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Epizyme Announces First Quarter 2016 Financial Results and Provides Update on Execution Against Multi-Year Company Vision

On May 9, 2016 Epizyme, Inc. (NASDAQ:EPZM), a clinical stage biopharmaceutical company creating novel epigenetic therapies for people with cancer, reported recent business and program highlights as part of its multi-year vision and financial results for the first quarter of 2016 (Press release, Epizyme, MAY 9, 2016, View Source [SID:1234512112]).

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"We have made significant progress in our clinical development program for tazemetostat and all four areas of our multi-year vision," said Robert Bazemore, President and Chief Executive Officer of Epizyme. "We are well underway with plans to expand the tazemetostat clinical program into combination studies and its third cancer indication, continuing to advance our discovery pipeline and collaborative research efforts and have strengthened our team and business operations. With a number of milestones on the horizon, we are positioned to continue this momentum."

Accelerate Tazemetostat Program in Non-Hodgkin Lymphoma and Solid Tumors

Epizyme has submitted an abstract to present a study update from its phase 2 program in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) at the 2016 American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting on Lymphoma Biology in June. This presentation will include a progress update on the study enrollment, safety experience for all patients enrolled and an early look at clinical activity in the patient populations that have surpassed their futility hurdle as confirmed by the Independent Data Monitoring Committee (IDMC). The three arms confirmed to have surpassed the futility hurdle are: germinal center diffuse large B-cell lymphoma (DLBCL) with an EZH2 mutation; germinal center DLBCL with wild-type EZH2; and non-germinal center DLBCL. Futility in each of the DLBCL arms is based on observing at least one objective response in the first ten patients enrolled. Responses have been observed in the two arms enrolling patients with follicular lymphoma; however, neither arm has yet reached its futility hurdle, which is at least two objective responses out of the first ten patients enrolled.

The IDMC recently approved Epizyme’s planned expansion of enrollment in all five arms of the phase 2 study in patients with NHL. The total population will increase to 270 patients from 150. The three arms enrolling patients with DLBCL will now enroll 60 patients each, and the two arms enrolling patients with follicular lymphoma will now enroll 45 patients each. This expansion will enable more precision around the level of activity in each patient population, which will provide guidance for determining next steps in each population and the statistical design of potential subsequent studies. Pending abstract submission and acceptance, the Company plans to present a second study update at the ASH (Free ASH Whitepaper) Annual Meeting in late 2016.

Epizyme recently expanded the number of arms in the phase 2 study in adult patients with certain genetically defined solid tumor (INI1-negative tumors, SMARCA4-negative tumors or synovial sarcomas) to five arms from three due to a higher accrual of patients with certain types of INI1-negative tumors than it anticipated. The two arms enrolling patients with rhabdoid tumors and synovial sarcomas remain unchanged. A third arm will continue to enroll patients with other INI1-negative tumors, and the Company has now separated out two specific INI1-negative cohorts from the third arm. One arm will enroll patients with renal medullary carcinoma and another will enroll patients with epithelioid sarcoma. Pending abstract submission and acceptance, the Company plans to present preliminary data from the phase 2 adult solid tumor study at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Molecular Targets and Cancer Therapeutics Symposium in late 2016.

The phase 1 dose-escalation and expansion study of tazemetostat in pediatric patients with certain INI1-negative tumors, including rhabdoid tumors and synovial sarcomas, is enrolling well, and the study has escalated to the second dose level.
Expand Tazemetostat Program

In May, the U.S. Food and Drug Administration (FDA) accepted the Company’s Investigational New Drug (IND) application for tazemetostat for the treatment of adult patients with mesothelioma characterized by BAP1 loss-of-function. The Company plans to initiate a phase 2 trial in patients with mesothelioma in the third quarter of 2016.

Earlier today, Epizyme announced that it has entered into a collaboration agreement with the Lymphoma Academic Research Organisation (LYSARC) for the first planned combination trial of tazemetostat. LYSARC is the operational arm of the Lymphoma Study Association, a premier cooperative French lymphoma group. This phase 1b/2 study will evaluate tazemetostat administered together with R-CHOP as a front-line therapy for elderly, high-risk patients with DLBCL, and is expected to begin in mid-2016.

Data presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) conference in April further characterized the dosing and administration of tazemetostat. The findings show that tazemetostat is only a weak inducer of CYP3A-mediated metabolism, suggesting a low potential interaction with other treatments metabolized through this pathway. Pharmacokinetic data presented at that meeting also show that tazemetostat can be dosed with or without food. These findings further guide tazemetostat development as a monotherapy and in combination regimens.
Growth Discovery Pipeline

Epizyme scientists continue to advance the development of small molecule inhibitors against five targets that have been selected and prioritized for research.
Maintain Established Leadership Position

Epizyme added strength to its leadership team with new hires: Matthew Ros as Chief Operating Officer, Susan Graf as Chief Business Officer, Jeannie Chu as Vice President of Program and Portfolio Management and Michael Boretti, Ph.D. as Vice President of Business Development.
Q1 2016 Financials Results and Guidance

Collaboration revenue was $0.5 million for the quarter ended March 31, 2016, compared to $0.9 million for the same period last year. The period-over-period decrease reflects increased recognition of deferred revenue from upfront payments from the Celgene collaboration in the first quarter of 2016 offset by decreased recognition of deferred revenue from upfront payments and research and development revenue related to the GlaxoSmithKline collaboration compared to the first quarter of 2015 as no revenue was recognized with respect to the GSK collaboration in the first quarter of 2016.

Research and development (R&D) expenses were $17.7 million for the quarter ended March 31, 2016, compared to $57.1 million for the first quarter of 2015. The period-over-period decrease was driven by the first quarter 2015 payment to Eisai of $40.0 million related to the reacquisition of the worldwide rights, excluding Japan, to tazemetostat, and was partially offset by increased spending on the tazemetostat clinical development program.

Epizyme expects that R&D expenses will increase in 2016, when compared to 2015. The planned increase is primarily related to the development costs of tazemetostat, including Epizyme’s trials in patients with non-Hodgkin lymphoma and adult and pediatric patients with certain genetically defined solid tumors, as well as planned combination studies in patients with DLBCL and the planned study in patients with mesothelioma. In addition, discovery and preclinical research costs are expected to increase as the Company advances its wholly owned small molecule programs against five novel targets and continues the research efforts under its Celgene collaboration.

General and administrative (G&A) expenses were $5.8 million for the quarter ended March 31, 2016, compared to $5.2 million for the same period last year. The increase in G&A expense was largely due to higher professional services costs and personnel-related expenses associated with the expansion of Epizyme’s operations. Epizyme expects that G&A spend will increase in 2016 as compared to 2015 due to increases in staffing and infrastructure to support expanded clinical trial activities, increased research investment and other expanded operational activities, including increased intellectual property costs.

Net loss was $22.9 million for the quarter ended March 31, 2016, compared to a net loss of $61.3 million for the quarter ended March 31, 2015.

Cash and cash equivalents were $312.7 million as of March 31, 2016, compared with $208.3 million as of December 31, 2015. This increase in cash was driven by the Company’s January 2016 financing.
Financial guidance from Epizyme states that the Company believes its cash and cash equivalents as of March 31, 2016 will be sufficient to fund the Company’s planned operations through at least the end of 2017.

Eagle Pharmaceuticals, Inc. Reports First Quarter 2016 Results; Bendeka Achieves 71% Total Market Share

On May 9, 2016 Eagle Pharmaceuticals, Inc. ("Eagle" or "the Company") (Nasdaq: EGRX) reported its financial results for the first quarter ended March 31, 2016 (Press release, Eagle Pharmaceuticals, MAY 9, 2016, View Source [SID:1234512110]). Highlights of and subsequent to the first quarter of 2016 include:

Business Highlights:

Bendeka was launched January 28, 2016 by Eagle’s marketing partner, Teva Pharmaceutical Industries (Teva); total market share, as of May 6, 2016, was 71% and 77% in core hospital outpatient and clinic segments combined (representing 70% of the total market);
Eagle entered into an agreement with the National Institutes of Health (NIH)/National Institute on Drug Abuse (NIDA) to explore the use of Ryanodex in the treatment of hyperthermia related to MDMA (Ecstasy) and Methamphetamine intoxication;
Eagle entered into an agreement to divest diclofenac-misoprostsol to a third party in exchange for $1.75 million and a 25% royalty on net profits for five years; and,
Eagle completed its first quarter with an internal salesforce fully focused on commercialization of Eagle’s in-market products.
Financial Highlights:

Total revenue was $29.6 million during the first quarter of 2016 compared to $36.3 million for the three months ended March 31, 2015;
Product sales increased to $14.1 million during the first quarter of 2016 compared to $3.1 million for the three months ended March 31, 2015;
Sales of Ryanodex grew 5% quarter over quarter to $1.9 million during the first quarter of 2016;
Net loss was $896,000, or $0.06 per basic and diluted share, compared to net income of $19.7 million, or $1.38 per basic and $1.31 per diluted share, for the three months ended March 31, 2016 and 2015, respectively; and,
Cash and cash equivalents were $78.3 million as of March 31, 2016.
"Our business outlook for the Company remains bright. Our bendamustine product family offers significant opportunity for growth and is being accepted well by physicians and patients. Assuming bendamustine generics do not come to market, and with Bendeka gaining momentum, based on its product profile which customers seem to prefer, we believe Bendeka is on track to reach Teva’s and our shared goal of 90% market share or greater and will be an important earnings driver for Eagle for years to come," said Scott Tarriff, President and Chief Executive Officer of Eagle Pharmaceuticals.

"In addition to our other product candidates, we believe Ryanodex has the potential for multiple additional clinical indications. These opportunities in treating exertional heat stroke and ecstasy and methamphetamine intoxication, if approved, would open up significant new markets for the product. We are encouraged by the potential of our products to deliver solutions that address life-threatening conditions and improve treatment outcomes and look forward to upcoming milestones that we expect will drive meaningful earnings growth," concluded Tarriff.

First Quarter 2016 Financial Results

Total revenue for the three months ended March 31, 2016 was $29.6 million, as compared to $36.3 million for the three months ended March 31, 2015. A summary of total revenue is outlined below:

Three Months Ended
March 31, Increase/(Decrease)
2016 2015
(in thousands)
Product sales $ 14,122 $ 3,056 $ 11,066
Royalty income 9,469 3,253 6,216
License and other income 6,000 30,000 (24,000 )
Total revenue $ 29,591 $ 36,309 $ (6,718 )

Product sales increased $11.1 million to $14.1 million in the first quarter of 2016 driven by $10.3 million in net product sales of Bendeka, 5% growth in Ryanodex net product sales to $1.9 million, $0.9 million in net sales of Docetaxel and increases in net sales of Diclofenac-misoprostol, offset by a decrease in Argatroban product sales to our commercial partners.

The $6.2 million increase in royalty income to $9.5 million was driven by the launch of Bendeka during the first quarter of 2016.

License and other income in the three months ended March 31, 2016 was $6 million compared with $30 million in the prior year quarter. This $6 million reflects revenue previously deferred from the 2010 sale of a non-core asset subject to a claw back provision, which has now expired.

Cost of revenue increased by $8.6 million to $14.5 million in the three months ended March 31, 2016 from $5.9 million in the three months ended March 31, 2015. This $8.6 million net increase resulted primarily from the cost of Bendeka product sales, Docetaxel and Diclofenac-misoprostol, offset by a decrease in cost of revenue for Ryanodex due to spoiled inventory, and lower Argatroban product sales.

Research and development expenses increased by $0.4 million to $6.7 million in the three months ended March 31, 2016, compared to $6.3 million in the prior year quarter. The increase is due primarily to the successful completion of the clinical treatment portion of the safety and efficacy study of Ryanodex for exertional heatstroke, investment in Kangio and other pipeline products, and higher R&D personnel costs offset by a decrease in spending related to bendamustine.

SG&A expenses were $11 million in the first quarter of 2016 compared to $4 million in the three months ended March 31, 2015. Personnel-related expenses accounted for the bulk of the $7 million increase and were due to overall expansion of the business.

Net loss for the first quarter was $896,000, or $0.06 per basic share and diluted share, compared to a net income of $19.7 million, or $1.38 per basic and $1.31 per diluted share in the three months ended March 31, 2015, as a result of the factors discussed above.

Liquidity

As of March 31, 2016, the Company had $78.3 million in cash and cash equivalents; $15 million in receivables due from Teva; $200.3 million in additional paid in ca

Dynavax Reports First Quarter 2016 Financial Results

On May 9, 2016 Dynavax Technologies Corporation (NASDAQ: DVAX) reported financial results for the first quarter ended March 31, 2016 (Press release, Dynavax Technologies, MAY 9, 2016, View Source [SID:1234512109]).

The Company had $166.8 million in cash, cash equivalents and marketable securities as of March 31, 2016, compared to $196.1 million at December 31, 2015. The net loss for the first quarter of 2016 was $27.0 million, compared to $26.2 million for the first quarter of 2015.

First Quarter Financials

Total revenues for the three months ended March 31, 2016 increased by $0.3 million, or 50%, compared to the same period in 2015.

Research and development expenses for the first quarter decreased by $2.2 million, or 10%, compared to the same period in 2015, reflecting an increase in employee headcount and activities in preparation for the anticipated commercial launch of HEPLISAV-B and a reduction in outside services expense due to lower activity related to HBV-23 following its completion in the fourth quarter of 2015.

General and administrative expenses for the three months ended March 31, 2016, increased by $3.3 million, or 68%, compared to the same period in 2015, as we added headcount and addressed information technology systems and other infrastructure needs in preparation for the anticipated commercial launch of HEPLISAV-B.

The net loss for the quarter ended March 31, 2016 was $27.0 million, or $0.70 per basic and diluted share compared to $26.2 million, or $0.97 per basic and diluted share for the quarter ended March 31, 2015.

Recent Progress

At the end of the quarter, the U.S. Food and Drug Administration (FDA) accepted for review the Biologics License Application (BLA) for HEPLISAV-B, the company’s vaccine for immunization against hepatitis B infection in adults 18 years of age and older. The FDA has established December 15th as the Prescription Drug User Fee Act (PDUFA) action date for the BLA.

"We are focused on working with the FDA to obtain approval of HEPLISAV-B before year end and on preparing for launch, including preparation for an advisory panel in case one is called, hiring of key commercial personnel, market and pricing research and manufacturing of launch inventory," said Dynavax Chief Executive Officer, Eddie Gray.

In April, we reported additional details from the HBV-23 pivotal Phase 3 HEPLISAV-B trial at the National Foundation for Infectious Diseases’ (NFID) 19th Annual Conference on Vaccine Research (ACVR).

Also in April, we presented encouraging additional data from Part 1 of the Phase 1/2 study evaluating our lead immunotherapy product candidate, SD-101, in lymphoma patients. The clinical data, along with preclinical SD-101 data, were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting.

Curis Reports First Quarter 2016 Financial Results

On May 09, 2016 Curis, Inc. (NASDAQ:CRIS), a biotechnology company focused on the development and commercialization of innovative and effective drug candidates for the treatment of human cancers, reported its financial results for the first quarter ended March 31, 2016 (Press release, Curis, MAY 9, 2016, View Source [SID:1234512108]).

"We are pleased with the initiation of the Phase 2 study with CUDC-907 earlier this year in patients with relapsed/refractory Diffuse Large B Cell Lymphoma (DLBCL) that harbor MYC alterations," said Ali Fattaey, Ph.D., Curis’s President and CEO. "At the recent AACR (Free AACR Whitepaper) annual conference, we presented preclinical data, which provide further evidence for CUDC-907’s effect on downregulating MYC and its anti-tumor activity in multiple lymphoma and solid tumor models with alterations in MYC oncogene."

Dr. Fattaey continued, "All IND enabling studies with CA-170 have been completed, and we remain on track to initiate a Phase 1 study in cancer patients in the first half of 2016 with CA-170 as our first oral immuno-oncology drug candidate. Additionally, preclinical development of small molecule leads that target PD-L1 and TIM3 in our second immuno-oncology program is progressing well and these candidates further underscore the potential of this discovery platform to generate multiple oral small molecule drug candidates that can modulate independent immune checkpoint targets."

First Quarter 2016 Financial Results

Curis reported a net loss of $9.4 million, or ($0.07) per share, on both a basic and diluted basis for the first quarter of 2016, as compared to a net loss of $31.8 million, or ($0.30) per share, on both a basic and diluted basis for the same period in 2015. The net loss for the prior year period includes a non-cash in-process research and development charge of $24.3 million related to Curis’s license agreement with Aurigene.

Revenues were $1.7 million for each of the first quarters of 2016 and 2015. Revenues for both periods are comprised primarily of royalty revenues recorded on Genentech and Roche’s net sales of Erivedge.

Operating expenses were $10.5 million for the first quarter of 2016, as compared to $32.7 million for the same period in 2015, and comprised the following:

Costs of Royalty Revenues. Costs of royalty revenues, primarily amounts due to third-party university patent licensors in connection with Genentech and Roche’s Erivedge net sales, were $89,000 for the first quarter of 2016, up from $84,000 during the first quarter of 2015.

In-Process Research and Development Expense. No in-process research and development expenses were recorded for the three months ended March 31, 2016 as compared to $24.3 million recorded during the first quarter of 2015 associated with the issuance of 17,120,131 shares of Curis common stock to Aurigene as partial consideration for the rights granted under the terms of our January 2015 collaboration agreement.

Research and Development Expenses. Research and development expenses were $6.8 million for the first quarter of 2016, as compared to $4.7 million for the same period in 2015. The increase was primarily due to increased direct spending related to clinical activities of CUDC-907 and programs under the Aurigene collaboration over the prior year period. Employee-related expenses increased over the prior year period primarily due to additional headcount to support the multiple programs.

General and Administrative Expenses. General and administrative expenses remained unchanged at $3.5 million for first quarter of 2016 and $3.5 million for the same period in 2015.

Other expense was $635,000 for the first quarter of 2016, as compared to $827,000 for the same period in 2015. Other expense primarily consisted of $740,000 and $867,000 in interest expense for the quarters ended March 31, 2016 and 2015, respectively, related to the loan made by BioPharma-II (an investment fund managed by Pharmakon Advisors) to Curis Royalty (a wholly-owned subsidiary of Curis).

As of March 31, 2016, Curis’s cash, cash equivalents, marketable securities and investments totaled $73.1 million and there were approximately 129.0 million shares of common stock outstanding.

Recent Operational Highlights

Precision oncology (HDAC / PI3K inhibitor program):

In April 2016, preclinical data were presented for CUDC-907 at the Annual Meeting of American Association of Cancer Research (AACR) (Free AACR Whitepaper) in New Orleans. The presentation included data for CUDC-907’s anti-tumor activity in multiple in vitro and in vivo MYC-altered disease models, including lymphomas and solid tumors, and the molecule’s effect on downregulating MYC levels.

In January 2016, Curis initiated an open label Phase 2 study to evaluate the efficacy and safety of CUDC-907 with and without rituximab in patients with relapsed/refractory MYC-altered DLBCL.
Immuno-oncology (PD-L1 / VISTA antagonist program):

In April 2016, preclinical data were presented for CA-170, a small molecule, orally available antagonist of PD-L1 and VISTA at the Annual AACR (Free AACR Whitepaper) meeting in New Orleans. The data presented included the pharmacologic and safety profile of CA-170 to support its progression into human clinical trials.
Immuno-oncology (PD-L1 / TIM-3 antagonist program):

In April 2016, preclinical data were presented from the orally available, small molecule PD-L1/TIM-3 immune checkpoint antagonist program. Results from in vitro studies with AUPM-327, a representative molecule from the PD-L1/TIM-3 program showed that AUPM-327 can selectively rescue T cell functions that are inhibited by PD-L1 or TIM-3 checkpoint proteins, but does not modulate the effects of other regulators such as VISTA, CTLA4, LAG-3, or CD-28, demonstrating its selectivity. Additionally, daily oral administration of the PD-L1/TIM-3 antagonist resulted in anti-tumor activity in multiple syngeneic tumor models including melanoma and colon cancer.
Precision oncology (IRAK4 inhibitor program):

In April 2016, preclinical data were presented for CA-4948, the oral IRAK4 inhibitor at the Annual AACR (Free AACR Whitepaper) meeting in New Orleans. The presentations outlined CA-4948’s detailed pharmacologic and biologic profile as well as data on its metabolism, pharmacokinetics properties and in vitro toxicity profile. CA-4948 demonstrated potent anti-tumor activity in two in vivo models of MYD88 mutant- DLBCL disease and anti-inflammatory effects in a rodent model of inflammation suggesting the potential use of an IRAK4 inhibitor in both cancer and inflammatory diseases.
Erivedge:

Roche initiated patient enrollment in a Phase 1 clinical study to evaluate the safety and efficacy of Erivedge in combination with ruxolitinib for the treatment of patients with intermediate- or high-risk myelofibrosis.
Roche initiated patient enrollment in a study of Erivedge in combination with pirfenidone in patients with idiopathic pulmonary fibrosis (IPF). The study is designed as a single arm, multicenter Phase 1b study to evaluate the safety and tolerability of Erivedge in combination with pirfenidone in participants with IPF currently being treated with pirfenidone.
Upcoming Activities

Curis expects that it will make presentations at the following scientific and investor conferences through June 2016:

American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2016 Annual Meeting on June 3-7 in Chicago
Jefferies Healthcare Conference on June 7-10 in New York City
21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) on June 9-12 in Copenhagen, Denmark
Our partner, Roche/Genentech expect to present data on Erivedge at ASCO (Free ASCO Whitepaper) 2016 Annual Meeting in Chicago from June 3-7.

bluebird bio Presents Oncology and Gene Therapy Data at the ASGCT 19th Annual Meeting

On May 9, 2016 bluebird bio, Inc. (Nasdaq:BLUE), a clinical-stage company committed to developing potentially transformative gene therapies for severe genetic and rare diseases and T cell-based immunotherapies for cancer, reported the presentation of pre-clinical data from its immuno-oncology and hematopoietic stem cell (HSC) gene therapy programs at the American Society of Gene & Cell Therapy (ASGCT) (Free ASGCT Whitepaper) 19th Annual Meeting, taking place May 4-7, 2016 in Washington, D.C (Press release, bluebird bio, MAY 9, 2016, View Source;p=RssLanding&cat=news&id=2166363 [SID:1234512103]).

Additionally, two oral presentations given by bluebird’s academic collaborators highlighted previously presented data from bluebird bio’s ongoing gene therapy clinical trials. David Williams, M.D., president of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center presented interim data from the Starbeam Study of Lenti-D in cerebral adrenoleukodystrophy, and Marina Cavazzana, M.D., Ph.D., of Hospital Necker, University Paris Descartes, presented interim data from the HGB-205 study of LentiGlobin in severe sickle cell disease and transfusion-dependent β-thalassemia.

"The preclinical data presented at ASGCT (Free ASGCT Whitepaper) are testament to bluebird’s commitment to developing next-generation immuno-oncology and gene therapies. We are particularly excited about our oncology presentations, which highlighted our progress toward the generation of T cells with sustained anti-tumor activity as well as research on small-molecule regulated multi-chain chimeric antigen receptors known as Darics," said Philip Gregory, D.Phil., chief scientific officer, bluebird bio. "For our hematopoietic stem cell programs, scalable manufacturing and transduction efficiency remain areas of focus and importance for bluebird. Multiple presentations at ASGCT (Free ASGCT Whitepaper) discussed encouraging examples of our efforts on these fronts – with more to come as we continue to innovate in this critical direction."

Oncology Presentations:

Oral Abstract #277: Small Molecule-regulated Antigen Recognition System for Inducible T Cell Targeting of Cancer Cells

Overview and results presented by Wai-Hang Leung, Ph.D., bluebird bio.

bluebird bio scientists presented data on a small-molecule regulated CAR (Daric) for applications where it may be useful to turn antigen-driven T cell activity on or off, such as minimizing off-tumor activity. In addition to potentially providing an enhanced safety profile for CAR T cells, this technology could be applied in other indications such as autoimmune disease.
Daric engineered CAR T cells possess minimal activity in the absence of dimerizing agents (rapamycin / AP21967), and antigen-specific cytotoxicity and cytokine production are significantly upregulated with the addition of rapamycin / AP21967.
Oral Abstract #747: Towards the Clinical Application of BCMA CAR T cells: The Importance of Reduced Tonic Signaling and Methods to Enhance Memory T Cells

Results presented by Kevin Friedman, Ph.D., bluebird bio.

bluebird bio has developed a potent CAR targeting BCMA (bb2121) to treat multiple myeloma and some lymphomas. The initial clinical application of this technology to treat patients with multiple myeloma began in February.
bluebird bio scientists demonstrated that a property called tonic signaling can reduce CAR T cell durability and tumor control, but careful CAR engineering can avoid this problem. Furthermore, simple manufacturing changes involving inhibition of the PI3K pathway can significantly increase the potency and fitness of CAR T cells.
Abstract #323: Efficient Generation of CART Cells by Homology Directed Transgene Integration into the TCR-Alpha Locus

Results presented by Baeckseung Lee, Ph.D., bluebird bio.

Homology directed transgene integration combines nuclease-mediated gene disruption with site-specific integration of novel genetic material. Using bluebird bio’s proprietary gene editing technology, megaTALs, bluebird scientists demonstrated that this can be efficiently accomplished in primary human T cells by introducing a CD19 CAR into the TCR alpha gene (TRAC).
Nuclease generated CAR T cells had similar cytotoxicity and cytokine production compared to those made by lentiviral vector transduction. These data demonstrate the potential for megaTAL-mediated targeted gene addition as a robust method for the genetic editing of CAR T cells.
HSC Gene Therapy Presentations

Abstract #221: Staurosporine Increases Lentiviral Transduction of Human CD34+ Cells

Results presented by Melissa Bonner, Ph.D., bluebird bio.

bluebird has been evaluating numerous compounds for the potential to increase vector copy number (VCN) and enhance cell transduction in lentiviral vector (LVV)-based gene therapy.
Limited staurosporine treatment prior to LVV transduction can increase the proportion of modified cells, including long-term repopulating cells, in a gene modified cell product.
This work received an "Outstanding Poster Award" from the ASGCT (Free ASGCT Whitepaper).
Abstract #229: PGE2 Increases Lentiviral Vector Transduction Efficiency of Human HSC

Results presented by Garrett C. Heffner, Ph.D., bluebird bio.

As part of its work to evaluate small molecules that may increase VCN and enhance cell transduction, bluebird identified PGE2 as a VCN enhancer in CD34+ cells.
PGE2 improves VCN approximately 2-fold from multiple healthy normal CD34+ cell donors as well as donors with primary hemoglobinopathies. These increases in VCN also result in an increased percentage of cells with integrated lentiviral vector leading to improved globin expression in in vitro preclinical models.
Abstract #458: Development of a stable producer cell line for scalable lentiviral vector production for gene therapy of hemoglobinopathies

Results presented by Sarah Slauson, bluebird bio

Current manufacturing of clinical grade lentiviral vectors commonly relies on transient infection of adherent 293T cells. An inducible producer cell line grown in suspension culture represents a potentially more scalable manufacturing process for vector production, eliminating the need for costly plasmid and transfection reagents.
bluebird bio scientists have developed 293F-based stable packaging and producer cell lines for inducible production of LentiGlobin BB305, and reported the successful production of LentiGlobin BB305 at research scale in suspension culture.
Abstract #473: Qualification of a p24 ELISA Assay for Quantitation of Total Lentiviral Vector Concentration

Results presented by Elisabeth Boucher, bluebird bio.

The availability of reliable analytical tools to characterize purified LVV product and in-process samples is critical to successful LVV process development. In support of late-stage process characterization, it is essential to qualify the assay and demonstrate its suitability to test in-process samples in different matrices.
Scientists at bluebird bio reported on the qualification of a p24 ELISA assay for LVV quantitation, showing precision, repeatability, specificity and accuracy within an established range, adequate to support late-stage process characterization activities.
Abstract #709: Characterization of Nanoparticles in Lentiviral Vector Preparations

Results presented by Erik Hansen, bluebird bio.

Progress to late-stage clinical development of lentivirus based gene therapies and CAR T therapies will require enhanced characterization of the purified lentivirus product. LVV preparations are complex and utilize host cells that produce not only the viral particles of interest, but also a variety of closely related impurities that can include microvesicles. These cell-derived impurities can overlap key biophysical and biochemical attributes of the LVV, making them challenging to analyze.
bluebird bio scientists reported on the use of various analytical tools to further characterize LVV preparations in terms of particle size distribution and counts, as well as methods for determining the total particle to infectious particle ratio.