalutamide, nivolumab + rucaparib
Figure 7. Median Concentration Time Profile for HPN424 in Given Dose Range of 1.3 – 96ng/kg HPN424 demonstrated dose proportional increase in Cmax and AUC with a geometric median T1/2 of 24.9 hours (range: 9.0 – 312 hours) Median clearance (CL) and volume of distribution (Vss) for HPN424 in the given dose range of 1.3 – 96 ng/kg appear to be dose independent, indicative of linear kinetics Figure 7. Median Concentration Time Profile for HPN424 in Given Dose Range of 1.3 – 96ng/kg Time (hours)
Dose-Dependent Increase in Cmax Median Cmax (ng/mL) Dose (ng/kg) C1D1 EOI for 1.3 ng/kg – 96 ng/kg cohorts
Low Frequency ADA Response to HPN424 ADA = Anti-drug antibodies nAb = neutralizing ADANA = not applicable Pt 001 Pt 002 Pt 003 Pt 005 Pt 006 Pt 007 Pt 009 Pt 010 Pt 011 Pt 012 Pt 013 Pt 014 Pt 015 Pt 016 ADA – – – – – – – + Pre-existing – – – – – – nAb NA NA NA NA NA NA NA + C7D1 NA NA NA NA NA NA Pt 019 Pt 020 Pt 021 Pt 022 Pt 023 Pt 024 Pt 025 Pt 026 Pt 027 Pt 028 Pt 029 Pt 031 Pt 033 ADA – + C2D1 – – – – – – – + C1D15 – – – nAb NA – NA NA NA NA NA NA NA + C4D1 NA NA NA Only 3 patients out of 27 tested for ADA were found to be positive Pt 010 – pre-existing and baseline positive; nAb activity was detected on C7D1 Pt 020 – treatment emergent, low titer and non-neutralizing ADA Pt 028 – treatment emergent ADA; nAb activity was detected on C4D1
Reduction in circulating tumor cells (CTCs) was seen in 12 of 27 patients with available CTC counts collected on C1D1 predose (baseline) and C1D15 predose (after 2 doses of HPN424) Figure 9. Post Treatment Changes in Circulating Tumor Cell Figure 9. Post Treatment Changes in Circulating Tumor Cells
HPN424-Mediated T Cell Margination Transient T cell margination from circulation, peaking around 5 hrs post infusions and returning to baseline after about 48 hrs, indicating T cell activation Similar trends observed in CD4 helper T and CD8 cytotoxic T cell subsets T cell margination also observed in patients receiving dexamethasone premedication
HPN424-1001 Phase 1 Dose Escalation Summary HPN424 represents a novel half-life extended PSMA-targeting T cell engager that can be safely administered once weekly Dose escalation comprises a heterogeneous, heavily pretreated population Evidence of half-life extension supports once weekly HPN424 administration Cytokine increases indicate T-cell activation and CTC reductions in a subset of patients support target engagement Adverse events have been transient, manageable and consistent with expected mechanism of action Early clinical signals have been observed, including 8 patients on treatment > 24 weeks and PSA reductions in multiple patients Dose escalation is ongoing to identify dose for expansion phase
HPN536 and Other Product Candidates Jerry McMahon, Ph.D., President and CEO
MSLN - Associated with Tumors with High Unmet Need and Low Survival Rates 60-65% 80-85% 85-90% 60-65%2 34-42% MSLN Expression Level (%)1 22,500 57,000 2,600 200,0003 40,0004 Annual Incidence (U.S.) Over 80,000 new patients diagnosed each year in U.S. with solid tumors known to have high MSLN expression Morello et al. Cancer Discov 2016;6:133-146 Represents MSLN expression levels across all lung cancer types Estimated as 80-85% of SEER-estimated lung cancer incidence Estimated as 15% of SEER-estimated breast cancer incidence
HPN536 – Targets MSLN for the Treatment of Ovarian Cancer, Pancreatic, Mesothelioma and Other MSLN-Expressing Tumors HPN536 is a tri-specific single chain molecule of ~50 kDa Mesothelin Expressing Target MSLN CD3 anti-MSLN anti-albumin anti-CD3ε Target antigen T cell Designed to bind to human mesothelin, CD3, and albumin Redirects T cells to kill MSLN-expressing target cells Target overexpressed in malignant cells, with limited expression in normal tissue Clinically validated and is overexpressed on a wide array of cancer types: ovarian, pancreatic, mesothelioma, NSCLC, TNBC Phase 1/2a trial initiated in patients with ovarian cancer and other MSLN-expressing solid tumors in April 2019
Dose escalation: single patient Dose escalation: 3 + 3 (3 – 6 pts per dose level) MTD or recommended Phase 2 dose Part 1 – Dose Escalation Part 2 – Expansion 3 parallel cohorts, ~20 patients each: Ovarian, Pancreatic and Mesothelioma cancers Treated at recommended Phase 2 dose determined in Part 1 ³ Gr 2 study drug related toxicity Target population Patients with advanced cancers associated with mesothelin expression who have failed standard available therapy Currently enrolling ovarian and pancreatic cancer patients Trial objectives Assess safety and tolerability at increasing dose levels Pharmacokinetic and pharmacodynamic data Evaluate preliminary anti-tumor activity Dosing & administration Weekly IV infusion of HPN536 Trial status Dose escalation ongoing: currently enrolling cohort 8 dosing at 210 ng/kg Expect interim data in H2 2020 HPN536 – Design of Open-label Ongoing Phase 1/2a Trial
Summary HPN536 Phase 1/2a Dose Escalation Cohort Dose (ng/kg) N Tumor Types Treated 1 6* 1 Ovarian 2 18* 1 Ovarian 3 54* 1 Ovarian 4 68 6 4 Ovarian, 2 Pancreatic 5 90 7 5 Ovarian, 2 Pancreatic 6 120 5 2 Ovarian, 3 Pancreatic 7 160 3 1 Ovarian, 2 Pancreatic 8 (Currently Enrolling) 210 1 1 Pancreatic Total 25 15 Ovarian, 10 Pancreatic 1 event of CRS (Grade 3) occurred at 54ng/kg in absence of dexamethasone premedication, shifting escalation into 3 + 3 design at 68ng/kg CRS resolved and patient was successfully re-treated with short-term dexamethasone premedication No DLTs observed to-date * No dexamethasone premedication administered at initiation of HPN536 treatment Dose escalation progressing quickly, once weekly administration well tolerated through 7 cohorts
Dose Proportional Increase in Cmax HPN536 serum concentration at end of infusion on C1D1 (first dose) 6 ng/kg to 160 ng/kg cohorts
PK Profile: Half-Life Extension & Linear Kinetics Serum HPN536 (ng/mL) Time (hours) Dose proportional increase in AUC with an overall median T1/2 of 87.4 hours (38.1 – 137 hours) Dose independent clearance and volume of distribution, indicating linear kinetics No apparent difference in PK parameters between ovarian and pancreatic cancer patients
HPN536 Program Summary Phase 1/2a trial currently in dose escalation, progressing well 25 patients treated to-date across 8 cohorts (6 – 210ng/kg) 15 ovarian, 10 pancreatic cancer patients enrolled Adverse events have been transient, manageable and consistent with expected mechanism of action 1 event of CRS (Grade 3) occurred at 54ng/kg in absence of dex premed, shifting escalation into 3 + 3 design at 68ng/kg CRS resolved and patient was successfully re-treated with short-term dex premed No DLTs observed to-date Evidence of half-life extension supports once weekly HPN536 administration Dose proportional increase in Cmax and AUC observed Overall median T1/2 of 87.4 hours Dose escalation is ongoing, including evaluation of alternative dosing schedules, to identify dose for expansion in multiple tumor types
Multiple myeloma is the 2nd most prevalent blood cancer in U.S. Constitutes over 40% of U.S./global heme-onc market, with significant projected growth Despite many currently approved therapies, patients ultimately relapse and new treatment options needed for disease control BCMA is a clinically validated target in multiple myeloma Clinical efficacy demonstrated with BCMA CAR-T and, off-the-shelf, antibody-based T-cell engagers Amgen presented promising clinical responses on continuous IV BiTE candidate (AMG420) HPN217: Treatment for Multiple Myeloma
HPN217 - Targets BCMA for the Treatment of Multiple Myeloma and Other BCMA-Expressing Tumors Designed to bind to human BCMA, CD3, and albumin Redirects T cells to kill BCMA-expressing target cells Covered by global licensing and option agreement with AbbVie Possible license after completion of Phase 1/2 clinical study HPN217 first patient dosed April 2020 Robust global clinical site initiations planned for 2020 Pharmacology data expected by end of 2020 to confirm half-life extension and target engagement HPN217 is a tri-specific single chain molecule of ~50 kDa BCMA Expressing Target BCMA CD3 anti-BCMA anti-albumin anti-CD3ε Target antigen T cell
Dose escalation: single patient Dose escalation: 3 + 3 (3 – 6 pts per dose level) MTD or recommended Phase 2 dose Part 1 – Dose Escalation Part 2 – Expansion Cohort treated at recommended Phase 2 dose determined in Part 1 ³ Gr 2 study drug related toxicity Trial design optimized for rapid development Key objectives Assess safety, pharmacokinetics, and efficacy; to identify a RP2D Target population Patients with relapsed/refractory multiple myeloma Disease progression on the prior systemic regimen At least three prior therapies including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody Prior BCMA-targeting agents allowed in escalation phase Dosing & administration Weekly IV infusion of HPN217 One cycle = 21 days (also DLT observation period) Assessment Standard MM disease assessment Additional assessments include BCMA IHC, cytokines, MRD CRS mitigation Premedication including glucocorticoid and planned step dosing HPN217 – Phase 1/2a Trial Enrolling and Driving to POC in 2021
HPN328 - Targets DLL3 for the Treatment of Small Cell Lung Cancer Designed to bind to human DLL3, CD3, and albumin Redirects T cells to kill DLL3-expressing target cells Preclinical data presentation at AACR-NCI-EORTC (Oct 2019), shows strong tumor cell killing in cell-based and animal SCLC models and stability data supporting at least once weekly dosing HPN328 is a tri-specific single chain molecule of ~50 kDa DLL3 Expressing Target DLL3 CD3 anti-DLL3 anti-albumin anti-CD3ε Target antigen T cell DLL3 – Delta-like 3
Initial target for Small Cell Lung Cancer, remains an unmet medical need Aggressive disease with limited treatment options 15% of all lung cancers addressable by targeting DLL3 Emerging data indicating DLL3 expression in other neuroendocrine tumors besides SCLC DLL3 as a promising target for T-cell engagers Checkpoint inhibitors releasing T cells leading to increased patient survival Opportunity to treat checkpoint refractory or relapsed SCLC patients and potential for combinations with chemo and checkpoint therapies High prevalence in SCLC Emerging data of DLL3 expression in various neuroendocrine tumors HPN328 IND submission on track for mid-year 2020 Nonclinical, manufacturing, and pre-IND meetings completed First patient anticipated to be dosed in 2H 2020 following IND acceptance HPN328 – Treatment for SCLC and Other Neuroendocrine Tumors
ProTriTAC: A Novel Prodrug Technology Platform Holger Wesche, Ph.D., Chief Scientific Officer
ProTriTAC: T Cell Engager Prodrug Platform to Target More Broadly Expressed Tumor Antigens Goal: Bring the clinical benefit of TriTACs to tumors that don’t express tumor specific antigens Approach: Develop a TriTAC prodrug that is inert in circulation and only active in tumors Benefits: Improved therapeutic index (TI) and the ability to target tumor types not yet successfully treated with T cell engagers, e.g. colorectal carcinoma
ProTriTAC Is Based on Clinically Validated TriTAC Components αALB αTarget αCD3 TriTAC ProTriTAC protease linker (red) masking moiety from αALB (orange) αALB αTarget αCD3 Starting point is a TriTAC Binders are rearranged Protease linker and masking moiety added
αALB αTarget αCD3 Long-lived, inactive prodrug Rapid clearance in circulation TUMOR CIRCULATION CIRCULATION Activation by tumor proteases & T cell-directed killing ProTriTAC Increases Therapeutic Index by Linking Prodrug Activation to Half-Life Extension Albumin
ProTriTAC Is a Robust T Cell Engager Prodrug Platform Consistent Masking in Vitro Superior PK Properties In Vivo Cell Killing Assay Non-Human Primate PK Prodrug Active drug Active drug Prodrug Reliable “plug-and-play” masking across multiple targets = platform established No accumulation of active drug in circulation = additional safety
ProTriTAC Has Improved Therapeutic Index In Vivo Better Efficacy in Mouse Better Safety in Non-Human Primates Control TriTAC ProTriTAC Both TriTAC and ProTriTAC dosed at 100 µg/kg Peak Cytokine Levels Both TriTAC and ProTriTAC dosed at 30 µg/kg Established Tumor Xenograft Model TriTAC ProTriTAC Improved therapeutic index also demonstrated in combined mouse efficacy/toxicity models
ProTriTAC: T Cell Engagers with Improved Therapeutic Index Developed unique and robust prodrug approach Single proteolytic cleavage for efficient prodrug conversion and to maintain efficacy Novel activation mechanism to avoid accumulation of activated drug Expanded therapeutic index in vivo Efficacy comparable to conventional T cell engagers with improved safety profile demonstrated in several, orthogonal in vivo models Established ProTriTAC pipeline First ProTriTAC clinical candidate entered IND-enabling studies Discovery pipeline progressing
Conclusions and 2020 Milestones Jerry McMahon, Ph.D., President and CEO
Anticipate four TriTAC product candidates in the clinic in 2020 Clinical Milestones Milestone Timing HPN424: Preliminary Phase 1 data January 2019 HPN536: Initiate Phase 1/2a clinical trial April 2019 HPN217: Submit IND H2 2019 HPN217: Initiate Phase 1/2 clinical trial April 2020 HPN424: Presentation of interim Phase 1 data at ASCO H1 2020 HPN536: Present interim data 2H 2020 HPN424: Initiate expansion cohort(s) 2H 2020 HPN328: Submit IND and initiate Phase 1 clinical trial 2H 2020 ✔ ✔ ✔ ✔ ✔