On June 4, 2018 Blueprint Medicines Corporation (NASDAQ:BPMC), a leader in discovering and developing targeted kinase medicines for patients with genomically defined diseases, and CStone Pharmaceuticals, a privately-held biopharmaceutical company devoted to developing a new generation of innovative drugs, reported an exclusive collaboration and license agreement for the development and commercialization of avapritinib, BLU-554 and BLU-667 in Mainland China, Hong Kong, Macau and Taiwan, either as monotherapies or combination therapies (Press release, Blueprint Medicines, JUN 4, 2018, View Source;p=irol-newsArticle&ID=2352948 [SID1234527134]). Discovered and developed by Blueprint Medicines, avapritinib, BLU-554 and BLU-667 are potent and highly selective investigational kinase medicines that have each demonstrated clinical proof-of-concept in genomically defined subsets of patients with cancer. Blueprint Medicines will retain all rights to the licensed products in the rest of the world.

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The collaboration strengthens CStone Pharmaceuticals’ portfolio with exclusive rights in the territory to three clinical-stage targeted therapies and expands Blueprint Medicines’ global efforts to address patient populations with high unmet needs. CStone Pharmaceuticals will lead clinical development of the licensed products in the territory by leveraging its regulatory expertise and broad local network, with the goal of commercializing the licensed products in the territory either as monotherapies or combination therapies. In addition, the companies plan to initiate a proof-of-concept clinical trial in China evaluating BLU-554 in combination with CS1001, a clinical-stage anti-programmed death ligand-1 (PD-L1) immunotherapy being developed by CStone Pharmaceuticals, as a first-line therapy for patients with hepatocellular carcinoma (HCC).

"Founded by seasoned executives with deep global and regional development experience and with a growing portfolio of potentially complementary cancer therapies, CStone Pharmaceuticals is an ideal partner in China," said Jeff Albers, Chief Executive Officer of Blueprint Medicines. "With recent regulatory reforms in China and the emergence of innovative companies like CStone Pharmaceuticals, we believe this forward-looking collaboration has the potential to expand our ability to address significant patient needs in Greater China while supporting global development of avapritinib, BLU-554 and BLU-667. In particular, we are excited to announce the expansion of the BLU-554 clinical development program in China, where more than half of all new cases of hepatocellular carcinoma worldwide occur each year."

"We are thrilled to enter into this collaboration with Blueprint Medicines, a leader in the discovery and development of highly selective kinase medicines, as the first step in a potentially long-term strategic partnership," said Frank Jiang, Chief Executive Officer of CStone Pharmaceuticals. "Based on the compelling clinical data reported to date, we believe Blueprint Medicines’ targeted therapies – avapritinib, BLU-554 and BLU-667 – hold promise for dramatically altering the treatment landscape for patients in China with gastrointestinal stromal tumors, hepatocellular carcinoma, non-small cell lung cancer and other cancers. In addition, our rich pipeline of investigational cancer medicines enables exploration of combination treatment approaches with the potential to further improve patient outcomes worldwide."

Subject to the terms of the agreement, Blueprint Medicines will receive an upfront cash payment of $40.0 million and will be eligible to receive up to approximately $346.0 million in potential milestone payments, including $118.5 million related to development and regulatory milestones and $227.5 million related to sales-based milestones. In addition, CStone Pharmaceuticals will be obligated to pay Blueprint Medicines tiered percentage royalties on a licensed product-by-licensed product basis ranging from the mid-teens to low twenties on annual net sales of each licensed product in the territory, subject to adjustment in specified circumstances.

Pursuant to the terms of the agreement, CStone Pharmaceuticals will be responsible for conducting all development and commercialization activities in the territory related to the licensed products. In addition, CStone Pharmaceuticals will be responsible for costs related to the development of the licensed products in the territory, other than specified costs related to the development of BLU-554 as a combination therapy in the territory that will be shared by the companies.

About Avapritinib

Avapritinib is an orally available, potent and highly selective inhibitor of KIT and PDGFRα. Preclinical data have shown that avapritinib is active across a broad spectrum of KIT and PDGFRα mutations, including KIT D816V, PDGFRα D842V and KIT exon 17 mutations, for which there are limited or no effective treatment options. Blueprint Medicines is initially developing avapritinib, an investigational medicine, for the treatment of patients with advanced gastrointestinal stromal tumors (GIST) and advanced systemic mastocytosis.

In June 2017, avapritinib received Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA) for the treatment of patients with unresectable or metastatic GIST harboring the PDGFRα D842V mutation. Previously, the FDA granted orphan drug designation and fast track designation to avapritinib. In addition, the European Commission has granted orphan drug designation to avapritinib. In May 2018, Blueprint Medicines announced plans to submit a New Drug Application to the FDA for avapritinib for the treatment of PDGFRα D842V-driven GIST in the first half of 2019.

About BLU-554

BLU-554 is an orally available, potent, irreversible inhibitor of FGFR4. BLU-554 was specifically designed by Blueprint Medicines to inhibit FGFR4 with exquisite selectivity, thereby sparing the paralogs FGFR1, FGFR2 and FGFR3. Blueprint Medicines is developing BLU-554, an investigational medicine, for the treatment of patients with FGFR4-activated HCC. Blueprint Medicines estimates that approximately 30 percent of patients with HCC have tumors with aberrantly activated FGFR4 signaling. The FDA has granted orphan drug designation to BLU-554.

About BLU-667

BLU-667 is an orally available, potent and highly selective inhibitor designed to target RET fusions, mutations and predicted resistance mutations. Blueprint Medicines is developing BLU-667, an investigational medicine, for the treatment of patients with RET-altered non-small cell lung cancer (NSCLC), medullary thyroid cancer and other solid tumors. BLU-667 was discovered by Blueprint Medicine’s research team leveraging its proprietary compound library. The FDA has granted orphan drug designation to BLU-667.

About CS1001

CS1001 is an investigational monoclonal antibody directed against PD-L1 being developed by CStone Pharmaceuticals. Authorized by the U.S.-based Ligand Corporation, CS1001 is a monoclonal antibody developed by the OMT transgenic animal platform, which can generate fully human antibodies in one step. As a fully human, full-length anti-PD-L1 monoclonal antibody, CS1001 mirrors natural G-type immune globulin 4 (IgG4) human antibody, which could reduce the risk of immunogenicity and potential toxicities in patients, a unique advantage over similar drugs.

A first-in-human Phase I study (CS1001-101) has been conducted by CStone Pharmaceuticals since October 2017 to evaluate the safety, tolerability, pharmacokinetics and anti-tumor activity of CS1001 in patients with advanced tumors in China. The Phase Ia (dose escalation) portion was completed in May 2018, and the Phase Ib (dose expansion) portion has recently started patient recruitment. In parallel, several pivotal studies are underway, including tumor types with high incidence and prevalence rates in China.

On June 4, 2018 Merck KGaA, Darmstadt, Germany, which operates its biopharmaceutical business as EMD Serono in the US and Canada, and Pfizer Inc. (NYSE: PFE) reported that updated efficacy and safety data from the pivotal JAVELIN Merkel 200 trial of BAVENCIO (avelumab) in patients with metastatic Merkel cell carcinoma (mMCC), will be presented as an oral abstract session at the 54th American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting on Monday, June 4 from 10:12-10:24 a.m. CDT in Chicago, IL (Press release, Pfizer, JUN 4, 2018, View Source [SID1234527150]). At this two year follow-up update of the pivotal study, BAVENCIO continues to demonstrate clinically meaningful durable responses and stable rates of progression-free survival (PFS) and overall survival (OS) from previous analyses in patients who responded to this treatment. Clinical activity was observed across all patient subgroups, irrespective of PD-L1 expression in tumor tissue or Merkel cell polyomavirus status. The safety profile for BAVENCIO in this trial has not changed with longer follow-up and remains consistent with that observed in the overall JAVELIN clinical development program.

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"These efficacy and safety results build upon the data that supported our FDA approval," said Luciano Rossetti, M.D., Executive Vice President, Global Head of Research & Development at the Biopharma business of Merck KGaA, Darmstadt, Germany. "Alongside our other data at ASCO (Free ASCO Whitepaper), this two-year analysis is a significant advance in our understanding of the utility of BAVENCIO in MCC patients."

In JAVELIN Merkel 200 – an open-label, single-arm Phase II study – patients with histologically confirmed mMCC whose disease had progressed on or after chemotherapy administrated for distant metastatic disease received BAVENCIO 10 mg/kg intravenously every two weeks until disease progression or unacceptable toxicity. Eighty-eight patients were followed for a median of 29.2 months (range 24.8-38.1 months). The confirmed overall response rate (ORR) of 33% (95% confidence interval [CI] 23.3-43.8; complete response in 11.4%) remained unchanged from previous analyses reported at both one year and 18 months. Responses remained ongoing in 19 of 29 patients who responded to treatment, including 12 patients whose duration of response exceeded two years. Durable responses led to stable rates of PFS (29% at 12 months, 29% at 18 months and 26% at 24 months). Median OS was 12.6 months (95% CI 7.5-17.1) and the two-year OS rate was 36% (50% at 12 months and 39% at 18 months). With a minimum follow-up of two years, no new safety signals were identified for BAVENCIO and was consistent with prior reports. Sixty-seven patients (76.1%) had a treatment-related adverse event (TRAE), 10 patients (11.4%) had a Grade 3 or less TRAE and 20 patients (22.7%) had an immune-related adverse event. No treatment-related deaths occurred.

"These results represent a key milestone for patients with mMCC, as chemotherapy has historically been the only treatment option for this devastating disease," said Chris Boshoff, M.D., Ph.D., Senior Vice President and Head of Immuno-Oncology, Early Development and Translational Oncology, Pfizer Global Product Development. "These data, alongside the additional real-world data which are also being presented at ASCO (Free ASCO Whitepaper), strengthen our confidence in BAVENCIO as a treatment option for this rare and aggressive skin cancer."

In addition to these updated JAVELIN Merkel 200 data, results from a global expanded access program for BAVENCIO as a second-line treatment for patients with mMCC will be presented. These data will be presented during a poster session on Monday, June 4 from
1:15-4:45 p.m. CDT.

The alliance’s JAVELIN clinical development program involves at least 30 clinical programs, including seven Phase III trials, and nearly 8,300 patients across more than 15 tumor types.

BAVENCIO (avelumab) was first approved in the US in 2017 by the US Food and Drug Administration (FDA) for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (mMCC). In addition to the FDA accelerated approval in mMCC, avelumab is also approved in the US under accelerated approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. These indications are approved under accelerated approval based on tumor response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

About JAVELIN Merkel 200

JAVELIN Merkel 200 is an international, multicenter, open-label, single-arm Phase II study of BAVENCIO conducted in 88 patients with metastatic MCC. Patients in this study were generally elderly (median age was 72.5 years, range 33-88 years) and pre-treated, with at least one line of chemotherapy (one [59.1%], two [29.5%] or three or more [11.4%] previous treatments). Patients received BAVENCIO 10 mg/kg intravenously once every two weeks. The protocol-defined analysis set for efficacy and safety consisted of all patients who received at least one dose of study treatment. The cut-off date for the planned primary analysis was six months after start of study treatment of the last patient. The primary endpoint of the study was confirmed best overall response according to RECIST v1.1 and assessed by an independent review committee. Secondary endpoints were duration of response, PFS, OS, response status by RECIST at six and 12 months, safety and tolerability, pharmacokinetics, and immunogenicity of BAVENCIO.

About Avelumab

Avelumab is a human anti-programmed death ligand-1 (PD-L1) antibody. Avelumab has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, avelumab has been shown to release the suppression of the T cell-mediated antitumor immune response in preclinical models.[2]-[4] Avelumab has also been shown to induce NK cell-mediated direct tumor cell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.[4]-[6] In November 2014, Merck KGaA, Darmstadt, Germany, and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.

Approved Indications in the US

The FDA granted accelerated approval for avelumab (BAVENCIO) for the treatment of (i) adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (mMCC) and (ii) patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. These indications are approved under accelerated approval based on tumor response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety Information from the US FDA Approval Label

BAVENCIO can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis, and evaluate suspected cases with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold BAVENCIO for moderate (Grade 2) and permanently discontinue for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis. Pneumonitis occurred in 1.2% (21/1738) of patients, including one (0.1%) patient with Grade 5, one (0.1%) with Grade 4, and five (0.3%) with Grade 3.

BAVENCIO can cause immune-mediated hepatitis, including fatal cases. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater hepatitis. Withhold BAVENCIO for moderate (Grade 2) immune-mediated hepatitis until resolution and permanently discontinue for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis. Immune-mediated hepatitis was reported in 0.9% (16/1738) of patients, including two (0.1%) patients with Grade 5, and 11 (0.6%) with Grade 3.

BAVENCIO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold BAVENCIO until resolution for moderate or severe (Grade 2 or 3) colitis, and permanently discontinue for life-threatening (Grade 4) or recurrent (Grade 3) colitis upon reinitiation of BAVENCIO. Immune-mediated colitis occurred in 1.5% (26/1738) of patients, including seven (0.4%) with Grade 3.

BAVENCIO can cause immune-mediated endocrinopathies, including adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus.

Monitor patients for signs and symptoms of adrenal insufficiency during and after treatment, and administer corticosteroids as appropriate. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Adrenal insufficiency was reported in 0.5% (8/1738) of patients, including one (0.1%) with Grade 3.

Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation. Manage hypothyroidism with hormone replacement therapy and hyperthyroidism with medical management. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) thyroid disorders. Thyroid disorders, including hypothyroidism, hyperthyroidism, and thyroiditis, were reported in 6% (98/1738) of patients, including three (0.2%) with Grade 3.

Type 1 diabetes mellitus including diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Withhold BAVENCIO and administer antihyperglycemics or insulin in patients with severe or life-threatening (Grade ≥ 3) hyperglycemia, and resume treatment when metabolic control is achieved. Type 1 diabetes mellitus without an alternative etiology occurred in 0.1% (2/1738) of patients, including two cases of Grade 3 hyperglycemia.

BAVENCIO can cause immune-mediated nephritis and renal dysfunction. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater nephritis. Withhold BAVENCIO for moderate (Grade 2) or severe (Grade 3) nephritis until resolution to Grade 1 or lower. Permanently discontinue BAVENCIO for life-threatening (Grade 4) nephritis. Immune-mediated nephritis occurred in 0.1% (1/1738) of patients.

BAVENCIO can result in other severe and fatal immune-mediated adverse reactions involving any organ system during treatment or after treatment discontinuation. For suspected immune-mediated adverse reactions, evaluate to confirm or rule out an immune-mediated adverse reaction and to exclude other causes. Depending on the severity of the adverse reaction, withhold or permanently discontinue BAVENCIO, administer high-dose corticosteroids, and initiate hormone replacement therapy, if appropriate. Resume BAVENCIO when the immune-mediated adverse reaction remains at Grade 1 or lower following a corticosteroid taper. Permanently discontinue BAVENCIO for any severe (Grade 3) immune-mediated adverse reaction that recurs and for any life-threatening (Grade 4) immune-mediated adverse reaction. The following clinically significant immune-mediated adverse reactions occurred in less than 1% of 1,738 patients treated with BAVENCIO: myocarditis with fatal cases, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response.

BAVENCIO can cause severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Patients should be premedicated with an antihistamine and acetaminophen prior to the first 4 infusions and for subsequent doses based upon clinical judgment and presence/severity of prior infusion reactions. Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. Permanently discontinue BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Infusion-related reactions occurred in 25% (439/1738) of patients, including three (0.2%) patients with Grade 4 and nine (0.5%) with Grade 3.

BAVENCIO can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus including the risk of fetal death. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least 1 month after the last dose of BAVENCIO. It is not known whether BAVENCIO is excreted in human milk. Advise a lactating woman not to breastfeed during treatment and for at least 1 month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants.

The most common adverse reactions (all grades, ≥ 20%) in patients with metastatic Merkel cell carcinoma (MCC) were fatigue (50%), musculoskeletal pain (32%), diarrhea (23%), nausea (22%), infusion-related reaction (22%), rash (22%), decreased appetite (20%), and peripheral edema (20%).

Selected treatment-emergent laboratory abnormalities (all grades, ≥ 20%) in patients with metastatic MCC were lymphopenia (49%), anemia (35%), increased aspartate aminotransferase (34%), thrombocytopenia (27%), and increased alanine aminotransferase (20%).

The most common adverse reactions (all grades, ≥ 20%) in patients with locally advanced or metastatic urothelial carcinoma (UC) were fatigue (41%), infusion-related reaction (30%), musculoskeletal pain (25%), nausea (24%), decreased appetite/hypophagia (21%), and urinary tract infection (21%).

Selected laboratory abnormalities (Grades 3-4, ≥ 3%) in patients with locally advanced or metastatic UC were hyponatremia (16%), increased gamma-glutamyltransferase (12%), lymphopenia (11%), hyperglycemia (9%), increased alkaline phosphatase (7%), anemia (6%), increased lipase (6%), hyperkalemia (3%), and increased aspartate aminotransferase (3%).

On June 4, 2018 Dynavax Technologies Corporation (NASDAQ:DVAX) reported data from its ongoing Phase 1b/2 study investigating SD-101, Dynavax’s intratumoral TLR9 agonist, in combination with KEYTRUDA (pembrolizumab), an anti-PD-1 therapy developed by Merck (known as MSD outside the United States and Canada) in patients with advanced melanoma (Press release, Dynavax Technologies, JUN 4, 2018, View Source [SID1234527166]).

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The company reported results on a total of 69 patients comparing two doses of SD-101, £ 2mg (n=30) versus 8mg (n=39) administered by intratumoral injection. These data are being presented in poster and discussion session today at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, in Chicago, IL. The primary endpoints of this dose-expansion/dose-finding study are safety and preliminary efficacy. The results of this study showed a 70% overall response rate (ORR) in advanced melanoma patients who received the £ 2 mg dose of SD-101 in up to four lesions versus a 38% ORR in the group receiving the 8 mg dose of SD-101 in one lesion. The combination of SD-101 and KEYTRUDA was well tolerated with adverse events related to SD-101 being transient, mild to moderate flu-like symptoms.

"These data provide further evidence of the potential for SD-101 to improve responses in first-line advanced melanoma patients in combination with an anti-PD-1 therapy," commented Eddie Gray, Chief Executive Officer. "Our studies continue to demonstrate the potential value of SD-101 across multiple tumor types. We plan to build upon this momentum and update our progress with additional data planned for a medical conference later in the year."

Highlights from Poster Presentation (Abstract #9513)

Overall response rate (ORR) of 70% (21 of 30), with a complete response (CR) rate of 17%, for advanced melanoma patients who received the £ 2 mg dose of SD-101 in up to four lesions

ORR of 38% (15 of 39) in patients who received the 8 mg dose of SD-101 in one lesion

Durable response in patients who received £ 2 mg dose of SD-101 with 74% 6-month progression free survival (PFS) rate

Observed responses in injected lesion(s) and distant lesions, including visceral metastases in the liver

Responders included 8 of 10 PD-L1 negative patients in the £ 2 mg dose cohort
AEs related to SD-101 treatment were transient, mild to moderate flu-like symptoms at both the £ 2mg and the 8 mg dosing levels

No increase in the frequency of immune-related adverse events over individual monotherapies reported in other studies1,2 nor evidence of any new safety signals
Additional details on response rates based on patient characteristics including stage of disease, ECOG score, and PD-L1 status are also included in the poster presentation which can be accessed here.

"We are moving forward with the 2mg dose of SD-101 for our Phase 3 trial which we believe is the optimal dose based on these efficacy, safety and biomarker data showing increased immune activation consistent with the biology of TLR9 activation. We continue to collect and analyze data from this trial to finalize details of the Phase 3 study design," stated Rob Janssen, Chief Medical Officer.

The details of the poster presentation and discussion session are as follows:

Phase 1b/2, open label, multicenter, study of the combination of SD-101 and pembrolizumab in patients with advanced melanoma who are naïve to anti-PD-1 therapy

Session Title: Melanoma/Skin Cancers

Abstract: 9513

Poster Board: 340

Poster Session Date/Time: Monday, June 4, 2018, 1:15 PM – 4:45 PM CDT

Poster Session Location: McCormick Place South, Hall A, Advanced Disease Poster Section

Discussion Session Date/Time: Monday, June 4, 2018, 4:45 PM – 6:00 PM CDT

Discussion Session Location: McCormick Place Lakeside Center, Level 4 – E451

Analyst/Investor Presentation

Today at 6:30pm CDT, Dynavax will host a presentation for analysts and investors. The presentation will be available via live webcast only and can be accessed in the "Investors and Media" section of the company’s website at www.dynavax.com.

About SYNERGY-001 (KEYNOTE-184)

SYNERGY-001, previously referred to as MEL-01, is the dose-escalation and expansion study of SD-101 in combination with KEYTRUDA which includes patients with histologically or cytologically confirmed unresectable Stage IIIC/IV melanoma. The primary endpoints of the trial are safety and preliminary efficacy of intratumoral SD-101 in combination with KEYTRUDA.

About SD-101

SD-101, the Company’s lead clinical candidate, is a proprietary, second-generation, Toll-like receptor 9 (TLR9) agonist CpG-C class oligodeoxynucleotide. Dynavax is evaluating this intratumoral TLR9 agonist in several clinical studies to assess its safety and activity, including a Phase 2 study in combination with KEYTRUDA (pembrolizumab), an anti-PD-1 therapy, in patients with advanced melanoma and in patients with head and neck squamous cell cancer, in a clinical collaboration with Merck. Dynavax maintains all commercial rights to SD-101.

On June 4, 2018 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported that encouraging new data from a Phase 1 study evaluating ivosidenib (AG-120) or enasidenib (IDHIFA; AG-221) in combination with azacitidine in newly diagnosed isocitrate dehydrogenase (IDH) mutant acute myeloid leukemia (AML) patients (Press release, Agios Pharmaceuticals, JUN 4, 2018, View Source [SID1234527119]). The data were featured at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

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"Patients with newly diagnosed AML who are ineligible for intensive "7+3" chemotherapy typically have poor outcomes and few available treatment options," said Courtney DiNardo, M.D., lead investigator and assistant professor, department of leukemia at the University of Texas MD Anderson Cancer Center. "With additional patients now treated in the ivosidenib arm of this Phase 1 study, the updated combination data demonstrate a favorable safety profile and impressive response rates vs. those expected with azacitidine alone. I look forward to further demonstrating the clinical benefit of utilizing an IDH inhibitor in combination with traditional frontline AML treatment as part of the ongoing Phase 1 and randomized trials."

About the Ongoing Phase 1/2 Study
The ongoing Phase 1/2 study is evaluating an investigational use of enasidenib or ivosidenib in combination with azacitidine in patients with newly diagnosed IDH mutant AML unable to receive intensive chemotherapy. In the Phase 1b portion of the study, 23 patients received 500 mg of ivosidenib daily plus azacitidine and 6 patients received enasidenib (n=3 at 100 mg and n=3 at 200mg) daily plus azacitidine.

As of the March 15, 2018 data cutoff, 19 patients remained on study (17 ivosidenib, 2 enasidenib).
Enrollment is complete for the ivosidenib Phase 1b portion. Enasidenib and azacitidine continue to be assessed in the randomized Phase 2 portion of the study.
Ivosidenib Results
Safety

The most common adverse events (AEs) regardless of causality were nausea (61%, n=14), anemia (52%, n=12) and thrombocytopenia (48%, n=11).
The most common Grade 3-4 AEs were anemia and thrombocytopenia (44%, n=10 each), and febrile neutropenia (39%, n=9).
IDH differentiation syndrome was reported in three patients.
Efficacy

Overall, 78% of patients (18/23) had a response
The combined CR/CRi/CRp rate was 65% (15/23).

44% (10 of 23 patients) had a complete response (CR)
22% (5 of 23 patients) had a complete response with incomplete hematologic or platelet recovery (CRi/CRp)
All patients with a CR, CRi or CRp response remain on treatment as of the data cutoff with patients on study up to 19 months. The median duration of response has not been reach .
The median time to first response was 1.8 months (range 0.7-3.8 months) and the median time to best response was 3.6 months (range 0.8-6.7 months).
IDH1 mutation clearance was observed in 7 of 21 patients with available longitudinal VAF profiling

Enasidenib Results
Updated data from the six patients in the enasidenib and azacitidine combination presented in December 2017 were also shown.

Safety

The most common AEs regardless of causality were hyperbilirubinemia (n=5) and abdominal pain, nausea, vomiting and pyrexia (n=4 each).
The most common Grade 3-4 AEs were anemia and thrombocytopenia (n=3 each) followed by hyperbilirubinemia, neutropenia, lung infection and pneumonia (n=2 each).
Efficacy

Overall, four out of six patients achieved a response, including 3 CRs and one MLFS.
IDH2 mutation clearance was observed in 3 of 6 patients with available longitudinal VAF profiling
Neither enasidenib nor ivosidenib are approved in any country for the treatment of patients with newly diagnosed AML or approved in combination with azacitidine.

About Acute Myelogenous Leukemia (AML)
AML, a cancer of blood and bone marrow characterized by rapid disease progression, is the most common acute leukemia affecting adults. Undifferentiated blast cells proliferate in the bone marrow rather than mature into normal blood cells. AML incidence significantly increases with age, and the median age of diagnosis is 68. The vast majority of patients do not respond to chemotherapy and progress to relapsed/refractory AML. The five-year survival rate for AML is approximately 27 percent. IDH1 mutations are present in about 6 to 10 percent of AML cases.

On June 4, 2018 Castle Biosciences, Inc., the skin cancer diagnostics company providing molecular diagnostics to improve cancer treatment decisions, reported the presentation of data highlighting the accuracy and performance of the DecisionDx-Melanoma gene expression profile (GEP) test at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting being held in Chicago, IL from June 1-5 (Press release, Castle Biosciences, JUN 4, 2018, View Source [SID1234527135]).

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The study titled, "Performance of a 31-gene expression profile melanoma test in clinically relevant clinicopathologic subgroups" (Abstract #9583), will be presented as a poster at the meeting. Results from the 690-patient study show that the DecisionDx-Melanoma test improved clinical risk prediction independent of traditional factors and consistent with findings from previous retrospective and prospective studies.

Key Study Findings:

Results from this multicenter study in 690 patients confirm that the DecisionDx-Melanoma test is an independent predictor of risk for recurrence, metastasis and melanoma-specific death, including clinically relevant subgroups.
The subgroup of American Joint Committee on Cancer (AJCC) Stage I-IIA patients who had a Class 2B result (highest risk) had significantly worse recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and melanoma-specific survival (MSS) rates compared to patients with a Class 1A result (lowest risk), important considerations that could impact surveillance and follow-up decisions.
For Stage IIIA patients, the DecisionDx-Melanoma test identified groups of patients with significantly different outcomes, which is increasingly important to inform decisions on adjuvant therapy and surveillance plans.
"Results from this multicenter study demonstrate that the GEP test can complement traditional AJCC staging factors by providing independent information that improves risk prediction for patients with melanoma," commented Brian Gastman, M.D., Cleveland Clinic Lerner Research Institute, Cleveland, Ohio. "With new options for patients increasing at a rapid pace, many clinical decisions are being made based on extrapolating data from different studies. Having additional, objective information is important to help patients and their treating physicians make definitive decisions, especially when there isn’t a clearly defined management plan."

Study Details:

Data from three previous DecisionDx-Melanoma validation studies were combined to enable analysis of clinically relevant subgroups. In this cumulative population of 690 Stage I-III patients, median age was 59 years, median time of follow-up was 6.5 years and median Breslow thickness was 1.3 mm. Seventy percent of patients had Stage I or II melanoma. The DecisionDx-Melanoma test was performed to determine molecular class for each patient, with a Class 1A result indicating the lowest 5-year risk of metastasis and a Class 2B result indicating the highest risk. Study endpoints included RFS (time to regional or distant metastatic event), DMFS (time to any metastatic event beyond the regional nodal basis) and MSS (time from diagnosis to death from melanoma).

Results confirm the prognostic accuracy of the DecisionDx-Melanoma test showing a significant difference among 5-year RFS rates for all groups. Patients with a Class 1A (lowest risk) result had an average RFS of 90% compared to 37% for Class 2B (highest risk) patients (p<0.0001). DMFS 5-year rates were 94% for Class 1A and 50% for Class 2B (p<0.0001). MSS 5-year rates were 99% for Class 1A and 75% for Class 2B (p<0.0001).

Based on Cox multivariate analysis in the Stage I-IIA subgroup, DecisionDx-Melanoma test class was found to be the only significant predictor of all three endpoints (RFS, DMFS and MSS; p<0.05 for all).

Additional Castle Biosciences Data at ASCO (Free ASCO Whitepaper) 2018

Preliminary data from the cutaneous squamous cell carcinoma (cSCC) development program will also be presented as a poster at the ASCO (Free ASCO Whitepaper) 2018 meeting (Abstract #9577). The study reports that preliminary gene expression based predictive models may offer important information about patient risk that builds on current staging methods. Results support the feasibility of the program to develop a clinically valuable test to predict which cSCC patients are at higher risk for local recurrence or regional/distant metastasis.

Additionally, an abstract highlighting the use of the DecisionDx-Melanoma test to identify a population of melanoma patients to assess risk of sentinel lymph node biopsy positivity (Abstract #e21611) will be included in the online ASCO (Free ASCO Whitepaper) 2018 proceedings.

About DecisionDx-Melanoma

The DecisionDx-Melanoma test uses tumor biology to predict individual risk of melanoma recurrence and sentinel lymph node positivity independent of traditional factors. Using tissue from the primary melanoma, the test measures the expression of 31 genes. The test has been validated in three multi-center studies that have included 690 patients and have demonstrated consistent results. Performance has also been confirmed in four prospective studies including 702 patients. The consistent high performance and accuracy demonstrated in these studies, which combined have included over 1,300 patients, provides confidence in disease management plans that incorporate DecisionDx-Melanoma test results. Prediction of the likelihood of sentinel lymph node positivity has also been validated in two prospective multicenter studies that included over 1,400 patients. Clinical impact has been demonstrated in multi-center and single-center studies showing that test results impact clinical management decisions for one of every two patients tested. More information about the test and disease can be found at www.SkinMelanoma.com.