On June 3, 2018 Celgene Corporation (NASDAQ:CELG) reported updated six-month safety and efficacy data from the TRANSCEND (NHL-001) study of lisocabtagene maraleucel (liso-cel; JCAR017), an investigational CD19-directed CAR T cell therapy, in patients with relapsed/refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (NHL) in a presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL (Press release, Celgene, JUN 3, 2018, View Source [SID1234527063]).

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"As liso-cel data mature, the durable response rates continue to demonstrate the potential of CAR T cell therapy in patients with DLBCL who have relapsed or are refractory to prior treatments," said principal investigator Jeremy Abramson, M.D., of Massachusetts General Hospital. "Added to the emerging side effect profile with liso-cel, this therapy has encouraging potential in diffuse large B-cell lymphoma."

The update provided today was based on a cutoff date of May 4, 2018 and included data from 114 liso-cel treated and 102 safety evaluable patients, of which 51 patients were treated at the pivotal dose of 100 million cells. Abramson highlighted 37 patients who meet the criteria for the planned pivotal patient population in TRANSCEND NHL-001 (including r/r DLBCL, transformed from follicular lymphoma (tFL), and poor-risk high-grade double/triple-hit lymphoma), and were treated with the pivotal cell dose. The new long-term follow up data add to those disclosed on May 16, 2018 in ASCO (Free ASCO Whitepaper) Abstract #7505.

At six months, 49% of patients remained in remission, with 46% maintaining a complete response (CR) in this cohort (n=37). When durability of response beyond six months was evaluated across all dosing levels ranging from 5 x 107 to 1 x 108 CAR T cells, 93% of patients in CR remained in CR at data cut off. Liso-cel therapy was available for 99% (132/134) of patients apheresed.

The most common treatment-emergent adverse events that occurred at ≥25% incidence included neutropenia (63%), anemia (53%), fatigue (46%), thrombocytopenia (34%), decreased appetite (29%), nausea (28%), hypotension (26%), cough (26%), headache (25%), dizziness (25%), constipation (25%), and diarrhea (25%). Cytokine release syndrome and neurotoxicity were observed at a rate of 37% and 23% for all grades, and 1% and 13% for grades 3 and 4, respectively (n=102). Based on this emerging safety profile, outpatient administration is being evaluated in the TRANSCEND trial.

"The updated efficacy and tolerability data for liso-cel continue to support a potential best-in-class CD19 CAR T profile," said Nadim Ahmed, President, Hematology and Oncology for Celgene. "With the TRANSCEND pivotal cohort now fully enrolled, we look forward to further progressing this critical program for poor-prognosis patients with relapsed or refractory aggressive NHL and investigating the clinical utility of liso-cel in earlier lines of therapy."

About Liso-cel and TRANSCEND

Liso-cel is an investigational defined composition CD19-directed CAR T cell product candidate using a 4-1BB costimulatory domain. TRANSCEND is an open-label, multicenter phase I study to determine the safety, pharmacokinetics, and antitumor activity of liso-cel in adult patients with relapsed or refractory diffuse large B cell lymphoma, primary mediastinal B-cell lymphoma, follicular lymphoma Grade 3B, and mantle cell lymphoma.

The pivotal cohort includes patients with DLBCL (NOS and transformed from follicular lymphoma) who are ECOG Performance Status 0-1. These patients represent a high-risk patient population, with approximately 90% of treated patients having one or more predictors of poor survival, including double or triple hit lymphoma, being chemorefractory to front-line or subsequent therapies, never reaching a complete remission with prior treatments, or never having undergone an autologous transplant.

On June 3, 2018 Galera Therapeutics, Inc., a clinical-stage biotechnology company focused on the development of drugs targeting oxygen metabolic pathways with the potential to transform cancer radiotherapy, reported data from the Phase 2b clinical trial evaluating GC4419, a highly selective and potent small molecule dismutase mimetic, were presented today during an oral session at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, Galera Therapeutics, JUN 3, 2018, View Source [SID1234527079]).

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The 223-patient, double blind, randomized, placebo-controlled trial evaluated the safety of GC4419 and its ability to reduce the duration of radiation-induced severe oral mucositis (SOM) in patients with locally advanced squamous cell head and neck cancer receiving seven weeks of radiation therapy plus cisplatin. Approximately 70 percent of patients receiving chemoradiotherapy develop SOM, as defined by the World Health Organization as Grade 3 or 4, which is the most debilitating side effect of the radiotherapy.

Patients in the trial were treated with either 30 mg or 90 mg of GC4419 or placebo by infusion on the days they received their radiation treatment. Patients were randomized to one of the three treatment groups (1:1:1) and the trial recruited patients in both the United States and Canada. In the trial’s intent-to-treat population, the 90 mg dose of GC4419 met the primary endpoint, demonstrating a statistically significant (p = 0.024) 92 percent reduction in the median duration of SOM from 19 days to 1.5 days.

"Galera is honored ASCO (Free ASCO Whitepaper) has recognized the clinically meaningful results from our Phase 2b trial of GC4419 by selecting the abstract for the Best of ASCO (Free ASCO Whitepaper) program," said Mel Sorensen, M.D., President and CEO of Galera. "This distinction, as well as the receipt of Breakthrough Therapy and Fast Track designations from the U.S. Food and Drug Administration, underscores GC4419’s potential to be an important new treatment for this prevalent toxic effect of radiotherapy. We look forward to working with the FDA to define the next step in the development of GC4419."

Other key highlights from the Phase 2b trial include:

GC4419 exhibited a safety profile comparable to placebo in the two treatment groups, and was well tolerated.
In the 90 mg arm, GC4419 demonstrated a clinically meaningful effect in pre-specified secondary endpoints (incidence and severity of SOM).
GC4419 achieved a 34 percent reduction through completion of radiation (p = 0.009), and a 36 percent reduction through 60 Gy of radiation (p = 0.010), in the overall incidence of SOM.
GC4419 reduced the severity of patients’ OM by 47 percent (p = 0.045).
"Oral mucositis is one of the most common and disruptive side effects experienced by patients undergoing radiation therapy for head and neck cancer, but there are no approved drugs to prevent or treat it," said Carryn Anderson, M.D., trial investigator and Radiation Oncologist, University of Iowa Hospitals and Clinics. "GC4419’s ability to significantly decrease severe oral mucositis while maintaining a favorable safety profile comparable to placebo is an especially encouraging sign of its promise to offer a novel treatment option."

About Oral Mucositis

Oral mucositis (OM) is a painful and problematic complication during cancer treatment, especially radiation therapy, caused by excessive superoxide generated during treatment that breaks down epithelial cells that line the mouth. Patients suffering from OM experience severe pain, inflammation, ulceration and bleeding of the mouth.

In the United States, more than 50 percent of patients with cancer receive radiotherapy at some time in their treatment. In patients with head and neck cancer, radiotherapy is a mainstay of treatment and approximately 70 percent of patients receiving chemoradiotherapy develop severe oral mucositis (SOM) as defined by the World Health Organization as Grade 3 or 4, which is the most debilitating side effect of the radiotherapy.

SOM can adversely affect cancer treatment outcomes by causing interruptions in radiotherapy, which may compromise the otherwise good prognosis for tumor control in many of these patients. SOM may also inhibit patients’ ability to eat solid food or even drink liquids, and can cause serious infections. Further, the costs of managing these side effects are substantial, particularly when hospitalization and/or surgical placement of PEG tubes to maintain nutrition and hydration are required. There is currently no drug approved to prevent or treat SOM in patients with head and neck cancer.

About GC4419

GC4419 is a highly selective and potent small molecule dismutase mimetic that closely mimics the activity of human superoxide dismutase enzymes. GC4419 works to reduce elevated levels of superoxide caused by radiation therapy by rapidly converting superoxide to hydrogen peroxide and oxygen. Left untreated, elevated superoxide can damage noncancerous tissues and lead to debilitating side effects, including oral mucositis (OM), which can limit the anti-tumor efficacy of radiation therapy. Conversion of elevated superoxide to hydrogen peroxide, which is selectively more toxic to cancer cells, can also enhance the effect of radiation on tumors, particularly with stereotactic body radiation therapy (SBRT), which produces high levels of superoxide.

GC4419 has been studied in patients with head and neck cancer, GC4419’s lead indication, for its ability to reduce the duration, incidence and severity of radiation-induced severe oral mucositis (SOM). Results from Galera’s 223-patient, double blind, randomized, placebo-controlled Phase 2b clinical trial demonstrated GC4419’s ability to dramatically reduce the duration of SOM from 19 days to 1.5 days (92 percent), the incidence of SOM through completion of radiation by 34 percent and the severity of patients’ OM by 47 percent, while demonstrating acceptable safety when added to a standard radiotherapy regimen. In addition, in multiple preclinical studies, GC4419 demonstrated an increased tumor response to radiation therapy while preventing toxicity in normal tissue.

The U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation to GC4419 for the reduction of the duration, incidence and severity of SOM induced by radiation therapy with or without systemic therapy. The FDA also granted Fast Track designation to GC4419 for the reduction of the severity and incidence of radiation and chemotherapy-induced OM.

On June 2, 2018 NantWorks, LLC reported that its affiliate companies, NantHealth, Inc., (NASDAQ: NH), a leading next-generation, evidence-based, personalized healthcare company and NantOmics, LLC, the leader in molecular analysis and a member of the NantWorks ecosystem of companies, the leader in molecular diagnostics and a member of the NantWorks ecosystem of families, reported that it will present data on three-fold overestimation of tumor mutation burden (TMB) using a 248 gene list as a panel to impute TMB during the tumor biology session at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2018 Annual Meeting, an event bringing together 30,000 oncology professionals from June 1-5, 2018 at McCormick Place in Chicago, Illinois. NantWorks will be exhibiting at booth #7147 during the event.

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The data presented here have significant implications on the use of immunotherapies such as Keytruda and Opdivo given previous data touting the effectiveness of these drugs in patients whose tumors bear high TMB. The NantWorks companies’ data presented here caution against overestimation of TMB and thus immunotherapy overuse when extrapolating TMB from smaller panel tests (<500 genes) versus simply identifying all actual mutations by surveying the entire genome. Further, whether performing analysis on the entire genome or in a panel test, clinical validity for the use of immunotherapies is made appreciably more precise by confirming the expression of identified mutations. The patient’s immune system recognizes and targets non-self proteins, not DNA, thus underscoring the need to append the mutated genomic data with expression data. Maximal accuracy as established in this presentation by the use of tumor-normal DNA interpretation of TMB from surveying all genes and further amplified by derivation of expressed TMB is what is required for future immunotherapies such as neoepitope vaccines.

"We’re excited to share our data from our retrospective analysis, which may impact ICT prescription and expectation of clinical benefit," said Patrick Soon-Shiong, MD, founder of NantWorks. "Our analysis builds on our breadth of actionable insight and molecularly driven support for cancer patients and their providers, and we look forward to continuing to build upon our diagnostic capabilities."

Presentation Details

Three-fold overestimation of tumor mutation burden using 248 gene panel versus whole exome, Abstract, #12117
WHO: NantHealth, LLC and NantOmics, LLC
WHAT: Tumor Biology Session
WHEN: June 4, 1:15-4:45 PM CST
WHERE: Hall A, McCormick Place

Presentation Summary

This study analyzed if actual TMB (aTMB), consisting of mutations across the exome, and expressed TMB (eTMB), consisting of expressed genes, would differ substantially from iTMB. Retrospective analysis of a database from a commercial DNA tumor:normal and RNAseq platform was carried out. 890 clinical samples were analyzed, composing of both primary and metastatic disease by whole genome sequencing (WGS) or WES and RNA sequencing (RNA-Seq), and compared true tumor mutational burden to a predicted tumor mutational burden from a list of 248 genes thought to drive cancer. The study showed an estimated tumor mutational burden based only on the list of 248 genes had an average of 15.79 mutations per megabase whereas WGS/WES derived TMB had an average of 5.09 mutations per megabase of coding DNA. As a result, the study indicates that a roughly 3-fold over-estimate of TMB was observed, which may impact ICT prescription and expectation of clinical benefit.

On June 2, 2018 Celldex Therapeutics, Inc. (NASDAQ:CLDX) today presented two programs at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, Celldex Therapeutics, JUN 2, 2018, View Source [SID1234527065]). Data from the Phase 1/2 study of Celldex’s varlilumab, a CD27 targeting investigational immune-activating antibody, and Bristol-Myers Squibb’s Opdivo (nivolumab), an anti-PD1 immunotherapy, for patients with ovarian cancer and colorectal cancer, were presented in an oral session by Rachel E. Sanborn, M.D., Co-director of the Providence Thoracic Oncology Program and Phase 1 Clinical Trials Program, at the Earle A. Chiles Research Institute, Providence Cancer Institute, in Portland, Ore. In addition, an overview of the Phase 2 study of the anti-ErbB3 antibody CDX-3379 in combination with Erbitux in advanced head and neck squamous cell cancer was presented in a "clinical trials in progress" poster session.

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"The data presented today continue to support that varlilumab holds considerable potential as an immune activator," said Dr. Sanborn. "This was particularly noteworthy in ovarian cancer where the combination with the anti-PD1 monoclonal antibody, Opdivo, turned "immune-cold" tumors "hot," which in turn correlated with improved clinical outcomes, including improved response rate and progression-free survival in these patients."

"Moving forward, we believe more work needs to be done to identify synergistic combinations and patient populations that have the best chance of responding to varlilumab treatment," said Tibor Keler, Ph.D., Executive Vice President and Chief Scientific Officer of Celldex Therapeutics. "We are continuing to explore these opportunities through inclusion in our ongoing Phase 1 study of CDX-1140, our CD40 agonist antibody, and several investigator-initiated studies."

"We also continue to enroll patients into our ongoing Phase 2 study of CDX-3379 in combination with Erbitux in patients with HPV negative, Erbitux-resistant, advanced head and neck squamous cell carcinoma. We look forward to completing enrollment to the first stage of this study in the third quarter of 2018 and are exploring other potential opportunities in indications where ErbB3 is believed to play a role," concluded Dr. Keler.

ASCO Highlights

Varlilumab

Varlilumab was featured in an oral presentation that highlighted the ongoing Phase 2 study of varlilumab in combination with Opdivo. The Phase 1/2 study includes cohorts in ovarian cancer, colorectal cancer, head and neck squamous cell carcinoma, renal cell carcinoma and glioblastoma, with data from ovarian cancer (n=66) and colorectal cancer (n=42) patients included in the presentation today. The majority of patients enrolled in the study had baseline tumors that were mostly "cold" (PD-L1 negative or low, and low tumor-infiltrating lymphocyte [TIL] levels) with low expectation of responding to checkpoint inhibition therapy. The combination was well tolerated at all varlilumab dose levels tested.

Results in Ovarian Cancer Experience: n=66, 8 patients in Phase 1; 58 patients in Phase 2; median of three prior lines of therapy; 91% had Stage IV disease; 66% with PD-L1 negative tumors; multiple varlilumab dosing regimens evaluated. Detailed information by dosing cohort is included in the presentation and is available on the Celldex website.

Overall response rate: 14% (n=9) across 64 response-evaluable patients (7 confirmed, 2 unconfirmed)
Response rate by PD-L1 status:
PD-L1 positive: 20% (n=4 of 20; 3 confirmed, 1 unconfirmed)
PD-L1 negative: 14% (n=5 of 37; 4 confirmed, 1 unconfirmed)
Disease control rate (DCR), defined as best response of stable disease or better for greater than or equal to three months, was 38% (n=24 of 64). As of the cut-off for analysis, five patients continued on treatment.
For patients with tumor samples available, most patients experienced increases in tumor expression of PD-L1 (n=14 of 23; 61%) and CD8+ TIL levels (n=14 of 24; 58%). These increases were associated with improved clinical outcome, including improved progression-free survival (PFS) and response rate.

Results in Colorectal Cancer Experience: n=42; 21 patients in Phase 1; 21 patients in Phase 2; median of four prior lines of therapy; 100% had Stage IV disease; 87% had PD-L1 negative tumors; one patient was MSI-high and 21 patients were MSI-low/mismatch repair (MMR) proficient; MSI status for the remaining 20 patients was unknown.

One patient with PD-L1 negative, MSI-high disease experienced a confirmed partial response in the Phase 2 study portion and continues on treatment. Of note, a patient with PD-L1 negative disease, initially considered MMR proficient as determined by standard screening laboratory analysis, achieved a near complete response in the Phase 1 portion of the study, which now continues at 35 months. As part of this study, an additional molecular analysis was conducted on this patient’s tumor. The tumor had a high mutational burden and mutations in genes regulating DNA repair, which together likely contributed to the response. DCR was 20% (8/41).
CDX-3379

CDX-3379 was featured in a "clinical trials in progress" poster presentation, available on the Celldex website, that highlighted the ongoing Phase 2 study of CDX-3379, a human monoclonal antibody designed to block the activity of ErbB3 (HER3), in combination with Erbitux in patients with human papillomavirus (HPV) negative, Erbitux-resistant, advanced head and neck squamous cell carcinoma. The proposed mechanism of action for CDX-3379 sets it apart from other drugs in development in this class due to its ability to block both ligand-independent and ligand-dependent ErbB3 signaling by binding to a unique epitope. It has a favorable pharmacologic profile, including a longer half-life and slower clearance relative to other drug candidates in this class. The multicenter, open-label, Simon two-stage design study is expected to enroll approximately 27 patients (Stage 1=13; Stage 2=14). The primary objective of the study is objective response rate. Secondary objectives include assessments of clinical benefit response, duration of response, progression-free survival and overall survival, and safety and pharmacokinetics associated with the combination. Four clinical trial sites are currently open to enrollment, and Celldex is targeting to complete enrollment to the first stage of the study by the end of the third quarter of 2018. The Company continues to explore potential other opportunities in additional indications where ErbB3 is believed to play a role.

On June 2, 2018 New Novartis data from two long-term Treatment-free Remission (TFR) studies in patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase (CP) reported that it will be presented during the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (Press release, Novartis, JUN 2, 2018, View Source [SID1234527100]). Results from the open-label Phase II trials, ENESTop and ENESTfreedom, show sustained TFR in patients treated with both front-line and second-line Tasigna (nilotinib) therapy. The 144-week trials evaluate the potential to maintain molecular response (MR) after stopping therapy in eligible adult patients with Ph+ CML-CP.

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"Treatment-free Remission is a new treatment goal in CML," said François-Xavier Mahon, Cancer Center of Bordeaux, Institut Bergonié and lead investigator of ENESTop. "Clinical studies like ENESTop and ENESTfreedom offer evidence that when a Ph+ CML-CP patient achieves a deep molecular response with Tasigna, along with other eligibility criteria, s/he can attempt TFR and have a nearly 50% chance of remaining treatment-free long-term. These results confirm an exciting opportunity for eligible patients – the opportunity to reduce time on drug for a chronic leukemia."

Data from ENESTop, presented today in an oral session (Abstract #7003) show that approximately half (48.4%; CI 95%, 39.4%-57.5%) of patients with Ph+ CML-CP who are eligible to stop second-line Tasigna therapy maintained disease remission over a prolonged period of time in the absence of treatment at 144 weeks of follow up, almost 3 years[1]. Patients in this trial took Tasigna following a switch from Glivec (imatinib)*. ENESTop data also show that of the patients who restarted Tasigna due to loss of major molecular response (MMR=BCR-ABL/ABL <=0.1% IS), during the study period, nearly all (97.1%) regained MMR and 95.8% regained MR4.5 (BCR-ABL1 IS =< 0.0032%)[1]. Study authors stress that frequent scheduled and compliant monitoring is necessary to assess for loss of response. Results of ENESTop at 144-weeks are consistent with previously reported data at both 96- and 48-weeks.

A second long-term clinical trial, ENESTfreedom, is also part of the ASCO (Free ASCO Whitepaper) Scientific Program this week. The authors will report on TFR results at 144 weeks in patients who started front-line CML therapy with Tasigna. Results from ENESTfreedom will be shared with ASCO (Free ASCO Whitepaper) attendees on Monday, June 4 (Abstract #7063). In this trial, researchers found that almost half (46.8%; CI 95%: 39.6%-54.2%) of Ph+ CML-CP patients eligible to stop Tasigna treatment remained in MMR following treatment discontinuation[2].

"Novartis continues to redefine treatment options for Ph+ CML patients," said Samit Hirawat, MD, Head of Novartis Oncology Global Drug Development. "The importance of achieving deep and sustained responses with Tasigna has been demonstrated in our TFR clinical program, which is the largest among all oncology companies. These long-term trials deliver on our commitment to the patient community to continue to look for more and better solutions for CML."

An update on the Phase III clinical trial design for Novartis’ investigational BCR-ABL1 inhibitor, asciminib, will also be presented as part of the ASCO (Free ASCO Whitepaper) Scientific Program (Abstract #TPS7081).

Novartis Commitment to CML
Novartis’ ongoing research in Ph+ CML has helped transform the disease from a fatal leukemia to a chronic condition in most patients. The company maintains an unwavering commitment to scientific innovation and access to care for patients worldwide. As an organization committed to patients, Novartis continues to reimagine CML by pursuing ambitious goals with courage, passion and commitment for the global CML community.

About ENESTop
ENESTop (Evaluating Nilotinib Efficacy and Safety Trial) is an open label Phase II study involving 163 Ph+ CML patients, conducted at 63 sites across 18 countries. The trial evaluated stopping treatment in 126 adults with Ph+ CML-CP receiving Tasigna for at least three years, after patients had achieved and sustained deep molecular response (DMR) for one year with Tasigna following Glivec. The study is ongoing with planned follow-up to evaluate the ability of patients to sustain remission for longer durations upon discontinuation of Tasigna.

Findings from ENESTop at 144-weeks found that 48.4% (CI 95%, 39.4%-57.5%) of 126 patients were able to remain in TFR at 144 weeks[1]. In the study, 58 patients with confirmed loss of MR4 (n=24; BCR-ABL1 IS =< 0.01%) or loss of MMR (n=34) restarted Tasigna by the cut-off date[1]. Of the 34 patients who restarted treatment with Tasigna due to loss of MMR, 91.2% regained MR4.5 (n=31; BCR-ABL1 IS =< 0.0032%)[1]. Of the 24 patients with loss of MR4 who restarted Tasigna, 95.8% (n=23) regained MR4.5,[1]. No new major safety findings were observed in ENESTop in patients treated with Tasigna beyond those in the known safety profile of Tasigna[1]. Among patients who remained in the TFR phase of the trial for more than 96 weeks (n=68), 10.3%, 51.5%, 19.1%, and 11.8% experienced any-grade musculoskeletal pain-related adverse events in the consolidation phase and first, second, and third 48-week phases of TFR, respectively[1].

About ENESTfreedom
ENESTfreedom (Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Following REsponsE in De nOvo CML-CP Patients) is an open label Phase II study involving 215 Ph+ CML patients in the chronic phase, conducted at 132 sites across 19 countries. ENESTfreedom evaluated stopping treatment in 190 adults with Ph+ CML-CP receiving Tasigna for at least three years, after the patients had achieved a response of MR4.5 with Tasigna and a sustained DMR for one year as a first-line treatment. The study is ongoing with planned follow-up to evaluate the ability of patients to sustain remission for longer durations following discontinuation of Tasigna.

Findings from ENESTfreedom at 144-weeks found that 46.8% of 190 eligible CML patients (CI 95%: 39.6%-54.2%) remained in MMR following discontinuation of Tasigna[2]. Of the 91 patients who restarted treatment with Tasigna due to loss of MMR by the cut-off date, 98.9% (n=90) and 92.3% (n=84) were able to regain MMR and MR4.5, respectively[2]. No new major safety findings were observed in ENESTfreedom in patients treated with Tasigna beyond those in the known safety profile of Tasigna[2]. Among patients who remained in TFR for more than 96 weeks (n=94), any-grade musculoskeletal pain-related AEs were 16.0%, 40.4%, 9.6% and 4.3% in the consolidation phase and first, second and third 48-week phases of TFR, respectively[2].

About Tasigna
Tasigna (nilotinib) is approved in more than 130 countries for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML) in chronic phase and with chronic and accelerated phase Ph+ CML resistant or intolerant to at least one prior therapy, including Glivec (imatinib). Tasigna is also approved for the treatment of pediatric patients with newly diagnosed Ph+ CML in the chronic phase and with resistance or intolerance to prior TKI therapy.

IMPORTANT SAFETY INFORMATION for TASIGNA (nilotinib) Capsules
Use with caution in patients with uncontrolled or significant cardiac disease and in patients who have or may develop prolongation of QTc. Low levels of potassium or magnesium must be corrected prior to Tasigna administration. Monitor closely for an effect on the QTc interval. Baseline ECG is recommended prior to initiating therapy and as clinically indicated. Cases of sudden death have been reported in clinical studies in patients with significant risk factors. Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors. Avoid food 2 hours before and 1 hour after taking dose.

Reactivation of hepatitis B can occur in patients who are chronic carriers of this virus after receiving TKI treatment.

Use with caution in patients with liver impairment, with a history of pancreatitis and with total gastrectomy. Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not use Tasigna. Tasigna may cause fetal harm in pregnant women. If pregnancy is planned during the treatment-free remission phase, the patient must be informed of a potential need to re-initiate treatment with Tasigna during pregnancy. Women should not breastfeed while taking Tasigna and for 2 weeks after the last dose.

Cases of cardiovascular events included ischemic heart disease-related events, peripheral arterial occlusive disease, and ischemic cerebrovascular events have been reported. Serious cases of hemorrhage from various sites including gastrointestinal were reported in patients receiving Tasigna. Grade 3 or 4 fluid retention including pleural effusion, pericardial effusion, ascites and pulmonary edema have been reported. Cases of tumor lysis syndrome have been reported in Tasigna-treated patients who were resistant or intolerant to prior CML therapy.

In pediatric patients the long-term effects of prolonged treatment with Tasigna is unknown.

Eligible patients who are confirmed to express the typical BCR-ABL transcripts, e13a2/b2a2 or e14a2/b3a2, can be considered for treatment discontinuation. Frequent monitoring of BCR-ABL transcript levels in patients eligible for treatment discontinuation must be performed with a quantitative diagnostic test validated to measure molecular response levels with a sensitivity of at least MR4.5 (BCR-ABL/ABL <=0.0032% IS). BCR-ABL transcript levels must be assessed prior to and during treatment discontinuation. Loss of major molecular response (MMR=BCR-ABL/ABL <=0.1% IS) or confirmed loss of MR4 (two consecutive measures separated by at least 4 weeks showing loss of MR4 (MR4=BCR-ABL/ABL <=0.01% IS) will trigger treatment re-initiation within 4 weeks of when loss of remission is known to have occurred. It is crucial to perform frequent monitoring of BCR-ABL transcript levels and complete blood count with differential in order to detect possible loss of remission. For patients who fail to achieve MMR after three months of treatment re-initiation, BCR-ABL kinase domain mutation testing should be performed.

Musculoskeletal pain, myalgia, pain in extremity, arthralgia, bone pain and spinal pain may occur upon discontinuing treatment with Tasigna within the framework of attempting treatment-free remission.

The most frequent Grade 3 or 4 adverse events are hematological (neutropenia, thrombocytopenia, anemia) which are generally reversible and usually managed by withholding Tasigna temporarily or dose reduction. Chemistry panels, including electrolytes, lipid profile, liver enzymes, and glucose should be checked prior to therapy and periodically. Tasigna can cause increases in serum lipase. The most frequent non-hematologic adverse events were rash, pruritus, nausea, fatigue, headache, alopecia, myalgia, constipation and diarrhea.

About asciminib
Asciminib (ABL001) is an investigational compound. Efficacy and safety have not been established. There is no guarantee this compound will become commercially available.

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