On December 7, 2020 OncoMyx Therapeutics, a privately-held oncolytic immunotherapy company, reported that The University of Western Ontario (Western) has assigned to OncoMyx the technology and patent rights associated with pioneering research on the use of myxoma virus in the treatment of cancer (Press release, OncoMyx Therapeutics, DEC 7, 2020, View Source [SID1234572370]). This research was led by OncoMyx cofounder Grant McFadden, Ph.D., when he was a Professor at Western and the Robarts Research Institute.

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Lisa Cechetto, the Executive Director of WORLDiscoveriesTM, the technology transfer office for Western, Robarts Research Institute, and Lawson Research Institute, said, "We are pleased to assign these patents to OncoMyx, as it is important that the outputs of pioneering research, such as Dr. McFadden’s use of myxoma virus to create novel oncolytic therapies, be further developed to improve the lives of cancer patients or others who may benefit."

"The assignment of this technology and intellectual property to OncoMyx further reinforces our IP portfolio protecting our use of myxoma virus and our pipeline of myxoma virotherapies for the treatment of cancer," said Steve Potts, Ph.D., MBA, cofounder and chief executive officer of OncoMyx. "The myxoma virus has a number of important attributes that we are leveraging to develop potentially impactful oncolytic immunotherapies with the goal of increasing the number of cancer patients who could benefit from immunotherapies."

"Oncolytic viruses are emerging as a new pillar of cancer care with the potential to expand the effectiveness of immunotherapies, such as immune checkpoint inhibitors," said Dr. McFadden. "I am pleased that OncoMyx has been assigned the patent rights associated with the pioneering myxoma research that was done at Western, as the myxoma virus is unique as a technology platform to build oncolytic immunotherapies."

About Myxoma Virotherapy for the Treatment of Cancer

The myxoma virus is highly immuno-interactive and can selectively infect and kill a broad range of cancer cell types. Because myxoma virus is not pathogenic to humans, myxoma virotherapy does not have to overcome pre-existing immunity. As a large dsDNA poxvirus, myxoma is engineerable to express multiple transgenic payloads, such as immunomodulatory proteins, to target multiple points in the cancer immunity cycle. The company’s preclinical data demonstrates efficacy of multi-armed myxoma virotherapies via intravenous (IV) and intratumoral (IT) delivery in a number of tumor models across multiple cancer indications and supports a pan-tumor approach to expand the therapeutic effectiveness of immunotherapies.

On December 7, 2020 Seagen Inc. (Nasdaq:SGEN) reported multiple ADCETRIS (brentuximab vedotin) data presentations at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, taking place virtually December 5-8, 2020 (Press release, Seagen, DEC 7, 2020, View Source [SID1234572321]). Data presentations include five-year updates from the phase 3 ECHELON-1 and ECHELON-2 clinical trials evaluating ADCETRIS plus a chemotherapy combination regimen in frontline advanced stage classical Hodgkin lymphoma (HL) and CD30-expressing frontline peripheral T-cell lymphoma (PTCL), respectively. In addition, first results were presented from an ongoing phase 2 clinical trial evaluating ADCETRIS in combination with Opdivo (nivolumab) in relapsed or refractory mediastinal gray zone lymphoma (MGZL), a rare type of non-Hodgkin lymphoma that express CD30 with no standard of care. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical HL and expressed on the surface of several types of non-Hodgkin lymphoma, including PTCL. ADCETRIS is being evaluated globally in more than 70 corporate- and investigator-sponsored clinical trials across multiple settings in lymphoma and other indications. ADCETRIS and Opdivo are not approved alone or in combination for the treatment of relapsed or refractory MGZL.

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"After five years of follow-up, an important clinical milestone, both the ECHELON-1 and ECHELON-2 clinical trials demonstrate that ADCETRIS plus chemotherapy resulted in superior and durable outcomes when compared with standard chemotherapy regimens," said Roger Dansey, M.D., Chief Medical Officer at Seagen. "As most relapses in Hodgkin lymphoma occur within five years of frontline treatment, the results of the ECHELON-1 study suggest that patients treated with ADCETRIS plus chemotherapy are more likely to experience long-term remissions compared to those treated with the ABVD regimen."

Brentuximab Vedotin with Chemotherapy for Patients with Previously Untreated, Stage III/IV Classical Hodgkin Lymphoma: 5-Year Update of the ECHELON-1 Study (Abstract #2973, poster presentation on Monday, December 7, 2020)

The ECHELON-1 clinical trial is evaluating ADCETRIS in combination with AVD (Adriamycin [doxorubicin], vinblastine, dacarbazine) compared to ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, dacarbazine) in patients with Stage III or IV frontline classical HL. As previously reported, the ECHELON-1 trial achieved its primary endpoint with the combination of ADCETRIS plus AVD resulting in a statistically significant improvement in modified progression-free survival (PFS) compared to the control arm of ABVD as assessed by independent review facility (IRF; hazard ratio (HR), 0.77; p=0.035). A five-year exploratory analysis was conducted to examine PFS outcomes per investigator assessment in the intent-to-treat population of 1,334 patients. Results include:

Patients in the ADCETRIS plus AVD arm had a 32 percent reduction in the risk of a progression event compared to patients in the ABVD arm. The five-year PFS rate for patients in the ADCETRIS plus AVD arm was 82.2 percent compared to 75.3 percentin the ABVD arm, an absolute difference of 6.9 percent (HR, 0.681 [95% CI: 0.534, 0.867]). Median follow-up time was 60.9 months.
Consistent benefit in PFS was observed among patients treated with ADCETRIS plus AVD compared with ABVD, independent of disease stage, age and prognostic score.
Consistent improvements compared to ABVD were observed in patients with Stage III (HR, 0.593; [95% CI: 0.385, 0.915]) and Stage IV (HR, 0.731; [95% CI: 0.545, 0.980]) disease.
As previously reported for the primary analysis, on the ADCETRIS plus AVD arm, peripheral neuropathy events were observed in 67 percent of patients compared to 43 percent in the ABVD arm. The five-year update shows that among patients with peripheral neuropathy, 85 percent in the ADCETRIS plus AVD arm and 86 percent in the ABVD arm reported complete resolution or improvement at last follow-up.
There were fewer secondary malignancies in the ADCETRIS plus AVD arm. Among 48 patients with reported secondary malignancies, 19 [(nine hematological malignancies and 10 solid tumors)] were in the ADCETRIS plus AVD arm and 29 [(15 hematological malignancies and 14 solid tumors)] were in the ABVD arm.
There were a higher number of pregnancies in the ADCETRIS plus AVD arm compared to the ABVD arm. A total of 150 pregnancies were reported among study participants and their partners, including 89 on the ADCETRIS plus AVD arm and 61 on the ABVD arm.
The ECHELON-2 Trial: 5-Year Results of a Randomized, Double-Blind, Phase 3 Study of Brentuximab Vedotin and CHP (A+CHP) Versus CHOP in Frontline Treatment of Patients with CD30-Positive Peripheral T-Cell Lymphoma (Abstract #1150, poster presentation on Saturday, December 5, 2020)

The ECHELON-2 clinical trial is evaluating ADCETRIS in combination with CHP (cyclophosphamide, Adriamycin [doxorubicin], prednisone) compared to CHOP (cyclophosphamide, Adriamycin [doxorubicin], vincristine, prednisone) in frontline CD30-expressing PTCL. As previously reported, the ECHELON-2 trial met its primary endpoint with the combination of ADCETRIS plus CHP resulting in a statistically significant improvement in PFS versus the control arm of CHOP per blinded independent central review (HR, 0.71; p=0.0110). A five-year post-hoc exploratory analysis was conducted to examine PFS outcome and overall survival (OS) per investigator assessment in the intent-to-treat population of 452 patients. Key findings include:

Patients in the ADCETRIS plus CHP arm had a 30 percent reduction in the risk of a progression event compared to patients in the CHOP arm. The five-year PFS rate for patients in the ADCETRIS plus CHP arm was 51.4 percent compared to 43 percent in the CHOP arm, an absolute difference of 8.4 percent (HR, 0.70 [95% CI: 0.53, 0.91]).
OS in the ADCETRIS plus CHP arm was improved compared to CHOP (HR=0.72 [95% CI: 0.53, 0.99]). This represents a 28 percent reduction in the risk of death. Median follow-up time was 66.8 months.
Among 316 systemic anaplastic large-cell lymphoma (sALCL) patients on study, patients in the ADCETRIS plus CHP arm had a 45 percent reduction in the risk of a progression event compared to patients in the CHOP arm (HR, 0.55 [95% CI: 0.39, 0.79]). There was a 34 percent reduction in the risk of death. Median follow-up time for PFS was 42.7 months.
Consistent improvement in both PFS and OS was observed among patients treated with ADCETRIS plus CHP arm compared to the CHOP arm across the majority of pre-specified subgroups.
The five-year update shows that among patients with peripheral neuropathy, 72 percent in the ADCETRIS plus CHP arm and 78 percent in the CHOP arm reported complete resolution or improvement at last follow-up. For ongoing peripheral neuropathy events, 98 percent in the ADCETRIS plus CHP arm and 98 percent in the CHOP arm were Grade 1 or 2.
Nivolumab Combined with Brentuximab Vedotin for Relapsed/Refractory Mediastinal Gray Zone Lymphoma: Primary Efficacy and Safety Analysis of the Phase 2 CheckMate 436 Study (Abstract #2045, poster presentation on Sunday, December 6, 2020)

Data from the ongoing CheckMate 436 phase 2 clinical trial of 10 patients with relapsed or refractory MGZL who received a combination of ADCETRIS plus Opdivo treatment after autologous stem cell transplant or two or more lines of multi-agent chemotherapy if ineligible for transplant will be presented for the first time. Patients were treated once every three weeks or until disease progression or unacceptable toxicity. The median age of patients was 35 years. Key findings include:

Of 10 response-evaluable patients, seven patients (70 percent) had an objective response, including five patients (50 percent) with a complete response and two patients (20 percent) with a partial response. Two patients (20 percent) had progressive disease and in one patient (10 percent) death occurred prior to disease assessment.
Median follow-up time was 12.4 months. Time to complete response was 1.2-4.8 months and the duration was 1.5+ to 3.2+ months before patients were assessed for subsequent therapy. All patients who achieved a complete response underwent a hematopoietic cell transplant and follow-up is ongoing.
The most common adverse events of any grade in at least 20 percent of patients were neutropenia and paresthesia (30 percent each); thrombocytopenia, anemia and peripheral sensory neuropathy (20 percent each). The most common Grade 3 adverse events were neutropenia and thrombocytopenia (10 percent each). Three patient deaths occurred due to disease progression.
About ADCETRIS

ADCETRIS 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 Seagen’s proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing cells.

ADCETRIS for injection for intravenous infusion has received FDA approval for six indications in adult patients with: (1) previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone, (2) previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine, (3) cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation, (4) cHL after failure of auto-HSCT or failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (5) sALCL after failure of at least one prior multi-agent chemotherapy regimen, and (6) primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.

Health Canada granted ADCETRIS approval with conditions in 2013 for patients with (1) HL after failure of autologous stem cell transplant (ASCT) or after failure of at least two multi-agent chemotherapy regimens in patients who are not ASCT candidates and (2) sALCL after failure of at least one multi-agent chemotherapy regimen. Non-conditional approval was granted for (3) post-ASCT consolidation treatment of patients with HL at increased risk of relapse or progression in 2017, (4) adult patients with pcALCL or CD30-expressing MF who have received prior systemic therapy in 2018, (5) for previously untreated patients with Stage IV HL in combination with doxorubicin, vinblastine, and dacarbazine in 2019, and (6) for previously untreated adult patients with sALCL, peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) or angioimmunoblastic T-cell lymphoma (AITL), whose tumors express CD30, in combination with cyclophosphamide, doxorubicin, prednisone in 2019.

ADCETRIS received conditional marketing authorization from the European Commission in October 2012. The approved indications in Europe are: (1) for the treatment of adult patients with previously untreated CD30-positive Stage IV Hodgkin lymphoma in combination with doxorubicin, vinblastine and dacarbazine (AVD), (2) for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT, (3) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, (4) for the treatment of adult patients with previously untreated sALCL in combination with cyclophosphamide, doxorubicin and prednisone (CHP), (5) for the treatment of adult patients with relapsed or refractory sALCL, and (6) for the treatment of adult patients with CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy.

ADCETRIS has received marketing authorization by regulatory authorities in more than 70 countries for relapsed or refractory Hodgkin lymphoma and sALCL. See U.S. important safety information, including Boxed Warning, below.

Seagen and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seagen has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seagen 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.

ADCETRIS (brentuximab vedotin) U.S. Important Safety Information

BOXED WARNING

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection resulting in PML and death can occur in ADCETRIS-treated patients.

Contraindication

ADCETRIS concomitant with bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).

Warnings and Precautions

Peripheral neuropathy (PN): ADCETRIS causes PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN is cumulative. Monitor for symptoms such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Institute dose modifications accordingly.
Anaphylaxis and infusion reactions: Infusion-related reactions (IRR), including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an IRR occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy. Premedicate patients with a prior IRR before subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.
Hematologic toxicities: Fatal and serious cases of febrile neutropenia have been reported with ADCETRIS. Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS.
Administer G-CSF primary prophylaxis beginning with Cycle 1 for patients who receive ADCETRIS in combination with chemotherapy for previously untreated Stage III/IV cHL or previously untreated PTCL.

Monitor complete blood counts prior to each ADCETRIS dose. Monitor more frequently for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.

Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in ADCETRIS-treated patients. Closely monitor patients during treatment for bacterial, fungal, or viral infections.
Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor and high tumor burden.
Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Avoid use in patients with severe renal impairment.
Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function. Avoid use in patients with moderate or severe hepatic impairment.
Hepatotoxicity: Fatal and serious cases have occurred in ADCETRIS-treated patients. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first ADCETRIS dose or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk. Monitor liver enzymes and bilirubin. Patients with new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.
PML: Fatal cases of JC virus infection resulting in PML have been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider PML diagnosis in patients with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.
Pulmonary toxicity: Fatal and serious events of noninfectious pulmonary toxicity, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, have been reported. Monitor patients for signs and symptoms, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.
Serious dermatologic reactions: Fatal and serious cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.
Gastrointestinal (GI) complications: Fatal and serious cases of acute pancreatitis have been reported. Other fatal and serious GI complications include perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, including severe abdominal pain, perform a prompt diagnostic evaluation and treat appropriately.
Hyperglycemia: Serious cases, such as new-onset hyperglycemia, exacerbation of pre-existing diabetes mellitus, and ketoacidosis (including fatal outcomes) have been reported with ADCETRIS. Hyperglycemia occurred more frequently in patients with high body mass index or diabetes. Monitor serum glucose and if hyperglycemia develops, administer anti-hyperglycemic medications as clinically indicated.
Embryo-fetal toxicity: Based on the mechanism of action and animal studies, ADCETRIS can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus, and to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.
Most Common (≥20% in any study) Adverse Reactions

Peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, pyrexia, constipation, vomiting, alopecia, decreased weight, abdominal pain, anemia, stomatitis, lymphopenia, and mucositis.

Drug Interactions

Concomitant use of strong CYP3A4 inhibitors or inducers has the potential to affect the exposure to monomethyl auristatin E (MMAE).

Use in Specific Populations

Moderate or severe hepatic impairment or severe renal impairment: MMAE exposure and adverse reactions are increased. Avoid use.

Advise males with female sexual partners of reproductive potential to use effective contraception during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.

Advise patients to report pregnancy immediately and avoid breastfeeding while receiving ADCETRIS.

On December 7, 2020 Geron Corporation (Nasdaq: GERN), a late-stage clinical biopharmaceutical company, reported that four oral presentations and six poster presentations containing clinical data and analyses related to imetelstat, the Company’s first-in-class telomerase inhibitor, were presented at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Geron, DEC 7, 2020, View Source [SID1234572339]). The presentations are available at www.geron.com/r-d/publications.

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"Our imetelstat presentations at this year’s ASH (Free ASH Whitepaper) provide strong support for our two registration-enabling Phase 3 clinical trials: IMerge, in lower risk MDS and IMpactMF, in refractory MF," said Aleksandra Rizo, M.D., Ph.D., Geron’s Chief Medical Officer. "We believe the analyses and data from our Phase 2 IMerge and IMbark trials provide strong evidence of imetelstat’s disease-modifying activity, as well as clinical benefits of durable transfusion independence in MDS and improvement in overall survival in MF."

Lower Risk Myelodysplastic Syndromes (MDS) – Oral Presentation

Title: Treatment with Imetelstat Provides Durable Transfusion Independence (TI) in Heavily Transfused Non-del(5q) Lower Risk MDS (LR-MDS) Relapsed/Refractory (R/R) to Erythropoiesis Stimulating Agents (ESAs) (Abstract #658)

The oral presentation reported long-term efficacy, safety and biomarker data from 38 patients in the IMerge Phase 2 clinical trial, based on a February 4, 2020 cut-off date and a median follow-up of 24 months. Consistent with prior presentations, 42% of patients achieved >8-week red blood cell transfusion independence (RBC-TI) with a median duration of 20 months, which is the longest so far reported with any agent in relapsed/refractory non-del(5q) lower risk MDS. In addition, 29% of patients were transfusion free more than a year. Reduction in the SF3B1 mutation, one of the key mutations correlated with ineffective erythropoiesis in lower risk MDS, correlated with longer transfusion independence and shorter onset to achieve transfusion independence. These biomarker data together with the durability of transfusion independence provide evidence for the disease-modifying activity of imetelstat. These data were previously presented at the European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress in June.

Relapsed/Refractory Myelofibrosis (MF) – Three Oral Presentations

Title: Potential Disease-Modifying Activity of Imetelstat Demonstrated By Reduction in Cytogenetically Abnormal Clones and Mutation Burden Leads to Clinical Benefits in Relapsed/Refractory Myelofibrosis Patients (Abstract #346)

This oral presentation reported significant dose-dependent reduction of mutation burden by imetelstat, including complete elimination of mutations in MF driver and non-driver genes. A greater than 20% reduction in variant allele frequency by imetelstat treatment correlated with improved clinical benefits, including higher rates of spleen and symptom responses, bone marrow fibrosis improvement and longer overall survival (OS). As concluded in the presentation, imetelstat demonstrated disease-modifying activity by targeting malignant clones, improvement in bone marrow fibrosis and OS.

Title: Telomerase Activity, Telomere Length and hTERT Expression Correlate with Clinical Outcomes in Higher-Risk Myelofibrosis (MF) Relapsed/Refractory (R/R) to Janus Kinase Inhibitor Treated with Imetelstat (Abstract #347)

This oral presentation reported dose-dependent inhibition of telomerase, as evaluated by reductions in telomerase activity, human reverse transcriptase (hTERT) levels and telomere length in patients treated with imetelstat in the IMbark Phase 2 clinical trial. Analyses of these biomarker data correlated with clinical responses and longer OS. In addition, dose-dependent reduction in variant allele frequency of driver mutations was noted, indicating that imetelstat has disease-modifying activity by targeting the underlying MF malignant clones. As expected for a telomerase inhibitor, treatment with imetelstat at 9.4 mg/kg improved clinical outcomes in patients with shorter telomeres and higher hTERT expression at baseline. These data are consistent with telomere biology in cancer cells and provide evidence for on-target mechanism of action of imetelstat through telomerase inhibition. These results were previously reported as a poster presentation at the EHA (Free EHA Whitepaper) Annual Congress in June.

Title: Favorable Overall Survival with Imetelstat Treatment Correlates with Other Clinical Benefits in Intermediate-2 or High-Risk Myelofibrosis Relapsed/Refractory to Janus Kinase Inhibitor (Abstract #53)

This oral presentation reported the correlation of overall survival results from the IMbark Phase 2 with clinical benefits observed with imetelstat treatment. The correlation analyses showed a trend of longer OS in patients who achieved symptom response, spleen volume reductions ranging from > 10% to > 35%, and statistically significant improvement in OS in patients with improved bone marrow fibrosis, in a dose-dependent manner. These results were previously reported as a poster presentation at the EHA (Free EHA Whitepaper) Annual Congress in June.

Relapsed/Refractory Myelofibrosis (MF) – Three Poster Presentations

Collectively, these poster presentations described on-target and disease-modifying activity of the higher dose of imetelstat from the IMbark Phase 2, and how that relates to better clinical outcomes, including OS, fibrosis improvement and symptom response, especially in a subset of patients defined as triple negative MF, known to have poor outcome.

Title: Correlation Analyses of Imetelstat Exposure with Pharmacodynamic Effect, Efficacy and Safety in A Phase 2 Study in Patients with Higher-risk Myelofibrosis Refractory to Janus Kinase Inhibitor Identified an Optimal Dosing Regimen for Phase 3 Study (Abstract #1283)

Title:Imetelstat Treatment Results in Clinical Benefits, Including Improved Overall Survival, in Patients with Higher-Risk Triple Negative Myelofibrosis Relapsed/Refractory to Janus Kinase Inhibitors (JAKi) (Abstract #3084)

Title:Treatment with Imetelstat Improves Myelofibrosis-Related Symptoms and Other Patient-Reported Outcomes in Patients with Relapsed or Refractory Higher-Risk Myelofibrosis (Abstract #3088)

Myeloproliferative Neoplasms (MPN) – Poster Presentation

Title: Imetelstat Inhibits Telomerase and Prevents Propagation of ADAR1-Activated Myeloproliferative Neoplasm and Leukemia Stem Cells (Abstract #1264)

Collaborators at UC San Diego reported non-clinical data on hTERT and ADAR1 activity in pre-leukemia stem cells and leukemia stem cells (LSC). In various lab experiments and animal models, treatment with imetelstat prevented pre-leukemia stem cells from evolving into LSCs, suggesting telomerase inhibition may be an effective strategy for preventing MPN progression.

Two Trials in Progress Poster Presentations – Ongoing IMerge Phase 3 and Upcoming IMpactMF Phase 3

Title:IMerge: A Phase 3 Study to Evaluate Imetelstat in Transfusion-Dependent Subjects with IPSS Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS) that is Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment (Abstract #3113)

The IMerge Phase 3 clinical trial is a double-blind, randomized, placebo-controlled clinical trial with registration intent. The trial is designed to enroll approximately 170 transfusion dependent patients with Low or Intermediate-1 risk myelodysplastic syndromes (MDS), also referred to as lower risk MDS, who have relapsed after or are refractory to prior treatment with an erythropoiesis stimulating agent (ESA). The IMerge Phase 3 is currently enrolling patients.

The primary endpoint is the rate of red blood cell (RBC) transfusion independence (TI) for any consecutive period of eight weeks or longer, or 8-week RBC-TI rate. Key secondary endpoints include the rate of RBC-TI lasting at least 24 weeks, or 24-week RBC-TI rate, and the rate of hematologic improvement-erythroid (HI-E), defined as a reduction of at least four units of RBC transfusions over eight weeks compared with the prior RBC transfusion burden.

Title:A Randomized Open-Label, Phase 3 Study to Evaluate Imetelstat Versus Best Available Therapy in Patients with Intermediate-2 or High-risk Myelofibrosis (MF) Refractory to Janus Kinase (JAK) Inhibitor (Abstract #2194)

The IMpactMF Phase 3 clinical trial in refractory MF is a registration-enabling trial with OS as the primary endpoint. Approximately 320 patients with Intermediate-2 or High-risk MF will be randomized to receive either imetelstat or best available therapy, which will exclude JAK inhibitors. Key secondary endpoints include symptom response, spleen response, progression free survival, complete response, partial response, clinical improvement, duration of response, safety, pharmacokinetics, and patient reported outcomes.

Geron expects the trial to be open for screening and enrollment in the first quarter of 2021.

About Phase 2 IMerge and IMbark Trials

The IMerge Phase 2 was an open label, single arm trial to assess the safety and efficacy of a 7.5 mg/kg dose of imetelstat administered as an intravenous infusion every four weeks in transfusion dependent lower risk MDS patients who had relapsed after or were refractory to prior treatment with ESA. The IMerge Phase 2 is no longer enrolling patients, and patients remaining in the treatment phase continue to receive imetelstat treatment, per investigator discretion.

The IMbark Phase 2 was designed to evaluate two dosing regimens of imetelstat (either 4.7 mg/kg or 9.4 mg/kg administered by intravenous infusion every three weeks) in patients with Intermediate-2 or High-risk myelofibrosis (MF) who have relapsed after or are refractory to prior treatment with a janus kinase inhibitor (JAKi). The co-primary efficacy endpoints for IMbark were spleen response rate, defined as the proportion of patients who achieve a reduction of at least 35% in spleen volume as assessed by imaging, and symptom response rate, defined as the proportion of patients who achieve a reduction of at least 50% in Total Symptom Score (TSS), at 24 weeks. Key secondary endpoints were overall survival (OS) and safety. The trial is complete and closed.

About Imetelstat

Imetelstat is a novel, first-in-class telomerase inhibitor exclusively owned by Geron and being developed in hematologic myeloid malignancies. Early clinical data strongly suggest that imetelstat has disease-modifying activity through the apoptosis of malignant stem and progenitor cells, which allows potential recovery of normal hematopoiesis. Current clinical studies of imetelstat include IMerge, an ongoing Phase 2/3 trial in lower risk myelodysplastic syndromes (MDS), and IMpactMF, an upcoming Phase 3 clinical trial in refractory myelofibrosis (MF). Imetelstat has been granted Fast Track designation by the United States Food and Drug Administration for both the treatment of patients with non-del(5q) lower risk MDS who are refractory or resistant to an erythropoiesis-stimulating agent and for patients with Intermediate-2 or High-risk MF whose disease has relapsed after or is refractory to janus kinase (JAK) inhibitor treatment.

On December 7, 2020 Provectus (OTCQB: PVCT) reported that updated preliminary patient response, safety, and immune correlative data, as well as new preliminary PV-10-treated lesion response data, from the Company’s ongoing Phase 1b/2 study of autolytic cancer immunotherapy PV-10, an injectable formulation of Provectus’ proprietary small molecule rose bengal disodium (RBD), in combination with KEYTRUDA (pembrolizumab) for the treatment of advanced cutaneous melanoma in patients refractory to immune checkpoint blockade (CB) was presented at Melanoma Bridge 2020, held online from December 3-5, 2020 (Press release, Provectus Biopharmaceuticals, DEC 7, 2020, View Source [SID1234572355]).

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The oral presentation, entitled "Response for combination of PV-10 autolytic immunotherapy and immune checkpoint blockade in checkpoint-refractory patients," was presented by Dr. Jonathan Zager, Chief Academic Officer at Moffitt Cancer Center (Moffitt), and a surgical oncologist and Senior Member in Moffitt’s Departments of Cutaneous Oncology and Sarcoma. Dr. Zager is also the Director of Regional Therapies at Moffitt’s Donald A. Adam Comprehensive Melanoma Research Center and a Professor of Surgery at the Morsani School of Medicine of the University of South Florida.

Presentation materials are available on Provectus’ website by clicking on the links immediately below:

A video of Dr. Zager’s oral presentation,
A copy of the presentation slides, and
A copy of the slides together with Dr. Zager’s print commentary.
Key highlights of the Melanoma Bridge 2020 presentation:

Safety data on 18 patients
Consistent with the established patterns for single-agent use of each drug
Principally grades 1 and 2 injection-site reactions to PV-10
Principally grades 1 to 3 immune-mediated reactions to KEYTRUDA
14 patients evaluable for overall efficacy
Investigator-assessed RECIST v1.1
All patients (14): 7% complete response (CR) (1/14), 36% overall response rate (ORR) (3/14), and 64% disease control rate (DCR) (8/14)
Refractory to anti-PD-1 (4): 75% ORR (3/4)
Refractory to anti-CTLA-4 and anti-PD-1 combination therapy (9): 11% CR (1/9) and 56% DRR (5/9)
16 lesions treated with PV-10
38% CR (6/16), 50% ORR (8/16), and 69% DCR (11/16)
5 patient-completed immune correlative assessments
DAMPs and T cells present in peripheral blood are indicative of innate and adaptive immune signaling, respectively
Upregulation of innate and adaptive immune responses appears to be maintained in CB-refractory subjects
PV-10-hallmark DAMP and functional T cell responses in CB-refractory patients are consistent with responses in CB-naïve patients who received either single-agent PV-10 or PV-10 and KEYTRUDA combination therapy in other Provectus melanoma clinical trials
Dominic Rodrigues, Vice Chair of the Company’s Board of Directors said, "Immune checkpoint blockade-refractory metastatic melanoma is a high unmet medical need that only continues to grow, with low response, poor survival rates, and limited patient treatment options. This need is particularly acute for deeply refractory melanoma patients who fail ipilimumab and nivolumab combination therapy. This study’s safety, efficacy, and immune correlative data suggest PV-10 may play a critical role in overcoming acquired resistance to checkpoint blockade."

About the Phase 1b/2 Combination Therapy Trial (NCT02557321)

A first expansion cohort of the Phase 1b portion of the study began enrolling patients with metastatic cutaneous melanoma who were CB-refractory in December 2018. This CB-refractory cohort extended an exploratory group of refractory patients enrolled into the study’s main cohort that primarily enrolled CB-naïve patients. CB-refractory patients with at least one injectable lesion and who were candidates for KEYTRUDA were eligible. Eligible subjects received the combination treatment of PV-10 and KEYTRUDA every three weeks for up to five cycles (i.e., over a period of up to 12 weeks), followed by only KEYTRUDA every three weeks for up to 24 months. The protocol allows for additional cycles of PV-10 beyond the fifth cycle for patients with additional injectable disease. The primary endpoint for the Phase 1b trial was safety and tolerability. ORR and progression-free survival were key secondary endpoints (both assessed via RECIST 1.1 after five treatment cycles, and then every 12 weeks thereafter).

About PV-10

Intralesional (IL) (aka intratumoral) administration of PV-10 for the treatment of solid tumor cancers can yield immunogenic cell death within hours of tumor injection, and induce tumor-specific reactivity in circulating T cells within days.1,2,3 This IL PV-10-induced functional T cell response may be enhanced and boosted in combination with CB.4 In CB-refractory advanced cutaneous melanoma, IL PV-10 may restore disease-specific T cell function, which may also be prognostic of clinical response. IL PV-10 has been administered to over 450 patients with cancers of the skin and of the liver. It is administered under visual, tactile or ultrasound guidance to superficial malignancies, and under CT or ultrasound guidance to tumors of the liver. In this Phase 1b/2 study, IL PV-10 was administered to melanoma tumors located at cutaneous, subcutaneous, soft tissue and nodal sites (it was not administered to visceral sites).

About Rose Bengal Disodium

RBD is 4,5,6,7-tetrachloro-2′,4′,5′,7′-tetraiodofluorescein disodium, a halogenated xanthene and Provectus’ proprietary lead molecule. Provectus’ current Good Manufacturing Practices (cGMP) RBD is a proprietary pharmaceutical-grade drug substance produced by the Company’s quality-by-design (QbD) manufacturing process to exacting regulatory standards that avoids the formation of uncontrolled impurities currently present in commercial-grade rose bengal. Provectus’ RBD and cGMP RBD manufacturing process are protected by composition of matter and manufacturing patents as well as trade secrets.

An IL formulation (i.e., by direct injection) of cGMP RBD drug substance, cGMP PV-10, is being developed as an autolytic immunotherapy drug product for solid tumor cancers. By targeting tumor cell lysosomes, RBD treatment may yield immunogenic cell death in solid tumor cancers that results in tumor-specific reactivity in circulating T cells, including a T cell mediated immune response against treatment refractory and immunologically cold tumors.1,2,3 Adaptive immunity can be enhanced by combining CB with RBD.4 IL PV-10 is undergoing clinical study for relapsed and refractory adult solid tumor cancers, such skin and liver cancers.

IL PV-10 is also undergoing preclinical study for relapsed and refractory pediatric solid tumor cancers, such as neuroblastoma, Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma.5,6

A topical formulation of cGMP RBD drug substance, PH-10, is being developed as a clinical-stage immuno-dermatology drug product for inflammatory dermatoses, such as atopic dermatitis and psoriasis. RBD can modulate multiple interleukin and interferon pathways and key cytokine disease drivers.7

Oral formulations of cGMP RBD are undergoing preclinical study for relapsed and refractory pediatric blood cancers, such as acute lymphocytic leukemia and acute myelomonocytic leukemia.8,9

Oral formulations of cGMP RBD are also undergoing preclinical study as prophylactic and therapeutic treatments for high-risk adult solid tumor cancers, such as head and neck, breast, pancreatic, liver, and colorectal cancers.

Different formulations of cGMP RBD are also undergoing preclinical study as potential treatments for multi-drug resistant (MDR) bacteria, such as Gram-negative bacteria.

Topical formulations of cGMP RBD are also undergoing preclinical study as potential treatments for diseases of the eye, such as infectious keratitis

Tumor Cell Lysosomes as the Seminal Cancer Drug Target

Lysosomes are the central organelles for intracellular degradation of biological materials, and nearly all types of eukaryotic cells have them. Discovered by Christian de Duve, MD in 1955, lysosomes are linked to several biological processes, including cell death and immune response. In 1959, de Duve described them as ‘suicide bags’ because their rupture causes cell death and tissue autolysis. He was awarded the Nobel Prize in 1974 for discovering and characterizing lysosomes, which are also linked to each of the three primary cell death pathways: apoptosis, autophagy, and necrosis.

Building on the Discovery, Exploration, and Characterization of Lysosomes

Cancer cells, particularly advanced cancer cells, are very dependent on effective lysosomal functioning.10 Cancer progression and metastasis are associated with lysosomal compartment changes11,12, which are closely correlated (among other things) with invasive growth, angiogenesis, and drug resistance13.

RBD selectively accumulates in the lysosomes of cancer cells upon contact, disrupting the lysosomes and causing the cells to die. Provectus1,14, external collaborators5, and other researchers15,16,17 have independently shown that RBD triggers each of the three primary cell death pathways: apoptosis, autophagy, and necrosis.

Cancer Cell Autolytic Death via RBD: RBD-induced autolytic cell death, or death by self-digestion, in Hepa1-6 murine hepatocellular carcinoma (HCC) cells can be viewed in this Provectus video of the process (ethidium homodimer 1 [ED-1] stains DNA, but is excluded from intact nuclei; lysosensor green [LSG] stains intact lysosomes; the video is provided in 30-second frames, with a duration of approximately one hour). Exposure to RBD triggers the disruption of lysosomes, followed by nucleus failure and autolytic cell death. Identical responses have been shown by the Company in HTB-133 human breast carcinoma (which can be viewed in this Provectus video of the process, with a duration of approximately two hours) and H69Ar human multidrug-resistant small cell lung carcinoma. Cancer cell autolytic cell death was reproduced by research collaborators in neuroblastoma cells to show that lysosomes are disrupted upon exposure to RBD.5

Tumor Autolytic Death via RBD: RBD causes acute autolytic destruction of injected tumors (via autolytic cell death), mediating the release of danger-associated molecular pattern molecules (DAMPs) and tumor antigens; release of these signaling factors may initiate an immunologic cascade where local response by the innate immune system may facilitate systemic anti-tumor immunity by the adaptive immune system. The DAMP release-mediated adaptive immune response activates lymphocytes, including CD8+ T cells, CD4+ T cells, and NKT cells, based on clinical and preclinical experience in multiple tumor types. Mediated immune signaling pathways may include an effect on STING, which plays an important role in innate immunity.9

Orphan Drug Designations (ODDs)

ODD status has been granted to RBD by the U.S. Food and Drug Administration for metastatic melanoma in 2006, hepatocellular carcinoma in 2011, neuroblastoma in 2018, and ocular melanoma (including uveal melanoma) in 2019.

Intellectual Property (IP)

Provectus’ IP includes a family of US and international (a number of countries in Asia, Europe, and North America) patents that protect the process by which cGMP RBD and related halogenated xanthenes are produced, avoiding the formation of previously unknown impurities that exist in commercial-grade rose bengal in uncontrolled amounts. The requirement to control these impurities is in accordance with International Council on Harmonisation (ICH) guidelines for the manufacturing of an injectable pharmaceutical. US patent numbers are 8,530,675, 9,273,022, and 9,422,260, with expirations ranging from 2030 to 2031.

The Company’s IP also includes a family of US and international (a number of countries in Asia, Europe, and North America) patents that protect the combination of RBD and CB (e.g., anti-CTLA-4, anti-PD-1, and anti-PD-L1 agents) for the treatment of a range of solid tumor cancers. US patent numbers are 9,107,887, 9,808,524, 9,839,688, and 10,471,144, with expirations ranging from 2032 to 2035; US patent application numbers include 20200138942.

On December 7, 2020 The Janssen Pharmaceutical Companies of Johnson & Johnson reported new data from the randomised Phase 2 GRIFFIN study showing that the addition of DARZALEX▼ (daratumumab) to lenalidomide, bortezomib and dexamethasone (D-RVd), followed by daratumumab plus lenalidomide (D-R) maintenance therapy, resulted in deeper and improved responses, including minimal residual disease (MRD) negativity, compared to RVd followed by R alone, in newly diagnosed, stem cell transplant-eligible patients with multiple myeloma (Press release, Janssen Pharmaceuticals, DEC 7, 2020, View Source [SID1234572372]).1 These data investigating the use of daratumumab in combination with RVd, which were shared in separate oral and poster presentations at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2020 Annual Meeting, provide further evidence that this regimen may provide greater efficacy for transplant-eligible, newly diagnosed multiple myeloma (NDMM) patients than standard therapy. This morning’s oral presentation (Abstract #549) shared longer-term follow-up data, and the poster presentation (Abstract #3243) featured additional data from the safety run-in cohort.1,2

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

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

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"The long-term GRIFFIN data show that maintenance therapy with daratumumab in combination with lenalidomide (D-R) resulted in deeper and longer responses compared to R alone in patients with multiple myeloma who are newly diagnosed and transplant-eligible," said Peter Voorhees, M.D.,* Atrium Health’s Levine Cancer Institute and GRIFFIN study investigator. "These data indicate that the addition of daratumumab to RVd followed by R maintenance results in improved response rates and depth of response during induction, consolidation and maintenance treatment cycles."

Key Findings from GRIFFIN (Abstract #549):
The GRIFFIN oral presentation featured updated safety and efficacy data based on longer follow-up for D-RVd and evaluated the potential role of D-R for maintenance therapy in patients with NDMM.1

Initial findings of GRIFFIN:
At the end of post-transplant consolidation (median follow-up, 13.5 months) in the response-evaluable population, the stringent complete response (sCR) rate favoured D-RVd vs. RVd (42.4 percent vs. 32.0 percent, P=0.0253).1
The complete response (CR) or better rate also favoured D-RVd vs. RVd (51.5 percent vs. 42.3 percent; P=0.0014).1
No new safety concerns were observed in the D-RVd arm receiving D-R maintenance therapy.1
The most common Grade 3/4 treatment-emergent adverse events (TEAEs) in the D-RVd arm receiving D-R maintenance therapy were neutropenia (43 percent), lymphopenia (23 percent), leukopenia (16 percent) and thrombocytopenia (15 percent).1
With an additional 12 months of D-R or R maintenance therapy (median follow up of 27.4 months), responses continued to deepen and remained higher for the daratumumab-containing arm.1
At the clinical cutoff date, the sCR rate favoured the daratumumab-containing arm (63.6 percent vs. 47.4 percent; P=0.0253).1
The CR or better rate continued to favour D-RVd vs. RVd (81.8 percent vs. 60.8 percent; P=0.0014).1
MRD negativity favoured D-RVd vs. RVd (62.5 percent vs. 27.2 percent, P=0.0001).1
No new safety concerns were observed with the D-R maintenance therapy.1
The 24-month progression-free survival (PFS) rate was 94.5 percent for D-RVd and 90.8 percent for RVd.1
Key Findings from GRIFFIN (Abstract #3243):
The poster presentation shared final results of the safety run-in cohort (n=16 patients) of the GRIFFIN study. These additional data showed that maintenance therapy with daratumumab and lenalidomide (D-R) improved both the sCR rate and MRD negativity rate in patients with NDMM who underwent D-RVd induction, autologous stem cell transplant (ASCT) and D-RVd consolidation. This deepening of responses was associated with durable remissions, and no new safety signals were observed with maintenance therapy.2

Initial findings from the safety run-in cohort for GRIFFIN:
By the end of post-transplant consolidation, the sCR rate was 56 percent.2
MRD negativity (10-5) at the end of consolidation was observed in 50 percent of patients, and no patients were MRD negative at 10-6.2
New findings:
The sCR rate improved to 94 percent by the end of both 12 and 24 months of D-R maintenance therapy.2
By the end of 24 months of D-R maintenance therapy, 81 percent of patients were MRD negative at 10-5, with five patients (31 percent) MRD negative at 10-6.2
At a median follow-up of 40.8 months, three of 16 patients had progressed, with estimated 24-month and 36-month PFS rates of 94 percent and 78 percent, respectively.2
With longer follow-up including two years of D-R maintenance therapy, no new safety concerns were identified.2
"The stringent complete response and minimal residual disease negativity rates with daratumumab combination maintenance therapy for transplant-eligible patients further solidify daratumumab as a foundational treatment for multiple myeloma," said Dr Catherine Taylor, Vice President, Medical Affairs Therapeutic Area Strategy, Europe, Middle East and Africa (EMEA), Janssen-Cilag Ltd., Middle East. "At Janssen, we remain focused on pursuing effective treatment combinations and investigating different endpoints, such as minimal residual disease, in order to provide effective treatments to patients across the spectrum of multiple myeloma."

"We continue to be encouraged by the GRIFFIN data showing deeper and improved responses in patients with newly diagnosed, ASCT-eligible multiple myeloma," said Andree Amelsberg, M.D., MBA, Vice President, U.S. Medical Affairs, Oncology Medical Affairs, Janssen Scientific Affairs, LLC. "These data show promising results for patients with newly diagnosed multiple myeloma and we remain committed to exploring the full potential of daratumumab and daratumumab subcutaneous formulation."

*Peter Voorhees is lead investigator of the GRIFFIN study and was not compensated for any media work.

#ENDS#

About the GRIFFIN Study3
The Phase 2 GRIFFIN (NCT02874742) study has enrolled and treated more than 200 adults ages 18-70 years with NDMM and who are eligible for high-dose therapy/autologous stem cell therapy (ASCT).

In the safety run-in cohort, patients received 25 mg of lenalidomide orally on Days 1-14; 1.3 mg/m2 of bortezomib subcutaneously on Days 1, 4, 8 and 11; and 20 mg of dexamethasone on Days 1, 2, 8, 9, 15 and 16, every 21 days during the induction and consolidation phases (Cycles 1-6). Daratumumab 16 mg/kg IV was given on Days 1, 8 and 15 of Cycles 1-4 and on Day 1 of Cycles 5-6.

During maintenance phase (Cycles 7-32), patients received 10 mg daily of lenalidomide (15 mg beginning at Cycle 10 if tolerated) on Days 1-21 every 28 days and daratumumab 16 mg/kg IV every 56 days; this was amended to every 28 days based upon emerging clinical pharmacokinetic data demonstrating improved target saturation with every 4-week maintenance dosing. Maintenance therapy with lenalidomide may be continued beyond Cycle 32 in both arms, per local standard of care.

In the subsequent randomised Phase 2 portion of the study, approximately 200 patients were randomised and received treatment with RVd, induction and consolidation, ASCT and maintenance therapy with lenalidomide; or daratumumab and RVd, ASCT and maintenance therapy with daratumumab and lenalidomide.

About daratumumab and daratumumab SC
In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialise daratumumab. Since launch, it is estimated that more than 154,000 patients have been treated with daratumumab worldwide.4 Daratumumab is the only CD38-directed antibody approved to be given subcutaneously to treat patients with multiple myeloma. Daratumumab SC is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE drug delivery technology.5

CD38 is a surface protein that is highly expressed across multiple myeloma cells, regardless of the stage of disease. Daratumumab SC binds to CD38 and induces myeloma cell death through multiple immune-mediated mechanisms of action, including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), as well as through apoptosis, in which a series of molecular steps in a cell lead to its death.6

Data across nine Phase 3 clinical trials in multiple myeloma and light chain (AL) amyloidosis, in both the frontline and relapsed settings, have shown that daratumumab-based regimens resulted in significant improvement in progression-free survival and/or overall survival.7,8,9,10,11,12,13,14 Additional studies are underway to assess the efficacy and safety of daratumumab SC in the treatment of other malignant and pre-malignant haematologic diseases in which CD38 is expressed, including smouldering myeloma and AL amyloidosis.15,16

For further information on daratumumab, please see the Summary of Product Characteristics at View Source

About Multiple Myeloma
Multiple myeloma (MM) is an incurable blood cancer that starts in the bone marrow and is characterised by an excessive proliferation of plasma cells.17 In Europe, more than 48,200 people were diagnosed with MM in 2018, and more than 30,800 patients died.18 Around 50 percent of newly diagnosed patients do not reach five-year survival,19,20 and almost 29 percent of patients with multiple myeloma will die within one year of diagnosis.21

Although treatment may result in remission, unfortunately, patients will most likely relapse as there is currently no cure.22 Relapsed and refractory myeloma is defined as disease that is nonresponsive while on salvage therapy, or progresses within 60 days of last therapy in patients who have achieved minimal response (MR) or better at some point previously before then progressing in their disease course.23 While some patients with MM have no symptoms at all, others are diagnosed due to symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems or infections.24 Patients who relapse after treatment with standard therapies, including proteasome inhibitors and immunomodulatory agents, have poor prognoses and require new therapies for continued disease control.25