On December 2, 2018 Novartis reported its results of a retrospective, real-world evidence study in patients with immune thrombocytopenia (ITP) treated with Revolade (eltrombopag), compared to other second-line therapies (Press release, Novartis, DEC 2, 2018, View Source [SID1234531762]). The data demonstrated that patients experienced better clinical outcomes with Revolade, in terms of fewer bleeding episodes. The data were presented during the 60th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in San Diego.

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"Despite advances in treating immune thrombocytopenia, many patients remain at risk for bleeding episodes," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "With these kind of real-world data, we can reimagine care by more clearly understanding the outcomes of a range of treatments and, in turn, helping healthcare providers better navigate available options with their patients."

Electronic health records (EHR) data from January 1, 2009 to September 30, 2016 from the Optum EHR database were used to evaluate the effect of second-line agents for ITP. Identified patients had the following characteristics: 18 years or older, evidence of previous treatment with steroids or immune globulin products, and activity in the database for at least 6 months prior to and 12 months post initiation of a second-line agent. Treatment outcomes evaluated included platelet counts, bleeding related episodes (BREs), and thrombotic events (TEs) over the 12-month period following starting a second-line therapy.

Of the 2,526 adults that met the inclusion criteria, 110 (4.4%) received eltrombopag, 189 (7.5%) romiplostim, 1,488 (58.9%) rituximab, and 260 (10.3%) splenectomy, with the remaining 479 (18.9%) receiving a mix of other second-line agents. Compared to baseline, platelet counts increased in all treatment cohorts. The proportion of patients who experienced BREs ranged from 25.5% (eltrombopag) to 36.5% (romiplostim), while TEs were observed in all treatment cohorts ranging from 11.6% (eltrombopag) to 15.7% (splenectomy). An additional analysis demonstrated that patients with ITP who had a splenectomy as second-line treatment had the highest mean platelet counts during the first 12 months post treatment initiation, but were at greatest risk for TEs (15.7%) (e.g., stroke, transient ischemic attack, myocardial infarction, deep vein thrombosis, and pulmonary embolism) compared to 11.6% (eltrombopag), 12.7% (romiplostim), and 13.9% (rituximab).

"These real-world data can help doctors as they weigh options for second-line therapy with their patients." Adam Cuker, MD, Assistant Professor of Medicine at the University of Pennsylvania. "They may also help explain the long-term trend toward deferring splenectomies until after other lines of treatment have been tried."

Immune thrombocytopenia is a rare and potentially serious blood disorder where there is an increased risk of bleeding due to a low number of platelets. As a result, patients with ITP experience bruising, bleeding and, in rare cases, serious hemorrhage that can be fatal.[1] The goal of treatment in chronic/persistent ITP is to maintain a safe platelet count that reduces the risk of bleeding.[1]

Promacta/Revolade (eltrombopag)
Eltrombopag, marketed as Promacta in the US and Revolade in countries outside the US, is approved in more than 90 countries worldwide for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenic purpura (ITP) who have had an inadequate response or are intolerant to other treatments. It is also approved for the treatment of patients with severe aplastic anemia (SAA) as first-line therapy in the US (patients 2 years and older) and Japan, and in many other countries for patients who are refractory to other treatments. In more than 40 countries, Promacta/Revolade is indicate for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow them to initiate and maintain interferon-based therapy. Promacta/Revolade is approved in the US and in the European Union for the treatment of thrombocytopenia in pediatric patients 1 year and older with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Promacta should only be used in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding.

Important Safety Information
Promacta can cause serious side effects, including liver problems, abnormal liver function tests, high platelet counts and higher risk for blood clots, and new or worsened cataracts (a clouding of the lens in the eye).

Promacta is not for treatment of people with a precancerous condition called myelodysplastic syndromes (MDS). If you have MDS and receive Promacta, your MDS condition may worsen and become AML. If MDS worsens to become AML, you may die sooner from AML.

For patients who have chronic hepatitis C virus and take Promacta with interferon and ribavirin treatment, Promacta may increase the risk of liver problems. Patients should tell a healthcare provider right away if they have any of these signs and symptoms of liver problems including yellowing of the skin or the whites of the eyes (jaundice), unusual darkening of the urine, unusual tiredness, right upper stomach area pain, confusion, swelling of the stomach area (abdomen).

A healthcare provider will order blood tests to check the liver before starting Promacta and during Promacta treatment. In some cases, treatment with Promacta may need to be stopped due to changes in liver function tests.

The risk of getting a blood clot is increased if the platelet count is too high during treatment with Promacta. The risk of getting a blood clot may also be increased during treatment with Promacta if platelet counts are normal or low. Some forms of blood clots, such as clots that travel to the lungs or that cause heart attacks or strokes can cause severe problems or death. A healthcare provider will check blood platelet counts, and change the dose of Promacta or stop Promacta, if platelet counts get too high. Patients should tell a healthcare provider right away if they have signs and symptoms of a blood clot in the leg, such as swelling, pain, or tenderness in the leg.

People with chronic liver disease may be at risk for a type of blood clot in the stomach area. Patients should tell a healthcare provider right away if they have stomach area pain that may be a symptom of this type of blood clot.

New or worsened cataracts have happened in people taking Promacta. A healthcare provider will check the patient’s eyes before and during treatment with Promacta. Patients should tell a healthcare provider about any changes in eyesight while taking Promacta.

Patients should tell a healthcare provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Promacta may affect the way certain medicines work. Certain medicines may keep Promacta from working correctly. Patients should take Promacta at least 4 hours before or 4 hours after taking products such as antacids used to treat stomach ulcers or heartburn and multivitamins or products that contain iron, calcium, aluminum, magnesium, selenium, and zinc, which may be found in mineral supplements. Patients should ask a healthcare provider if they are not sure if the medicine is one that is listed above.

Patients should avoid situations and medications that may increase the risk of bleeding while taking Promacta.

The most common side effects of Promacta when used to treat chronic ITP in adults are: nausea; diarrhea; upper respiratory tract infection (symptoms may include runny nose, stuffy nose, and sneezing); vomiting; muscle aches; urinary tract infection (symptoms may include frequent or urgent need to urinate, low fever in some people, pain or burning with urination); pain or swelling (inflammation) in the throat or mouth (oropharyngeal pain and pharyngitis); abnormal liver function tests; back pain; flu-like symptoms (influenza), including fever, headache, tiredness, cough, sore throat, and body aches; skin tingling, itching, or burning; and rash.

The most common side effects of Promacta in children 1 year and older when used to treat chronic ITP are: upper respiratory tract infections (symptoms may include runny nose, stuffy nose, and sneezing); pain or swelling (inflammation) in the nose and throat (nasopharyngitis); cough; diarrhea; pyrexia; runny, stuffy nose (rhinitis); stomach (abdominal) pain; pain or swelling (inflammation) in the throat or mouth; toothache; abnormal liver function tests; rash; runny nose (rhinorrhea).

The most common side effects when Promacta is used in combination with other medicines to treat chronic HCV are: low red blood cell count (anemia); fever; tiredness; headache; nausea; diarrhea; decreased appetite; flu-like symptoms (influenza), including fever, headache, tiredness, cough, sore throat, and body aches; feeling weak; trouble sleeping; cough; itching; chills; muscle aches; hair loss; and swelling in the ankles, feet, and legs.

The most common side effects of Promacta when used to treat severe aplastic anemia (SAA) are: nausea, feeling tired, cough, diarrhea, headache, pain in arms, legs, hands or feet, shortness of breath, fever, dizziness, pain in nose or throat, abdominal pain, bruising, muscle spasms, abnormal liver function tests, joint pain, and runny nose. Laboratory tests may show abnormal changes to the cells in bone marrow.

The most common side effects of Promacta when used to treat adults and pediatric patients 2 years and older with SAA in combination with standard immunosuppressive therapy are: abnormal liver function tests, rash and skin discoloration including darkening of skin patches
(hyperpigmentation).

On December 1, 2018 Oncopeptides AB (Nasdaq Stockholm: ONCO) reported a presentation of the first interim data with melflufen (Ygalo) from the ongoing phase I/II study ANCHOR at the 60th ASH (Free ASH Whitepaper) meeting in San Diego, California, USA (Press release, Oncopeptides, DEC 1, 2018, View Source [SID1234531802]).

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Overall conclusions

The combinations of melflufen and dexamethasone (dex) with either bortezomib or daratumumab in relapsed-refractory multiple myeloma (RRMM) patients are well tolerated
No dose limiting toxicity has been observed at the melflufen 30 and 40 mg dose levels in either regimens. The 40 mg dose level is still recruiting patients
An Overall Response Rate (ORR) of 86% was observed with melflufen and dexamethasone in combination with daratumumab (CD38-directed monoclonal antibody)
An Overall Response Rate (ORR) of 100% was observed with melflufen and dexamethasone in combination with bortezomib (proteasome inhibitor)
The data are presented in a poster that can be found at: www.oncopeptides.com / presentations / 60th ASH (Free ASH Whitepaper)

CEO comments

"Although, these are early data and small patient samples, it is encouraging to see that melflufen is well tolerated and has a very high level of activity with no cross resistant pattern in combination regimens. These patients have undergone 2-3 prior lines of therapy and have developed resistant disease. The interim data show a very good efficacy profile for melflufen in combination with either bortezomib or daratumumab. In a cross-study comparison in RRMM patients treated with combination regimens our interim data with an ORR in the range 86-100% stand out positively. The treatment landscape changes over time and there is a high need of new treatment options with a novel mechanism of action like melflufen" said Jakob Lindberg, CEO of Oncopeptides.

About the ANCHOR study

The study recruitment is ongoing. ANCHOR is a phase I/II study where melflufen and dexamethasone (dex) is dosed in combination with either bortezomib or daratumumab. All patients must have 1-4 prior lines of therapy and be refractory (or intolerant) to an immunomodulary agent (IMiD) or a proteasome inhibitor (PI) or both.

In combination with bortezomib (Regimen A) patients cannot be refractory to a PI and in combination with daratumumab (Regimen B) patients cannot be previously exposed to any anti-CD38. Patients will be treated until documented disease progression or unacceptable toxicity. The primary objective of the phase I part of the study is to determine the optimal dose of melflufen and dex, up to a maximum of 40 mg, in combination with bortezomib or daratumumab. An additional 20 patients per regimen will be recruited in the phase II part of the study where the primary objective is ORR.

Summary of the ANCHOR interim data

Melflufen in combination with bortezomib – Regimen A

At the time of the data cut-off November 12, 2018, 3 patients had been treated with 30 mg melflufen and dex in combination with bortezomib. Median age was 81 years with a median of 3 prior lines of therapy. All patients were relapsed-refractory and 2 out of 3 patients were last line refractory (disease progression while on therapy). All patients were ongoing at the time of the data cut-off with a median treatment duration of 5.8 months.

The patients received a total of 17 cycles of treatment with a median of 7. All 3 patients achieved partial response (PR). No dose limiting toxicities were observed at the 30 mg melflufen dose level and the melflufen 40 mg has been opened for enrollment. The regimen was well tolerated with clinically manageable G3/4 hematological AEs and the low number of non-hematological AEs was noteworthy.

Melflufen in combination with daratumumab – Regimen B

At the time of the data cut-off, November 12, 2018, 9 patients had been treated with melflufen in combination with daratumumab and dex. Median age was 63 years with a median of 2 prior lines of therapy. No patient had achieved CR in any previous line of therapy, 67% were IMiD refractory and 56% were last line refractory (disease progression while on therapy). All patients were ongoing at the time of the data cut-off.

All 9 patients were still ongoing with a median treatment duration of 3.9 months. They received a total of 39 cycles of treatment with a median of 4.

Overall response rate N/A*
ORR CR VGPR PR MR SD PD
total, N=9 86% 0 4 2 0 1 0 2
*2 of the 9 patients were still in their first cycle of treatment and were therefore not evaluable for response as described at time for data cut.

4 patients were treated with 30 mg melflufen and 5 patients were treated with 40 mg melflufen with no dose limiting toxicity observed. The combination of melflufen, dexamethasone and daratumumab was well tolerated with clinically manageable G3/4 hematological AEs and the low number of non-hematological AEs was noteworthy.

About Melflufen

Melflufen (Ygalo), a peptide conjugated alkylator belonging to a novel class of peptidase-enhanced compounds, targets multiple myeloma (MM) cells with a unique mechanism of action. Aminopeptidases are enzymes found in all cells but are over-expressed in several cancers including MM. Ygalo selectively targets MM cells through aminopeptidase-driven accumulation. In vitro experiments show a 50-fold enrichment of the active substance in MM cells compared with administration of equal amount of an alkylator not enriched by aminopeptidases. The enrichment results in selective cytotoxicity (increased on-target potency and decreased off-target toxicity), and that resistance pathways of existing myeloma treatments (including alkylators) is overcome. Melflufen also demonstrates strong anti-angiogenic properties.

Melflufen in clinical development

Melflufen (Ygalo) has been used to treat late-stage RRMM patients in both phase I and phase II clinical studies (O-12-M1) with favorable results. Currently, melflufen is being studied in four clinical trials for the treatment of multiple myeloma. The current studies are OCEAN, HORIZON, ANCHOR and BRIDGE.

The current clinical study program is intended to demonstrate better results from treatment with melflufen compared to established alternative drugs for patients with multiple myeloma. Melflufen could potentially provide physicians with a new treatment option for patients suffering from this serious disease.

Melflufen has been investigated in the treatment of late-stage relapsed refractory multiple myeloma (RRMM) patients. This was done in the clinical study O-12-M1 where strong final results were reported in December 2017. Currently, four clinical studies are ongoing with melflufen.

OCEAN is Oncopeptides pivotal Phase III study where melflufen is compared directly with current standard of care, pomalidomide, in late-stage RRMM patients.

HORIZON is a Phase II study that studies the effect of melflufen in late-stage RRMM patients with few or no remaining established treatment options. Updated interim data from this study will be presented at ASH (Free ASH Whitepaper) in December 2018.

ANCHOR is a phase I/II study where melflufen is administered in combination with either bortezomib or daratumumab in RRMM patients. The results of this study aim to create understanding and knowledge among treating physicians for how melflufen can be used in combination with these drugs. In addition, the results could open up for the use of melflufen in earlier lines of treatment.

BRIDGE is a phase II study, where melflufen is used in RRMM patients with impaired renal function. This is a positioning study to show melflufen’s treatment profile in these patients.

On December 1, 2018 MaaT Pharma reported the results from its ODYSSEE (NCT02928523) Phase 1b/2a clinical trial demonstrating that the Company’s proprietary MaaT Microbiome Restoration Biotherapeutic (MMRB) therapeutic is able to restore a functional microbiome in acute myeloid leukemia (AML) patients after having undergone intensive chemotherapy and multiple courses of antibiotics (Press release, MaaT Pharma, DEC 1, 2018, View Source [SID1234531791]). The study was designed to investigate the safety and feasibility of reestablishing a functional microbiome using MaaT Pharma’s therapeutic as well as evaluating initial signs of efficacy including reduction of intestinal inflammation and the control of detrimental antibiotic-resistant bacteria. Due to the harsh treatment regimens, AML patients lose their functional microbiome and experience a variety of severe complications that dramatically impact outcomes and quality of life. MaaT Pharma’s MMRB therapeutic aims to restore microbiome function and improve clinical outcomes in these patients. The data were presented at 6:15 pm Pacific Time on December 1st, 2018 at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition held in San Diego, California.

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In total 25 AML patients were treated in the clinical trial. At the time of admission, fecal microbiota was collected from each patient, conditioned, processed and frozen according to GMP conditions. Following the first round of chemotherapy and antibiotic treatment, patients were administered two doses of the collected fecal microbiota as an enema 24 hours apart after hematopoietic recovery and before undergoing the second round of chemotherapy. Blood and fecal samples were collected on three separate days, (1) on day 0, at the time of patient inclusion in the trial, (2) on day 29, following hematopoietic recovery after the first round of intensive treatments and (3) on day 40, before the start of the consolidation chemotherapy. Microbiome profile evolution was analyzed using high-resolution metagenome sequencing and patient follow-up was scheduled for 6 months and 12 months after inclusion.

"The results from the ODYSSEE clinical trial are impressive and demonstrate proof-of-concept for the ability of our approach to restore a functional microbiome, following antibiotics and chemotherapies, in AML patients and that reestablishing the microbiome has the potential to improve survival outcomes," commented Professor Mohamad Mohty, MD, PhD, Professor of Hematology at Sorbonne University and Head of the Hematology and Cellular Therapy Department at the Saint Antoine Hospital in Paris. "Acute myeloid leukemia patients have limited treatment options and the intensive chemotherapy and antibiotic therapy regimens they have to endure significantly contribute to poor quality of life and low survival outcomes. Given these positive results, we look forward to our planned randomized trial with the off-the-shelf capsule formulation MaaT033, as the next step."

Overall, reintroduction of the patient’s own gut microbiome through MaaT Pharma’s proprietary process was well tolerated and no severe adverse events were reported. Metagenomic analysis of the patient samples collected on days 0, 29 and 40 using MaaT Pharma’s proprietary big data analysis platform, GutPrint showed that the MMRB therapeutic restored significantly greater than 90% of the microbial species diversity and structure at day 40, ten days after treatment, including a 43% reduction of the overall expression of antibiotic resistance genes. Most importantly, gut inflammation was significantly reduced to near-baseline levels following MMRB treatment as measured by fecal neopterin biomarker. These results also correlated with the significant reduction of pro-inflammatory bacterial families and restoration of beneficial species among the Lachnospiraceae and Ruminococcaceae families.

"Our commitment has always been to improve outcomes in patients with life-threatening diseases. The results and experience from this trial support our investment in developing standardized, reproducible and high diversity microbiome biotherapeutic products using our MMRB therapeutic and cGMP production facility to treat patients with blood cancers and the complications arising from its treatment," added Hervé Affagard, Co-founder and CEO of MaaT Pharma. "Our lead product, MaaT013, which is manufactured from pooled donors, was developed based on the positive data we collected from this trial and the scientific and clinical evidence showing that restoring the microbiome has therapeutic potential. MaaT013 is currently being tested in a Phase 2 clinical study to treat acute graft-versus-host-disease, a severe consequence of stem cell transplantation. We are also very pleased to have just been awarded Orphan Drug Designation by the EMA for this product after already receiving the designation by the FDA earlier this year."

The poster is available on the company website under "News" or by accessing the following link View Source

On December 1, 2018 The Janssen Pharmaceutical Companies of Johnson & Johnson reported long-term results from the Phase 3 ALCYONE study showing that the addition of Darzalex (daratumumab) to bortezomib, melphalan and prednisone (VMP) continued to demonstrate significant improvement in progression-free survival (PFS) in patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) (Press release, Johnson & Johnson, DEC 1, 2018, View Source [SID1234531790]).1 These data (Abstract #156), as well as updates from the Phase 2 LYRA (Abstract #152) and GRIFFIN (Abstract #151) studies in patients with multiple myeloma, were featured during an oral abstract session at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, CA.

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Long-term Phase 3 ALCYONE results for daratumumab frontline combination therapy1

At a median follow-up of 27.8 months, study results showed the addition of daratumumab to VMP reduced the risk of disease progression or death by 57 percent compared to VMP alone (Hazard Ratio [HR] = 0.43; 95 percent confidence interval [CI] 0.35-0.54, p<0.0001).1 Daratumumab-VMP resulted in a 24 month PFS rate of 63 percent compared to 36 percent with VMP alone.1 The median PFS for daratumumab-VMP has not yet been reached, whereas the control arm of VMP alone had a median PFS of 19.1 months.1 In addition, a significantly higher overall response rate (ORR) (91 percent vs. 74 percent, respectively) was observed with the daratumumab combination compared to VMP alone.1 Daratumumab-VMP resulted in deeper responses, significantly improving the rate of very good partial response (VGPR) or better (73 percent vs. 50 percent) and more than doubling the rate of stringent complete response (sCR) (22 percent vs. 8 percent) compared to VMP alone.1 Daratumumab-VMP induced a higher rate of sustained minimal residual disease (MRD) negativity compared to VMP alone (10 percent vs. 2 percent, respectively).1 The previously reported primary results of this study formed the basis of the European Commission approval of daratumumab in combination with VMP in patients with newly diagnosed multiple myeloma who are ineligible for ASCT.

"Longer-term data from the pivotal ALCYONE trial show that daratumumab combination therapy continued to show improvement in progression-free survival and response rates in newly diagnosed patients with multiple myeloma, including older patients who are less likely to respond to treatment," said Meletios A. Dimopoulos, M.D., Professor and Chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine, Athens, Greece, and principal investigator. "These promising results support the use of daratumumab earlier in the treatment paradigm when transplant ineligible patients are more likely to benefit from therapy, and that continued therapy with daratumumab confers benefit."

In the ALCYONE study, the most common Grade 3/4 treatment-emergent adverse events (TEAEs) during Cycle 10 and onward for daratumumab-VMP included anaemia (4 percent), neutropenia (2 percent) and bronchitis (1 percent).1 No new safety signals emerged, and Grade 3/4 infections continued to be manageable.1

Phase 2 LYRA and GRIFFIN data support efficacy and safety of daratumumab in newly diagnosed patients, including those who are eligible for high-dose therapy/ASCT, and in relapsed patients2,3

Response rates from the Phase 2 LYRA study were presented for the investigational use of daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in patients with newly diagnosed and relapsed multiple myeloma.2 The ORR and VGPR or better rates in 86 newly diagnosed patients were 79 percent and 44 percent, respectively, after 4 Cycles and increased to 81 percent and 56 percent, respectively, at the end of induction (median 6 Cycles).2 In addition, the VGPR or better rate in 14 relapsed multiple myeloma patients was 57 percent after 4 Cycles and increased to 64 percent at the end of induction, and the ORR stayed consistent at 71 percent (median 7.5 Cycles).2 The 18-month PFS rate was 78 percent in non-transplant newly diagnosed patients and 53 percent in relapsed patients.2 Additionally, the study, which investigated splitting the first dose of daratumumab to shorten the infusion time on Cycle 1, Day 1 (C1D1), showed a safety profile consistent with previous studies.2 Infusion reactions (IRs) occurred in 49 percent of patients on C1D1 and four percent on Cycle 1, Day 2 (C1D2). Fifty-four percent of newly diagnosed patients experienced IRs, the most frequent being chills (14 percent), dyspnea, pruritus and nausea (8 percent each), and cough (7 percent). Fifty-seven percent of relapsed patients experienced IRs, the most frequent being cough (21 percent), hyperhidrosis, dyspnea, and chills (7 percent each). Only two patients experienced a Grade 3 IR, and there were no Grade 4 IRs. There were no daratumumab discontinuations due to IRs. Median infusion time was 4.5 hours for C1D1 and 3.8 hours for C1D2.2 Grade 3/4 TEAEs were reported for 56 percent of patients and the most common (≥10 percent) was neutropenia (13 percent).2

Data presented on the Phase 2 GRIFFIN study investigated daratumumab in combination with bortezomib, lenalidomide and dexamethasone (VRd) in a 16-patient safety cohort of newly diagnosed patients with multiple myeloma who were eligible for high-dose therapy and ASCT.3 Results showed that by the end of consolidation therapy following ASCT, all patients enrolled in the safety run-in obtained VGPR or better, and 63 percent achieved complete response (CR) or better, including 25 percent of patients who achieved sCR.3 Additionally, 94 percent of patients remained progression-free on study treatment at a median follow-up of 16.8 months.3 In addition, 8 of the 16 patients (50 percent) were MRD negative at a level of 10-5 by the end of consolidation.3 Fourteen patients (88 percent) experienced Grade 3/4 TEAEs with 10 (63 percent) related to treatment with daratumumab.3 The most common Grade 3/4 TEAEs (≥10 percent) included neutropenia, pneumonia, thrombocytopaenia, lymphopenia, febrile neutropenia, leukopenia, rash and hypophosphataemia.3 Thirteen patients (81 percent) experienced infections of any grade, including upper respiratory tract infection (six patients), pneumonia (four patients), bronchitis (two patients), and otitis and viral gastroenteritis (two patients each).3 No deaths due to serious adverse events were reported and no patient discontinued treatment due to an adverse event.3 These data suggest that daratumumab induction does not negatively impact stem cell mobilisation as all 16 patients underwent successful mobilisation with subsequent ASCT.3

"Daratumumab offers consistent clinical benefit across all lines of therapy in multiple myeloma and the positive data from the ALCYONE, LYRA and GRIFFIN studies build on the strong body of evidence supporting daratumumab-based regimens," said Dr Catherine Taylor, Haematology Therapy Area Lead, Europe, Middle East and Africa (EMEA), Janssen-Cilag Limited. "These are important findings for patients which also provide additional insight into the most effective ways to manage care."

#ENDS#

About the ALCYONE Trial4

The randomised, open-label, multicentre Phase 3 ALCYONE (MMY3007) study enrolled 706 newly diagnosed patients with multiple myeloma who were ineligible for high-dose chemotherapy with ASCT. The median age was 71 years (range: 40-93). Patients were randomised to receive up to nine Cycles of either daratumumab-VMP or VMP alone. In the daratumumab-VMP arm, patients received 16 mg/kg of daratumumab once weekly for the first week (Cycle 1), followed by once every three weeks (Cycles 2-9). Following the nine cycles, patients in the daratumumab-VMP arm continued to receive 16 mg/kg of daratumumab once every four weeks until disease progression.

About the LYRA Trial5

The ongoing, multicentre, single-arm, open-label Phase 2 LYRA (MMY2012) study enrolled 100 adult patients 18 years or older. Patients received 4-8 Cycles of daratumumab combination therapy comprised of oral cyclophosphamide 300 mg/m2 on Days 1, 8, 15 and 22; subcutaneous bortezomib 1.5 mg/m2 on Days 1, 8 and 15; and oral or IV dexamethasone 40 mg weekly every 28 days. Daratumumab was administered at 8 mg/kg IV on Days 1 and 2 of Cycle 1, 16 mg/kg weekly from Cycle 1, Day 8 through Cycle 2, 16 mg/kg every 2 weeks for Cycles 3-6, and 16 mg/kg every 4 weeks for Cycles 7-8. After induction, patients could undergo ASCT. All patients receive 12 cycles of maintenance daratumumab 16 mg/kg IV every 4 weeks.

About the GRIFFIN Trial6

The randomised, open-label Phase 2 GRIFFIN (MMY2004) study has enrolled and treated more than 200 adults 18-70 years eligible for high-dose therapy/ASCT,7 including 16 patients in a safety run-in phase performed to assess potential dose limiting toxicities during Cycle 1 of daratumumab combination with VRd. Patients in the safety run-in received four infusion Cycles of daratumumab and VRd every 21 days followed by stem cell mobilisation, high-dose therapy and ASCT; two consolidation Cycles of daratumumab and VRd; and maintenance therapy with daratumumab and lenalidomide for Cycles 7-32. During induction and consolidation (Cycles 1-6), 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. 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 (Cycles 7-32), patients receive 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. Maintenance therapy with lenalidomide may be continued beyond Cycle 32 per local standard of care. In the subsequent randomised Phase 2 portion of the study, approximately 200 patients were randomised and received treatment with VRd, ASCT and maintenance therapy with lenalidomide or daratumumab and VRd, ASCT and maintenance therapy with daratumumab and lenalidomide.7

About daratumumab

Daratumumab is a first-in-class biologic targeting CD38, a surface protein that is highly expressed across multiple myeloma cells, regardless of disease stage.8 Daratumumab is believed to induce tumour 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.9 A subset of myeloid derived suppressor cells (CD38+ MDSCs), CD38+ regulatory T cells (Tregs) and CD38+ B cells (Bregs) were decreased by daratumumab.9 Daratumumab is being evaluated in a comprehensive clinical development programme across a range of treatment settings in multiple myeloma, such as in frontline and relapsed settings.10,11,12,13,14,15,16,17 Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant haematologic diseases in which CD38 is expressed, such as smouldering myeloma.18,19 For more information, please see www.clinicaltrials.gov.

In Europe, daratumumab is indicated for use in combination with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant, as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy, and in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.9 For further information on daratumumab, please see the Summary of Product Characteristics at View Source

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive licence to develop, manufacture and commercialise daratumumab.20

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.21 More than 45,000 people were diagnosed with multiple myeloma in Europe in 2016, and more than 29,000 patients died.22 Up to half of newly diagnosed patients do not reach five-year survival,23 and almost 29% of patients with multiple myeloma will die within one year of diagnosis.24

Although treatment may result in remission, unfortunately, patients will most likely relapse as there is currently no cure.25 Refractory multiple myeloma is when a patient’s disease progresses within 60 days of their last therapy.26,27 Relapsed cancer is when the disease has returned after a period of initial, partial or complete remission.28 While some patients with MM have no symptoms at all, most patients are diagnosed due to symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems or infections.29 Patients who relapse after treatment with standard therapies, including PIs and immunomodulatory agents, have poor prognoses and few treatment options available.30

On December 1, 2018 Oxford BioMedica plc ("Oxford BioMedica" or "the Group") (LSE:OXB), a leading gene and cell therapy group, reported by Novartis on the longer-term analyses of both the ELIANA and JULIET pivotal trials in children and young adult patients with relapsed or refractory (r/r) acute lymphoblastic leukaemia (ALL) and adult patients with r/r diffuse large B-cell lymphoma (DLBCL), respectively. Kymriah (tisagenlecleucel) continued to demonstrate strong efficacy with durable responses and maintained a consistent and well-characterised safety profile (Press release, Oxford BioMedica, DEC 1, 2018, View Source [SID1234531789]). These data are being presented at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting. Additionally, today, the New England Journal of Medicine published online the 14-month results from JULIET, the study led by the Abramson Cancer Center at the University of Pennsylvania 1.

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In the 24-month follow-up analysis of the ELIANA study in children and young adults with r/r B-cell ALL, Kymriah demonstrated deep and durable responses without subsequent therapy in a significant portion of patients in this population. Among 79 evaluable patients, who were followed for at least three months or discontinued earlier, 82% (95% confidence interval [CI], 72% – 90%) achieved complete response (CR) or CR with incomplete blood count recovery (CRi) within three months of infusion; and among these responding patients, 98% had negative minimal residual disease (MRD). The relapse-free survival rate was 62% at 24 months; and the median duration of remission (mDOR) and median overall survival (mOS) remained unreached, signifying responses are deep and sustained, and further reinforcing the potential for Kymriah to be a definitive therapy for many patients. The probability of OS was 76% (95% CI, 65% – 85%) at 12 months and 66% (95% CI, 58% – 79%) at 24 months. The safety profile observed in this updated analysis was consistent with previously reported results, with no emergence of new safety signals. Grade 3/4 cytokine release syndrome (CRS) – as defined by the rigorous Penn Grading Scale – occurred in 49% of patients. Within eight weeks of infusion, 13% of patients experienced grade 3 neurological events, with no grade 4 events or cerebral oedema2. These updated data will be presented in an oral session at the ASH (Free ASH Whitepaper) annual meeting (Abstract # 895; Monday, December 3, 4:30PM PST).

Results from the 19-month analysis from the JULIET study of Kymriah in adult patients with r/r DLBCL (n=99) indicated prolonged durability of response in patients who had previously been through multiple rounds of chemotherapy and unsuccessful stem cell transplants (Abstract # 1684). The overall response rate (ORR) after a median of 19 months of follow-up was 54% (95% CI, 43% – 64%; CR, 40%; partial response [PR], 13%) among patients who were followed for at least 3 months or discontinued earlier. The mDOR was not reached at the time of analysis indicating most responders were still experiencing a response at the time of analysis; and the relapse-free probability, which was 66% (95% CI, 51%-78%) at 6 months, remained consistent at 64% (95% CI, 48%-76%) between 12-month and 18-month analyses. Further, 54% (15/28) of patients who had achieved a PR converted to CR. Median OS for all infused patients was 11.1 months (95% CI, 6.6 months-NE) and not reached (95% CI, 21 months-NE) for patients in CR. The OS probability was 48% (95% CI, 38%-57%) at 12 months and 43% (95%CI, 33%-53%) at 18 months (max follow-up, 29 months). Analyses of ORR, DOR and OS data showed consistent results across all patient subgroups, regardless of relapsed/refractory status, age and high-risk cytogenetics.

The safety profile observed in the 19-month follow-up from JULIET continued to be consistent with previous reports and no deaths occurred due to causes other than disease progression in this longer-term follow up analysis. Within eight weeks of infusion with Kymriah, Grade 3/4 CRS, as defined by the Penn Grading Scale, was reported in 23% of patients. CRS management was conducted per the Penn CRS management algorithm, which is specific to Kymriah. Tocilizumab and steroids were used in 16% and 11% of patients, respectively, to treat CRS. Eleven percent of patients had Grade 3/4 neurologic adverse events, which were managed with supportive care3.

Oxford BioMedica is the sole manufacturer of the lentiviral vector used in Kymriah. The Group signed an agreement with Novartis in July 2017 for the commercial and clinical supply of lentiviral vectors used to generate Kymriah and other undisclosed CAR-T products. This collaboration has reached important milestones in 2018 with the US FDA approval of Kymriah to treat adult patients with r/r DLBCL, and the approval of Kymriah in these two distinct indications in the European Union, Canada and Switzerland. These important achievements follow the initial US launch of Kymriah in paediatric and young adult patients with r/r B-cell ALL in 2017. Oxford BioMedica signed an agreement with Novartis in July 2017 for the commercial and clinical supply of lentiviral vectors used to generate CTL019 and other undisclosed CAR-T products, for which Oxford BioMedica could potentially receive in excess of $100m from Novartis over the next three years.

Notes for editors

About the ELIANA Trial

ELIANA is the first paediatric global CAR-T cell therapy registration trial, examining patients in 25 centres in 11 countries across the US, Canada, Australia, Japan and the EU, including: Austria, Belgium, France, Germany, Italy, Norway and Spain, demonstrating effective distribution of Kymriah across four continents using a global supply chain. In 2012, Novartis and Penn entered into a global collaboration to further research, develop and commercialize CAR-T cell therapies, including Kymriah, for the investigational treatment of cancers.

About the JULIET Trial

JULIET is the first multi-centre global registration study for Kymriah in adult patients with r/r DLBCL. JULIET, led by researchers at the University of Pennsylvania, is the largest and only global registration study examining a CAR-T cell therapy in DLBCL, enrolling patients from 27 sites in 10 countries across the US, Canada, Australia, Japan and Europe, including Austria, France, Germany, Italy, Norway and the Netherlands.

About Kymriah

In August 2017, Kymriah became the first available chimeric antigen receptor T cell (CAR-T) therapy when it received FDA approval for children and young adults with B-cell acute lymphoblastic leukaemia (ALL) that is refractory or has relapsed at least twice. Kymriah is a novel immunocellular therapy and a one-time treatment that uses a patient’s own T cells to fight cancer. Kymriah uses the 4-1BB costimulatory domain in its chimeric antigen receptor to enhance cellular expansion and persistence.