Our services

ADC Review
is made possible by:




PEER-REVIEWED ARTICLES

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.

Creative Commons License

This work is published by InPress Media Group, LLC (Four Ways to Show Nonobviousness of ADC Inventions) and is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. Non-commercial uses of the work are permitted without any further permission from InPress Media Group, LLC, provided the work is properly attributed. Permissions beyond the scope of this license may be available at adcreview.com/about-us/permission.


Copyright © 2010 – 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.

Share

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.

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.

Share

U.S. FDA Approves Inotuzumab Ozogamicin for Treatment of Patients with R/R B-cell precursor Acute Lymphoblastic Leukemia

The United States Food and Drug Administration (FDA) approved inotuzumab ozogamicin (Besponsa™, Wyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc.) for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

Acute lymphoblastic leukemia (ALL) is an aggressive type of leukemia with a poor prognosis in adults.[1] The current foundational treatment is intensive, long-term chemotherapy.[2] In 2017, it is estimated that 5,970 cases of ALL will be diagnosed in the United States, with about 2 in 5 cases occurring in adults.[3] Approximately 20 to 40% of newly diagnosed adults with ALL are cured with current treatment regimens.[4] For patients with relapsed or refractory adult ALL, the five-year overall survival rate is less than 10%.[5]

The approval was based on data from INO-VATE ALL (NCT01564784INotuzumab Ozogamicin trial to in VestigAte Tolerability and Efficacy), a randomized (1:1), open label, international, multicenter study in 326 patients with Philadelphia chromosome-negative or Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL. Patients were required to have ≥5% bone marrow blasts and to have received one or two previous induction chemotherapy regimens for ALL.

NCT01564784 (CLINICAL TRIAL / INOTUZUMAB OZOGAMYCIN / CMC-544)
Illustration: Inotuzumab ozogamicin is an antibody – drug conjugate (ADC) comprised of a monoclonal antibody (mAb) targeting CD22, a cell surface antigen expressed on approximately 90 percent of B – cell malignancies , linked to a cytotoxic agent. When inotuzumab ozogamicin binds to the CD22 antigen on malignant B – cells, it is absorbed into the cell, at which point the cytotoxic agent calicheamicin is released to destroy the cell. Calicheamicin is a natural product of bacteria that was first discovered in caliche clay and was found to be toxic to normal and cancerous cells.

In this trial, patients with Philadelphia chromosome positive B cell precursor ALL were required to have disease that failed treatment with at least one tyrosine kinase inhibitor and standard chemotherapy.

Patients were randomized to receive either inotuzumab ozogamicin (n=164) or investigator’s choice of chemotherapy (n=162). Of the initial 218 randomized patients, 35.8% of those who received inotuzumab ozogamicin experienced complete remission (CR) for a median 8.0 months and 89.7% of those patients achieved minimal residual disease (MRD)-negativity. Of the patients who received chemotherapy, 17.4% experienced CR for a median 4.9 months and 31.6% of those patients achieved minimal residual disease MRD-negativity.

Adverse events
The most common adverse reactions occurring in greater than 20% of patients were thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, gamma-glutamyltransferase increased, and hyperbilirubinemia.

The most common (≥2%) adverse reactions reported as the reason for permanent discontinuation were infection, thrombocytopenia, hyperbilirubinemia, transaminases increased, and hemorrhage.

For the first cycle, the recommended dose of inotuzumab ozogamicin for all patients is 1.8 mg/m2 per cycle, administered as three divided doses on day 1 (0.8 mg/m2), day 8 (0.5 mg/m2), and day 15 (0.5 mg/m2).

The recommended dosing for subsequent cycles depends on response to treatment. Details are available in the full prescribing information. [6]

Breakthrough Therapy
A Biologics License Application (BLA) for inotuzumab ozogamicin was accepted for filing and granted Priority Review by the U.S. Food and Drug Administration (FDA) in February 2017.

In October 2015 inotuzumab ozogamicin received Breakthrough Therapy designation from the FDA in for ALL. Priority Review status accelerates FDA review time from 10 months to a goal of six months from the day of acceptance of filing, and is given to drugs that may offer major advances in treatment or may provide a treatment for which no adequate therapy exists. The Prescription Drug User Fee Act (PDUFA) goal date for a decision by the FDA is in August 2017.

Antibody-drug conjugate
Inotuzumab ozogamicin is an antibody-drug conjugate (ADC) comprised of a monoclonal antibody (mAb) targeting CD22, a cell surface antigen expressed on cancer cells in almost all B-ALL patients, linked to a cytotoxic agent.[7] When BESPONSA binds to the CD22 antigen on B-cells, it is internalized into the cell, where the cytotoxic agent calicheamicin is released to destroy the cell.[8]

The drug originates from a collaboration between Pfizer and Celltech (now UCB). Under the terms of this agreement, Pfizer has sole responsibility for all manufacturing and clinical development activities of the agent. Pfizer also collaborated with SFJ Pharmaceuticals Group on the registrational program (INO-VATE ALL) for inotuzumab ozogamicin.


Last Editorial Review: August 17, 2017

Featured Image: Leukemia white blood cells, Cancer cells. Courtesy: © 2017. Fotolia 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.

Share

Inotuzumab ozogamicin Approved in the EU for Adult Patients with Relapsed or Refractory B-cell Precursor Acute Lymphoblastic Leukemia

The European Commission has approved inotuzumab ozogamicin (Besponsa®; Pfizer) as monotherapy for the treatment of adults with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL).

This indication includes treatment of adults with Philadelphia chromosome positive (Ph+) as well as Philadelphia chromosome negative (Ph-) relapsed or refractory B-cell precursor ALL. Adults with Ph+ relapsed or refractory CD22-positive B-cell precursor ALL should have failed treatment with at least one tyrosine kinase inhibitor (TKI). With this approval, inotuzumab ozogamicin becomes the first and only antibody-drug conjugate or ADC available for patients with this type of leukemia in the European Union.

“The European Commission’s approval of inotuzumab ozogamicin represents an important milestone for patients, the oncology community and Pfizer,” said Andreas Penk, M.D., regional president, Pfizer Oncology. “This is the first approval for inotuzumab ozogamicin and provides patients in the EU, who are battling an especially hard-to-treat leukemia, with a new treatment option beyond chemotherapy.”

ALL is an aggressive type of leukemia that can be fatal within a matter of months if left untreated.[1] The goal of treatment in relapsed or refractory (resistant) ALL is to achieve complete remission without excessive toxicity so patients may proceed to additional therapeutic intervention, particularly stem cell transplant, which is the most recognized option to prolong patient survival, maintenance therapy or other therapy.[2]

In adult patients with relapsed or refractory ALL, median overall survival is just three to six months.[3][4][5] The current standard of care is intensive chemotherapy [6], which is effective in less than 50 percent of relapsed or refractory patients and associated with poor long-term survival, high toxicities, lengthy inpatient stays and continuous infusions.[7]

“Acute lymphoblastic leukemia that has recurred or is refractory following first-line therapy is a rare and rapidly progressive disease with poor prognosis,” said Professor David Marks, Department of Hematology, University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom.

“The approval of inotuzumab ozogamicin provides a much needed treatment option for physicians and patients alike, that may help improve outcomes for some of the most vulnerable leukemia patients in Europe,” Marks added.

Illustration: Inotuzumab ozogamicin is an antibody – drug conjugate (ADC) comprised of a monoclonal antibody (mAb) targeting CD22, a cell surface antigen expressed on approximately 90 percent of B – cell malignancies , linked to a cytotoxic agent. When inotuzumab ozogamicin binds to the CD22 antigen on malignant B – cells, it is absorbed into the cell, at which point the cytotoxic agent calicheamicin is released to destroy the cell. Calicheamicin is a natural product of bacteria that was first discovered in caliche clay and was found to be toxic to normal and cancerous cells.

INO-VATE ALL
The European Commission’s approval of inotuzumab ozogamicin is supported by results from the Phase III INO-VATE ALL trial, (NCT01564784; INotuzumab Ozogamicin trial to in VestigAte Tolerability and Efficacy) in which 326 adult patients with relapsed or refractory B-cell precursor ALL were enrolled and which compared inotuzumab ozogamicin to standard of care chemotherapy.

The INO-VATE ALL study had two primary endpoints, complete response with or without hematologic recovery (CR/CRi) and overall survival (OS).

Results from the trial were published in The New England Journal of Medicine in June 2016.

Breakthrough Therapy
In the United States, inotuzumab ozogamicin received Breakthrough Therapy designation from the Food and Drug Administration (FDA) in October 2015 for ALL. A Biologics License Application (BLA) for inotuzumab ozogamicin for the treatment of adult patients with relapsed or refractory B-cell precursor ALL was accepted for filing and granted Priority Review by the FDA in February 2017. The Prescription Drug User Fee Act (PDUFA) goal date for a decision by the FDA is August 2017.

With a growing hematology pipeline, Pfizer is committed to extending therapeutic progress in acute and chronic leukemias that leverage select pathways and mechanism of actions (MOAs). Specifically, our investigational products aim to treat some of the hardest to treat leukemias and lymphomas including, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and mantle cell lymphoma (MCL).

Antibody-drug Conjugate
Inotuzumab ozogamicin is an antibody-drug conjugate (ADC) comprised of a monoclonal antibody (mAb) targeting CD22, a cell surface antigen expressed on cancer cells in almost all B-ALL patients, linked to a cytotoxic agent.[8] When the agent binds to the CD22 antigen on B-cells, it is internalized into the cell, where the cytotoxic agent calicheamicin is released to destroy the cell.[9]

The drug originates from a collaboration between Pfizer and Celltech (now UCB). Under the terms of this agreement, Pfizer has sole responsibility for all manufacturing and clinical development activities of the agent. Pfizer also collaborated with SFJ Pharmaceuticals Group on the registrational program (INO-VATE ALL) for inotuzumab ozogamicin.


Last Editorial Review: June 30, 2017

Featured Image: Empty tubes for blood tests | screening. Courtesy: © 2017. Fotolia 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.

Share

Skip to toolbar