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ASH 2018 Highlights Progress in Ongoing Development of Brentuximab Vedotin

As the premier hematology event in malignant and non-malignant hematology, the annual meeting of the American Society of Hematology (ASH), held this year from December 1 – 4, 2018 in San Diego, CA, is expected to present an invaluable educational experience and an opportunity to examine the latest clinical advances on topics covering malignant and non-malignant hematology, explore the year’s most significant scientific discoveries and relevant updates in key areas of the field, build new partnerships, stay current on industry trends and learn about the latest products and services available in research and patient care to meet the need of patients.

Brentuximab vedotin
During the annual meeting, expect to see 31 abstracts featuring data from the broad brentuximab vedotin (Adcetris®) development program.  Brentuximab vedotin is an Antibody-drug Conjugate or ADC directed to CD30, which is expressed on the surface of Hodgkin lymphoma (HL) cells and several types of non-Hodgkin lymphoma.

The drug, being developed by Seattle Genetics and Takeda, is being evaluated globally as the foundation of care for CD30-expressing lymphomas in more than 70 corporate- and investigator-sponsored clinical trials.

The data being presented includes both oral and poster presentations. Some of the presentations includes the latest updated of brentuximab vedotin in combination with other drugs, including Nivolumab (Opdivo®; Bristol-Myers Squibb)

NCT01777152 (ECHELON-2) (CLINICAL TRIAL / BRENTUXIMAB VEDOTIN / SGN-035 / ADCETRIS®)
Schematic 1.0: The phase III ECHELON-2 clinical trial.

ECHELON-2 clinical trial
Data latest, updated from the phase III ECHELON-2 clinical trial evaluating brentuximab vedotin in combination with chemotherapy in previously untreated patients with CD30-expressing peripheral T-cell lymphoma (PTCL) patients will be presented in an oral presentation on Monday, December 3, 2018 at 6:15 p.m. PT.

Seattle Genetics and partner Takeda reported positive top-line results from the ECHELON-2 trial in October 2018. The trial demonstrated a statistically significant improvement in the primary endpoint of progression-free survival (PFS) of brentuximab vedotin in combination with CHP (cyclophosphamide, doxorubicin, prednisone) versus the control arm, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). The brentuximab vedotin plus CHP arm also demonstrated superior overall survival (OS), a key secondary endpoint, compared to CHOP. The ECHELON-2 trial is the first trial to demonstrate an OS advantage in this difficult to treat type of non-Hodgkin lymphoma.

Seattle Genetics expects to submit in November 2018 a supplemental Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for approval of brentuximab vedotin plus CHP in frontline CD30-expressing PTCL.

ECHELON-1 clinical trial

In addition to clinical trial data from the ECHELON-2 trial, expect to see several analyses from the phase III ECHELON-1 clinical trial evaluating brentuximab vedotin in combination with chemotherapy in frontline Stage III or IV classical HL adult patients, which formed the basis of FDA approval in this indication in March 2018.

Data presentations include additional analyses from the ECHELON-1 study, including PFS per investigator and outcomes in younger patients (18-30 years of age). These analyses are consistent with the previously reported modified PFS data and demonstrate improved outcomes in the ADCETRIS plus AVD (doxorubicin, vinblastine, dacarbazine) arm versus ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine).

Preliminary results from a phase II study of brentuximab vedotin in combination with nivolumab among patients with relapsed or refractory primary mediastinal large B-cell lymphoma (CHECKMATE 436 trial), as well as updated results from an ongoing phase I/II study evaluating the combination therapy in relapsed or refractory HL.

“There will be more than 30 data presentations from both corporate- and investigator-sponsored studies presented at the 2018 ASH Annual Meeting evaluating ADCETRIS in a variety of CD30-expressing lymphoma settings. These presentations are reflective of a robust ADCETRIS clinical development program that we, in partnership with the oncology community, are conducting to improve the treatment outcomes for patients,” said Roger Dansey, M.D., Chief Medical Officer of Seattle Genetics.

“[Together with our partner Takeda, we’re looking forward to presentation, on Monday, December 3rd, outlining the] results of the phase III ECHELON-2 clinical trial evaluating brentuximab vedotin in combination with CHP chemotherapy in frontline CD30-expressing peripheral T-cell lymphoma patients.  These data are the basis for our planned supplemental Biologics License Application to the FDA requesting approval of brentuximab vedotin in this setting, which we intend to submit in November 2018,” Dansey concluded.

Oral and poster presentations
Data presented during the meeting includes a series of different presentations:

Saturday, December 1, 2018
Abstract #1647 (poster) Brentuximab Vedotin with Chemotherapy in Adolescents and Young Adults (AYA) with Stage III or IV Hodgkin Lymphoma: A Subgroup Analysis from the Phase 3 ECHELON-1 Study ()
Abstract #1618 (poster) Older Patients (pts) with Previously Untreated Classical Hodgkin Lymphoma (cHL): A Detailed Analysis from the Phase 3 ECHELON-1 Study
Abstract #1635 (poster) Phase 1/2 Study of Brentuximab Vedotin in Combination with Nivolumab in Patients with Relapsed or Refractory Classic Hodgkin lymphoma: Part 3 (Concurrent Dosing) Results and Updated Progression-Free Survival Results from Parts 1 and 2 (Staggered Dosing) ()
Abstract #1636 (poster) Phase 1 Study of MDR1 Inhibitor Plus Brentuximab Vedotin in Relapsed/Refractory Hodgkin Lymphoma
Abstract #1633 (poster) Real World Prevalence of Diagnostic Revision Among Patients with Peripheral T-cell Lymphomas (PTCL) in the US: Results of an Administrative Claims and Electronic Medical Record Analyses
Abstract #1646 (poster) Superior Clinical Benefit of Brentuximab Vedotin in Mycosis Fungoides Versus Physician’s Choice Irrespective of CD30 Level of Large Cell Transformation Status in the Phase 3 ALCANZA Study
Abstract #1654 (poster) A Phase II Study of Brentuximab Vedotin plus Adriamycin and Dacarbazine without Radiation in Non-Bulky Limited Stage Classical Hodgkin Lymphoma.
Abstract #1656 (poster) Treatment Patterns and Outcomes of Relapsed/Refractory Peripheral T-Cell Lymphoma (RR-PTCL) Patients Treated in the Community Oncology Setting.
Abstract #1691 (poster) Nivolumab Combined with Brentuximab Vedotin for Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Preliminary Results From the Phase 2 CheckMate 436 Trial.
Abstract #2261 (poster) The Development and Validation of an Electronic Health Record (EHR)-Based Algorithm for Identifying Treatment Failure in Newly Diagnosed Hodgkin Lymphoma (HL) Treated in a US Community Oncology Setting.
Abstract #2268 (poster) Real World Evidence in Relapsed/Refractory Classical Hodgkin Lymphoma Patients Who Are Ineligible for Stem Cell Transplant in the United States (US).
Abstract #1625 (poster) Toxicity Profile of Brentuximab Vedotin in Combination with Chemotherapy for Newly Diagnosed Patients with ALK+ ALCL: a Children’s Oncology Group Study ANHL12P1.
Abstract #1431 (poster) Phase I Study of the Antibody-Drug Conjugate Brentuximab Vedotin Combined with Re-Induction Chemotherapy in Patients with CD30-Expressing Relapsed/Refractory Acute Myeloid Leukemia.
Abstract #1644 (poster) Phase 1 Results from a Phase 1/2 Study to Assess the Safety, Tolerability and Recommended Phase 2 Dose (RP2D) of Brentuximab Vedotin Plus Doxorubicin, Vinblastine and Dacarbazine (A+AVD) in Pediatric Patients (Pts) with Advanced Stage Newly Diagnosed Classical Hodgkin Lymphoma (cHL).
Sunday, December 2, 2018
Abstract #2904 (poster) Brentuximab Vedotin Plus Chemotherapy in Patients with Advanced-Stage Classical Hodgkin Lymphoma (cHL): Evaluation of Modified Progression-Free Survival (mPFS) and Traditional PFS in the Phase 3 ECHELON-1 Study.
Abstract #2921 (poster) Resolution of Peripheral Neuropathy (PN) in Patients Who Received A+AVD or ABVD in the Phase 3 ECHELON-1 Trial.
Abstract #2917 (poster) Interim Analysis Results from an International, Multi-Centre, Non-Interventional Retrospective Study to Describe Treatment Pathways, Outcomes, and Resource Use in Patients with Classical Hodgkin Lymphoma: B-CD30+ Hodgkin Lymphoma International Multi-Centre Retrospective Study of Treatment Practices and Outcomes (B-HOLISTIC).
Abstract #2923 (poster) Combining Brentuximab Vedotin with DHAP as Salvage Treatment in Relapsed/Refractory Hodgkin Lymphoma: the Phase II HOVON/LLPC Transplant BRaVE Study.
Abstract #2938 (poster) Peripheral T-Cell Lymphomas in Spain: Profiling Clinical, Phenotypic and Genetic Characteristics in Spanish Population.
Abstract #2959 (poster) Primary Mediastinal B-Cell Lymphoma: Evaluation of Clinicopathologic Diagnosis Compared to Gene Expression Based Diagnosis in a Clinical Trial with CD30+ B-Cell Lymphomas.
Abstract #2978 (poster) Utilization of a Novel Method of Detection of CD30 Expression in Diffuse Large B-cell Lymphoma.
Abstract #3587 (poster) Health-Related Quality of Life (HRQL) Trajectories during Treatment for Advanced Stage Pediatric Hodgkin Lymphoma (HL).
Monday, December 3, 2018
Abstract #997 (oral presentation at 6:15 p.m. PT) The ECHELON-2 Trial: Results of a Randomized, Double-Blind, Active-Controlled Phase 3 Study of Brentuximab Vedotin and CHP (A+CHP) Versus CHOP in the Frontline Treatment of Patients with CD30+ Peripheral T-Cell Lymphomas.
Abstract #623 (oral presentation at 8:00 a.m. PT) Longitudinal Adverse Event Assessment of the Combination of Ipilimumab, Nivolumab And Brentuximab Vedotin in Relapsed/Refractory Hodgkin Lymphoma: A Trial of the ECOG-ACRIN Cancer Research Group (E4412: Arms A-F)
Abstract #679 (oral presentation at 10:30 a.m. PT) A Phase I Study with an Expansion Cohort of the Combinations of Ipilimumab, Nivolumab and Brentuximab Vedotin in Patients with Relapsed/Refractory Hodgkin Lymphoma: A trial of the ECOG-ACRIN Research Group (E4412: Arms G-I)
Abstract #926 (oral presentation at 4:45 p.m. PT) B-CAP (brentuximab vedotin, cyclophosphamide, doxorubicin and predniso(lo)Ne) in Older Patients with Advanced-Stage Hodgkin Lymphoma: Results of a Phase II Intergroup Trial By the German Hodgkin Study Group (GHSG) and the Nordic Lymphoma Group (NLG)
Abstract #927 (oral presentation at 5:00 p.m. PT) Response-Adapted Therapy with Nivolumab and Brentuximab Vedotin (BV), Followed by BV and Bendamustine for Suboptimal Response, in Children, Adolescents, and Young Adults with Standard-Risk Relapsed/Refractory Classical Hodgkin Lymphoma.
Abstract #975 (oral presentation at 5:00 p.m. PT) Productivity Loss Among Parent Caregivers is Associated with Poor Health-Related Quality of Life (HRQL) at the Initial Diagnosis Of Pediatric Advanced Stage Hodgkin Lymphoma (HL).
Abstract #2837 (poster) Baseline Tumor Transcriptome Characteristics Associated with the Response of Relapsed/Refractory Hodgkin Lymphoma Patients to Brentuximab Vedotin in Combination with Nivolumab (
Abstract #4786 (poster) Patient and Physician Preferences for First-Line Treatment of Classical Hodgkin Lymphoma in the United States.
Abstract #2907 (poster) Prolonged Overall Survival (OS) in a Subset of Responders to the Combination of Brentuximab Vedotin (Bv) and Bendamustine (B) in Heavily Treated Patients with Relapsed or Refractory Hodgkin Lymphoma (HL): Results of an International Multi-Center Phase I/II Experience.

Editorial Review: November 30, 2018

Featured Image: ASH – San Diego, 2018 #ASH18 Courtesy: © 2010 – 2018 American Society of Hematology. Used with permission.

Copyright © 2018 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Supplemental Biologics License Application for Brentuximab Vedotin in Frontline Treatment of CD30-Expressing Peripheral T-Cell Lymphomas Submitted to US FDA

Seattle Genetics has submitted a supplemental Biologics License Application (BLA) for brentuximab vedotin (Adcetris®) to the U.S. Food and Drug Administration (FDA).

The submission is based on data from the phase III ECHELON-2 trial evaluating brentuximab vedotin in combination with chemotherapy for the frontline treatment of patients with CD30-expressing peripheral T-cell lymphoma (PTCL). The positive topline results of the Phase III ECHELON-2 clinical trial were announced in October 2018 and full data will be presented at the upcoming annual meeting of the American Society of Hematology (ASH), held December 1-4, 2018 in San Diego, California.

Lymphoma
Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. There are more than 60 subtypes of non-Hodgkin lymphomas which are broadly divided into two major groups: B-cell lymphomas, which develop from abnormal B-lymphocytes, and T-cell lymphomas, which develop from abnormal T-lymphocytes. There are many different forms of T-cell lymphomas, some of which are extremely rare. T-cell lymphomas can be aggressive (fast-growing) or indolent (slow-growing).


Results from the ECHELON-2 trial demonstrated a statistically significant and clinically meaningful improvement in progression-free survival and importantly, overall survival, in patients with previously untreated CD30-expressing peripheral T-cell lymphoma who were treated with [brentuximab vedotin] in combination with CHP chemotherapy over standard of care CHOP chemotherapy.


Peripheral T-cell lymphoma, which accounts for approximately 10% of non-Hodgkin lymphoma cases in the United States and Europe and may be as high as 24% in parts of Asia, is defined as a diverse group of aggressive lymphomas that develop from mature-stage white blood cells called T-cells and natural killer (NK) cells.

The disease is classified as a subtype of non-Hodgkin’s lymphoma (NHL). NHL affects two particular types of white blood cells: B-cells and T-cells. Peripheral T-cell lymphoma specifically affects T-cells, and results when T-cells develop and grow abnormally.

It is the origin of the disease in the lymphatic system that gave it the name peripheral T-cell lymphoma. In the case of peripheral T-cell lymphoma, the term “peripheral” does not refer to the extremities, but identifies the disease as a cancer that arises in the lymphoid tissues outside of the bone marrow such as lymph nodes, spleen, gastrointestinal tract, and skin.

Frontline treatment
The proposed treatment option, brentuximab vedotin, is an antibody-drug conjugate (ADC) directed to CD30, which is expressed on the surface of several types of peripheral T-cell lymphoma. The drug, which is on of four approved and commercially available antibody-drug conjugates is currently not approved for the frontline treatment of patients with peripheral T-cell lymphoma.

“CD30 is expressed in several subtypes of peripheral T-cell lymphoma, an aggressive type of non-Hodgkin lymphoma, and the current standard of care for frontline treatment consisting of a multi-agent chemotherapy regimen called CHOP has not changed in several decades,” explained Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

“Results from the ECHELON-2 trial demonstrated a statistically significant and clinically meaningful improvement in progression-free survival and importantly, overall survival, in patients with previously untreated CD30-expressing peripheral T-cell lymphoma who were treated with [brentuximab vedotin] in combination with CHP chemotherapy over standard of care CHOP chemotherapy. We believe these superior results over standard of care represent a significant advance for patients with CD30-expressing peripheral T-cell lymphoma and for the medical community, and we look forward to working with the FDA during the review process of this application to bring this potential new treatment regimen to patients as quickly as possible.”

NCT01777152 (ECHELON-2) (CLINICAL TRIAL / BRENTUXIMAB VEDOTIN / SGN-035 / ADCETRIS®)
Illustration: The randomized, double-blind, placebo-controlled ECHELON 2 is a phase III trial is investigating brentuximab vedotin plus CHP (cyclophosphamide, doxorubicin, prednisone) versus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) as frontline therapy in patients with CD30-expressing peripheral T-cell lymphoma, also known as mature T-cell lymphoma. The primary endpoint is progression-free survival (PFS) per Independent Review Facility assessment, with events defined as progression, death, or receipt of chemotherapy for residual or progressive disease. Secondary endpoints include PFS in patients with systemic anaplastic large cell lymphoma (sALCL), complete remission rate, overall survival and objective response rate, in addition to safety. The multi-center trial was conducted at sites across North America, Europe and Asia and was designed to enroll 450 patients, approximately 75% of whom were to be diagnosed with sALCL. The ECHELON-2 trial is being conducted under a Special Protocol Assessment (SPA) agreement from the U.S. Food and Drug Administration (FDA) and the trial also received European Medicines Agency (EMA) scientific advice.

ECHELON-2 trial
The phase III ECHELON-2 clinical trial evaluated the combination of [brentuximab vedotin] plus CHP (cyclophosphamide, doxorubicin, prednisone) compared to a recognized standard of care chemotherapy regimen, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), in previously untreated CD30-expressing peripheral T-cell lymphoma. The ECHELON-2 study met its primary endpoint demonstrating a statistically significant improvement in progression-free survival (PFS) as assessed by an Independent Review Facility (IRF; hazard ratio=0.71; p-value=0.0110).

The brentuximab vedotin plus CHP arm also demonstrated superior overall survival (OS), a key secondary endpoint, compared to CHOP (hazard ratio=0.66; p-value=0.0244). All other key secondary endpoints, including PFS in patients with systemic anaplastic large cell lymphoma (sALCL), complete remission rate and objective response rate were statistically significant in favor of the brentuximab vedotin plus CHP arm. The safety profile of brentuximab vedotin plus CHP in the ECHELON-2 trial was comparable to CHOP and consistent with the established safety profile of brentuximab vedotin in combination with chemotherapy.

Reference
Oral Session: Hodgkin Lymphoma and T/NK Cell Lymphoma—Clinical Studies: T-Cell Lymphoma: Chemotherapy and Targeted Approaches (Abstract #997) | Date/Location: Monday, December 3, 2018 at 6:15 p.m. PT, San Diego Convention Center, Room 6F | Presenter: Steven Horwitz, M.D.,Department of Medicine, Lymphoma Service, Memorial Sloan-Kettering Cancer Center, New York.


Last Editorial Review: November 6, 2018

Featured Image: Clinical trial. Courtesy: © 2010 – 2018 Fotolia. Used with permission.

Copyright © 2018 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Four Ways to Show Nonobviousness of ADC Inventions

When the first antibody-drug conjugate (ADC) was approved by the U.S. Food and Drug Administration (FDA) in 2000,[1] only a handful of patent applications claiming ADCs had been published.[2] As research continues to progress and the scientific community’s appreciation for the power of ADCs has grown, so have the numbers. FDA has now approved at least four ADCs,[3] and hundreds more are in development.[4] The number of patent applications has also grown, with the U.S. Patent and Trademark Office (USPTO) publishing over two hundred patent applications with claims to ADC inventions in the last two years alone.[5]

But filing an application with the USPTO does not guarantee that a patent will be obtained. Among other requirements, inventions worthy of U.S. patent protection must not have been obvious to a person of ordinary skill in the art at the time of invention (or, under current U.S. patent law, at the time the patent application was filed). In considering whether an invention would have been obvious, the USPTO will consider what was already known in the art, how the claimed invention differs from what was already known, and whether the differences would have been obvious. An invention may be deemed nonobvious if, for example, there was no motivation to modify what was known or no reasonable expectation of success in achieving the claimed invention, or if the invention enjoys commercial success or demonstrates results that would have been unexpected at the time of invention.

Four ways to demonstrate nonobviousness of an ADC invention are to show that (1) the claimed antibody, drug, or linker was not previously known; (2) a person having ordinary skill in the art would not have been motivated to modify known components to achieve the claimed ADC; (3) the skilled artisan would have had no reasonable expectation of success; or (4) the claimed ADC demonstrates unexpected results. These types of arguments have been presented to the USPTO in ADC-based patent applications, often in combination with each other and with amendments to the pending claims.

Provided below are three examples of patents that issued after such nonobviousness arguments were made to the USPTO: U.S. Patent Nos. 8,603,483 (the ’483 patent); 9,308,278 (the ’278 patent); and 9,850,312 (the ’312 patent). Companies seeking patent protection for their own ADC inventions should consider these and other examples when developing their own nonobviousness positions. The authors have not independently analyzed the obviousness of the claims discussed below, but provide these merely as examples of strategies used to secure allowance of claims directed to ADCs before the USPTO. Readers are encouraged to seek legal counsel in considering their own ADC inventions and these examples.


Example 1: Arguments of No Motivation, No Reasonable Expectation of Success, and Unexpected Results During the Prosecution of U.S. Patent No. 8,603,483 [6]

The USPTO issued the ’483 patent to Janssen Biotech, Inc. and ImmunoGen, Inc. on December 10, 2013, with claims to ADCs, pharmaceutical compositions comprising the ADCs, articles of manufacture comprising the ADCs, methods of producing the ADCs, methods of treating cancer using the ADCs, and methods of inhibiting the growth of cancer cells using the ADCs. For example, independent claim 1 is as follows:

1. An antibody-drug conjugate of the formula:

wherein the antibody is a human alphaV integrin specific antibody, and said antibody is capable of being internalized by a cell expressing said alphaV integrin, and wherein said antibody comprises (i) all of the heavy chain complementary determining region (CDR) amino acid sequences of CNTO 95 as shown in SEQ ID NOS: 1, 2, and 3, and (ii) all of the light chain CDR amino acid sequences of CNTO 95 as shown in SEQ ID NOS: 4, 5, and 6; and wherein the maytansinol is esterified at C-3; R1 and R2 are Me; X1 and X2 are H[;] n is 2; p is 2; and m is 3-4, and the pharmaceutically acceptable salts and esters thereof.

On June 3, 2011, during prosecution of the application that issued as the ’483 patent, the USPTO examiner rejected the then-pending claims for obviousness over combinations of four references. According to the examiner, the first reference taught an immunoconjugate comprising the antibody of CNTO 95 linked to a cytotoxin, the second reference taught that blockade of integrin receptors by CNTO 95 inhibited the growth of new blood vessels in vitro and growth of human melanoma tumors in nude mice, and the third reference taught that CNTO 95 has antitumor and antiangiogenic activity in vivo.

The examiner wrote that the invention of the then-pending claims differed from these teachings only by the recitation that the conjugate has the formula of [C‑L]m‑A, wherein C is DM4 (R1 and R2 are Me and n=2). According to the examiner, the fourth reference taught a conjugate comprising the huMy9-6 monoclonal antibody chemically coupled to maytansinoid DM4 via an N-succinimidyl 4-(2-yridyldithio)butanoate, and it would have been obvious to one of ordinary skill in the art to substitute hyMy9-6 antibody with the CNTO-95 antibody.

In a response dated December 2, 2011, the applicant amended the claims and argued that one of skill in the art at the time of invention would not have been motivated to substitute the CNTO 95 antibody for the huMy9-6 monoclonal because the two antibodies are “very different.” The applicant also argued that an artisan would not have reasonably expected success in substituting one antibody with another antibody that is structurally and chemically very different. In addition, the applicant argued that the art did not suggest that conjugating an anti-alphaV antibody to a cytotoxic drug would provide an important improvement or advantage over the use of the unconjugated CNTO 95 antibody. In support of the arguments, the applicant submitted three declarations. In the first, a named inventor declared that the effectiveness of the CNTO 95-maytansinoid conjugate CNTO 365 in treating tumors was surprising. In the second, a scientist declared that an artisan would not have been motivated to substitute huMy9-6, a highly selective antibody, with CNTO 95, an antibody with high reactivity with normal tissue, and would not have had a reasonable expectation of success. In the third, another scientist provided results from a phase I clinical study using CNTO 365, which the applicant argued showed unexpected and surprisingly low toxicity.

On January 12, 2012, the USPTO examiner maintained the obviousness rejections of the then-pending claims over the same art. The examiner wrote that while CNTO 95 was unexpectedly well tolerated in human clinical trials, the unexpected results did not overcome clear and convincing evidence of obviousness.

In a response dated September 12, 2012, the applicant amended the claims to “closely encompass the CNTO 365 conjugate described and tested in the application,” and argued that the claimed conjugates demonstrated unexpected results because they had a more than four-fold lower EC50 in toxicity studies relative to even other CNTO 95 conjugates. The USPTO examiner issued a notice of allowance, and then the ’483 patent issued on December 10, 2013. The examiner wrote that the amended claims were allowed because CNTO 365 was shown to have superior efficacy.


Example 2: Arguments of No Motivation and Unexpected Results During the Prosecution of U.S. Patent No. 9,308,278 [7]

The USPTO issued the ’278 patent to Agensys, Inc. on April 12, 2016, with claims to ADCs and pharmaceutical compositions comprising the ADCs. For example, independent claim 1 is as follows:

1. An antibody drug conjugate obtained by a process comprising the step of:

conjugating an antibody or antigen binding fragment thereof to monomethyl auristatin F (MMAF), which antibody or antigen binding fragment thereof is expressed by a host cell comprising a nucleic acid sequence encoding an amino acid sequence of a VH region consisting of SEQ ID NO:7, from residues 20 to 142, and a nucleic acid sequence encoding an amino acid sequence of a VL region consisting of SEQ ID NO:8, from residues 20 to 127, thereby producing the antibody drug conjugate.


On July 2, 2015, the USPTO examiner rejected the then-pending claims for obviousness over combinations of five references. According to the examiner, four of the references taught cancer immunotherapy using anti-161P2F10B antibodies such as H16-7.8 conjugated to auristatins such as monomethyl auristatin E (MMAE) for use in treating cancer, and the fifth reference taught that MMAF is an antimitotic auristatin derivative with a charged C-terminal phenylalanine residue that attenuates its cytotoxic activity compared to its uncharged counterpart, MMAE. The examiner wrote that an artisan would have been motivated to replace MMAE with MMAF based on the fifth reference’s showing of improved therapeutic effects.

In a response dated September 23, 2015, the applicant argued that the first four references would not have motivated an artisan to conjugate the H16-7.8 antibody with MMAF or to target cells expressing 161P2F10B protein with the claimed ADC because the references broadly disclosed more than twenty different monoclonal antibodies and more than fifty different cytotoxic agents, not one of which was MMAF. The applicant also argued that the claimed ADC comprising the claimed H16-7.8 antibody conjugated to MMAF produced surprising results. In support of this argument, the applicant relied on data showing that the H16-7.8 MMAF conjugate inhibited tumor growth for sixty days, a result not obtained with either the H16-1.11 MMAF conjugate or the H16-7.8 MMAE conjugate. The USPTO withdrew the obviousness rejections, and then the ’278 patent issued on April 12, 2016. The examiner wrote that the applicant’s argument of unexpected results was persuasive.


Example 3: Arguments of New Components, No Motivation, and No Reasonable Expectation of Success During the Prosecution of U.S. Patent No. 9,850,312 [8]

The USPTO issued the ’312 patent to Daiichi Sankyo Company, Limited and Sapporo Medical University on December 26, 2017, with claims to ADCs, pharmaceutical compositions comprising the ADCs, antitumor drugs and anticancer drugs containing the ADCs, and methods of treating cancer using the ADCs. For example, independent claim 1 is as follows:

1. An antibody-drug conjugate, wherein a linker and an antitumor compound represented by the following formula and anti-TROP2 antibody are connected:

-(Succinimid-3-yl-N)—CH2CH2CH2CH2CH2—C(=O)-GGFG-NH—CH2—O—CH2—C(=O)—(NH-DX) . . .

wherein the anti-TROP2 antibody comprises CDRH1 consisting of the amino acid sequence of SEQ ID NO: 23, CDRH2 consisting of the amino acid sequence of SEQ ID NO: 24 and CDRH3 consisting of the amino acid sequence of SEQ ID NO: 25 in its heavy chain variable region and CDRL1 consisting of the amino acid sequence of SEQ ID NO: 26, CDRL2 consisting of the amino acid sequence of SEQ ID NO: 27 and CDRL3 consisting of the amino acid sequence of SEQ ID NO:28 in its light chain variable region.


On October 21, 2016, the USPTO examiner rejected the then-pending claims for obviousness over three references. According to the examiner, the first reference taught drug delivery systems in which exatecan is linked to a GGFG tetrapeptide, but not the ADC with anti-TROP2 antibody and the linkers in the then-pending claims. The examiner wrote that the second reference taught ADCs using maleimidocaproyl attached to an amino acid spacer attached to a maytansinoid drug moiety, and that the third reference taught ADCs having the anti-TROP2 antibody hRS7 with a drug. The examiner wrote that it would have been obvious to prepare the ADC using the first reference’s exatecan linked to a GGFG tetrapeptide composition with the maleimidocaproyl of the second reference and the anti-TROP2 antibody of the third reference.

In a response dated January 18, 2017, the applicant amended the claims and argued that the claimed ADC comprised a novel linker having a specific structure and a novel anti-TROP2 antibody. The applicant argued that even if exatecan was known in the art, its ability to maintain and exert antitumor activity in the claimed structure was “a totally new finding” and there was no expectation of success. The applicant also argued that the only cited reference that disclosed an anti-TROP2 antibody did not disclose one with the claimed CDR sequences. The applicant argued that the references did not teach or suggest the claimed antibody or provide the necessary motivation to arrive at the claimed antibody with a reasonable expectation of success. The examiner issued a notice of allowance, and then the ’302 patent issued on December 26, 2017.

Conclusion
Companies developing ADCs should strategically obtain patent protection for their products, keeping in mind that their ability to have a patent granted may hinge on the success of their arguments of nonobviousness of the invention. As seen from the examples above, applicants often use a combination of arguments and claim amendments when responding to an obviousness rejection. By considering how other companies have responded to obviousness rejections by the USPTO, companies can gain insight into how to obtain and preserve patent protection for their own ADC inventions.


How to cite:
Eaton J, Miller P, Cyr SK. Four Ways to Show Nonobviousness of ADC Inventions (2018),
DOI: 10.14229/jadc.2018.10.05.001.


Original manuscript received: August 25, 2018 | Manuscript accepted for Publication: August 21, 2018 | Published online September 27, 2018 | DOI: 10.14229/jadc.2018.10.05.001.

Last Editorial Review: October 5, 2018

Featured Image: Patent Concept button. Courtesy: © Fotolia. Used with permission.

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New Hydrophilic Auristatin Payload Improves Antibody-Drug Conjugate Efficacy and Biocompatibility

Antibody-drug conjugates or ADCs, which link an antibody to a potent, small-molecule, cytotoxic, cell-killing, chemotherapeutic agent, use the target-specificity of monoclonal antibodies or antibody fragments, to adhere exclusively to specific membrane receptors that are characteristic of tumor cells. Following internalization, the potent, anti-cancer drugs, are releases and kill the malignant cell.

This approach creates an excellent control mechanism of drug activation, resulting in an increase of the therapeutic window and, thereby, increasing the use attached drug. However, the therapeutic window of antibody-drug conjugates is still quite narrow, making research in developing a more safe and efficacious ADC technology with a wider therapeutic window a viable field of study.

Current technology
Antibody-drug Conjugates are currently used for the treatment of lymphoma and metastatic breast cancer. Today, four Antibody-drug Conjugates have been approved by the U.S. Food and Drug Administration (FDA). These agents include brentuximab vedotin (Adcetris®; Seattle Genetics) for Hodgkin and anaplastic large cell lymphoma, ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche) for HER2-positive metastatic breast cancer, gemtuzumab ozogamicin (Mylotarg®; Pfizer) for acute myeloid leukemia and inotuzumab ozogamicin (Besponsa®; Pfizer) for the treatment of acute lymphoblastic leukemia.

Unique properties
The unique properties of an antibody-drug conjugate are determined by the balance of its components. One key part is the cytotoxic payload. The efficacy of of the payload are determined by the drug-to-antibody ratio (DAR) – the number of attached drug molecules to the antibody.

Homogeneous DAR = 8 antibody-drug conjugate can be easily prepared by conjugation to the four accessible antibody hinge cystines. And antibody-drug conjugates with higher drug-to-antibody ratios have greater in vitro potency than the current clinically approved ADCs with a DAR of 2 – 4. Furthermore,  the higher DAR antibody-drug conjugates are especially effective against cells with low copy numbers of the target antigen. [1]

However, many clinical programs with higher a DAR have suffered from unwanted toxicity and insufficient efficacy against tumors. In turn, the use of hydrophobic payloads has effectively permitted only DAR = 2–4. This is, in part, due to poor pharmacokinetics and aggregation and systemic exposure. For example, DAR = 8 monomethyl auristatin E (MMAE) antibody-drug conjugates have been shown to be inferior to both ADCs with a drug loading of DAR of 2 and DAR of 4 in vivo. [1][2]

Researchers have shown that by reducing hydrophobicity of homogeneous antibody-drug conjugates it is possible to improve the pharmacokinetics and therapeutic index. These researchers demonstrated that by masking the hydrophobic payloads by hydrophilic linker moieties,antibody-drug conjugates with a drug loading of DAR = 8 and improved in vivo biodistribution and efficacy can be achieved [3].

A novel payload
Tero Satomaa and colleagues at  Glykos Finland, in Helsinki, Finland and OcellO, in Leiden, The Netherlands, generated a novel homogeneous antibody-drug conjugate (MC-Val-Cit-PABC-MMAU) with a DAR = 8.  Their antibody-drug conjugate includes a novel monomethyl auristatin β-D-glucuronide (MMAU).[4]

Their glycoside payload contributed to overall hydrophilicity of the antibody-drug conjugates, reducing aggregation. Furthermore, compared to standard drug loading of DAR 2 and 4, the cytotoxicity of the homogeneous ADC with a DAR of 8 was improved to low-picomolar IC50 values against cancer cells in vitro.

Although unconjugated MMAU was relatively non-toxic to cells, the bystander efficacy was restored after internalization and subsequent cleavage of the glycoside. The researchers concluded that their novel monomethyl auristatin β-D-glucuronide (MMAU) antibody-drug conjugate with a DAR of 8 was effective against target antigen-expressing xenograft tumors. Furthermore, studied in 3D in vitro patient-derived xenograft (PDX) assays, these antibody-drug conjugates outperformed clinically used ADC.

Overall, the researchers found that MMAU is a promising novel payload and can overcome many challenges of ADC technology. They demonstrated that the increased hydrophilicity of the payload contributed to the hydrophilicity and stability of antibody-drug conjugates as well as the safety to non-target cells, while significantly improving cytotoxicity to malignant cells and enabling bystander efficacy.


Last Editorial Review: June 22, 2018

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AACR 2018: Highlighting Novel Antibody-Drug Conjugate Technologies and Immuno-Oncology

This year, the American Association for Cancer Research (AACR) will host their annual meeting April 14 – 18, 2018 in the McCormick Place North/South in Chicago, Illinois, USA.

Since the 2017 annual meeting, a dramatic wave of progress in against cancer has come to fruition and basic science findings have resulted in new drug approvals. Much has been accomplished in expanding the  use of genomic data for precision medicine and a greater focus on “big data” has helped accelerate progress in cancer research. ‘Big data’ has become crucial in helping scientists use mathematics, engineering, and artificial intelligence to diagnose cancer at an earlier stage, which helps improves outcomes.

In the last 12 months there has been a more focused and concentrated efforts to help eliminate persistent disparities – helping minorities and the medically underserved.

These developments are definitely reflected in the theme of the American Association for Cancer Research annual meeting: ‘Driving Innovative Cancer Science to Patient Care.’

The meeting is expected to draw more than 20,000 scientists, clinicians, advocates, and others to discuss advances in the field of cancer science. The multidisciplinary program will include an outstanding roster of speakers, hundreds of invited talks.

Antibody-drug Conjugates
Among the many papers and presentations, expect to find data highlights from nine presentations showcasing the Seattle Genetics’ innovative, proprietary antibody-drug conjugate or ADC platform technologies as well as its emerging immuno-oncology pipeline.

The data to be presented includes preclinical and clinical advances with brentuximab vedotin (Adcetris®; Seattle Genetics/Takeda), ladiratuzumab vedotin, SGN-CD48A and SGN-2FF as well as  the first preclinical data describing the novel empowered antibody SEA-BCMA, being developed by Seattle Genetics.

“We are an emerging multi-product company, advancing a substantial pipeline of targeted therapies for patients with solid tumors and blood cancers,” said Dennis Benjamin, Ph.D., Senior Vice President of Research at Seattle Genetics.

“New data featured in nine presentations underscore our commitment to scientific innovation and the needs of patients. These data presentations highlight the potential combination of ADCs with checkpoint inhibitors, novel ADC payloads, antibody masking technologies and progress with our immuno-oncology program, SGN-2FF. We are also presenting preclinical data for our new multiple myeloma program, SEA-BCMA, which has a phase 1 study scheduled to start this year,” Benjamin added.

Presentations
The information presented includes an oral and poster presentations on Sunday and Monday, April 15 and 16, 2018, respectively (Abstracts #930, 2803), showcasing preclinical data evaluating proprietary NAMPT inhibitors and auristatins as ADC payloads. The data show NAMPT inhibitors have a unique mechanism of action and encouraging therapeutic window. Preclinical data also describe the development of novel auristatin payloads with potential application across multiple tumor types.

An innovative approach to masking antibodies for tumor specific activation will be featured in a poster presentation on Sunday, April 15, 2018 (Abstract #250). Preclinical data demonstrate that coiled-coil masked antibodies and antibody-drug conjugates show improved tolerability and equivalent antitumor activity compared to unmasked counterparts. The data suggest this technology may be applied to a range of antibodies or ADCs and could enable their development against previously inaccessible cancer targets.

The novel preclinical program SEA-BCMA will be highlighted in a poster presentation on Tuesday, April 17, 2018 (Abstract #3833). The cell surface protein BCMA is expressed on cells of several cancer types, including multiple myeloma and other B cell malignancies. SEA-BCMA is an antibody empowered using Seattle Genetics’ proprietary Sugar Engineered Antibody (SEA) technology designed to enhance antibody effector functions. The preclinical data support initiation of a phase I trial for multiple myeloma, which is planned for 2018.

Clinical biomarker data from a phase I trial evaluating the novel immuno-oncology agent SGN-2FF in patients with advanced solid tumors will be shown in a poster presentation on Wednesday, April 18, 2018 (Abstract #5551). The preliminary data demonstrate the biological effects of SGN-2FF and support further development of this novel immuno-oncology agent.

Three poster presentations on Monday and Wednesday, April 16 and 18, 2018 (Abstracts #1789, 2742, and 5619) will highlight preclinical data evaluating the ability of brentuximab vedotin, ladiratuzumab vedotin and SGN-CD48A, each of which are auristatin-based ADCs, to elicit additional mechanisms of action, including immunogenic cell death. These data support clinical evaluation in combination with checkpoint inhibitors. Brentuximab vedotin and ladiratuzumab vedotin are being evaluated in combination with checkpoint inhibitors in multiple ongoing clinical trials.

ADC Therapeutics
Other data includes the latest updated from investigational programs highlight strong preclinical data for its two new investigational programs ADCT-601 targeting AXL and ADCT-701 targeting DLK-1 being developed by ADC Therapeutics. In addition, Jaewoong Lee, Ph.D, of The Beckman Institute of the City of Hope is expected to present the latest update on novel preclinical data for ADCT-301 targeting CD25.

“Our two new investigational programs show compelling efficacy and safety in preclinical studies,” noted Jay M. Feingold, MD, Ph.D, Chief Medical Officer and Senior Vice President of Clinical Development at ADC Therapeutics.

“These results provide an important step to advance ADCT-601 and ADCT-701 into the clinic and enlarge our pipeline of PBD-based ADCs in multiple ongoing clinical trials for the treatment of both solid and hematological cancers,” Feingold added.

Presentations
Presentations include updated about ADCT-701, a novel pyrrolobenzodiazepine (PBD) dimer-based antibody-drug conjugate (ADC) targeting DLK1-expressing tumors. (Abstract #744, April 15, 1:00 pm – 5:00 pm CT). The ADC is site-specifically conjugated using GlycoConnect™ technology to PL1601, which contains a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199. The investigational agent has demonstrated potent and specific in vitro and in vivo anti-tumor activity in DLK1-expressing cancer-derived models and it was stable and well tolerated in rats.

Another updated includes the latest update of the preclinical activity of ADCT-601, a novel pyrrolobenzodiazepine (PBD) dimer-based antibody-drug conjugate (ADC) targeting AXL-expressing tumors (Abstract #2792A, April 16, 1:00 pm – 5:00 pm CT). ADCT-601 is an ADC composed of a humanized IgG1 antibody against human AXL, site-specifically conjugated using GlycoConnect™ technology to PL1601, which contains a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199. The investigational agent has demonstrated potent and specific in vitro and in vivo anti-tumor activity in various cancer-derived models with different levels of membranous AXL, and it was stable and well tolerated in rats.

CD25 enables oncogenic BCR- and TCR-signaling and represents a therapeutic target in lymphoblastic malignancies (Abstract #2983, April 16, 2018, 4:05 PM – 4:20 PM). Novel data identifies CD25 as a previously unrecognized feedback regulator of oncogenic B/TCR-signaling supporting CD25 as a therapeutic target in refractory lymphoid malignancies. ADC Therapeutics’ ADCT-301 has demonstrated durable remissions in patient-derived Ph+ ALL cells PDX models

Eleven Biotherapeutics
Eleven Biotherapeutics, a late-stage clinical company developing next-generation antibody-drug conjugate therapies is expected to present preclinical data from the company’s novel, next-generation ADC program using an innovative deBouganin cytotoxic protein payload.

“We have uniquely designed our deBouganin payload to address tumor indications that can only be reached through systemic delivery. Our data show that deBouganin exhibits certain advantages over first-generation ADCs, which use more conventional small molecule cytotoxins, with respect to cell killing power, including the ability to kill cancer stem cells, circumvent multi-drug resistance and avoid cross-resistance mechanisms,” said Gregory P. Adams, Ph.D., Chief Scientific Officer of Eleven Biotherapeutics.

“We are pleased to be presenting these promising data highlighting the potential activity and differentiation of our approach compared to first-generation ADCs,” he added.

Presentations
DeBouganin is a proprietary de-immunized variant of bouganin, a ribosome inactivating protein that when internalized blocks protein synthesis, thereby leading to cell death. Eleven Biotherapeutics will present data from its VB6-845d program, a next-generation ADC comprised of a Fab fragment specific for the epithelial cell adhesion molecule (EpCAM) genetically linked to deBouganin via a furin protease sensitive peptide. Data being presented suggest that VB6-845d mediates tumor cell killing by an immunogenic cell death (ICD) pathway. The potential cross-priming effect initiated by VB6-845d-induced ICD suggests that VB6-845d in combination with immune checkpoint inhibitors may enhance their effectiveness in EpCAM-positive epithelial cancers. Poster presentation: VB6-845d Tumor Cell Killing Elicits Biologic Features of Immunogenic Cell Death (Date and Time: April 16, 2018 from 1:00 to 5:00 p.m. CT)

Targeted protein therapeutics or TPTs are single-protein therapeutics composed of targeting moieties genetically fused via peptide linker to cytotoxic protein payloads. TPTs are designed to overcome efficacy and safety challenges inherent within ADCs. Poster presentation: Engineering and Characterization of Anti-PSMA Humabody-DeBouganin Fusion Proteins (April 18, 2018 from 8:00 a.m. to 12:00 p.m. CT).


Last Editorial Review: April 12, 2018

Featured Image: New Orleans, LA – The AACR 2016 Annual Meeting. Courtesy: © AACR/Scott Morgan. Used with permission.

Copyright © 2013 – 2018 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Brentuximab Vedotin in Combination with Chemotherapy Approved for Adults with Previously Untreated Stage III or IV Classical Hodgkin Lymphoma

The U.S. Food and Drug Administration (FDA) has approved brentuximab vedotin (Adcetris®; Seattle Genetics/Takeda) in combination with chemotherapy in adult patients with previously untreated Stage III or IV classical Hodgkin lymphoma. This is the first FDA-approved regimen in this disease in more than 40 years

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Classical Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell expresses CD30.

According to the American Cancer Society, approximately 8,500 cases of Hodgkin lymphoma will be diagnosed in the United States during 2018 and more than 1,000 will die from the disease. Approximately half of all newly diagnosed Hodgkin lymphoma patients have Stage III/IV disease. According to the Lymphoma Coalition, over 62,000 people worldwide are diagnosed with Hodgkin lymphoma each year and approximately 25,000 people die each year from this cancer.


…this label expansion, based on clinical Trial Results from the Phase III ECHELON-1 Clinical Trial, represents fifth U.S. Food and Drug Administration (FDA) indication for brentuximab vedotin in the United States… and… the ECHELON-1 Clinical Trial also converts prior accelerated approval to regular approval in treatment of relapsed systemic anaplastic large cell lymphoma…


In finding a treatment option for major unmet medical needs, researcher at Seattle Genetics and their global partner Takeda, developed the targeted drug brentuximab vedotin,  an antibody-drug conjugate or ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE).  The drug utilizing Seattle Genetics’ proprietary linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

Successful outcome
The approval is based on the successful outcome of the phase III ECHELON-1 clinical trial that compared brentuximab vedotin plus AVD (Adriamycin, vinblastine and dacarbazine) to ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine).

In addition, data from the ECHELON-1 trial converted the U.S. accelerated approval of brentuximab vedotin for the treatment of adults with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one multi-agent chemotherapy regimen to regular approval.

In October 2017, the FDA granted Breakthrough Therapy Designation (BTD) to brentuximab vedotin in combination with chemotherapy for the frontline treatment of patients with advanced classical Hodgkin lymphoma. The FDA also granted Priority Review for the supplemental Biologics License Application (BLA), and the Prescription Drug User Fee Act (PDUFA) target action date was May 1, 2018.

“The standard of care for treating newly diagnosed advanced Hodgkin lymphoma has not changed in more than four decades. For years, the physician community has been conducting clinical trials to identify improved regimens that are both less toxic and more effective to no avail,” said Joseph M. Connors, M.D., FRCPC, Clinical Director, Center for Lymphoid Cancer at BC Cancer in Vancouver, Canada.

“The ECHELON-1 study results demonstrated superior efficacy of the brentuximab vedotin plus chemotherapy regimen when compared to the standard of care while removing bleomycin, an agent that can cause unpredictable and sometimes fatal lung toxicity, completely from the regimen. This represents a meaningful advance for this often younger patient population,” Connors added.

Approved indications
This is the fifth FDA-approved indication for brentuximab vedotin, which also has regular approval for adult patients with: classical Hodgkin lymphoma (cHL) at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation, cHL after failure of auto-HSCT or failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, sALCL after failure of at least one prior multi-agent chemotherapy regimen, and primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.

“Currently, up to 30% of newly diagnosed advanced-stage classical Hodgkin lymphoma patients will experience disease progression after treatment with the current standard of care, representing a significant need for improved treatment options for these often younger patients,” said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

Schematic: The ECHELON-1 trial is a Phase III trial in Frontline Therapy of Patients With Advanced Classical Hodgkin Lymphoma (NCT01712490).

“The ECHELON-1 trial was a bold, five-year effort to redefine the frontline treatment of Stage III/IV classical Hodgkin lymphoma and provide patients with a more effective treatment regimen. In the ECHELON-1 study, brentuximab vedotin plus AVD was shown to have superior efficacy to ABVD. With today’s FDA approval, the physician and patient community have a new treatment option for previously untreated Stage III or IV Hodgkin lymphoma patients. We want to thank all of the patients, physicians and their staff who participated in the ECHELON-1 trial which supported the FDA approval of this novel regimen,” Siegal added.

FDA approval
The FDA approval is based on positive results from a phase 3 trial called ECHELON-1 that were presented at the 59th American Society of Hematology (ASH) annual meeting in December 2017 with simultaneous publication in the New England Journal of Medicine.[1] Results from the ECHELON-1 trial in 1,334 Stage III or IV classical Hodgkin lymphoma patients confirmed that the trial achieved its primary endpoint with the combination of brentuximab vedotin plus AVD resulting in a statistically significant improvement in modified progression-free survival (PFS) versus the control arm of ABVD as assessed by an Independent Review Facility (IRF) (HR 0.77; 95% CI, 0.60-0.98; p-value=0.035). This corresponds to a 23 percent reduction in the risk of progression, death or need for additional anticancer therapy in patients not in complete response (CR) after frontline treatment.

Overall survival (OS) was a key secondary endpoint and the rate of CR per IRF assessment at the end of the randomized regimen was a secondary endpoint. At the time of the modified PFS analysis, an interim OS analysis trended in favor or the brentuximab vedotin plus AVD arm, but did not demonstrate significant difference (HR 0.72; 95% CI, 0.44-1.17; p-value=0.19). The CR rate was 73% on the brentuximab vedotin plus AVD arm and 70 percent on the ABVD arm.

The safety profile of brentuximab vedotin plus AVD in the ECHELON-1 trial was generally consistent with that known for the single-agent components of the regimen.

Adverse events
The most common adverse events of any grade that occurred in at least 10 percent of patients in the ADCETRIS plus AVD arm were: anemia, neutropenia, peripheral sensory neuropathy, constipation, vomiting, diarrhea, pyrexia, decreased weight, stomatitis, abdominal pain, febrile neutropenia, bone pain, insomnia, decreased appetite, back pain, rashes/eruptions/exanthemas, dyspnea, peripheral motor neuropathy, and increased alanine aminotransferase.

In both the brentuximab vedotin plus AVD and ABVD arms, the most common Grade 3 or 4 events were neutropenia, febrile neutropenia, and anemia.

Based on ECHELON-1 clinical trial results, prophylactic growth factors (G-CSF) should be administered starting at cycle one for Stage III or IV classical Hodgkin lymphoma patients receiving brentuximab vedotin plus AVD.

More trials
Brentuximab vedotin is being evaluated broadly in more than 70 clinical trials. This includes two ongoing phase III studies, the ECHELON-2 trial in frontline mature T-cell lymphomas and the CHECKMATE 812 trial of brentuximab vedotin in combination with nivolumab (Opdivo®; Bristol-Myers Squibb Company) for relapsed/refractory Hodgkin lymphoma.


Last Editorial Review: March 20, 2018

Featured Image: Micrograph of Hodgkin lymphoma. Lymph node FNA specimen. Field stain. The micrograph shows a mixture of cells common in Hodgkin Lymphoma, including Eosinophils, Reed-Sternberg cells, Plasma cells and Histocytes.. Courtesy: © 2018 Fotolia. Used with permission.

Copyright © 2013 – 2018 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Brentuximab Vedotin Receives European Commission Approval for CD30-Positive Cutaneous T-Cell Lymphoma after Prior Systemic Therapy

The European Commission has extended the current conditional marketing authorization for brentuximab vedotin (Adcetris®; Takeda/Seattle Genetics) to include the treatment of adult patients with CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy.

Brentuximab vedotin is an antibody-drug conjugate or (ADC) directed to CD30, which is expressed on the surface of Hodgkin lymphoma cells and several types of non-Hodgkin lymphoma, including CTCL.

The agent includes an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), using Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.


The approval of brentuximab vedotin in this setting brings a much needed, effective treatment option to patients living with CTCL … who have received one prior systemic therapy…


The decision to approve brentuximab follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) on November 9, 2017, and is based on positive results from the phase III ALCANZA Trial which demonstrated a highly statistically significant improvement in rate of objective response lasting at least four months, median progression-free survival, and improvement in symptom burden in the trial’s brentuximab vedotin arm.

Lymphoma
Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Cutaneous lymphomas are a category of non-Hodgkin lymphoma that primarily involve the skin. According to the Cutaneous Lymphoma Foundation, CTCL is the most common type of cutaneous lymphoma and typically presents with red, scaly patches or thickened plaques of skin that often mimic eczema or chronic dermatitis.

The most common subtypes of CTCL include mycosis fungoides and primary cutaneous anaplastic large cell lymphoma. Progression from limited skin involvement may be accompanied by skin tumor formation, ulceration and exfoliation, complicated by itching and infections. Advanced stages are defined by involvement of lymph nodes, peripheral blood and internal organs. The standard treatment for CTCL patients includes skin-directed therapies, radiation and systemic therapies. Prior to the FDA approval of brentuximab vedotin, systemic therapies approved for treatment demonstrated 30 to 45 percent objective response rates, with low complete response rates.

Debilitating and disfiguring
“CD30-positive cutaneous T-cell lymphoma or CTCL is a debilitating and disfiguring disease with few effective and durable treatment options,” said Clay Siegall, Ph.D., President and Chief Executive Officer at Seattle Genetics, Takada’s North American Partner and co-developer of brentuximab vedotin.

“[This disease] is a subtype of non-Hodgkin lymphoma that primarily involves the skin; it typically presents with red, scaly patches or thickened plaques of skin that often mimics eczema or psoriasis and can have a substantial impact on patients’ self-esteem. There are few approved CTCL treatment options with only limited efficacy, creating a significant unmet need for these patients,” explained Julia Scarisbrick, M.D., Department of Dermatology, University Hospital Birmingham, Birmingham, UK.

“The approval of brentuximab vedotin in this setting brings a much needed, effective treatment option to patients living with CTCL and I am looking forward to be able to offer this treatment to CD30-positive patients who have received one prior systemic therapy,” she added.

Collaboration
“The approval of [brentuximab vedotin] for use in the European Union in CD30-positive CTCL patients represents a meaningful advance for patients with CTCL. We are pleased that our partner Takeda is able to make this therapeutic option available to patients in Europe. Since [brentuximab vedotin] was first approved by the U.S. Food and Drug Administration (FDA) in 2011, Seattle Genetics and Takeda have made significant progress in our goal to establish [brentuximab vedotin] as the foundation of care for CD30-expressing lymphomas, and we are working together on our next milestone of securing FDA approval and European Union marketing authorization for the use of brentuximab vedotin as a treatment for frontline advanced Hodgkin lymphoma,” Siegall added.

“Today’s approval is an important milestone for the CTCL community in Europe, and further reinforces the role brentuximab vedotin may have in improving outcomes and quality of life for patients with CD30-positive malignancies,” said Jesus Gomez Navarro, M.D., Vice President, Head of Oncology Clinical Research and Development, Takeda. “The clinical data that supported this approval are exceptionally strong. We are proud to be the company to bring a novel treatment option with impressive efficacy and a manageable safety profile to appropriate CTCL patients in the European Union.”

Foundation of care
“As a distinct subset of non-Hodgkin lymphoma, cutaneous lymphoma is generally visible on the skin, and can cause significant discomfort. This can result in serious emotional distress and impacts qualify of life for patients who are afflicted,” said Susan Thornton, CEO, Cutaneous Lymphoma Foundation. “There is no known cure, and only a few new treatment options have been introduced over the last several years. This is a welcome new treatment option for cutaneous lymphoma patients in Europe.”

European Union
The marketing authorization for brentuximab vedotin is valid in 28 countries of the European Union (EU), Norway, Liechtenstein and Iceland. It is based on positive results from a phase 3 trial called brentuximab vedotin that were presented at the 58th American Society of Hematology (ASH) annual meeting in December 2016, published online in the Lancet in June 2017, and recently updated in a poster presentation at the 59th ASH annual meeting in December 2017.

Alcanza trial
Figure 1.0: The Alcanza trials is a randomized , open label, Phase III study of Brentuximab Vedotin vs. Physician’s Choice (Methotrexate or Bexarotene) in patients with CD30+ Cutaneous T-Cell Lymphoma. (Study: NCT01578499).

The trial achieved its primary endpoint with the brentuximab vedotin treatment arm demonstrating a highly statistically significant improvement in the rate of objective response lasting at least four months (ORR4) versus the control arm as assessed by an independent review facility. The ORR4 was 56.3 percent in the brentuximab vedotin arm compared to 12.5 percent in the control arm (p-value <0.001).

The key secondary endpoints specified in the protocol, including complete response rate, progression-free survival and reduction in skin symptom burden as measured by the Skindex-29 questionnaire, were all highly statistically significant in favor of the brentuximab vedotin arm. The safety profile associated with brentuximab vedotin from the ALCANZA trial was generally consistent with the existing prescribing information. The most common adverse events of any grade include: anemia, peripheral sensory neuropathy, nausea, diarrhea, fatigue and neutropenia.

In November 2017, the U.S. Food and Drug Administration (FDA) approved brentuximab vedotin for the treatment of adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy based on the results of the phase III ALCANZA clinical trial. Together, pcALCL and CD30-expressing MF comprise approximately 70 percent of CTCL diagnoses and the majority of patients who require systemic therapy. Brentuximab vedotin is currently not approved as a frontline therapy for Hodgkin lymphoma.

Joint development
Seattle Genetics and Takeda are jointly developing brentuximab vedotin. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize brentuximab vedotin in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for brentuximab vedotin on a 50:50 basis.  In Japan Takeda is solely responsible for development costs.


Last Editorial Review: January 23, 2018

Featured Image: Flags in front of the EU Commission building in Brussels, Belgium Courtesy: © 2010 – 2017 Fotolia. Used with Permission.

Copyright © 2010 – 2018 InPress Media Group, LLC. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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The Expanding Field of Antibody-Drug Conjugates

Antibody-drug conjugates or ADCs have emerged as a powerful and strategy tool in the targeted treatment of cancer.  These relatively novel agents combine the ability of monoclonal antibodies to specifically target tumor cells, which express specific antigens on their surface, with the highly potent killing activity of a cytotoxic drug with payloads which is generally too toxic for systemic administration. In contrast to conventional, standard, treatments, antibody-drug conjugates cause less damage to healthy tissues.[1]

This approach, has, over the last two decades led to a paradigm shift in cancer chemotherapy.

Today, a number of different ADC-based treatments options are available for both including hematological malignancies and solid tumors. These options have dramatically increased the efficacy of treatment and are now considered among the most promising strategies used for targeted therapy of patients with a variety of malignancies.

Although much progress has been made, the therapeutic success of future antibody-drug conjugates depends on closely choosing the target antigen, increasing the potency of the cytotoxic cargo, improving the properties of the linker, and reducing drug resistance.[1]


Antibody-drug Conjugates are an integral part of an evolving cancer treatment paradigm, and we are committed to bringing important new treatments to patients in need…


Approved drugs
Today, there are 4 antibody-drug conjugates approved and commercially available in the United States. Until the summer of 2017 brentuximab vedotin (Adcetris®; Seattle Genetics) and ado-trastuzumab entansine (Kadcyla®; Genetech/Roche) were the only commercially available ADCs. Then, on August 17, 2017, the U.S. Food and Drug Administration (FDA) approved inotuzumab ozogamicin (Besponsa™, Wyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc.) for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) and only weeks later, gemtuzumab ozogamicin (Mylotarg™, previously known as CMA-676; Wyeth Pharmaceuticals, a subsidiary of Pfizer) for the treatment of adults with newly diagnosed CD33-positive acute myeloid leukemia or AML, and adults and children 2 years and older with relapsed or refractory CD33-positive AML was again approved, bringing the number of commercially available ADCs to four.

In addition, there are nearly 175 investigational ADCs in development – from early discovery to pivotal, late stage, clinical phase III studies (see Drugmap in ADC Review | Journal of Antibody-drug Conjugates).

J.P. Morgan Healthcare Conference
Earlier this year, during the 36th Annual J.P. Morgan Healthcare Conference in San Francisco, Seattle Genetics highlighted the progress of its pipeline of antibody-drug conjugates.

Through both internal efforts and efforts of its collaborators, Seattle Genetics’ Antibody-drug Conjugate technology is being employed in more than 20 clinical trial programs.  Some of these study programs include a number of late-state development programs across both hematologic malignancies and solid tumors.

Important therapeutic modality
“ADCs continue to advance as an important therapeutic modality, both as single agents and as part of various combination regimens, across hematologic malignancies and solid tumors,” noted Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

“We are the industry leader in ADC technology driven by our scientific expertise in monoclonal antibodies, drug payloads and stable linker technologies. Our leadership is further illustrated by the continued clinical and commercial expansion of brentuximab vedotin (Adcetris®; Seattle Genetics), progress with our late-stage programs enfortumab vedotin and tisotumab vedotin, and the breadth of our pipeline of other ADCs and empowered antibodies,” Siegall further noted.

Addressing the success of the company’s partners, Siegal observed: “Our collaborators are making significant advances with several programs using our technology. Antibody0drug Conjugates ADCs are an integral part of an evolving cancer treatment paradigm, and we are committed to bringing important new treatments to patients in need,”

CD30-Expressing Lymphomas
Overexpression of CD30, a 120-kDa type I trans-membrane glycoprotein belonging to the tumor necrosis factor (TNF) receptor superfamily, has been reported in Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL). Treatment with CD30-targeted antibody-drug conjugates, including brentuximab vedotin can lead to promising clinical benefit.

Brentuximab vedotin, which is developed by Seattle Genetics and Takeda Pharmaceuticals on a 50:50 basis is commercially available in 70 countries worldwide and generated more than $600 million in global sales in 2017.

On January 2, 2018 the U.S. Food and Drug Administration (FDA) accepted Seattle Genetics’ filing for supplemental Biologics License Application (BLA) of brentuximab vedotin in combination with chemotherapy for the frontline treatment of patients with advanced classical Hodgkin lymphoma.

Schematic: The ECHELON-1 trial is a Phase III trial in Frontline Therapy of Patients With Advanced Classical Hodgkin Lymphoma (NCT01712490).

The FDA granted Priority Review for the application, and the Prescription Drug User Fee Act (PDUFA) target action date is May 1, 2018. The submission of the supplemental BLA is based on positive results from a phase III clinical trial called ECHELON-1. In October 2017, the FDA granted Breakthrough Therapy Designation (BTD) for brentuximab vedotin in frontline advanced Hodgkin lymphoma based on the ECHELON-1 study results.

Enfortumab vedotin
In addition to advancing brentuximab vedotin, Seattle Genetics and its collaborator Astellas have initiated a pivotal phase II clinical trial of enfortumab vedotin for patients with locally advanced or metastatic urothelial cancer who have been previously treated with checkpoint inhibitor (CPI) therapy. The study is designed to support potential registration under the FDA’s accelerated approval regulations.

Seattle Genetics, in collaboration with its development partner Genmab, also plans to initiate a phase II clinical trial of tisotumab vedotin for patients with recurrent and/or metastatic cervical cancer. This study is intended to support potential registration under the FDA’s accelerated approval regulations.

Late stage trials
A number of companies, including GlaxoSmithKline, Genentech/Roche and AbbVie are including Seattle Genetics’ proprietary ADC-technologies in the development of their ADC-programs. These programs include:

  • GSK2857916, an ADC being developed by GlaxoSmithKline (GSK) for multiple myeloma. GSK recently reported encouraging data from the program at the 59th American Society of Hematology (ASH) annual meeting in December 2017;
  • Polatuzumab vedotin, an ADC being developed by Genentech/Roche. Positive results were presented at ASH from a phase 2 trial in advanced-stage diffuse large B-cell lymphoma. A phase 3 trial is underway; and,
  • Depatuxizumab mafodotin, an ADC for glioblastoma in development by AbbVie. Encouraging data have been reported from this ADC, which is currently in a phase 3 clinical trial.

Genentech/Roche’s Polatuzumab vedotin and GlaxoSmithKline’s GSK2857916 have both received Breakthrough Therapy Designation from the FDA and PRIority MEDicines (PRIME) designations from the European Medicines Agency. These designations signify the importance of therapies such as these in addressing significant unmet medical need.

“Through our robust internal development efforts and our strong licensing and co-development agreements, we are extending the potential of ADCs globally. We look forward to future results of studies that include Seattle Genetics’ novel technologies both as monotherapies, as well as in combination with checkpoint inhibitors and other agents,” said Siegall concluded.

Anti-CD30-LDM ADC
The development of novel antibody-drug conjugates is rapidly expanding. Researchers at Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, China, are working on the development of a novel enediyne-integrated antibody-drug conjugate.[2]

This development involves lidamycin or LDM, which consists of an apoprotein LDP and an active enediyne chromaphore AE. Lidamycin is a member of the enediyne antibiotic family and one of the most potent antitumor agents. Researchers consider lidamycin to be an ideal payload for the preparation of ADCs.

In one study, the researchers demonstrated that the anti-CD30-LDM ADC, a novel ADC consisting of the intact anti-CD30 antibody and lidamycin, is highly cytotoxic to Hodgkin lymphoma and anaplastic large cell lymphoma cell lines with IC50 values of 5~50 pM. In using a Karpas299 xenograft model, the ADC inhibited tumor growth by 87.76% in mice treated with the investigational agent. Interestingly, the researchers did not observe discernible adverse effects.

Based on the results of their study, the researchers concluded that the anti-CD30-LDM offers attractive tumor targeting capability and anti-tumor efficacy both in vitro and in vivo and could be a promising candidate for the treatment of CD30+ lymphomas.

Other programs
Altough the first-generation ADCs have been commercialized, researchers around the globe are concerned that that the amount of the cytotoxic payload that can be loaded onto a single antibody molecule is still relatively low. Theeir concern also includes the fact that synthetic linkers used in some antibody-drug conjugates may be unstable, and, that as a result the cytotoxic payload may become detached, leading to the onset of adverse drug reactions. As such, ADC technologies are still evolving, and many companies are currently working to develop next-generation ADC technologies.

Among these next generation ADCs is trastuzumab deruxtecan (also known as DS-8201), being developed by Daiichi Sankyo. Trastuzumab deruxtecan is an antibody-drug conjugate comprised of a humanised antibody against HER2, a novel enzyme-cleavable linker and irinotecan, a topoisomerase I inhibitor, payload, which stimulates DNA synthesis.

Daiichi Sankyo’s ADCs also utilize proprietary technologies characterized by a structure of unique linkers connecting the drug and the antibody. The technology being developed also allows for the linker and the payload to be combined with various antibodies. By capitalizing on this characteristic, researchers at the company aim to maximize the value of these technologies through internal efforts and possibly through external collaboration

Mersana’s Dolaflexin
During the 2018 36th Annual J.P. Morgan Healthcare Conference, Anna Protopapas, President and Chief Executive Office of Mersana Therapeutics outlined her company’s goals. The company is a clinical-stage biopharmaceutical company focused on discovering and developing a pipeline of antibody drug conjugates (ADCs) based on its Dolaflexin® and other proprietary platforms.

“2017 was a year of exceptional execution as we positioned the company for achieving key clinical milestones in 2018 and beyond. Last year, we advanced two lead ADC product candidates, XMT-1522 and XMT-1536, into the clinic and supported our partner Takeda in selecting its first Dolaflexin-based ADC for initiation of IND enabling studies,” Protopapas said.

“We’re looking forward to 2018, as we plan to complete the dose escalation phase of the Phase I study for XMT-1522 and present the data at a scientific conference, as well as substantially complete recruitment of the dose expansion cohorts for XMT-1522. We also expect to continue dose escalation for XMT-1536 and select our next ADC candidate for clinical development. We will persist in building a strong organization that is passionately dedicated to scientific excellence, focused execution and addressing patient needs,” she added.

Mersana’s pipeline includes two compounds in Phase I clinical trials:

  • XMT-1522, a Dolaflexin ADC targeting HER2-expressing breast cancer, non-small cell lung cancer (NSCLC) and gastric cancer, which, in  dose escalation studies, has been administered to six dose cohorts with the sixth dose cohort currently in safety evaluation.  Preclinical data on XMT-1522 presented at AACR 2017 supported potential synergy with immune checkpoint inhibitors, and
  • XMT-1536, a first-in-class Dolaflexin ADC targeting NaPi2b, a clinically validated ADC target broadly expressed in epithelial ovarian cancer and non-squamous NSCLC, as well as a number of other tumor types. In dose escalation studies, XMT-1536 has enrolled and cleared the first dose level.

Protopapas explained that she expects to continue the dose escalation study to establish Maximum Tolerated Dose (MTD) for XMT-1522, and will be able to select Recommended Phase II Dose (RP2D) and substantially enroll dose expansion cohorts. She also expects to continue the dose escalation study to establish MTD for XMT-1536.

New platform technologies
In addition to the results of these investigational agents, Protopapas confirmed that the company has ongoing, robust research programs in place, which positions Mersana to deliver an additional investigational new drug (IND) every 12-24 months.  She expects that the company will be able to disclose pre-clinical data of the next ADC clinical candidate at an upcoming scientific meeting. More excitedly, she  also hopes to disclose new proprietary platform technologies at an upcoming scientific meeting.


Last Editorial Review: January 19, 2018

Featured Image: The San Francisco Bay Bridge Courtesy: © 2010 – 2017 Sunvalley Communication/Evan Wendt.

Copyright © 2010 – 2018 InPress Media Group, LLC. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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U.S. FDA Grants Priority Review for Brentuximab Vedotin in Frontline Advanced Hodgkin Lymphoma

Based on positive results from the Phase III ECHELON-1 clinical trial, the U.S. Food and Drug Administration (FDA) has accepted for filing a supplemental Biologics License Application (BLA) for brentuximab vedotin (Adcetris®; Seattle Genetics) in combination with chemotherapy for the frontline treatment of patients with advanced classical Hodgkin lymphoma.

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Classical Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell.

The Reed-Sternberg cell expresses CD30. Although the currently used standard of care frontline combination chemotherapy can result in durable responses, up to 30% of patients with advanced Hodgkin lymphoma relapse or are refractory to frontline treatment.


…the data demonstrated superior activity of the brentuximab vedotin-containing regimen over standard of care…


According to the American Cancer Society, approximately 8,260 cases of Hodgkin lymphoma will be diagnosed in the United States during 2017 and more than 1,000 will die from the disease. According to the Lymphoma Coalition, over 62,000 people (including early and advanced stage) worldwide are diagnosed with Hodgkin lymphoma each year and approximately 25,000 people die each year from this cancer.

ECHELON-1 trial
The randomized, open-label, Phase III ECHELON-1 trial (NCT01712490) is investigating brentuximab vedotin, an antibody-drug conjugate or ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to the microtubule disrupting agent monomethyl auristatin E (MMAE), using Seattle Genetics’ proprietary technology, plus AVD (Adriamycin, vinblastine, dacarbazine) versus ABVD (AVD + bleomycin) as frontline therapy in patients with advanced classical Hodgkin lymphoma. The primary endpoint is modified PFS per Independent Review Facility assessment using the Revised Response Criteria for Malignant Lymphoma. [1]

Schematic: The ECHELON-1 trial is a Phase III trial in Frontline Therapy of Patients With Advanced Classical Hodgkin Lymphoma (NCT01712490).

Modified PFS is defined as the time to progression, death or receipt of additional anticancer therapy for patients who are not in complete response after completion of frontline therapy per Independent Review Facility. Secondary endpoints include overall survival, complete remission and safety. The multi-center trial was conducted in North America, Europe, South America, Australia, Asia and Africa. The study enrolled 1,334 patients who had a histologically-confirmed diagnosis of Stage III or IV classical Hodgkin lymphoma and had not been previously treated with systemic chemotherapy or radiotherapy. The ECHELON-1 trial was conducted under a Special Protocol Assessment (SPA) agreement from the FDA and the trial also received EMA scientific advice.

The FDA granted Priority Review for the application, and the Prescription Drug User Fee Act (PDUFA) target action date is May 1, 2018. The submission of the supplemental BLA is based on positive results from a Phase III clinical trial called ECHELON-1 that was designed to determine if brentuximab vedotin in combination with chemotherapy could extend modified progression-free survival (modified PFS) in previously untreated advanced classical Hodgkin lymphoma patients. Brentuximab vedotin is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical Hodgkin lymphoma.

Photo 1.0: Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

Foundation of care
Brentuximab vedotin is being evaluated globally as the foundation of care for CD30-expressing lymphomas in more than 70 corporate- and investigator-sponsored clinical trials. Brentuximab vedotin is currently not approved as a frontline therapy for Hodgkin lymphoma.

“The FDA’s filing of our supplemental BLA with Priority Review represents a significant milestone in our goal to redefine the frontline treatment of advanced Hodgkin lymphoma,” said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

“We recently reported the primary data from the Phase III ECHELON-1 clinical trial in the Plenary Scientific Session of the [2017 Annual Meeting of the American Society of Hematology (ASH)] with simultaneous publication in the New England Journal of Medicine. The data demonstrated superior activity of the brentuximab vedotin-containing regimen over standard of care, and we are working with the FDA to make this bleomycin-free regimen available to newly diagnosed advanced Hodgkin lymphoma patients as soon as possible,” Siegall concluded.

Breakthrough Therapy Designation
In October 2017, the FDA granted brentuximab vedotin Breakthrough Therapy Designation based on the ECHELON-1 study results. The FDA’s Breakthrough Therapy Designation is intended to expedite the development and review of promising drug candidates for serious or life-threatening conditions. It is based upon clinical evidence of substantial improvement over existing therapies in one or more clinically significant endpoints.

The ECHELON-1 study evaluated a combination of brentuximab vedotin plus AVD compared to a recognized standard of care chemotherapy regimen, ABVD, in frontline advanced classical Hodgkin lymphoma. The positive results from the Phase III ECHELON-1 trial were featured in the Plenary Scientific Session of the 59th American Society of Hematology (ASH) Annual Meeting with simultaneous publication in the New England Journal of Medicine in December 2017.

Results from the ECHELON-1 trial included 1,334 Hodgkin lymphoma patients.

The trial achieved its primary endpoint with the combination of brentuximab vedotin plus AVD resulting in a statistically significant improvement in modified PFS versus the control arm of ABVD as assessed by an Independent Review Facility (IRF) (p-value=0.035). This corresponds to a 23% reduction in the risk of progression, death or need for additional anticancer therapy. Per IRF assessment, the two-year modified PFS rate for patients in the brentuximab vedotin plus AVD arm was 82.1% compared to 77.2% in the control arm.

The investigator assessment of modified PFS also demonstrated a statistically significant advantage for brentuximab vedotin plus AVD versus the control arm of ABVD (p-value <0.01).

All secondary endpoints, including interim analysis of overall survival, trended in favor of the brentuximab vedotin plus AVD arm.

The safety profile of brentuximab vedotin plus AVD in the ECHELON-1 trial was generally consistent with that known for the single-agent components of the regimen.


Last editorial review: January 2, 2018

Featured Image: Micrograph of Hodgkin lymphoma. Lymph node FNA specimen. Field stain. The micrograph shows a mixture of cells common in Hodgkin Lymphoma, including Eosinophils, Reed-Sternberg cells, Plasma cells and Histocytes. Courtesy: © 2017 – 2018. Fotolia | Used with permission. Photo 1.0: Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. Courtesy: © 2017 – 2018. Seattle Genetics. | Used with permission.

Copyright © 2010 – 2018 InPress Media Group, LLC. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Phase III ECHELON-1 Clinical Trial of Brentuximab Vedotin Meets Primary Endpoint – Demonstrates a Statistically Significant Improvement in Modified Progression-Free Survival

Data from the Phase III ECHELON-1 clinical trial evaluating brentuximab vedotin (Adcetris®; Seattle Genetics | Takeda) as part of a frontline combination chemotherapy regimen in untreated advanced classical Hodgkin lymphoma were presented in the Plenary Scientific Session at the 59th American Society of Hematology (ASH) annual meeting on Sunday, December 10, 2017.[1]

The data, simultaneously published online in the New England Journal of Medicine*, demonstrates that the ECHELON-1 trial met its primary endpoint of a statistically significant improvement in modified progression-free survival (modified PFS or mPFS) per Independent Review Facility (IRF) versus the control arm. [2]. The modification is to include, as an event, the receipt of chemotherapy or radiotherapy for patients not in complete remission at the end of initial treatment.[3]

The ECHELON-1 trial, which enrolled 1,334 patients, is a randomized, open-label, two-arm, multi-center Phase III study designed to compare brentuximab vedotin + AVD (Adriamycin [doxorubicin], vinblastine and dacarbazine) to ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine and dacarbazine) as frontline therapy in patients who had histologically-confirmed diagnosis of Stage III (36%) or IV (64%) Hodgkin lymphoma – referred to as advanced classical Hodgkin lymphoma – and had not been previously treated with systemic chemotherapy or radiotherapy.

The patients participating in the study were randomized (58% male; median age 35 year [range 18–83]; ≥45 year, 34%; ≥60 year, 14%) to receive brentuximab vedotin + AVD (brentuximab vedotin 1.2 mg/kg, doxorubicin 25 mg/m2, vinblastine 6 mg/m2, dacarbazine 375 mg/m2) or ABVD (doxorubicin 25 mg/m2, bleomycin 10 units/m2, vinblastine 6 mg/m2, dacarbazine 375 mg/m2) IV on Days 1 and 15 of up to six 28-day cycles. The multi-center trial was conducted at 218 sites in 21 countries across North America, Europe, South America, Australia, Asia and Africa.[1]

Schematic: The ECHELON-1 trial is a Phase III trial in Frontline Therapy of Patients With Advanced Classical Hodgkin Lymphoma (NCT01712490).

Novel treatment option
Brentuximab vedotin is an antibody-drug conjugate or ADC directed to CD30, a defining marker of classical Hodgkin lymphoma but is currently not approved as a frontline therapy for the treatment of patients with Hodgkin lymphoma. The imunoconjugate includes a payload called monomethyl auristatin E (MMAE), a spindle poison, and is approved for classical Hodgkin lymphoma after failure of autologous stem cell transplantation (ASCT) or ≥2 prior chemotherapy regimens and as consolidation post‑ASCT for increased risk Hodgkin lymphoma.[3]

Unmet medical need
The lymphatic system, a network of tissues and organs including lymph nodes, spleen, thymus gland, and bone marrow, helps rid the body of toxins, waste and other unwanted materials. The system is the body’s disease-fighting network. Cancers originating in the lymphatic system are generally referred to as lymphomas.[4]

Hodgkin lymphoma and non-Hodgkin lymphoma are two major categories of lymphoma. Classical Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. Reed-Sternberg cells, which express CD30, are large, cancerous cells found in Hodgkin lymphoma tissues and named for the scientists who first identified them.

Although multidrug chemotherapeutic regimens, with or without radiotherapy, have been highly successful in achieving long-term remissions in the majority of patients with advanced-stage Hodgkin lymphoma – the disease is one of the most curable forms of cancer – approximately 30% of patients with advanced disease do not achieve long-term remission with front-line treatment using standard regimens, such as ABVD.[5][6][7]

The number of patients with advanced disease not achieving long-term remission can be reduced by about 5 to 10% with the use of much more intensive escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine [Matulane], prednisone) -therapy, developed by the German Hodgkin Study Group (GHSG) to increase dose density of chemotherapy as compared with ABVD and other regimens used in advanced-stage Hodgkin lymphoma. However, this treatment carries the risk of significant short- and long-term morbidity,

According to the American Cancer Society, approximately 8,260 cases of Hodgkin lymphoma will be diagnosed in the United States during 2017 and more than 1,000 will die from the disease. The Lymphoma Coalition, estimates that worldwide over 62,000 people are diagnosed with Hodgkin lymphoma each year and approximately 25,000 people will die each year from this cancer.

This represents a major unmet medical need.

“For patients with advanced stage Hodgkin lymphoma, approximately one in three do not achieve long-term remission after standard frontline therapy, which is why the results of ECHELON-1 could be important to this group of patients,” said Jesús Gomez Navarro, M.D., Vice President, Head of Oncology Clinical Research and Development, Takeda.

Statistical Significant Improvement
“The trial demonstrated that combination treatment with [brentuximab vedotin] resulted in a statistically significant improvement in modified progression-free survival versus the control arm. For patients treated with brentuximab vedotin +AVD, there was a 23% reduction in the occurrence of an event, defined as progression, death or need for subsequent anti-cancer therapy for patients not in a complete response, compared to those who were treated with ABVD,” Gomez Navarro added

“We are excited about these clinical trial results and the potential impact brentuximab vedotin may have in the treatment of patients with advanced stage Hodgkin lymphoma if approved by health authorities for frontline use,” he concluded.

Standard treatment
Altough very effective in treating the disease, the original treatments for Hodgkin lymphoma were developed in the 1960s and 1970s. Some of these treatments caused serious side effects later in life, including infertility, cardiovascular problems, as well as secondary cancers, such as lung cancer and breast cancer. Overall, these long-term problems were partly caused by the types of chemotherapy and high doses of radiation therapy delivered to large areas of the body.[4]

“The standard of care in the treatment of Hodgkin lymphoma has not changed over the last several decades and there remains an unmet need for additional regimens in frontline treatment. Current regimens include bleomycin, which is known to be associated with unpredictable and potentially fatal pulmonary toxicity,” said Joseph M. Connors, M.D., FRCPC, Clinical Director, Center for Lymphoid Cancer at BC Cancer in Vancouver, Canada.

“Increasing the durable response rate with a frontline therapy that also removes bleomycin from the regimen, represents a major step forward for the Hodgkin lymphoma community. Reducing the risk of relapse, is an important concern for patients and their physicians. In the trial, 33% fewer patients treated in the [brentuximab vedotin] containing regimen required subsequent salvage chemotherapy or high dose chemotherapy and transplant compared to the patients treated with ABVD. Lastly, the safety profile of [brentuximab vedotin]+AVD in the trial was generally consistent with that known for the single-agent components of the regimen, Connors added”

Photo 1.0: Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

“The ECHELON-1 Phase III clinical trial results were selected by the American Society of Hematology as one of only six abstracts to be featured in the Plenary Scientific Session, and the data were also published simultaneously today in the New England Journal of Medicine. This study represents a bold effort that began more than five years ago to improve upon the current standard of care regimen that has not significantly changed in more than four decades. We’d like to thank the many patients and physicians who participated in this landmark trial,” noted Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

“These data demonstrate statistically superior activity of an brentuximab vedotin-containing regimen over ABVD, the current standard of care, including the primary endpoint of modified PFS per IRF, and secondary endpoints trended in favor of the brentuximab vedotin-containing regimen as well. Importantly, patients treated with the brentuximab vedotin-containing regimen required fewer subsequent therapies after frontline treatment,” Siegal further said.

“The results of the ECHELON-1 study supported FDA Breakthrough Therapy Designation for brentuximab vedotin in combination with chemotherapy for frontline advanced classical Hodgkin lymphoma, and we recently submitted a supplemental Biologics License Application to the FDA. Our goal is to make this regimen available to patients in the U.S. with advanced Hodgkin lymphoma in the first half of 2018,” Siegal concluded.

Key findings
The key findings, presented during the annual meeting and published in the New England Journal of Medicine confirm that the trial achieved its primary endpoint with the combination of [brentuximab vedotin]+AVD resulting in a statistically significant improvement in modified Progessive Free Survival (mPFS) versus the control arm of ABVD as assessed by an Independent Review Facility (IRF) (HR 0.77; p-value=0.035). This corresponds to a 23% percent reduction in the risk of progression, death or need for additional anticancer therapy.

Per IRF assessment, the two-year modified PFS rate for patients in the [brentuximab vedotin] +AVD arm was 82.1% compared to 77.2 percent in the control arm. Furthermore, per investigator assessment, the two-year modified PFS rate for patients in the [brentuximab vedotin]+AVD arm was 81.0% compared to 74.4% in the control arm (HR 0.73; p-value=0.007). This corresponds to a 27% reduction in the risk of progression, death or need for additional anticancer therapy.

All secondary endpoints trended in favor of the [brentuximab vedotin]+AVD arm, including interim analysis of overall survival (OS; HR 0.72; p-value=0.19). Other secondary endpoints include:

  • Complete response (CR) rate at the end of randomized regimen in the [brentuximab vedotin]+AVD arm was 73% compared to 70% in the control arm (p-value=0.22).
  • Objective response rate (ORR) at the end of randomized regimen in the [brentuximab vedotin]+AVD arm was 86% compared to 83% in the control arm (p-value=0.12).
  • Deauville score ≤2 after completion of frontline therapy was 85% in the [brentuximab vedotin]+AVD arm compared to 80% in the control arm (p-value=0.03).
  • Certain pre-specified subgroups of patients appeared to benefit more with [brentuximab vedotin]+AVD versus ABVD including: patients treated in North America; patients with involvement of >1 extranodal site; patients with International Prognostic Score (IPS) 4 – 7; males; patients with Stage IV disease; and patients aged <60 years.
  • In the [brentuximab vedotin]+AVD arm, 33% fewer patients received subsequent salvage chemotherapy or high-dose chemotherapy and transplant

Safety and adverse events
The safety profile of [brentuximab vedotin]+AVD in the ECHELON-1 trial was generally consistent with that known for the single-agent components of the regimen.

The most common clinically relevant adverse events of any grade that occurred in at least 15 percent of patients in the [brentuximab vedotin]+AVD and ABVD arms were: neutropenia (58 and 45%, respectively), constipation (42 and 37%, respectively), vomiting (33 and 28%, respectively), fatigue (both 32%), peripheral sensory neuropathy (29 and 17%, respectively), diarrhea (27 and 18%, respectively), pyrexia (27 and 22%, respectively), peripheral neuropathy (26 and 13%, respectively), abdominal pain (21 and 10%, respectively) and stomatitis (21 and 16%, respectively).

In both the [brentuximab vedotin]+AVD and ABVD arms, the most common Grade 3 or 4 events were neutropenia, febrile neutropenia and neutrophil count decrease.

Febrile neutropenia was reduced through the use of prophylactic growth factors (G-CSF) in a subset of patients. In the [brentuximab vedotin]+AVD arm of the study, the rate of febrile neutropenia without the use of G-CSF was 21 percent and with the use of G-CSF was reduced to 11 percent. G-CSF primary prophylaxis with [brentuximab vedotin]+AVD resulted in overall comparable safety profile to ABVD, decreasing incidence of febrile neutropenia, neutropenia and serious adverse events. Primary prophylaxis with G-CSF was recommended for all patients.

On the [brentuximab vedotin]+AVD arm, peripheral neuropathy events were observed in 67% of patients compared to 43% on the control arm. In the [brentuximab vedotin]+AVD arm, the majority of peripheral neuropathy events were Grade 1 or 2. Grade ≥3 events were reported in 11 percent of patients and Grade 4 events were reported in less than one percent of patients. In the control arm, Grade ≥3 events were reported in two percent of patients and there were no Grade 4 events.

Two-thirds of the patients with peripheral neuropathy in the [brentuximab vedotin]+AVD arm reported resolution or improvement at last follow-up. Pulmonary toxicity was reported in two percent of patients in the [brentuximab vedotin]+AVD arm versus seven percent of patients in the ABVD arm; Grade ≥3 events were reported in less than one percent versus three percent, in the brentuximab vedotin and control arms respectively.

Nine on study deaths occurred in the [brentuximab vedotin]+AVD arm, of which seven were due to neutropenia or associated complications (all occurred in patients who had not received primary prophylaxis with G-CSF with the exception of one patient who entered the trial with pre-existing neutropenia).

The remaining two deaths were due to myocardial infarction. In the control arm, there were 13 on study deaths, of which 11 were due to or associated with pulmonary-related toxicity, one was due to cardiopulmonary failure and one death had unknown cause.

Regulatory approval
The U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for brentuximab vedotin in combination with chemotherapy for the frontline treatment of patients with advanced classical Hodgkin lymphoma.

Seattle Genetics and Takeda are jointly developing brentuximab vedotin. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize brentuximab vedotin in the rest of the world. Based on this devision, Seattle Genetics submitted a supplemental Biologics License Application to the FDA on November 1, 2017, while Takeda has begun to submit data from the ECHELON-1 trial to regulatory agencies in its territories, starting with the European Medicines Agency (EMA) on November 29, 2017.


* The data will be published in the January 25, 2018 print edition of the New England Journal of Medicine.
**

Last Editorial Review: December 11, 2017

Featured Image: American Society of Hematology | Anual Meeting. Courtesy: © 2017. American Society of Hematology. Used with permission. Photo 1.0: Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. Courtesy: © 2017. Seattle Genetics. Used with permission.

Copyright © 2017 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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