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New Data Uncover Deeper Insight into Tebentafusp (IMCgp100) Clinical Activity in Patients with Advanced Melanoma, Including Uveal

On November 11, 2019 Immunocore Limited, a leading T cell receptor (TCR) biotechnology company, reported new findings from its Phase 1/2 tebentafusp (IMCgp100) clinical trial programme demonstrating a correlation between treatment-induced immune response and improvement in overall survival and tumour shrinkage, in patients with advanced uveal and cutaneous melanoma (Press release, Immunocore, NOV 11, 2019, View Source [SID1234550869]). The new analyses from two clinical trials (IMCgp100-101, IMCgp100-102) were presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting in National Harbor, Maryland.

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"We are gaining valuable insights from our clinical data to further our understanding of the mechanism of action of our bispecific, soluble TCR," said Bahija Jallal, Chief Executive Officer of Immunocore. "Advancing the science underlying TCR recognition of antigens supports our efforts to further develop our platform and maximize its value on behalf of patients."

Tebentafusp is an investigational novel bispecific protein comprised of a soluble T cell receptor fused to an anti-CD3 immune-effector function. It is engineered to specifically target gp100, a lineage antigen expressed in melanocytes and melanoma, and is the first molecule developed using Immunocore’s ImmTAC technology platform designed to redirect and activate T cells to recognise and kill tumour cells. Pivotal tebentafusp clinical trials are currently underway in metastatic uveal melanoma (UM), a rare form of eye cancer.

"When using a therapy designed to induce an immune response, it’s not unexpected to see inflammatory events like rash or cytokine response syndrome," said Alexander N. Shoushtari, M.D., study investigator and medical oncologist at Memorial Sloan Kettering Cancer Center in New York. "While these were general low-grade events that resolved with treatment and time, it was interesting to see their potential connection to overall survival and other clinical outcomes. These findings are encouraging and will help to inform future research and treatment protocols."

SITC Presentation Highlights:

Induction of serum CXCL10 by tebentafusp, a gp100-CD3 bispecific fusion protein, was associated with survival in uveal melanoma in a Phase 1/2 study

The goal of this analysis was to increase understanding of the biological effects of tebentafusp and association between rash seen with treatment, CXCL10 and clinical outcomes in UM. Researchers focused on the initial 42 patient cohort enrolled in IMCgp100-102, a Phase 1/2 study in patients with HLA-A2+ positive advanced UM. Patients were treated using a weekly intra-patient dose-escalation regimen and the occurrence of rash within 21 days following treatment initiation was evaluated as a predictor of overall survival.

The findings showed a transient increase in peripheral cytokines after treatment with tebentafusp, reaching maximal changes at 8-24 hours post treatment, with CXCL10 having the greatest increment between 12-24 hours. Patients treated with tebentafusp experienced induced type 1/2 IFN pathways and neutrophil, eosinophil signatures and reduced CD4, CD8 and NK cell signatures in the blood. Tebentafusp-treated patients with rash and those with a greater increase in serum CXCL10 following the first treatment dose appeared to be associated with improved overall survival. In a multivariate Cox proportional hazards model, both rash (p<0.001) and CXCL10 induction (p=0.01) were independent predictors of survival.

Cytokine release syndrome following treatment with tebentafusp, a novel bispecific TCR-anti-CD3 directed against gp100, in patients with advanced melanoma

The goal of this analysis was to better understand the incidence, severity and resolution of cytokine release syndrome (CRS) following tebentafusp treatment, an adverse event commonly associated with CD3-bispecifics, and its association with clinical outcomes in advanced melanoma. Researchers analysed data from IMCgp100-101, a Phase 1 first-in-human clinical trial assessing the safety and tolerability of tebentafusp in 84 HLA-A2+ patients with metastatic melanoma (n=61 cutaneous, n=19 uveal, n=4 other) resistant to standard treatment regimens or for which no standard treatments exist. This post-hoc analysis evaluated adverse events, serious adverse events, vital signs, and concomitant medications reported by investigators to identify episodes of CRS.

The findings show that patients treated with tebentafusp experienced a low incidence of severe CRS. Despite no corticosteroid pre-treatment, CRS occurrence was generally low grade, reversible with standard management (i.e., IVF and short course corticosteroids), decreased in frequency and severity after the initial doses, and infrequently led to the discontinuation of treatment. The most frequent CRS adverse events were mild-to-moderate fever, fatigue, nausea, hypotension and headache. Patients with a < 1°C increase in body temperature eight hours following treatment were less likely to develop subsequent moderate or higher-grade CRS. Consistent with tebentafusp’s hypothesized mode of action, transient increases in peripheral cytokines occurred within hours of treatment administration, and tended to be greater in patients with higher grade CRS. The incidence of CRS following the first dose of tebentafusp appeared to be associated with the greatest reductions in tumour size.

About ImmTAC Molecules

Immunocore’s proprietary T cell receptor (TCR) technology generates a novel class of bispecific biologics called ImmTAC (Immune mobilising monoclonal TCRs Against Cancer) molecules that are designed to redirect the immune system to recognise and kill cancerous cells. ImmTAC molecules are soluble TCRs engineered to recognise intracellular cancer antigens with ultra-high affinity and selectively kill these cancer cells via an anti-CD3 immune-activating effector function. Based on the demonstrated mechanism of T cell infiltration into human tumours, the ImmTAC mechanism of action holds the potential to treat hematologic and solid tumours, regardless of mutational burden or immune infiltration, including immune "cold" low mutation rate tumours.

About Tebentafusp

Tebentafusp is a novel bispecific protein comprised of a soluble T cell receptor fused to an anti-CD3 immune-effector function. Tebentafusp specifically targets gp100, a lineage antigen expressed in melanocytes and melanoma, and is the first molecule developed using Immunocore’s ImmTAC technology platform designed to redirect and activate T cells to recognise and kill tumour cells. Tebentafusp has Fast Track Designation and Orphan Drug Designation in the US and Promising Innovative Medicine designation under the UK Early Access to Medicines Scheme for metastatic uveal melanoma. For more information about enrolling tebentafusp clinical trials for metastatic uveal melanoma, please visit ClinicalTrials.gov (NCT03070392).

About Uveal Melanoma

Uveal melanoma is a rare and aggressive form of melanoma, which affects the eye. Metastatic uveal melanoma typically has a poor prognosis and has no currently accepted optimal management or treatment.[i],[ii] Although it is the most common primary intraocular malignancy in adults, the diagnosis is rare, with approximately 8,000 new patients diagnosed globally each year (1,600-2,000 cases/year in the US).[iii],[iv],[v] Up to 50% of people with uveal melanoma will eventually develop metastatic disease.1,2 When the cancer spreads beyond the eye, only approximately half of patients will survive for one year.[vi]

ASLAN PHARMACEUTICALS ANNOUNCES TOPLINE RESULTS FROM TREETOPP GLOBAL PIVOTAL STUDY OF VARLITINIB IN BILIARY TRACT CANCER

On November 11, 2019 ASLAN Pharmaceuticals (Nasdaq:ASLN, TPEx:6497), a clinical-stage oncology and immunology focused biopharma company, reported topline data from the TreeTopp (TREatmEnT OPPortunity with varlitinib in biliary tract cancer) study in second line biliary tract cancer (BTC) patients (Press release, ASLAN Pharmaceuticals, NOV 11, 2019, View Source [SID1234550867]). Varlitinib did not met the primary endpoints of progression-free survival (PFS) and overall response rate (ORR) as assessed by ICR according to RECIST. The safety findings were consistent with the known profile of varlitinib.

The global, double-blind, randomised two-arm study enrolled 127 patients, who had failed first line therapy, from 56 sites in the US, Europe, Japan, Australia and other Asian countries. The median PFS was 2.83 months for varlitinib in combination with capecitabine arm of the study versus median PFS of 2.79 in the control arm. ORR was 9.4% in the varlitinib arm versus 4.8% in the control arm.

Although the trial did not reach statistical significance, pre-planned exploratory analyses did identify a sub-group which appeared to show improved efficacy. This finding has been supported by retrospective review of the JADETREE study which tested varlitinib in combination with capecitabine in second line BTC patients in China. Further analysis of the data is ongoing.

Dr Carl Firth, Chief Executive Officer of ASLAN Pharmaceuticals, said: "The results from the study are disappointing. They will, however, provide the scientific community with important insights into an aggressive and under-researched disease that presents a growing burden of care worldwide as prevalence rises. I would like to extend our thanks to the patients, trial investigators and site personnel who participated in the study and to the ASLAN team for their commitment to the development of varlitinib. ASLAN remains focused on the promising molecules in its portfolio, including the ongoing study in atopic dermatitis of ASLAN004, our IL-13 receptor antibody which blocks signalling through IL-4 and IL-13. We look forward to the interim readout in early 2020."

About varlitinib

Varlitinib (ASLAN001) is a highly potent, oral, reversible, small molecule pan-HER inhibitor that targets the human epidermal growth factor receptors HER1, HER2 and HER4. These receptors can be mutated or overexpressed in many tumours, which can cause excessive proliferative activity and uncontrolled growth. Therefore, by inhibiting the activation of the HER receptors, varlitinib could inhibit proliferation and control tumour growth. Varlitinib has been granted orphan drug designation in the United States for gastric cancer and cholangiocarcinoma, a sub-type of biliary tract cancer, and was awarded orphan drug designation for the treatment of biliary tract cancer by the Ministry of Food and Drug Safety in South Korea. Varlitinib is currently being tested in combination with paclitaxel in an ongoing investigator-initiated phase 2 umbrella study in second line HER1/HER2 gastric cancer (the K-MASTER study).

Akesobio Presents Phase 1 Clinical Data from First-in-class Bispecific Drug Candidate AK104 (PD1/CTLA4) As Oral Presentation, at 2019 SITC Annual Meeting

On November 11, 2019 Akeso Biopharma ("Akeso") reported that results of phase 1 study of its first-in-class bispecific drug candidate AK104, in patients with advanced solid tumors in 2019 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) ("SITC") (Press release, Akeso Biopharma, NOV 11, 2019, View Source [SID1234550866]). AK104 is a novel, tetrameric bispecific antibody targeting both PD-1 and CTLA-4.

Dr. Ben Markman, MBBS(Hons) FRACP from Monash Health, Australia gave the oral presentation at the SITC (Free SITC Whitepaper) Single Agent Phase 1 Clinical Trials Session chaired by Dr. Helen Chen from National Cancer Institute and Dr. Naiyer Rizvi of Columbia University Medical Center. "AK104 has shown excellent tolerability so far with encouraging signs of anti-tumor activity. I very much look forward to tracking the further development of this exciting tetrameric bispecific antibody targeting PD1 and CTLA4", commented Dr. Ben Markman.

Updated results from Phase 1a study (NCT03261011):

AK104 showed encouraging anti-tumor activities across a range of tumor types.
– Among 25 PD-1/L1 naïve response-evaluable patients administrated with ≥ 2 mg/kg AK104, ORR: 24% ( DoR ranging from 2+ to 11.1+ months); DCR: 44%.
AK104 had an acceptable safety profile. Early data suggested that AK104 may have improved tolerance compared with the combination of a PD-1 inhibitor and CTLA-4 inhibitor.
– With 55 patients enrolled, most common treatment-related AE includes rash, infusion reaction, nausea, and fatigue.
– ≥ Grade 3 treatment-related AE (TRAE) rate was 11% with only one Grade 4 event reported. Grade 3 immune-related AE (irAE) rate was 3.6%.
AK104 commenced a Phase 1a study in patients with advanced solid tumors in Australia in October 2017, received NMPA IND approval in May 2018, and IND approval from the FDA in April 2019. AK104 is currently in Phase Ib/II clinical trials globally for multiple indications and has exhibited promising clinical safety and efficacy results in monotherapy and combination therapy.

Details of the material used in oral presentation can be found at SITC (Free SITC Whitepaper) website.

About AK104

AK104 is a potential next-generation, first-in-class humanized IgG1 tetrameric bi-specific antibody drug candidate that is based on Akeso’s proprietary "TETRABODY" technology and simultaneously targets two immune checkpoint molecules: PD-1 and CTLA-4. PD-1 and CTLA-4 co-express in tumor infiltrating lymphocytes (TILs), but not in normal peripheral tissues. AK104 is in a tetrameric form, which is designed to bind to PD-1 and CTLA-4 simultaneously to achieve the efficacy of PD-1 and CTLA-4 combination blockade with lowered toxicity.

New Chief Medical Officer Comes to UH Seidman Cancer Center from Dana-Farber Cancer Institute

On November 11, 2019 A quality expert and lead oncology hospitalist from the Dana-Farber Cancer Institute in Boston – the principal teaching affiliate for Harvard Medical School and one of the nation’s highest-ranked cancer hospitals – is the new Chief Medical Officer of University Hospitals Seidman Cancer Center (Press release, University Hospitals, NOV 11, 2019, View Source [SID1234550865]).

Brett Glotzbecker, MD, brings 15 years of experience at Brigham and Women’s Hospital/Dana-Farber Cancer Institute. As an assistant professor at Harvard Medical School, Dr. Glotzbecker was honored with awards from the Dana-Farber/Harvard Cancer Center for excellence in teaching and quality achievement. She had been the principal investigator on multiple funded projects, most recently to compare outcomes for hematopoietic cell transplant patients and another to improve communication toward a more efficient discharge process.

"The UH Seidman Cancer Center family is so fortunate to have attracted a physician leader of Dr. Glotzbecker’s stature. Her expertise in patient experience, quality and clinical care delivery will help us achieve our stated goal of being the US leader in value based cancer care," said Theodoros N. Teknos, MD, President and Scientific Director of UH Seidman Cancer Center.

Dr. Glotzbecker received her medical degree and a bachelor’s degree in bioengineering from the University of Pennsylvania in Philadelphia. She completed her residency in internal medicine and her clinical/research fellowship in hematology and medical oncology from Beth Israel Deaconess Medical Center in Boston.

As Chief Medical Officer, Dr. Glotzbecker will oversee quality and the patient experience for all disease teams and tumor conferences, providing focused leadership for achieving all key certifications. She will be the senior physician liaison for cancer practitioners throughout the system. Dr. Glotzbecker will work closely with Nursing, Medical Staff and Quality. As a physician of University Hospitals Medical Group and the Department of Medicine Division of Hematology and Oncology, Dr. Glotzbecker also will provide inpatient clinical care or other care, such as consults, tumor boards and call coverage.

Replimune Reports Second Fiscal Quarter Financial Results and Provides Corporate Update

On November 11, 2019 Replimune Group Inc. (Nasdaq: REPL), a biotechnology company developing oncolytic immuno-gene therapies derived from its Immulytic platform, reported financial results for its second fiscal quarter, ended September 30, 2019, and provided a corporate update (Press release, Replimune, NOV 11, 2019, View Source [SID1234550863]).

"It has been a very productive and exciting period for Replimune," said Robert Coffin, Ph.D., President and CEO of Replimune. "The highlight was the SITC (Free SITC Whitepaper) 2019 presentation of RP1 clinical data which confirmed the expected mechanism of action, initial safety profile, and evidence of anti-tumor efficacy providing strong support for our ongoing and expanded programs in CSCC and melanoma. Based directly on this data, the decision was taken to conduct a new clinical trial in solid organ transplant patients with CSCC and in melanoma patients who are refractory to prior treatment with anti-PD1 directed therapy. We were also very pleased to have initiated the first clinical trial of our second clinical product candidate, RP2. Overall we are thrilled with Replimune’s progress in the quarter and excited for the future as we continue to execute upon our mission to make our oncolytic immuno-gene therapies a cornerstone of cancer treatment."

Recent Business Highlights and Upcoming Events

RP1 – Presented initial data from the Phase 1/2 clinical trial of RP1 alone and in combination with Opdivo at SITC (Free SITC Whitepaper) 2019. The data presented demonstrated that RP1 used alone and in combination with Opdivo is well tolerated and showed clear anti-tumor efficacy in target tumor types that provides strong support for Replimune’s ongoing and planned development programs in melanoma and CSCC. This clinical trial is being conducted under a clinical trial collaboration and agreement with Bristol Myers Squibb (BMS) for the supply of Opdivo.

RP1 – Initiated the registration-directed Phase 2 clinical trial of RP1 in combination with Libtayo in CSCC. This multi-center, randomized, controlled clinical trial is intended to enroll approximately 240 patients with CSCC. The clinical trial’s primary objective is to compare the response rate following treatment with RP1 in combination with Libtayo to the response rate achieved with Libtayo alone. Libtayo is an FDA-approved anti-PD-1 therapy developed by Regeneron and Sanofi for the treatment of patients with metastatic or locally-advanced CSCC who are not candidates for curative surgery or radiation. This clinical trial is being conducted under the Company’s collaboration agreement with Regeneron, whereby the Company and Regeneron will split equally development and supply costs. Recruitment into this clinical trial is expected to take approximately 18 to 24 months.

RP1 – Recruitment ongoing in the Phase 2 part of the Phase 1/2 trial of RP1 in combination with Opdivo. The Phase 2 part of the clinical trial is currently enrolling 30-patient cohorts of patients with melanoma, non-melanoma skin cancers, metastatic bladder cancer and microsatellite instability high (MSI-H) tumors.

RP1 – New clinical trial planned of RP1 as monotherapy in organ transplant recipients with CSCC. CSCC represents a significant unmet medical need in organ transplant recipients where it is the most prevalent tumor type in a population at higher risk for malignancy in general, and where anti-PD-1 therapy provides a significant risk of rejection of the transplanted organ. The U.S. Food and Drug Administration (FDA) has accepted the protocol for this clinical trial under the Company’s previously accepted Investigational New Drug Application for RP1. The clinical trial is intended to enroll approximately 30 patients and assess the safety and efficacy of RP1 in liver and kidney transplant recipients with recurrent CSCC. Replimune expects to initiate the clinical trial in the first quarter of 2020.

RP1 – Additional clinical trial intended of RP1 in combination with an anti-PD-1 therapy in anti-PD-1 refractory melanoma patients. Based on the clinical efficacy data to date with RP1 in melanoma, the Company has decided to conduct a new clinical trial of RP1 in combination with an anti-PD-1 therapy in anti-PD-1 refectory melanoma patients. Discussions are underway to determine the particular anti-PD-1 therapy to be used. The trial is expected to begin enrollment in 2020.

RP2 – Initiation of the Phase 1 clinical trial of RP2 alone and in combination with Opdivo. RP2 is based on RP1 but additionally expresses a genetically encoded anti-CTLA-4 antibody-like molecule. The addition of anti-CTLA-4 is intended to block the inhibition of the initiation of immune responses otherwise caused by CTLA-4. The clinical trial is designed to assess the safety, tolerability and to determine the optimal dose of RP2 alone and in combination with Opdivo and is being conducted under a clinical trial collaboration and agreement with BMS for the supply of Opdivo.

RP3 – The Phase 1 clinical trial of RP3 alone and in combination with an anti-PD1 therapy remains on track to initiate in 2020. RP3 is a further armed oncolytic immuno-gene therapy which expresses two immune co-stimulatory activating ligands (CD40L and 4-1BBL) in addition to the GALV-GP R- fusogenic protein and anti-CTLA-4.

Build-out of Replimune’s manufacturing facility to support late-stage development and commercialization remains on schedule. The 63,000-square-foot facility in Framingham, MA is intended to provide multi-product manufacturing capabilities for Replimune’s Immulytic product candidates. The capacity of this facility will be sufficient to support full commercialization of the Company’s product candidates. An occupancy certificate for the facility has been obtained and technology transfer is underway.
Financial Highlights

Replimune reported a net loss of $11.1 million for the quarter ended September 30, 2019 compared with $6.5 million for the same period in the prior year.

Research and development expenses for the quarter ended September 30, 2019 were $8.2 million compared with $5.0 million for the same period in the prior year. The increase in research and development expenses was primarily driven by additional costs related to Replimune’s preclinical and clinical development activities for its pipeline.

General and administrative expenses for the quarter ended September 30, 2019 were $4.1 million compared with $2.1 million for the same period in the prior year. The increase in general and administrative expenses was primarily due to an increase in employee headcount, professional fees and facility costs.

Replimune ended the quarter with $109.9 million in cash, cash equivalents, and short-term investments, compared with $134.8 million as of March 31, 2019.

Based on its current operating plan, Replimune expects that its current cash, cash equivalents, and short-term investments will enable it to fund its operating expenses and capital expenditure requirements into the second half of calendar year 2021.