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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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Interim Results from Ongoing Studies of Brentuximab Vedotin + Nivolumab in Frontline or Relapsed Hodgkin Lymphoma Presented at ISHL 2018

Multiple presentations evaluating brentuximab vedotin (Adcetris®; Seattle Genetics/Takeda*) across a broad range of Hodgkin lymphoma (HL) settings were presented at the 11th International Symposium on Hodgkin Lymphoma (ISHL) taking place in Cologne, Germany, October 27-29, 2018.  This year’s presentations will highlighted Phase III and other clinical data from brentuximab vedotin and continue to build upon our research in CD30-positive lymphoma.

More than 1,100 delegates from over 70 countries participated in an intensive scientific discourse organized by the German Hodgkin Study Group (GHSG).

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.


After more than a decade of dedicated clinical research with brentuximab vedotin, we have made significant progress in improving the treatment outcomes for patients with Hodgkin lymphoma…


Trial evaluation
The data presented at the 11th International Symposium on Hodgkin Lymphoma included both encore and additional 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 U.S. Food and Drug Administration (FDA) approval in this indication in March 2018.

Interim results will be presented from two ongoing clinical trials evaluating brentuximab vedotin in combination with nivolumab (Opdivo®; Bristol-Myers Squibb Company), including in newly diagnosed older HL patients.

Finaly, five-year follow-up from the phase III AETHERA clinical trial were presented.

Antibody-drug Conjugate
Bentuximab vedotin is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical HL that plays a role in tumor pathogenesis.  The agent uses a protease-cleavable linker system that is designed to be stable in the bloodstream but to release monomethyl auristatin E (MMAE), a microtubule disrupting agent, upon internalization into CD30-expressing tumor cells.

Brentuximab vedotin is being evaluated globally as the foundation of therapy for HL in more than 50 ongoing clinical trials. Brentuximab vedotin and nivolumab are not approved in combination for the treatment of HL.

Progresss
“After more than a decade of dedicated clinical research with brentuximab vedotin, we have made significant progress in improving the treatment outcomes for patients with Hodgkin lymphoma,” said Nancy Whiting, Pharm.D., Senior Vice President, Clinical Development and Global Medical Affairs at Seattle Genetics.

“At ISHL, we [presented] additional analyses from the ECHELON-1 trial, which demonstrated that Brentuximab vedotin plus AVD improves upon a frontline standard of care regimen, ABVD, in advanced patients and resulted in the first change in advanced stage HL in over 40 years. In addition, three oral presentations will highlight brentuximab vedotin plus nivolumab combination data in frontline and relapsed/refractory HL and five-year data from the phase III AETHERA trial. We are pleased to share these results from our broad brentuximab vedotin clinical development program with the Hodgkin lymphoma community.”

“The presented data a continue to reinforce our dedication to advancing treatment for those affected by Hodgkin lymphoma,” said Jesús Gómez-Navarro, MD, Vice President, Head of Oncology Clinical Research and Development, Takeda.

“[Overal,] the progress we have made in the development of brentuximab vedotin serves as a true testament to the leadership role we have established in the treatment of CD30-positive malignancies, which confirm the long-term benefits of brentuximab vedotin across treatment lines and support its role as an important targeted therapy for Hodgkin lymphoma,” he added.

Analyses
Data from four analyses of the phase III ECHELON-1 clinical trial were be presented at ISHL. Among the presentations are an oral and poster presentation included an analysis from the ECHELON-1 study (Abstract #0038) showing PFS data per investigator that is consistent with the previously reported modified PFS data per Independent Review Facility (IRF).

The ECHELON-1 abstracts included the following:

  • Frontline brentuximab vedotin plus chemotherapy exhibits superior modified progression-free survival vs chemotherapy alone in patients with stage III or IV Hodgkin lymphoma: Phase III ECHELON-1 study (Abstract #0038, oral presentation and poster on Monday, October 29 at 07:30-07:50 CEST)
  • Population pharmacokinetic modeling and exposure-response assessment of brentuximab vedotin efficacy and safety in patients with advanced classical Hodgkin lymphoma from the Phase III ECHELON-1 study (Abstract #0137, poster presentation)
  • Serum sCD30 and TARC do not correlate with PET-based response assessment in patients with stage III or IV classical Hodgkin lymphoma (cHL): phase III ECHELON-1 study of brentuximab vedotin plus chemotherapy vs. chemotherapy alone (Abstract #0159, poster presentation)
  • Brentuximab vedotin plus chemotherapy in high risk advanced-stage classical Hodgkin lymphoma (cHL) patients: Results of pre-specified sub-group analyses from the ECHELON-1 study (Abstract #0136, poster presentation)

Combination
Additional data presentations at 11th International Symposium on Hodgkin Lymphoma also included the results from a follow-up results from the Phase I/II study with brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin Lymphoma  (Abstract #0005, oral presentation on Monday, October 29 at 14:40-14:50 CEST)

Thi presentation included data from 62 patients with relapsed or refractory HL who received the combination regimen of brentuximab vedotin plus nivolumab after failure of frontline therapy. In this study patients were treated once every three weeks, with up to four cycles of combination therapy in the outpatient setting. After completion of the fourth cycle of treatment, patients were eligible to undergo an autologous stem cell transplant (ASCT). The median age of patients was 37 years. The majority of patients (95%) were refractory or had relapsed after receiving the standard of care frontline treatment ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine) or some variation of the standard of care (ABVE-PC, R-ABVD). Key findings were presented in an oral presentation by Alex Herrera, M.D., Assistant Professor at the City of Hope Medical Center, Duarte, California.

Herrera showed that of 61 response-evaluable patients, 49 patients (80%) had an objective response, including 37 patients (61%) with a complete response and 12 patients (20 percent) with a partial response.
Of the 61 response-evaluable patients, the estimated 21-month overall survival (OS) and PFS were 95 % and 82%, respectively.

The median follow-up time was 21.8 months and both median OS and PFS were not yet reached. Of 42 patients who underwent ASCT directly after treatment with brentuximab vedotin plus nivolumab, estimated PFS at 21-months was 97 percent and median PFS was not yet reached.

PFS was evaluated by response to treatment. The estimated PFS at 21-months for patients with a complete response was 97%, for patients with a partial response was 83% and patients with stable disease was 50 percent.

As previously reported, the most common adverse events (AEs) of any grade occurring prior to ASCT or subsequent salvage therapy in at least 20% of patients were nausea, infusion-related reaction (IRR), fatigue, pruritus, diarrhea, headache, vomiting, cough, pyrexia, dyspnea and nasal congestion.

Schematic: The AETHERA trial (NCT01100502) is a randomized, double-blind, placebo-controlled, multicenter phase 3 trial to evaluate the efficacy and safety of brentuximab vedotin (SGN-35) and best supportive care (BSC) compared to placebo and BSC in treatment of residual Hodgkin lymphoma (HL) following autologous stem cell transplant (ASCT).

Combination in patients older than 60 years
Another presentation discussed the results from a phase II study of frontline brentuximab vedotin plus nivolumab in patients with Hodgkin Lymphoma aged ≥60 years (Abstract #0153, oral presentation on Monday, October 29 at 15:05-15:15 CEST).

Jonathan Friedberg, M.D., Director of the University of Rochester Medical Center, NY and presented the interim results from an ongoing Phase II clinical trial evaluating brentuximab vedotin in combination with nivolumab as frontline therapy for HL patients age 60 years or older. The reported results included data from 14 patients. The median age of patients was 71.5 years. The majority of patients (79%) had stage III/IV disease at the time of diagnosis.

Friedberg showed that of 11 response-evaluable patients with a median follow-up time of eight months, nine patients (82%) had an objective response, including six patients (55%) with a complete response and three patients (27%) with a partial response. In addition, two patients (18%) had stable disease which equates to all 11 patients (100%) experiencing disease control (complete response + partial response + stable disease) as a result of treatment with brentuximab vedotin in combination with nivolumab.

The most common Adverse Events of any grade occurring in at least 25% of patients were fatigue, diarrhea, constipation, nausea, arthralgia, chills, decreased appetite, pyrexia, IRR, aspartate aminotransferase increased and peripheral sensory neuropathy.

Grade 3 or higher adverse events occurred in seven patients (50%), and the most common were peripheral neuropathy and lipase increased (three patients each); nausea and alanine aminotransferase increased (two patients each).

Five patients (36%) had IRRs, with the majority of symptoms at Grade 1 and there were no Grade 3 or higher symptoms. Four patients (29%) were treated with corticosteroid and no patients discontinued treatment due to an IRR.

Consolidation after Autologous Stem-Cell Transplantation
Five-Year Progression-Free Survival Outcomes from a Pivotal Phase III Study of Consolidative Brentuximab Vedotin after Autologous Stem-Cell Transplantation (ASCT) in Patients with Hodgkin Lymphoma at Risk of Relapse or Progression (AETHERA) (Abstract #0110, oral presentation on Monday, October 29 at 17:10-17:20 CEST)

The five-year follow-up efficacy and safety data from the Phase III AETHERA clinical trial designed to evaluate the potential of single-agent brentuximab vedotin to extend PFS post-ASCT in patients with classical HL who were at high risk of relapse or progression were presented by Craig Moskowitz, M.D., Physician in Chief, Sylvester Comprehensive Cancer Center, University of Miami.

Brentuximab vedotin was approved by the FDA in August 2015 for the treatment of adult patients with classical HL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation.

Moskowitz showed that the five-year PFS rate per investigator was 59% in the brentuximab vedotin arm compared to 41% in the placebo arm. Median PFS per investigator was not yet reached in the brentuximab vedotin arm versus 15.8 months in the placebo arm. The hazard ratio was 0.521 indicating a 48% reduction in the risk of progression or death with treatment of brentuximab vedotin compared to placebo.

Fewer patients in the brentuximab vedotin arm of the study received subsequent anti-cancer therapies versus the placebo arm (32% versus 54%, respectively). In addition, fewer patients in the brentuximab vedotin arm received allogeneic stem-cell transplants versus the placebo arm (17 patients versus 31 patients).

A PFS analysis evaluating subgroups included patients in the brentuximab vedotin arm with either two or more or three or more risk factors, showed patients with a greater number of risk factors for relapse post-ASCT appeared to have the greatest benefit from brentuximab vedotin consolidation therapy. In both subgroups evaluating either two or more or three or more risk factors, median PFS was not reached in the brentuximab vedotin arm and was 9.7 months and 6.3 months, respectively, in the placebo arm.
In the brentuximab vedotin arm, 112 patients (67%) reported peripheral neuropathy.

To date, 90% of these patients had resolution or improvement in symptoms, with 73% having complete resolution.


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

Last Editorial Review: November 3 , 2018

Featured Image: Adcetris/Takeda booth at ISHL 2018 . Courtesy: © 2010 – 2018 ISHL/Ralf Juergens. 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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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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Long-term Data of Brentuximab Vedotin Redifines Treatment of Frontline Mature T-Cell Lymphoma.

Data highlighted at the 59th annual meeting of the American Society of Hematology (ASH) held in Atlanta, Georgia, December 9-12, 2017 shows final five-year survival results from a phase I clinical trial evaluating  brentuximab vedotin (Adcetris®; Seattle Genetics/Takeda), a drug directed to CD30, which is expressed on the surface of Hodgkin lymphoma cells and several types of non-Hodgkin lymphoma, in the treatment of patient with mature T-cell lymphoma (MTCL).

An Antibody-drug Conjugate
Brentuximab vedotin is 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), utilizing Seattle Genetics’ proprietary technology.


The current standard of care for frontline MTCL treatment has not changed for several decades and there remains a significant need for improved therapeutic options…


Unmet medical need
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.

Non-Hodgkin lymphomas 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. In the United Stated T-cell lymphomas account for approximately 15% of all non-Hodgkin lymphoma.

There are a number of different forms of T-cell lymphomas, which can be aggressive of indolent. Some of these are extremely rare. Almost all types of T-cell lymphoma fall under the category of mature T-cell lymphoma, also known as peripheral T-cell lymphoma.

According to the American Cancer Society and analysis of literature sources, approximately 4,300 patients will be diagnosed with CD30-expressing mature T-cell lymphoma in the United States during 2017. While, over the last years, a number of treatments have been developed, overall, a significant unmet medical need persists in older patients, as well as for those patients who have relapsed or refractory (R/R) disease.

Highlights
The data highlighted during the annual meeting focused on durability data from a phase I clinical trial of brentuximab vedotin in combination with chemotherapy for the treatment of patients with newly diagnosed MTCL, also known as peripheral T-cell lymphoma (PTCL).

“Approximately 4,000 patients are diagnosed with MTCL each year. The current standard of care for frontline MTCL treatment has not changed for several decades and there remains a significant need for improved therapeutic options.” noted Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.

“The results of this phase I trial support the ongoing phase III ECHELON-2 clinical trial and our goal to redefine frontline MTCL treatment with a novel brentuximab vedotin combination regimen,” he added.

“The final results from the Phase I study were presented today, with five-year progression-free survival and overall survival rates of 52 and 80%, respectively. No patients have experienced any disease progression events since the three-year follow-up results. Importantly, after more than five years of follow-up, patients who remain in remission have the potential to be cured. These data continue to support the phase III ECHELON-2 trial, from which we anticipate reporting data in 2018,” Drachman concluded.

Figure 1.0: ECHELON-2 (NCT01777152) is a Clinical Trial designed to establish brentuximab vedotin (Adcetris®) as the foundation of care for CD30-expressing lymphomas and redefine frontline treatment in Hodgkin lymphoma and mature T-cell lymphoma (MTCL), a generally aggressive form of non-Hodgkin lymphoma that is currently underserved by existing chemotherapy regimens.

A combination
Data were reported from 26 frontline MTCL patients who received the combination regimen of brentuximab vedotin plus cyclophosphamide, doxorubicin and prednisone (CHP).

Patients who achieved at least a partial remission with combination therapy following six cycles of brentuximab vedotin plus CHP were eligible to receive up to ten additional cycles of single-agent brentuximab vedotin treatment.

The median age of patients was 56 years. Nineteen patients (73%) had a subtype of MTCL called systemic anaplastic large cell lymphoma (sALCL), including 16 patients with anaplastic lymphoma kinase (ALK)-negative disease, which is typically associated with a poor prognosis.

Seven patients (27%) had a diagnosis of other types of MTCL. The majority of patients had advanced stage disease and were considered high risk. All patients on the trial achieved an objective response, including 92 percent with a complete response and eight percent with a partial response.

Updated key findings based on a median observation time of 60 months from first dose of therapy showed that at five-year follow-up, there have been no progression events or deaths in this trial since the three-year follow up. The results also showed that the estimated five-year progression-free survival rate was 52%, with no patients receiving a consolidative stem cell transplant in first remission. The median progression-free survival has not yet been reached.

While the media overall survival has not yet been reached, the researchers involved were able to confirm an estimated five-year overall survival rate was 80%.

Adverse events
Seventy-three percent of patients (19 of 26) experienced peripheral neuropathy, the majority of which was Grade 1 or 2. Ninety-five percent of these patients had complete resolution or some improvement of their symptoms at last follow-up with a median time to resolution of 4.2 months and median time to improvement of symptoms was 2.6 months.

A global phase III study called ECHELON-2 completed enrollment in November 2016. The ECHELON-2 trial is a randomized, double-blind, placebo-controlled, multi-center trial designed to investigate brentuximab vedotin plus CHP versus CHOP as frontline therapy in patients with CD30-expressing MTCL.

The trial enrolled 452 patients (approximately 225 patients per treatment arm) randomized to receive brentuximab vedotin plus CHP or CHOP every three weeks for six to eight cycles. Data from the ECHELON-2 trial are expected in 2018.


Last Editorial Review: December 10, 2017

Featured Image: Scientists at 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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Antibody-Drug Conjugates at the 59th American Society of Hematology Annual Meeting

This year, in Atlanta, the South’s largest and most vibrant city, the 59th annual meeting and exposition of the American Society of Hematology, to be held December 9-12, 2017, is expected to bring an invaluable educational experience and the opportunity to review thousands of scientific abstracts highlighting updates in the hottest topics in hematology.

The world’s most comprehensive hematology event of the year will provide an opportunity to Network with top minds in the field and a global community of more than 25,000 hematology professionals from every subspecialty.

New developments in antibody-drug conjugates are expected to create excitement.

Changing landscape
The landscape of antibody-drug conjugates is rapidly changing. [1]

In January 2017 only two ADCs were commercially available in the United States.  This included brentuximab vedotin (Adcetris®; Seattle Genetics), an anti-CD30 monomethyl auristatin E (MMAE) conjugate indicated for the treatment of patients with relapsed/refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, and ado-trastuzumab emtansine (also know as T-DM1; Kadcyla®; Genentech/Roche), an anti-HER2 DM1 conjugate used to treat HER2-metastatic breast cancer. a


For an overview of oral and poster presentations about antibody-drug conjugates (ADCs) to be presented during the annual meeting of the American Society of Hematology, December 9 – 12, 2017, Click here.


Then in the late summer of this year the number of commercially available antibody-drug conjugates approved by the U.S. Food and Drug Administration (FDA) doubles with the approval, inotuzumab ozogamicin (Besponsa®; Pfizer) for treatment of relapsed/refractory acute lymphoblastic leukemia (ALL) and gemtuzumab ozogamicin (Mylotarg®; Pfizer) b, for relapsed/refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma.

With four commercially available antibody-drug conjugates, the majority of which are for the treatment of liquid cancers, and with a better understanding of cancer biology and many technological advances, this class of novel (anti-cancer) agents is finally beginning to deliver on decades old expectations and hope for better therapeutic outcomes.

But some of the hope and expectation are still ‘locked’ in early and preclinical research, as is evidenced by the fact there are more than 150 ADC and ADC-like agents in development programs.

Penelope Drake and David Rabuka, in a recent article published in BioDrugs, discuss how our better understanding and advances are based upon a large – and increasing – body of investigational studies which, taken together, offer a deeper knowledge and comprehension of the absorption, distribution, metabolism, and excretion (ADME), drug metabolism and pharmacokinetics (DMPK) fates of the intact conjugate and its small-molecule drug component.[1]

This year, during the annual meeting of the American Society of Hematology a number of  companies will again present their latest developments.

IMGN632 and IMGN779
ImmunoGen, will highlight two experimental ADC therapies, IMGN632 and IMGN779, a CD33-targeted ADC for the treatment of acute myeloid leukemia or Acute Myeloid Leukemia currently in Phase I testing.

Both IMGN779 and IMGN632 use ImmunoGen’s novel indolino-benzodiazepine payloads called IGNs. These ultra-potent, DNA-acting IGNs alkylate DNA without crosslinking, which preclinically has resulted in potent anti-leukemia activity with relative sparing of normal hematopoietic progenitor cells.

Acute Myeloid Leukemia is a cancer of the bone marrow cells that produce white blood cells. It causes the marrow to increasingly generate abnormal, immature white blood cells (blasts) that do not mature into effective infection-fighting cells. The blasts quickly fill the bone marrow, impacting the production of normal platelets and red blood cells. The resulting deficiencies in normal blood cells leave the patient vulnerable to infections, bleeding problems and anemia.

It is estimated that, in the U.S. alone, 21,380 patients will be diagnosed with AML this year and 10,590 patients are expected to die from the disease [2]

IMGN632 is a humanized anti-CD123 antibody-drug conjugate that is a potential treatment for for hematological malignancies, including AML and blastic plasmacytoid dendritic cell neoplasm (BPDCN), myelodysplastic syndrome, B-cell acute lymphocytic leukemia, and other CD123-positive malignancies.

Earlier this year, ImmungGen announced that the Investigational New Drug application for IMGN632 is active and it expects to open a Phase I trial later this year.

IMGN779 is a novel ADC that combines a high-affinity, humanized anti-CD33 antibody, a cleavable disulfide linker, and one of ImmunoGen’s novel indolino-benzodiazepine payloads, called IGNs, which alkylate DNA without crosslinking, resulting in potent preclinical anti-leukemia activity with relative sparing of normal hematopoietic progenitor cells.

IMGN779 is in Phase I clinical testing for the treatment of AML.

“The clinical and preclinical data to be presented at ASH demonstrate the early potential of our novel IGN portfolio,” said Richard Gregory, Ph.D., executive vice president and chief scientific officer of ImmunoGen.

“One of our strategic priorities is to accelerate the development of these unique and highly differentiated assets. IMGN779 and IMGN632 use our IGN payloads, which were designed to meet the dual challenges of achieving high potency against target cells, while having a tolerability profile that enables continued patient treatment,” Gregory added.

In a poster presentation, the ImmunoGen is expected to report updated data evaluating the safety and anti-leukemia activity from the dose escalation phase of the IMGN779 first-in-human trial. In a separate presentation, preclinical data evaluating the mechanism, anti-leukemia efficacy, and tolerability of repeated dosing of IMGN779 and cytarabine in combination using in vitro and in vivo human AML preclinical models will be reported.

Preclinical data reporting the prevalence of CD123 expression in acute lymphoblastic leukemia (ALL), and assessing the anti-leukemia activity of IMGN632 on ALL cells will be presented in a poster presentation.

Novel payloads: Antibody-targeted Amanitin conjugates
Today, most antibody-drug conjugates, both commercially available and in clinical trials, includes just a limited number of cytotoxic payloads, generally limited to microtubuli- or DNA-targeting toxins including auristatins and maytansines or duocarmycins and pyrrolobenzodiazepines (PBDs). These payloads are mainly targeting proliferating cells potentially leading to limited efficacy in diseases with a low proliferation rates such as indolent lymphomas or multiple myeloma.

Researchers at the German Cancer Research Center, Heidelberg, Baden-Württemberg, Germany in collaboration with Heleidelberg Pharma are developing a novel antibody-drug conjugate with amanitin as toxic payload with an alternative toxicity mechanisms that could enhance the therapeutic potential of ADCs.

Amanitin is the most well-known toxin of the amatoxin family and binds to the eukaryotic RNA polymerase II, inhibiting the cellular transcription process at very low concentrations irrespective of the proliferation status of the target cell.

During this year’s annual meeting, researchers from the German Cancer Research Center will present results of a study assessing in vitro and in vivo specificity and efficacy of HDP-101, an ATAC targeting BCMA (B cell maturation anti­gen; CD269), which is expressed on cells of the B cell lineage, predominantly on plasma blasts and plasma cells. BCMA is highly expressed on malignant plasma cells and therefore considered an ideal target in multiple myeloma, is not expressed on naïve, germinal center, and memory B cells.

The researchers conclude that the mode of action of the amanitin payload led to an efficient anti-tumor response in vitro and in vivo with good tolerability in non-human primate studies yielding a very favorable therapeutic index.

A first-in-human trial with HDP-101 as a potential treatment for multiple myeloma is expected to start in 2018.

Brentuximab vedotin
This year 18 abstracts will featuring data from the broad brentuximab vedotin (Adcetris®; Seattle Genetics) development program. Brentuximab vedotin, an ADC directed to CD30, which is expressed on the surface of Hodgkin lymphoma cells and several types of non-Hodgkin lymphoma, is being evaluated globally as the foundation of care for CD30-expressing lymphomas in more than 70 corporate- and investigator-sponsored clinical trials.

The presentations during this years annual meeting include data from the phase III ECHELON-1 clinical trial evaluating brentuximab vedotin in combination with chemotherapy in frontline advanced classical Hodgkin lymphoma patients.

Based on the positive results from the ECHELON-1 trial, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to ADCETRIS in combination with chemotherapy for the frontline treatment of patients with advanced classical Hodgkin lymphoma.

During the annual meeting numerous oral and poster presentations will highlight additional progress within the brentuximab vedotin development program including:

  • Updated durability results from the phase III ALCANZA clinical trial in patients with CD30-expressing mycosis fungoides and primary cutaneous anaplastic large cell lymphoma, the most common subtypes of cutaneous T-cell lymphoma (CTCL). Based on the positive results from the ALCANZA trial, a supplemental BLA for brentuximab vedotin in CTCL was accepted for filing by the FDA. The FDA granted Priority Review for the application and the Prescription Drug User Fee Act (PDUFA) target action date is December 16, 2017. brentuximab vedotin previously received FDA Breakthrough Therapy Designation in this setting;
  • Updated results from a phase I/II study of brentuximab vedotin in combination with the ahuman programmed death receptor-1 (PD-1) blocking antibody nivolumab (Opdivo®; Bristol-Myers Squibb Company) among patients with relapsed or refractory Hodgkin lymphoma;
  • Final five-year survival and durability results in patients with CD30-expressing peripheral T-cell lymphomas who received brentuximab vedotin with cyclophosphamide, hydroxydaunorubicin, and prednisone (CHP) as frontline therapy

“At this year’s ASH Annual Meeting, we will present data from 18 abstracts, highlighting several [brentuximab vedotin] clinical program advancements that support our plans to establish ADCETRIS as the foundation of care for CD30-expressing lymphomas,” noted Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

“Importantly, the results of the phase III ECHELON-1 clinical trial evaluating brentuximab vedotin combination therapy in frontline advanced Hodgkin lymphoma patients was selected from over 6,000 abstracts submitted to be featured in the Plenary Scientific Session. These data are the basis for our planned supplemental biologics license application to the FDA requesting approval of brentuximab vedotin in this setting. The breadth of data being presented with brentuximab vedotin in CD30-expressing lymphomas demonstrates the power of antibody-drug conjugates with a goal of improving patient outcomes,” Siegall added

Brentuximab vedotin is currently not approved for the treatment of frontline Hodgkin lymphoma, CTCL, or as combination therapy for Hodgkin lymphoma or non-Hodgkin lymphoma.

For an overview of oral and poster presentations about antibody-drug conjugates, click here.


Ado-trastuzumab emtansine is currently the only antibody-drug conjugate available for the treatment of solid tumors.

In 2000 gemtuzumab ozogamicin, a calicheadmicin conjugates, became the first aDC to be approved in the United States. However, the drug, indicated for the treatment of CD33-positive acute myeloid leukemia (AML) was withdrawn from the market in 2010 due to treatment-related toxicity concerns.

Last Editorial Review: November 11, 2017

Featured Image: American Society of Hematology meeting 2016. Courtesy: © ASH. Used with permission.

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Long-Term Data Continues to Support Development Strategy to Establish Brentuximab Vedotin as Foundation of Therapy for CD30-Expressing Lymphomas

Final data from the pivotal phase II trial with brentuximab vedotin (Adcetris®; Seattle Genetics/Takada)   in relapsed* or refractory** (r/r) systemic anaplastic large cell lymphoma (sALCL) were published in the journal Blood. The manuscript, which summarizes the five-year, end-of-study results, highlights durable, long-term remissions in sALCL patients treated with brentuximab vedotin monotherapy.[1]

Brentuximab vedotin is an antibody-drug conjugate (ADC) directed to CD30, which is expressed on the surface of Hodgkin lymphoma cells and several types of non-Hodgkin lymphoma, including sALCL. The drug is being evaluated globally as the foundation of therapy for CD30-expressing lymphomas in more than 70 corporate- and investigator-sponsored clinical trials.

Anaplastic large cell lymphoma is a rare type of non-Hodgkin lymphoma, and one of the subtypes of T-cell lymphoma. The disease comprises about one percent of all non-Hodgkin lymphomas and, according to data from the lymphoma research foundation, approximately 16% of all T-cell lymphomas. Anaplastic large cell lymphoma it typically has a less aggressive disease course than systemic disease.

Patients with systemic anaplastic large cell lymphoma or sALCL are generally divided into two main groups. This division depending on whether or not the cells have an abnormal form of a protein, called anaplastic lymphoma kinase or ALK, on their surface. And while both diseases are treated as aggressive or fast-growing, lymphomas, the disease course may be different in patients who have ALK-positive  compared with those with ALK-negative anaplastic large cell lymphoma. [2]

Poor prognosis
“Historically, sALCL patients who have recurrent or refractory disease have a poor prognosis and outcome with few effective and durable treatment options,” noted Barbara Pro, MD., Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, and lead author of the Blood manuscript.

“Publication of the five-year follow up from the pivotal phase II clinical trial results represents a significant milestone for the sALCL community by demonstrating that treatment with single-agent brentuximab vedotin resulted in high response rates and durable, long-term remissions in conjunction with a manageable safety profile,” she added.

“These data from the pivotal trial in sALCL demonstrate the long-term clinical benefit of brentuximab vedotin in the treatment of this disease, with an estimated five-year survival rate of 60 percent and progression-free survival rate of 39%,” said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.

“In addition to achieving sustained remissions in the relapsed sALCL treatment setting, these data support the evaluation of brentuximab vedotin in earlier lines of therapy, including in the ongoing Phase III ECHELON-2 clinical trial in frontline mature T-cell lymphoma, also known as peripheral T-cell lymphoma,” Drachman added.

“With the five-year data of brentuximab vedotin in relapsed or refractory classical Hodgkin lymphoma published in Blood in July 2016, these results in sALCL represent the second CD30-expressing malignancy in which five-year data has confirmed clinically significant durable remissions,” said Jesús Gomez-Navarro, M.D., Vice President, Head of Oncology Clinical Research and Development, Takeda.

NCT01777152 (ECHELON-2) (CLINICAL TRIAL / BRENTUXIMAB VEDOTIN / SGN-035 / ADCETRIS®)
Figure 1.0: ECHELON-2 (NCT01777152) is a Clinical Trial designed to establish brentuximab vedotin (Adcetris®) as the foundation of care for CD30-expressing lymphomas.

“These findings further substantiate our goal to establish brentuximab vedotin as the foundation of therapy for CD30-expressing lymphomas,” Navarro further said.

Pivotal trial
The pivotal, single-arm trial, which supported approvals of brentuximab vedotin by the FDA in 2011 and the European Medicines Agency (EMA) in 2012 for this indication, was conducted in 58 relapsed or refractory sALCL patients to assess the efficacy and safety of single-agent brentuximab vedotin. After a follow-up period of approximately five years, the final results from the pivotal trial include:

The median overall survival was not yet reached and median progression-free survival was estimated at 20 months (95% confidence interval [CI]: 9.4, -). The estimated five-year overall survival and progression-free survival rates were 60% and 39%, respectively.

Of the 58 patients treated, 38 patients (66%) had a complete remission, with the median response duration not reached. For patients who had a complete remission, the median overall survival and progression-free survival were not yet reached.

Sixteen of the 38 patients (42%) who achieved a complete remission continued to be followed and remained in remission for over five years at study closure. Of these patients, eight underwent either autologous or allogenic consolidative stem cell transplants while in remission, and eight received no further therapy.

Adverse events
The most common adverse events of any grade occurring in 20% or more of patients were peripheral neuropathy, nausea, fatigue, pyrexia, diarrhea, rash, constipation and neutropenia. Of the 33 patients who experienced peripheral neuropathy, 30 patients (91%) experienced complete resolution or some improvement of symptoms at last follow-up.


* First progression occurs in the absence of any therapy following successful initial therapy.
** A disease that is progressing despite active treatment

Last Editorial Review: October 5, 2017

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Positive Phase III ECHELON-1 Trial Data Leads to FDA Breakthrough Therapy Designation for Brentuximab Vedotin in Frontline Advanced Hodgkin Lymphoma

U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to 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.


“The decision by the FDA to grant this designation recognizes the need for new options that can change the care of people with newly diagnosed advanced Hodgkin lymphoma”


The positive topline results of the phase III ECHELON-1 clinical trial were announced in June 2017 and full data will be presented at the upcoming American Society of Hematology (ASH) annual meeting, December 9-12, 2017 in Atlanta, Georgia.

Brentuximab vedotin is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical Hodgkin lymphoma. The drug includes an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The drug employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-positive tumor cells.

Breakthrough Therapy Designation
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 on one or more clinically significant endpoints.

“The phase III ECHELON-1 study that supports the Breakthrough Therapy Designation for brentuximab vedotin in combination with chemotherapy showed superior activity versus the standard of care chemotherapy regimen in the treatment of frontline advanced classical Hodgkin lymphoma patients,” said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

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

“The decision by the FDA to grant this designation recognizes the need for new options that can change the care of people with newly diagnosed advanced Hodgkin lymphoma. The designation supports our goal to make brentuximab vedotin available to patients in this setting as soon as possible. We look forward to presenting the data from our phase III ECHELON-1 trial at the upcoming ASH annual meeting and intend to submit a supplemental Biologics License Application to the FDA before the end of 2017,” Siegall added.

ECHELON-1 study
The Breakthrough Therapy Designation was based on data from the ECHELON-1 clinical trial, a randomized, open-label, phase III trial investigating a combination of brentuximab vedotin plus AVD (Adriamycin, vinblastine, dacarbazine) versus ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine), a recognized standard of care chemotherapy regimen in previously untreated advanced classical Hodgkin lymphoma, as frontline therapy in patients with advanced classical Hodgkin lymphoma.

The ECHELON-1 study met its primary endpoint of a statistically significant improvement in modified progression-free survival (PFS) of the brentuximab vedotin containing regimen versus the control arm as assessed by an Independent Review Facility (hazard ratio=0.770; p-value=0.035). The two-year modified PFS rate for patients in the brentuximab vedotin arm was 82.1% compared to 77.2% in the control arm. Interim analysis of overall survival, the key secondary endpoint, also trended in favor of the brentuximab vedotin plus AVD arm.

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

(CLINICAL TRIAL / BRENTUXIMAB VEDOTIN / SGN-035 / ADCETRIS®)
The Phase III Echeolon-1 (NCT01712490) Trial investigating Brentuximab Vedotin (Adcetris®; Seattle Genetics) met its primary endpoint of a statistically significant improvement in modified progression-free survival (PFS) of the brentuximab vedotin containing regimen versus the control arm as assessed by an Independent Review Facility.

Trial Design
The  primary endpoint of the ECHELON-1 study is modified PFS per Independent Review Facility assessment using the Revised Response Criteria for Malignant Lymphoma. 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. The endpoint was chosen since it provides a clearer picture of the efficacy of frontline chemotherapy and eliminates the confounding impact of salvage and consolidation chemotherapies and radiotherapy. 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 is being conducted under a Special Protocol Assessment (SPA) agreement from the FDA and the trial also received European Medicines Agency (EMA) scientific advice.

Clinical trial program
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.

These trials include the ECHELON-1 trial in frontline classical Hodgkin lymphoma from which positive topline results were recently reported, the ongoing ECHELON-2 trial in frontline mature T-cell lymphomas, the completed ALCANZA trial in cutaneous T-cell lymphoma that supported the supplemental BLA with a Prescription Drug User Fee Act (PDUFA) target action date of December 16, 2017, and the recently initiated CHECKMATE 812 trial of brentuximab vedotin in combination with Opdivo (nivolumab) for relapsed/refractory Hodgkin lymphoma.

Submission of Supplemental Biologics License Application for brentuximab vedotin in Frontline Advanced Hodgkin Lymphoma Planned Before the End of 2017.


Last Editorial Review: October 2, 2017

Featured Image: Seattle Genetics laboratory. Courtesy: © 2017. Seattle Genetics. Used with permission. Packaging of brentuximab vedotin/Adcetris Courtesy: © 2017. Seattle Genetics. 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.

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U.S. FDA Grants Priority Review for Brentuximab Vedotin in Cutaneous T-Cell Lymphoma

The United States Food and Drug Administration (FDA) has accepted for filing a supplemental Biologics License Application (BLA) based on data from the Phase III ALCANZA trial and two phase II investigator-sponsored trials of brentuximab vedotin (Adcetris®; Seattle Genetics/Takeda) in patients with cutaneous T-cell lymphoma (CTCL).

Brentuximab vedotin is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing 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-positive tumor cells.

Unmet Medical need
The treatment of CTCL represent an mayor unment medical need.

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 systemically pre-treated CTCL includes skin-directed therapies, radiation and systemic therapies. The systemic therapies currently approved for treatment have demonstrated 30 to 45 percent objective response rates, with low complete response rates.

Breakthrough Therapy
In November 2016, the FDA granted brentuximab vedotin Breakthrough Therapy Designation (BTD) for the treatment of patients with CD30-expressing mycosis fungoides and primary cutaneous anaplastic large cell lymphoma who require systemic therapy and have received one prior systemic therapy.

The FDA granted Priority Review for the application and the Prescription Drug User Fee Act (PDUFA) target action date is December 16, 2017. Brentuximab vedotin is currently not approved for the treatment of CTCL.

“The FDA’s filing of our supplemental BLA with Priority Review status represents a significant milestone towards our goal of making [brentuximab vedotin] available to CTCL patients who require systemic therapy,” said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development of Seattle Genetics.

“Results from our positive phase III ALCANZA trial demonstrated that using [brentuximab vedotin] in this setting significantly improved the rate of objective responses lasting at least four months with a manageable safety profile. Data from two investigator-sponsored trials in a broader patient population were included in the submission to further support [brentuximab vedotin] in use in this disease setting. We look forward to working with the FDA during the review of our application for [brentuximab vedotin] in CTCL, which, if approved, would be the fourth indication for this product.”

llustration: The ALCANZA study is a randomized, open-label, phase III Trial of brentuximab vedotin (SGN-35) versus Physician’s Choice (methotrexate or bexarotene) in Patients With CD30-Positive Cutaneous T-Cell Lymphoma (NCT01578499).

Positive trial results
The supplemental BLA is primarily based on positive results from a phase III trial called ALCANZA that were presented at the 58th American Society of Hematology (ASH) annual meeting held in December 2016 and published online in the Lancet in June 2017.

The ALCANZA trial in 128 CTCL patients requiring systemic therapy 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 results from the trial also showed that the ORR4, as assessed by Global Response Score, was 56.3% in the brentuximab vedotin arm compared to 12.5% in the control arm (p-value <0.0001).

Key secondary endpoints specified in the protocol, including complete response rate, progression-free survival and reduction in the burden of symptoms during treatment (Skindex-29), 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.

Based on discussions with the FDA, additional data from two investigator-sponsored phase II trials have also been incorporated into the supplemental BLA to support the potential for a broader label in CTCL.

Other trials
Brentuximab vedotin is being evaluated broadly in more than 70 ongoing clinical trials, including four phase III studies: the ECHELON-1 trial in frontline classical Hodgkin lymphoma from which positive top-line results were recently reported, the ongoing ECHELON-2 trial in frontline mature T-cell lymphomas, the completed ALCANZA trial in cutaneous T-cell lymphoma that supported the supplemental BLA to the FDA, and the recently initiated CHECKMATE 812 trial of brentuximab vedotin in combination with nivolumab (Opdivo®; Bristol-Myers Squibb Company) for relapsed/refractory Hodgkin lymphoma.


Last Editorial Review: August 16, 2017

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Antibody-drug Conjugates: Technologies and Global Markets

Less than 3 decades old, antibody-drug conjugate or ADC-technology is a relatively new.  Due to many technological advances, recognition of appropriate target antigens, success in the development on novel monoclonal antibodies (mAbs) and increasing demand for biologics and biotherapeutics the market of targeted therapies, including ADCs, is rapidly increasing.

This week, ReportLinker, an award-winning market research organization published the latest industry data covering ADCs. According to the authors of the report, developed by BCC research, the global market for antibody drug conjugates was valued at $1.3 billion in 2016 and is expected to reach $4.2 billion by 2021, growing at a compound annual growth rate or CAGR of 25.5% from 2016 to 2021. [1]

In 2016, the market for ADCs in North American was valued at $588.6 million and should reach $2.0 billion by 2021, growing at a CAGR of 27.2% from 2016 to 2021. In Europe this market was valued $395.0 million in 2016 and is expected to reach $1.2 billion by 2021, growing at a CAGR of 24.1% from 2016 to 2021.

Currently approved ADCs
Advances in targeting antibodies, potent payloads and drug-linker technologies that facilitate improved ADC stability, potency and targeting efficiency have led to the development of two commercially viable ADCs. BCC Research’s goal in conducting this study is to provide an overview of the current and future characteristics of the global market for antibody drug conjugates.

The new report explores present and future strategies within the antibody-drug conjugates market, which includes, by type of payload (cytotoxic agent), by type of monoclonal antibodies and by type of linker. The inception of the market, and its demands and restraints are discussed in this report. Classification, comparisons and usage of ADC products are also presented in this report.

The authors analyzed the structure of the antibody-drug conjugate industry and broke down revenues by region, with sales estimated for the five-year period from 2016 through 2021. Applications of antibody drug conjugates and significant patents and their allotments in each category discussed.

Study background
Advancements in research have changed the way many diseases are treated. ADCs represent an innovative class of drugs that are mainly developed by conjugating already-developed or marketed small molecules and biologics. ADCs have shown great potential in cancer therapy. ADC products are becoming an important part of the biomedical industry and have the potential to replace conventional treatment options.

Research & Development spending, along with increasing competition, patent expires and new technologies are providing a new direction to the market. Advancements, new product launches and changing lifestyles are expected to influence the future growth of the market. This study looks at the majority of the systems affected by these factors.

Acquisition strategies and collaborations by companies are also covered in this report. This study also discusses the strength and weaknesses of each type company in light of the new technologies, growing competition and changing customer needs.

Scope
Antibody drug conjugates are mainly used to treat cancer and are safer and more effective than many other cancer therapies. This report focuses on the global market for antibody drug conjugate products and provides an updated review, including their basic design and application in various areas of the biomedical sciences.

The report covers three main areas of application, breast cancer, lymphoma and other cancers, including acute myeloid leukemia or AML. The scope of this study includes the current market for ADCs. The report also discusses regulatory aspects, current and developing technologies, market projections and market shares. An analysis of clinical trials, innovations and opportunities and the latest trends in ADC market are also discussed in the report.

Also included in the report is an analysis of relevant patents and profiles of companies, including Seattle Genetics, Takeda Pharmaceuticals and Genentech/Roche that lead the antibody-drug conjugate product market.

Sales data for the global and regional markets were corroborated for the present and forecasted values via statistical analysis, and sales are broken down geographically into North America, Europe, Asia- Pacific and the emerging markets. The application of ADCs in various types of cancer is discussed from both a commercial perspective and that of a research and development (R&D) perspective.

The report only covers antibody-drug conjugates in which an antibody is conjugated with small-molecule cytotoxins (payload) through a linker. Other forms of antibody conjugates such as radioisotopes conjugated with an antibody are beyond the scope of this report.

Information Sources
For this report, the authors surveyed many companies to obtain data for this study. This included manufacturers and end users of antibody-drug conjugate products. Data was also gathered from various industry sources.  The authors spoke with officials within the industry, consulted newsletters, company literature, product literature and a host of technical articles, journals, indexes and abstracts. Exhaustive database searches were conducted using key terminology. In addition, data were compiled from current financial, trade and government sources.

Methodology
Both primary and secondary research methodologies were used in preparing this study. The authors also conducted a comprehensive literature search, which included technical newsletters and journals, including ADC Review | Journal of Antibody-drug Conjugates, and many other sources and conducted interviews experts and key opinion leaders. Projections were based on estimates such as the current number of end users, potential end users, mergers and acquisitions, and market trends.

Highlights
Antibody-drug conjugates, representing the convergence of chemistry with biology, include an antibody linked with a cytotoxic drug called payload. They combine the extraordinary affinity and specificity of antibodies with the anticancer potential of payloads. Continuous efforts to improve the therapeutic potential of biologics and to develop novel efficacious drugs either by modification or derivatization led to the development of ADCs.

Over the last decades, ADCs have revolutionized the field of cancer treatment. Unlike conventional chemotherapeutics, which damage normal cells along with the cancer cells, ADCs target only cancer cells. Through the synergistic combination of monoclonal antibody with the cytotoxic drug, via a stable linker, an extremely efficacious class of anticancer drugs has been emerged. To date, three ADCs have gained entry into the market, of which only two remain. Gemtuzumab ozogamicin (Mylotarg®), marketed by Pfizer, became the first FDA approved ADC in 2000.

This drug was approved for the treatment of relapsed acute myeloid leukemia. In 2010, a decade after its approval, gemtuzumab ozogamicin was withdrawn from the market due to serious hepatotoxicity issues.

However, in late January 2017 Pfizer’s Biologics License Application (BLA) for gemtuzumab ozogamicin (Mylotarg®; previously known as CMA-676) was accepted for filing by the U.S. Food and Drug Administration (FDA). And a Marketing Authorization Application (MAA) for review by the European Medicines Agency (EMA) was validated in December 2016.[2]

The Biological License Application (BLA) was based on additional data from a Phase III study that evaluated the potential benefits of adding gemtuzumab ozogamicin to standard induction chemotherapy in the treatment of patients with acute myeloid leukemia aged 50–70 years old. The FDA’s decision on the application is expected sometime in September 2017.

Only brentuximab vedotin (Adcetris®; marketed by Seattle Genetics and Takeda Pharmaceutical) and ado-trastuzumab emtansine (Kadcyla®; marketed by Genentech/Roche), are commercially available. Brentuximab vedotin was approved in 2011 for relapsed Hodgkin lymphoma and relapsed anaplastic large-cell lymphoma, and ado-trastuzumab emtansine was approved in 2013 for human epidermal growth factor receptor 2 (HER2)-expressing breast cancer.

Technological advancements, the growing number of cancer patients and increasing demand for biologics for the treatment of chronic diseases are the prime factors that are driving the market for ADCs.

North America continues to lead the market for ADCs as it has the advanced technologies needed to develop ADCs. In addition, rising healthcare expenditures and huge government initiatives are also driving the North American market. Improving economic conditions, demand for better healthcare facilities, increasing health awareness, increasing incidence of chronic diseases and growing R&D activities will help the market for ADCs grow in Asia-Pacific.

The ADC industry involves a specialization business model, more specifically a technology licensing model. In specialization models, certain companies discover and license its ADC technology to pharmaceutical companies. The two main ADC technology companies in terms of sheer numbers of licensing deals to date are ImmunoGen and Seattle Genetics. ImmunoGen, with its maytansinoid-based targeted antibody payload (TAP-) technology, produced ado-trastuzumab emtansine with Genentech.

Brentuximab vedotin is developed by Seattle Genetics and includes the company’s ADC linker and cytotoxin expertise coupled with an antibody from Millennium Pharmaceuticals, now part of the Takeda Pharmaceutical.

Innovation in ADCs typically occur through the development of new cytotoxic agents as well as new linkers that are adequately stable and at the same time can be cleaved efficiently to deliver the cytotoxic drug. Thus, key future trends in the market for ADCs include the development of novel payloads, new linker chemistry and the site-specific conjugation technology. All these advancements are expected to lead to the development of more specialized, personalized and targeted ADCs.

The manufacturing of antibody-drug conjugates requires specific manufacturing facilities. In turn, this requires high capital investment and extensive specialized training of operators and both of these requirements indicates the trend towards the contract development and manufacturing of ADCs.

Product pipeline
The product pipeline is a key determinant of any industry’s future growth. And that is also the case with antibody-drug conjugates. The industry’s acceptance of ADC technology is evident from the continual increase in novel ADCs entering clinical trials during the past few years. During 2003-2007, 10 ADCs reached Phase I trials and this number increased to 30 during 2008-2012. About 24 novel ADCs entered Phase I trials during 2012- 2016.

A number of ADCs with promising preliminary data are in the clinical trial pipeline. Mirvetuximab soravtansine, also known as IMGN853, sacituzumab govitecan and vadastuximab talirine are in late stage phase III clinical development. These three ADCs are expected to reach the market during forecast period.

Inotuzumab ozogamicin, an anti-CD22 ADC being developed by Pfizer for the treatment of relapsed or refractory acute lymphoblastic leukemia, is expected to be approved by FDA at the end of 2017. It received priority review designation from the FDA in February 2017. Through the FDA’s priority review program, Pfizer is expected to receive the FDA’s decision on inotuzumab ozogamicin with breakthrough therapy designation within six months.

In October 2016 rovalpituzumab tesirine, also known as Rova-T, an antibody-drug conjugate being developed by AbbVie/Stemcentrx, was recognized at the 7th Annual World Antibody Drug Conjugate (ADC) Awards as the “Most Promising Clinical Candidate” for fighting cancer. The novel biomarker-specific ‘smart-bomb’ antibody-drug conjugate targets the delta-like protein 3 or DLL3 protein, expressed in more than 80% of small-cell lung cancers (SCLC) patient tumors, appears to be safe and shows efficacy in treating patients with advanced SCLC. The authors expect this investigational agent to also reach the market during the forecast period.

Market expectation
The market for ADCs was worth approximately $1.3 billion in 2016 with just two approved drugs, and its potential remains very large. Total revenues, representing product sales (collaboration and royalty revenues are not considered), are expected to be $4.2 billion worldwide by 2021 at a CAGR of 25.5% from 2016 through 2021.

These revenues reflect the estimated addition of other ADCs that are directed toward acute lymphocytic leukemia and ovarian cancer. Much of the market growth is expected to come from added indications for both the marketed ADCs. In addition, the expected approval of several other antibody-drug conjugates, such as Pfizer’s gemtuzumab ozogamicin and inotuzumab ozogamicin, during the forecast period will help the market for ADCs to grow significantly.

North America led the antibody drug conjugate market due to the presence of major pharmaceutical companies working on the development of antibody drug conjugate drugs there. Both the North American and European markets benefited from the fast track approval of ADCs. Expanded access to ADCs in Asia-Pacific and the emerging markets drove the market for ADCs in these geographies.

The two most common therapeutic areas for ADCs from 2014 to 2016 were lymphoma and breast cancer, with breast cancer representing 61.3% of ADC revenues in 2016. By 2021, with the approval of two novel ADCs to treat acute myeloid leukemia and ovarian cancer, breast cancer ADCs will represent a market share of 47.1%.


Last editorial review: July 20, 2017

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Copyright © 2017 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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