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Gracell Data on Multi-center Investigation of FasT CAR-19 Therapy Shows Positive First Impact in Patients with Relapsed or Refractory B-cell Acute Lymphoblastic Leukemia

On June 20, 2019 Gracell Biotechnologies Co., Ltd. ("Gracell"), a clinical-stage cellular immunotherapy company, reported preliminary results of a multi-center pilot study designed for evaluating the safety and efficacy of Gracell’s patented FasT CAR-19 (GC007F) investigational cell gene therapy (Press release, Gracell Biotechnologies, JUN 20, 2019, View Source [SID1234539455]). The customized treatment which genetically modifies patient’s T-cells to express CD19-specific chimeric antigen receptor (CAR), showed a clinically meaningful and positive result in the treatment of B-cell acute lymphoblastic leukemia (B-ALL). The results of the study were announced during the CAR-TCR Summit Asia, held June 18-20, 2019 in Shanghai.

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B-ALL is a sub-type of ALL, a cancer of the lymphoid line of blood cells. For a vast number of patients, B-ALL can be treated by chemotherapy and stem cell transplant. However, for the many patients who develop relapsed or refractory (r/r) B-ALL, significant complications in treatment remain. With characteristically low life expectancy, r/r B-ALL is one of the most devastating forms of malignancies. Anti-CD19 CAR-T products have been developed specifically for these late-stage patients.

Currently approved anti-CD19 CAR-T bioprocessing takes on average two weeks to manufacture and seven days to pass quality test. With Gracell’s FasT CAR solution, preparation time can be cut to 24 hours, significantly reducing production cost and waiting time. In addition, FasT CAR can be administered vein-to-vein (time from when cells are extracted to when they are infused back into the patient) within seven days after leukapheresis, providing substantial meaning and significant benefitto physicians and patients.

With a manufacturing success rate of 19/19 (100%) without patient loss, FasT CAR-19 cells are considered much more potent and durable in comparison to currently available alternatives. With these advantages, FasT CAR-19 is highly cost-effective and has considerable potential to establish a new standard in CAR-T treatment for r/r B-ALL.

The multi-center investigational study enrolled 19 adolescent and adult patients aged from 14 to 70 years, who suffered from relapsed or refractory B-ALL and had failed to respond to multiple prior lines of therapy. As of June 12, all patients received a single infusion of FasT CAR-19 following lymphodepleting chemotherapy. FasT CAR-19 was administered at three dose levels from low to high, equivalent to 1/30-1/10 of the standard CAR-T therapy dose, respectively.

The treatment efficacy was assessed in 16 patients, of which:

16 (100%) achieved complete remission with or without complete blood count recovery (CR/CRi);
14 (87%) achieved undetectable minimal residual disease (uMRD) (< 10-4 detectable leukemic cells in bone marrow);
15 (94%) experienced an ongoing response by June 12. Notably, one adolescent patient achieved CR and uMRD after 28 days of regular follow-up treatment, turned MRD positive at week 12, and converted back to uMRD again at week 20 with the ongoing response status remaining up to June 12.
During the over six month-durable remission period, FasT CAR-19 demonstrated a good level of persistence. In terms of safety, all 19 patients tolerated the single infusion of FasT CAR-19 at different dose levels, with no dose-limiting toxicities observed. The most common safety concerns were cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) where mild to moderate side effects were observed. In comparison to the high dose group, patients administered low to middle dose levels experienced mild adverse events. Across 14 patients in the low to mid doses group, only 2 (14%) Grade 3 CRS and 1 (7%) manageable Grade 3 ICANS were reported; while in the 4 patients of the high dose group, there were 3 (75%) Grade 3 CRS and 2 (50%) Grade 1-2 ICANS.

"We are very excited to see that the patients with relapsed or refractory B-ALL in this study gained substantial clinical benefit from FasT CAR-19," said CEO Dr. William CAO. "Although the potential of FasT CAR technology is yet to be unlocked, the results of this study have enhanced our confidence to move on with dose expansion studies and to apply FasT CAR to products for various indications, including multiple myeloma and non-Hodgkin lymphoma. We are eager to see Gracell’s highly efficacious, but affordable FasT CAR-T therapies benefit patients globally."

About FasT CAR-19

FasT CAR-19, or GC007F, is an investigational CD19-targeted CAR-T cell therapy for adolescent and adult patients with relapsed or refractory B-ALL, as well as aggressive non-Hodgkin lymphoma. Thanks to Gracell’s patented FasT CAR technology, the bioprocessing of GC007F has been significantly reduced to 24 hours with substantially lower cost. The younger and less exhausted T cell phenotype exhibited superior proliferation capabilities, potency, and extensive bone marrow migration making GC007F a potential best-in-class therapy for relapsed or refractory B-ALL.

About ALL

Acute lymphoblastic leukemia, although rare, is one of the most common forms of cancer in children between the ages of two and five and adults over the age of 50[1]. In 2015, ALL affected around 876,000 people globally and resulted in 110,000 deaths worldwide[2]. It is also the most common cause of cancer and death from cancer among children. ALL is typically treated initially with chemotherapy aimed at bringing about remission. This is then followed by further chemotherapy carried out over several years.

Verastem Oncology Announces Leadership Changes

On June 20, 2019 Verastem, Inc. (Nasdaq: VSTM) (Verastem Oncology or the Company), a biopharmaceutical company focused on developing and commercializing medicines seeking to improve the survival and quality of life of cancer patients, reported that Robert Forrester has decided to step down as President and Chief Executive Officer (Press release, Verastem, JUN 20, 2019, View Source [SID1234537274]). Mr. Forrester has agreed to continue serving Verastem Oncology in an advisory capacity.

Dan Paterson, the Company’s Chief Operating Officer, has been appointed to serve as President and Chief Operating Officer and will assume the leadership of the executive team while the Board of Directors conducts a search to identify a successor. Mr. Paterson will be supported by other members of the senior leadership team, including Chief Financial Officer, Rob Gagnon, whose role is being expanded to include Chief Business Officer.

Mr. Paterson joined Verastem Oncology in 2011 and has served as its Chief Operating Officer since 2014. He brings more than 25 years of experience at healthcare and biotechnology companies, including leadership roles as Chief Business Officer (CBO), Chief Operating Officer (COO) and Chief Executive Officer (CEO), with specific expertise in oncology drug and diagnostic product development, business development and launch planning.

"On behalf of the entire Board, I want to thank Robert for his countless contributions and leadership for the past six years and his unwavering commitment to Verastem Oncology’s patients, employees and shareholders," said Michael G. Kauffman, MD, PhD, Verastem Oncology’s Lead Director. "We remain confident in the growth potential of COPIKTRA and we intend to hire a CEO with commercial expertise who will build on the foundation that Robert has established and execute on our ambitious goals for the future."

"With COPIKTRA, the experienced team and the resources we have in place, we are in a strong position to continue executing on our mission to improve outcomes for patients," said Mr. Paterson. "I look forward to working closely with the Company’s Board, executive leadership, and the broader management team to accelerate the COPIKTRA launch and the future expansion of this important medicine into other hematologic malignancy indications."

"It has been a true honor to serve as the CEO of Verastem Oncology over the past six years," said Mr. Forrester. "I am extremely proud of the Verastem Team, the progress we have made, and our many accomplishments aimed at improving the lives of patients diagnosed with cancer, one patient at a time. I have great confidence in Verastem Oncology’s potential and I will work with the entire team to ensure a seamless transition for all of our stakeholders."

The Company is reiterating its previously issued financial guidance for the full year 2019. The Company continues to expect net product revenue from the sales of COPIKTRA to be in the range of $10-12 million, based on product revenue to date, current run rates and near-term expectations.

Progenics Pharmaceuticals to Initiate a Basket Trial by Year End to Support an Expanded Label for AZEDRA® (iobenguane I 131) in Multiple MIBG Avid Neuroendocrine Tumors

On June 20, 2019 Progenics Pharmaceuticals, Inc. (NASDAQ:PGNX) ("Progenics" or the "Company"), an oncology company developing innovative targeted medicines and artificial intelligence to find, fight and follow cancer, reported that the Company has reached alignment with the U.S. Food and Drug Administration (FDA) on the clinical development plan to pursue a tissue agnostic indication to support an expanded label for AZEDRA (iobenguane I 131) for the treatment of patients with unresectable or metastatic neuroendocrine tumors (NETs) who are MIBG avid (Press release, Progenics Pharmaceuticals, JUN 20, 2019, View Source [SID1234537205]). Following a Type B meeting with the FDA, the Company plans to conduct a basket study that will evaluate AZEDRA in patients with NETs that are MIBG avid, including gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and other NETs, with a dosing regimen that potentially enables outpatient administration. AZEDRA is the first and only approved therapy in the U.S. for the treatment of adult and pediatric patients 12 years and older with iobenguane (MIBG) scan positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma who require systemic anticancer therapy.

NETs are a group of rare tumors of neural crest origin, most commonly found in the gastrointestinal or respiratory tracts, although they may also be found in the central nervous system, thyroid gland, skin, breast, colon, and urogenital system, including prostate cancer, among other locations. NETs overexpress the norepinephrine reuptake transporter on their cell surface. MIBG is a known substrate for the transporter and, therefore, MIBG avidity can be used to enrich for patients who are most likely to respond to AZEDRA therapy. NETs are considered rare tumors, although the incidence has continued to increase in the last 10-15 years, with approximately 12,000 patients being diagnosed in the U.S. each year.

"Following our productive discussions with the FDA, we have a clear path forward to expand the reach of AZEDRA to patients with other MIBG avid NETs who have failed or are ineligible for available therapies which represents a very high unmet need," said Mark Baker, Chief Executive Officer of Progenics. "Should this trial support an expanded label, we believe there is the potential to increase by many multiples the size of the commercial market of AZEDRA. We expect to initiate our AZEDRA basket study by the end of the year, reinforcing our commitment to rapidly advance our portfolio of life-saving radiopharmaceutical oncology treatments."

"In an effort to expedite late stage oncology drug development, FDA has recently provided guidance on a type of trial design that tests a single drug in different tumor types defined by genetic or other biomarkers," said Asha Das, MD, Chief Medical Officer. "We have received strong interest from key opinion leaders in using this study design to evaluate AZEDRA in multiple NET subtypes defined by MIBG avidity, especially with a dosing regimen that potentially enables outpatient administration."

The basket study is expected to enroll approximately 120 patients at sites in the U.S. Progenics plans to initiate the study by the end of 2019.

About AZEDRA

Indication

AZEDRA (iobenguane I 131) is indicated for the treatment of adult and pediatric patients 12 years and older with iobenguane scan positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma who require systemic anticancer therapy.

Important Safety Information

Warnings and Precautions:

Risk from Radiation Exposure: AZEDRA contributes to a patient’s overall long-term radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. These risks of radiation associated with the use of AZEDRA are greater in pediatric patients than in adults. Minimize radiation exposure to patients, medical personnel, and household contacts during and after treatment with AZEDRA consistent with institutional good radiation safety practices and patient management procedures.

Myelosuppression: Among the 88 patients who received a therapeutic dose of AZEDRA, 33% experienced Grade 4 thrombocytopenia, 16% experienced Grade 4 neutropenia, and 7% experienced Grade 4 anemia. Five percent of patients experienced febrile neutropenia. Monitor blood cell counts weekly for up to 12 weeks or until levels return to baseline or the normal range. Withhold and dose reduce AZEDRA as recommended in the prescribing information based on severity of the cytopenia.

Secondary myelodysplastic syndrome, leukemia, and other malignancies: Myelodysplastic syndrome (MDS) and acute leukemias were reported in 6.8% of the 88 patients who received a therapeutic dose of AZEDRA. The time to development of MDS or acute leukemia ranged from 12 months to 7 years. Two of the 88 patients developed a non-hematological malignancy.

Hypothyroidism: Hypothyroidism was reported in 3.4% of the 88 patients who received a therapeutic dose of AZEDRA. Initiate thyroid-blocking medications starting at least 1 day before and continuing for 10 days after each AZEDRA dose to reduce the risk of hypothyroidism or thyroid neoplasia. Evaluate for clinical evidence of hypothyroidism and measure thyroid-stimulating hormone (TSH) levels prior to initiating AZEDRA and annually thereafter.

Elevations in blood pressure: Eleven percent of the 88 patients who received a therapeutic dose of AZEDRA experienced a worsening of pre-existing hypertension defined as an increase in systolic blood pressure to ≥160 mmHg with an increase of 20 mmHg or an increase in diastolic blood pressure to ≥ 100 mmHg with an increase of 10 mmHg. All changes in blood pressure occurred within the first 24 hours post infusion. Monitor blood pressure frequently during the first 24 hours after each therapeutic dose of AZEDRA.

Renal toxicity: Of the 88 patients who received a therapeutic dose of AZEDRA, 7% developed renal failure or acute kidney injury and 22% demonstrated a clinically significant decrease in glomerular filtration rate (GFR) measured at 6 or 12 months. Monitor renal function during and after treatment with AZEDRA. Patients with baseline renal impairment may be at greater risk of toxicity; perform more frequent assessments of renal function in patients with mild or moderate impairment. AZEDRA has not been studied in patients with severe renal impairment.

Pneumonitis: Fatal pneumonitis occurred 9 weeks after a single dose in one patient in the expanded access program. Monitor patients for signs and symptoms of pneumonitis and treat appropriately.

Embryo-fetal toxicity: Based on its mechanism of action, AZEDRA can cause fetal harm. Verify pregnancy status in females of reproductive potential prior to initiating AZEDRA. Advise females and males of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with AZEDRA and for 7 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the final dose.

Risk of infertility: Radiation exposure associated with AZEDRA may cause infertility in males and females. Radiation absorbed by testes and ovaries from the recommended cumulative dose of AZEDRA is within the range where temporary or permanent infertility can be expected following external beam radiotherapy.

Adverse Reactions:

The most common severe (Grade 3–4) adverse reactions observed in AZEDRA clinical trials (≥ 10%) were lymphopenia (78%), neutropenia (59%), thrombocytopenia (50%), fatigue (26%), anemia (24%), increased international normalized ratio (18%), nausea (16%), dizziness (13%), hypertension (11%), and vomiting (10%). Twelve percent of patients discontinued treatment due to adverse reactions (thrombocytopenia, anemia, lymphopenia, nausea and vomiting, multiple hematologic adverse reactions).

Drug Interactions:

Based on the mechanism of action of iobenguane, drugs that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells and therefore interfere with dosimetry calculations or the efficacy of AZEDRA. These drugs were not permitted in clinical trials that assessed the safety and efficacy of AZEDRA. Discontinue the drugs listed in the prescribing information for at least 5 half-lives before administration of either the dosimetry dose or a therapeutic dose of AZEDRA. Do not administer these drugs until at least 7 days after each AZEDRA dose.

Medicenna Presents New Preclinical Results For its IL-2 Superkine Platform, MDNA109

On June 20, 2019 Medicenna Therapeutics Corp. ("Medicenna" or "the Company") (TSX: MDNA,OTCQB: MDNAF), a clinical stage immunotherapy company developing first-in-class Superkines and Empowered Cytokines, presented new pre-clinical data on its IL-2 Superkine program, MDNA109 (Press release, Medicenna Therapeutics, JUN 20, 2019, View Source [SID1234537203]). The data was presented in a poster entitled "Engineering a long-acting CD122 biased IL-2 superkine displaying potent anti-tumoral responses" at the Inaugural Immuno-Oncology Pharma Congress, held from June 18-20, 2019 during World Pharma Week in Boston, MA.

"We are excited with the pre-clinical results from our second oncology platform being built around MDNA109, on the back of promising clinical results from our Phase 2b MDNA55 recurrent glioblastoma trial presented this week at the same conference," said Dr. Fahar Merchant, President and CEO of Medicenna. "Unlike other engineered versions of IL-2 under development where both CD25 and, to a lower extent, CD122 activity is masked when compared to recombinant IL-2 (marketed as Proleukin), our long acting MDNA109 variant has disabled CD25 binding but stimulates potent CD122 activity relative to Proleukin. Disabled CD25 activity provides a much better safety profile while superior CD122 stimulation ensures potent recruitment of immune cells (Effector T cells and NK cells) responsible for attacking cancer," added Dr. Merchant.

Highlights from the presentation by Dr. Moutih Rafei, Associate Professor in the Department of Pharmacology and Physiology at the Université de Montreal and Head of Discovery at Medicenna, included the following

Durable Tumor Control With Strong Memory Response: When MDNA109-LA was co-administered with the immune-checkpoint blocker anti-cytotoxic T-Lymphocyte-Associated Protein (CTLA)4 in a colon cancer mouse model, 67% of animals with pre-established tumors remained tumor-free for over 100 days. When these animals received a second and third re-challenge of the tumor without further treatment, 100% and 75% remained tumor free, respectively, demonstrating a strong memory response.
Blunted Treg Activity But Potent Activation Of Naïve CD8 T Cells: A long-acting variant, MDNA109-LA1, engineered to mitigate Treg activation by abolishing binding to the CD25 had 50-fold decreased Treg activity and 6-fold higher activity towards naïve CD8 T cells for an overall 300-fold preferential activation of cancer killing T cells than recombinant IL-2.
Absence Of CD25 Binding: In addition, binding affinity studies using surface plasmon resonance confirmed absence of CD25 binding by MDNA109-LA1.
Potent Effects With Minimal Dosing: To further validate the potency of MDNA109-LA1 mice with pre-established aggressive B16F10 melanoma tumors showed potent tumor control with a weekly dosing schedule.
"These data show that MDNA109 long-acting variants can be expected to drive clinical efficacy beyond that seen with other treatments," states Dr. Rafei, "The use of Proleukin for the treatment of skin and renal cancer remains limited due to the poor half-life and severe toxicity. Data show that MDNA109-LA1 may not only minimize adverse effects, but could also eliminate immunosuppression caused by Tregs using a dosing schedule that is compatible with immune-checkpoint blockers. It’s clear from these recent data that MDNA109 is a highly versatile platform for multiple uses in immuno-oncology without complex manufacturing and lack of immunogenicity as demonstrated by in-silico analysis.

About MDNA109
Developed by scientists at Stanford University, MDNA109 is an engineered version of IL-2 that binds up to 200 times more effectively to IL-2Rβ (CD122), thus greatly increasing its ability to activate and proliferate the immune cells needed to fight cancer. MDNA109 is an IL-2 Superkine that preferentially drives the expansion and responses of effector T cells and Natural Killer (NK) cells over Treg cells. It is the only IL-2 in development with a distinct mechanism by virtue of its high affinity towards CD122 allowing it to effectively combat NK cell anergy (exhaustion) which occurs frequently after cancer immunotherapy.

Syntrix Pharmaceuticals Announces Dosing of First Patient in Phase 1/2 Clinical Trial of SX-682 in Combination with KEYTRUDA® (pembrolizumab) in Metastatic Melanoma

On June 20, 2019 Syntrix Pharmaceuticals reported that it has dosed the first patient in its Phase 1/2 clinical trial that will combine SX-682 with KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy (Press release, Syntrix, JUN 20, 2019, View Source [SID1234537202]). SX-682 is an oral dual inhibitor of CXCR1 and CXCR2 (CXCR1/2) being developed for the treatment of cancer.

This open-label clinical trial will evaluate the safety, tolerability, immune response markers, and overall response rates achieved with SX-682 in combination with KEYTRUDA in up to 77 patients with metastatic melanoma. The study is being conducted at the Massachusetts General Hospital and Dana-Farber Cancer Institute.

Patients will receive daily SX-682 monotherapy for three weeks followed by treatment with daily SX-682 in combination with KEYTRUDA. The study will evaluate biomarkers identified from paired biopsies taken before and after the three-weeks of monotherapy and combination treatments, as well as clinical outcomes observed over the course of the trial. Syntrix expects to report initial clinical data from the trial in the first half of 2020.

"CXCR1/2 is involved in virtually all human tumor types, where it suppresses anti-tumor immunity," said Stuart Kahn, MD, chief medical officer at Syntrix. "This clinical trial will allow us to explore the potential synergies between SX-682 and KEYTRUDA and offers the potential to treat metastatic melanoma that is otherwise poorly responsive to checkpoint inhibitors."

In preclinical studies, SX-682 enhances both PD-1 immune checkpoint blockade and T cell receptor engineered T cell immunotherapies (JCI Insight, Nature and Cancer Cell). Effects include a reduction of myelosuppressive cells in the tumor microenvironment and augmentation of NK and T cell infiltration into the tumor site. Clinical studies show an inverse correlation between CXCR1/2 ligands in the blood and survival of patients treated with anti-PD1 therapy.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

ABOUT SX-682: SX-682 is a clinical-stage oral allosteric small-molecule inhibitor of CXCR1 and CXCR2 (CXCR1/2). CXCR1/2 are a combined "master switch" of the immunosuppressive tumor microenvironment. Clinical studies have shown an inverse correlation between blood CXCR1/2 ligands and anti-PD1 response and survival. SX-682 has been validated in major solid tumor models, where it exhibits mono-agent activity, blocks metastasis, depletes MDSCs, activates infiltration and killing by immune effector cells, reverses chemo-resistance, and enhances anti-PD1.