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First-In-Human Trials using Non-Viral Sleeping Beauty System to Express CD19-Specific CAR in T cells Published in Journal of Clinical Investigation

On August 4, 2016 ZIOPHARM Oncology, Inc. (Nasdaq:ZIOP), a biopharmaceutical company focused on new immunotherapies, reported the publication of data highlighting the benefits of using the non-viral Sleeping Beauty (SB) system to genetically modify T-cells to express a chimeric antigen receptor (CAR) for use against leukemias and lymphomas (Press release, Ziopharm, AUG 4, 2016, View Source [SID:1234514282]). The article, titled "Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells," was published in the Journal of Clinical Investigation (doi:10.1172/JCI86721), and is available online here.

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In the paper, 26 patients with multiply relapsed B-lineage acute lymphoblastic leukemia (ALL, n=17) or B-cell non-Hodgkin lymphoma, (NHL, n=9) were enrolled in two investigator-initiated clinical trials at the University of Texas MD Anderson Cancer Center infusing SB-modified T cells after autologous (n=7) or allogeneic (n=19) hematopoietic stem-cell transplantation (HSCT).

Autologous CAR-T: Seven patients with advanced NHL were treated with autologous HSCT followed by administration of patient-derived CAR T cells. Six of the seven patients remain in complete remission (CR) and the 30-month progression-free survival (PFS) and overall survival (OS) rates were 83.3% and 100%, respectively.
Allogeneic CAR-T: Nineteen patients (ALL n=17, NHL n=2) received donor-derived CAR T cells. The patients had advanced disease at the time of HSCT and CAR T cells were administered without additional lymphodepletion. Eleven of 19 patients remain in remission with 1-year PFS and OS rates of 53% and 63%, respectively.
HLA partially-matched allogeneic CAR-T: When the subset of allogeneic recipients of HSCT receiving haplo-identical CAR T cells were examined, eight patients had 1-year PFS and OS rates of 75% and 100%, respectively.
SB-mediated gene transfer and stimulation resulted in large ex vivo expansion of T cells while retaining CAR expression and without integration hotspots. Autologous and allogeneic T cells survived after infusion an average of 201 and 51 days, respectively. No unexpected acute infusion or delayed toxicities were noted in the autologous or allogeneic recipients. Mild elevations in cytokines were observed without cytokine storm.

Francois Lebel, M.D., Executive Vice President, Research and Development, Chief Medical Officer at ZIOPHARM, states: "By following these patients over an extended duration, as we do in these studies, we can better understand the added benefit of CAR-T over HSCT alone. Although the primary objective of these trials was not to establish efficacy, the recipients’ outcomes are encouraging with apparent doubling of survivals compared to historical controls. We are encouraged by these clinical data and look forward to results from our Phase 1 study infusing our next generation CD19-specific CAR T cells in patients with advanced lymphoid malignancies."

Supported by results from two Phase I clinical studies conducted by investigators at MD Anderson Cancer Center, the publication describes how the use of the SB transposon/transposase platform could reduce the costs and complexity associated with recombinant viral vector-based immunotherapy. Additionally, by infusing a CD19-specific CAR T cells to target minimal residual disease after autologous and allogeneic HSCT, the SB system may improve tolerability by avoiding cytokine storm.

"The use of the non-viral Sleeping Beauty platform provides us with leverage to both decrease the cost of modifying T cells and reduce the T-cell manufacturing steps requiring GMP," said Laurence Cooper, M.D., Ph.D., Chief Executive Officer of ZIOPHARM. "As we continue to advance Sleeping Beauty engineered designs, ZIOPHARM benefits from both viral and non-viral approaches within CAR-T, while focusing efforts on non-viral gene delivery for TCR given its unique ability to enable personalized therapies for patients with solid tumors."

Juno Therapeutics Reports Second Quarter 2016 Financial Results

On August 4, 2016 Juno Therapeutics, Inc. (NASDAQ: JUNO), a biopharmaceutical company focused on re-engaging the body’s immune system to revolutionize the treatment of cancer, reported financial results and business highlights for the second quarter 2016 (Press release, Juno, AUG 4, 2016, View Source;p=RssLanding&cat=news&id=2193215 [SID:1234514279]).

"The JCAR015 Phase II ROCKET trial is open again after we amended the protocol to return to a cyclophosphamide-only preconditioning regimen. If the ROCKET data are in the range of the Phase I results, where most patients were treated using this preconditioning regimen, we will have the opportunity to change the standard of care and offer improved hope for adult patients with relapsed or refractory ALL," said Hans Bishop, Juno’s President and Chief Executive Officer. "Additionally, we continue to enroll patients in our JCAR017 trial. We are encouraged that JCAR017, the backbone of our CD19 franchise, will change the standard of care again across a range of B cell malignancies with approvals projected to occur as early as 2018."
Second Quarter 2016 and Recent Corporate Highlights
Clinical Update:

CD19 Portfolio:

JCAR015
Announced the removal on July 12, 2016 by the U.S. FDA of a clinical hold that the agency had placed on the Phase II ROCKET trial on July 6, 2016. The ROCKET trial continues using JCAR015 with cyclophosphamide (cy) preconditioning alone. Juno’s trials and plans for its other CD19-directed CAR T cell product candidates, including JCAR017, were not affected.

Announced interim results, as of May 19, 2016, in Memorial Sloan Kettering Cancer Center’s (MSK) Phase I trial of JCAR015 in adult relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) patients:
Complete remission was observed in 23/30 (77%) patients with morphologic disease and in 18/20 (90%) patients with minimal disease. In patients who achieved a complete remission and had adequate evaluation for minimal residual disease by flow cytometry or polymerase chain reaction, complete molecular remission (CmR) was observed in 19/21 (90%) patients with morphologic disease and in 14/18 (78%) patients with minimal disease.

Median overall survival (OS) for patients with minimal disease treated with JCAR015 had not been reached yet, and that for morphologic patients treated with JCAR015 was 9 months; median OS follow-up for all patients was 13 months with 40% of patients alive at two years.

Durable responses and survival observed in patients who received JCAR015 were comparable between groups that received a subsequent stem cell transplant and those that did not.

Severe cytokine release syndrome (sCRS) was observed in 14/51 (27%) patients and severe neurotoxicity was observed in 15/51 (29%) patients. For patients with minimal disease, 1/20 (5%) patients experienced sCRS and 4/20 (20%) patients had severe neurotoxicity.

JCAR017
Announced Phase I non-Hodgkin lymphoma (NHL) preliminary efficacy and safety data for the ongoing trial. As of early July, 13 patients were evaluable for safety. Two, or 15%, experienced severe neurotoxicity and no patients experienced sCRS. There are early signs of efficacy with an overall response rate of eight out of ten efficacy-evaluable patients, or 80%, and a complete response rate of seven out of ten, or 70%. We plan to update results with more patients and durability data at a future scientific meeting.

Announced interim results, as of May 17, 2016, from Seattle Children’s ongoing Phase I/II study of JCAR017 in pediatric and young adults with r/r ALL (n=42) demonstrating 39/42 (93%) patients experienced a complete remission, all of which were a CmR by flow cytometry. In patients who received fludarabine/cyclophosphamide (flu/cy) preconditioning followed by JCAR017, 14/14 (100%) achieved a complete remission and a CmR. sCRS was observed in 10/42 (24%) patients and severe neurotoxicity was observed in 10/42 (24%) patients. The rates of sCRS and severe neurotoxicity were similar in the flu/cy and cy cohorts of this trial.
JCAR014 – Announced interim results, as of May 18, 2016, from Fred Hutchinson Cancer Research Center’s (FHCRC) ongoing Phase I/II study of JCAR014 in adults with advanced B cell malignancies:
In efficacy-evaluable ALL patients (n=34), complete remission was reported in 34/34 (100%) patients and a CmR as measured by flow cytometry was achieved in 32/34 (94%) patients. In the cohort that received flu/cy preconditioning followed by JCAR014, 22/22 (100%) of the efficacy-evaluable patients achieved a complete remission, all of which were a CmR. Median disease free survival (DFS) and OS have not yet been reached in this cohort of patients, with follow-up for up to 18 months. sCRS was observed in 14/36 (39%) patients and severe neurotoxicity was observed in 14/36 (39%) patients.

In patients with multiple NHL histologies (n=20), predominantly diffuse large B-cell lymphoma, who received flu/cy preconditioning followed by JCAR014 dose level 2 (2×106/kg), 16/20 (80%) had an overall response (OR), of which 10/20 (50%) experienced a complete response (CR). CRs continued in 70% of patients, ranging from 3 to 11+ months. sCRS was observed in 2/20 (10%) patients and severe neurotoxicity was observed in 2/20 (10%) patients. Notably, 16/20 (80%) patients treated with flu/cy preconditioning followed by JCAR014 dose level 2 were treated in the outpatient setting, and 6/20 (30%) did not require hospitalization during the first 30 days of treatment.

A total of 13 high-risk chronic lymphocytic leukemia (CLL) patients (complex karyotype, del17p, ibrutinib-refractory, ibrutinib-intolerant) received JCAR014 and either non-flu/cy (n=2) or flu/cy (n=11) preconditioning. In the flu/cy patients, the OR rate was 10/11 (91%) patients, of which 5/11 (45%) patients achieved CR. CRs were ongoing in 100% of these five patients with a range of 3 to 19+ months. sCRS was observed in 3/13 (23%) patients and severe neurotoxicity was observed in 3/13 (23%) patients.
JCAR018 – Investigators presented interim data, from the ongoing Phase I study in pediatric and young adult r/r ALL patients at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 (AACR 2016), showing all three patients at dose level 2 (1 x 106 cells/kg) achieved a complete remission and CmR as measured by flow cytometry. These patients remained in complete remission with follow-up ranging from 3 to 6 months. Limited cytokine release syndrome and no severe neurotoxicity was seen at dose level 2. Dose limiting toxicity was observed at higher doses, so dosing will continue at dose level 2 (1 x 106 cells/kg).

JTCR016 – In the first three solid organ tumor patients treated on the trial, all with mesothelioma, preliminary data, as of early April, presented at AACR (Free AACR Whitepaper) 2016 showed one patient with an ongoing partial response to the WT-1 TCR. The clinical activity appeared to correlate with the pharmacokinetics of the engineered T cells, as the patient with the partial response had the best T cell expansion and persistence. JTCR016 was generally well-tolerated in these three refractory mesothelioma patients, with no evidence of sCRS or severe neurotoxicity.

Corporate News:
Celgene Corporation exercised its option to develop and commercialize CAR product candidates from Juno’s CD19 program outside of North America and China. With the exercise of this option, Celgene paid Juno a fee of $50.0 million and the companies will now generally share worldwide research and development expenses for CAR product candidates in the CD19 program. Celgene has commercial rights outside of North America and China, and will pay Juno a royalty at a percentage in the mid-teens on any future net sales in Celgene’s territories of CAR therapeutic products developed through the CD19 program. Juno retains commercialization rights in North America and China.

Juno entered into an exclusive license agreement with MSK and Eureka Therapeutics, Inc. for a novel, fully-human binding domain targeting B-cell maturation antigen (BCMA), along with antibodies against two additional undisclosed multiple myeloma targets to be used for the potential development and commercialization of CAR cell therapies for patients with multiple myeloma. MSK and Eureka Therapeutics are eligible to receive an undisclosed upfront payment, additional payments upon the achievement of undisclosed clinical, regulatory, and commercial milestones, and royalties on net sales. The parties expect the BCMA CAR to enter human testing as early as the first half of 2017.

Juno acquired RedoxTherapies, a privately held company. The acquisition provides Juno with an exclusive license to vipadenant, a small molecule adenosine A2a receptor antagonist that has the potential to disrupt important immunosuppressive pathways in the tumor microenvironment in certain cancers. Juno intends to explore this molecule in combination with its engineered T cell platform and may over time explore it in other areas as well. The upfront consideration for the RedoxTherapies acquisition was $10.0 million in cash. The seller is also eligible to receive payments upon the achievement of clinical, regulatory, and commercial milestones.

Second Quarter 2016 Financial Results
Cash Position: Cash, cash equivalents, and marketable securities as of June 30, 2016 were $1.11 billion compared to $1.13 billion as of March 31, 2016 and $1.22 billion as of December 31, 2015.

Cash Burn: Cash burn in the second quarter of 2016, excluding the $50.0 million opt-in fee from Celgene and cash inflows and outflows from business development, was $55.2 million. Including the cash inflow from Celgene of $50.0 million, and excluding cash inflows and outflows from business development activities, cash burn in the second quarter of 2016 was $5.2 million, compared to $18.5 million in the second quarter of 2015. Included in cash burn in the three months ended June 30, 2016 and 2015 are cash outflows for capital expenditures of $7.4 million and $6.8 million, respectively.

Revenue: Revenue for the three and six months ended June 30, 2016 was $27.6 million and $37.4 million, respectively, compared to $12.5 million for the three and six months ended June 30, 2015. The increase of $15.1 million and $24.9 million in the three and six months ended June 30, 2016, respectively, was due primarily to revenue recognized in connection with the Celgene collaboration and CD19 opt-in as well as milestone revenue from Novartis. Included in revenue for the three and six months ended June 30, 2015 was an upfront fee of $12.3 million received in connection with the Novartis sublicense agreement.

R&D Expenses: Research and development expenses for the three and six months ended June 30, 2016, inclusive of non-cash expenses and computed in accordance with GAAP, were $72.3 million and $146.0 million, respectively, compared to $60.2 million and $118.0 million for the same periods in 2015. The increases in 2016 were primarily due to increased costs incurred to execute Juno’s clinical development strategy, manufacture its product candidates, and expand its overall research and development capabilities, milestones achieved in 2016, and an increase in stock-based compensation expense. These increases were offset by upfront payments made to Fate Therapeutics and Editas in 2015, the gains recognized during the first two quarters of 2016 related to the change in the estimated value of Juno’s contingent consideration liabilities, and the difference between the periods in expense related to Juno’s estimated success payment liability. For the three months ended June 30, 2016 and 2015, Juno recorded expenses of $3.5 million and $4.0 million, respectively, related to Juno’s success payment liability. For the six months ended June 30, 2016, Juno recorded a gain of $3.1 million related to Juno’s success payment liability, compared to an expense of $42.9 million for the same period in 2015, resulting in a decrease of $46.0 million in research and development expense for the six months ended June 30, 2016.

Non-GAAP R&D Expenses: Non-GAAP research and development expenses for the three and six months ended June 30, 2016 were $72.1 million and $152.3 million, respectively, compared to $23.9 million and $40.9 million for the same periods in 2015. Non-GAAP research and development expenses for the three and six months ended June 30, 2016 include $8.9 million and $18.0 million of stock-based compensation expense, respectively, compared to $2.3 million and $4.1 million for the same periods in 2015. Non-GAAP research and development expenses in the first half of 2016 exclude the following:
An expense of $3.5 million for the three months ended June 30, 2016 and a gain of $3.1 million for the six months ended June 30, 2016 associated with the change in the estimated value and elapsed service period for Juno’s potential success payment liabilities to FHCRC and MSK.

Non-cash stock-based compensation expense of $1.2 million and $2.4 million for the three and six months ended June 30, 2016, respectively, related to a 2013 restricted stock award to a co-founding director that became a consultant upon his departure from Juno’s board of directors in 2014.

A gain of $4.5 million and $5.5 million for the three and six months ended June 30, 2016, respectively, associated with the change in the estimated fair value of the contingent consideration liabilities recorded in connection with the Stage and X-Body acquisitions.
Non-GAAP research and development expenses in the first half of 2015 exclude the following:
Expense of $4.0 million and $42.9 million for the three and six months ended June 30, 2015, respectively, associated with the change in estimated value and elapsed accrual period for Juno’s potential success payment liabilities to FHCRC and MSK.

Non-cash stock-based compensation expense of $1.7 million and $3.6 million for the three and six months ended June 30, 2015, respectively, related to a 2013 restricted stock award to a co-founding director that became a consultant upon his departure from Juno’s board of directors in 2014.

An expense of $0.1 million for the three and six months ended June 30, 2015, associated with the change in the estimated fair value of the contingent consideration liabilities recorded in connection with the Stage and X-Body acquisitions.

Upfront payments related to license agreements of $30.8 million for the three and six months ended June 30, 2015 associated with the Editas and Fate Therapeutics collaborations.

G&A Expenses: General and administrative expenses on a GAAP basis for the three and six months ended June 30, 2016 were $16.8 million and $32.8 million, respectively, compared to $20.2 million and $27.6 million for the same periods in 2015. The decrease in the second quarter of 2016 compared to the same period in 2015 was primarily due to lower litigation and business development costs, offset by increased personnel costs, including non-cash stock-based compensation expense, and increased consulting fees including costs related to commercial readiness. The increase in the first half of 2016 compared to the first half of 2015 was primarily due to increased personnel costs, including non-cash stock-based compensation expense, and consulting fees including costs related to commercial readiness, offset by lower litigation and business development expenses. General and administrative expenses include $5.5 million and $10.4 million of non-cash stock-based compensation expense for the three and six months ended June 30, 2016, respectively, compared to $3.0 million and $4.8 million for the same periods in 2015.

GAAP Net Loss: Net loss for the three and six months ended June 30, 2016 was $64.8 million, or $0.64 per share, and $135.9 million, or $1.35 per share, respectively, compared to $66.0 million, or $0.79 per share and $130.9 million, or $1.58 per share for the same periods in 2015.

Non-GAAP Net Loss: Non-GAAP net loss, which incorporates the non-GAAP R&D expense, for the three and six months ended June 30, 2016 was $64.6 million, or $0.64 per share and $142.1 million, or $1.40 per share, respectively, compared to $29.6 million, or $0.35 per share and $53.8 million, or $0.65 per share, respectively, for the same periods in 2015.
A reconciliation of GAAP net loss to non-GAAP net loss is presented below under "Non-GAAP Financial Measures."

2016 Financial Guidance
Juno reaffirms 2016 cash burn guidance, excluding cash inflows or outflows from business development activities, of between $220 million and $250 million.
Operating burn estimated to be between $170 million and $195 million.
Capital expenditures estimated to be between $40 million and $55 million, the vast majority of which are related to one-time infrastructure build-outs.

Alnylam Pharmaceuticals Reports Second Quarter 2016 Financial Results and Highlights Recent Period Progress

On August 4, 2016 Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, reported its consolidated financial results for the second quarter 2016, and highlighted recent progress in advancing its pipeline (Press release, Alnylam, AUG 4, 2016, View Source;p=RssLanding&cat=news&id=2193147 [SID:1234514268]).

"We continue to advance our pipeline of now ten investigational RNAi therapeutics, an entirely new and innovative class of medicines, across a broad range of diseases. We believe our two latest stage programs, patisiran and revusiran, have demonstrated encouraging progress for patients with hATTR amyloidosis," said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. "We also recently presented new results in our hemophilia program showing that a once-monthly, subcutaneous regimen of fitusiran can achieve a median estimated annualized bleeding rate of zero in hemophilia A and B patients. In addition, we presented encouraging initial data in hemophilia patients with inhibitors. Through the end of the year, we are anticipating a very data rich period marked with over six planned clinical readouts – we look forward to sharing our continued progress."

Second Quarter 2016 and Recent Significant Corporate Highlights

Advanced investigational pipeline programs in Genetic Medicine Strategic Therapeutic Area (STAr).
Advanced investigational RNAi therapeutic programs for the treatment of transthyrethin (TTR)-mediated amyloidosis (ATTR amyloidosis).
Reported positive initial 24-month data from ongoing Phase 2 open-label extension (OLE) study with patisiran for the treatment of hereditary ATTR amyloidosis with polyneuropathy (hATTR-PN). Results showed that patisiran can potentially halt or improve neuropathy progression. Patisiran administration was also found to be generally well tolerated in hATTR-PN patients out to 25 months, with no drug-related serious adverse events (SAEs) reported through the data transfer date.
Presented baseline demographic data from APOLLO Phase 3 study of patisiran, revealing enrollment of a globally representative patient population with a wide range of disease severity and TTR mutations.
Reported initial 12-month results from ongoing Phase 2 OLE study with revusiran for the treatment of hereditary ATTR amyloidosis with cardiomyopathy (hATTR-CM).
Initiated Phase 1 clinical trial for ALN-TTRsc02, an Enhanced Stabilization Chemistry (ESC)-GalNAc-siRNA conjugate targeting TTR for the treatment of ATTR amyloidosis, which is expected to enable a low volume, once quarterly, subcutaneous dosing regimen.
Reported positive interim clinical results from Phase 1 study of fitusiran for the treatment of hemophilia and rare bleeding disorders (RBD).
Fitusiran achieved a median estimated annualized bleeding rate (ABR) of zero in hemophilia patients without inhibitors. In the initial low-dose cohort of patients with inhibitors, fitusiran achieved antithrombin lowering, increased thrombin generation, and preliminary evidence for reduced bleeding. Fitusiran administration was generally well tolerated in patients with and without inhibitors, with no SAEs related to study drug, and no thromboembolic events or laboratory evidence (based on D-dimer, platelet count, fibrinogen, and/or PT/INR) of pathologic clot formation through the data transfer date.
Continued dosing hemophilia patients in ongoing Phase 1/2 OLE study, with patients currently having received up to 13 months of dosing.
The Company also updated its guidance for Phase 3 initiation, and now plans to start studies in early 2017.
Reported initial clinical results in patients with paroxysmal nocturnal hemoglobinuria (PNH) from ongoing Phase 1/2 study of ALN-CC5 for the treatment of complement-mediated diseases.
Initial data support the potential for ALN-CC5 to reduce the dose and frequency of eculizumab, as well as to improve disease control in eculizumab inadequate responders.
ALN-CC5 was generally well tolerated in patients with PNH after multiple doses, with the majority of adverse events (AEs) being mild or moderate in severity. There were no drug related SAEs or discontinuations due to AEs in the study through the data transfer date.
The Company announces today that the European Medicines Agency (EMA) has granted Orphan Drug Designation to ALN-AS1 for the treatment of acute hepatic porphyrias.
The Company also announces today the publication of pre-clinical data with ALN-GO1 for the treatment of primary hyperoxaluria type 1 (PH1) in the Journal of the American Society of Nephrology (Liebow et al., J Am Soc Nephrol, 2016; doi:10.1681/ASN.2016030338).
Advanced investigational pipeline programs in Cardio-Metabolic Disease STAr.
The Medicines Company announced completion of enrollment in its Phase 2 ORION-1 study for ALN-PCSsc (also known as PCSK9si). The trial enrolled 501 patients with atherosclerotic cardiovascular disease (ASCVD), exceeding the original enrollment target of 480 patients.
Advanced investigational pipeline programs in Hepatic Infectious Disease STAr.
Initiated Phase 1/2 clinical trial with ALN-HBV for the treatment of hepatitis B virus (HBV) infection.
Broke ground on new manufacturing facility in Norton, Massachusetts. The 200,000 square foot, state-of-the-art facility is being built to support the Company’s expanding development pipeline and transition toward commercial stage.
Expanded Management Team with appointments of Adrian Dana, M.D., Vice President of Drug Safety and Pharmacovigilance; Brendan Martin, General Manager, UK and Ireland; Jeffrey Miller, Vice President, General Manager, CC5 Program; and Andrew Slugg, Vice President of Regulatory Affairs.
Upcoming Events in 2H 2016

Alnylam announces today that it plans to present clinical data at these upcoming conferences:
Complete data from Parts A and B (single and multiple ascending dose, respectively) of the ongoing Phase 1 clinical trial of ALN-AS1 in patients who are asymptomatic "high excreters" (ASHE) at the 2016 Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium, being held September 6 – 9, 2016 in Rome, Italy, in an oral presentation on Wednesday, September 7, at 2:15 pm Central European Summer Time (8:15 am ET).
Initial clinical results from the ongoing Phase 1/2 study of ALN-GO1 at the 17th Congress of the International Pediatric Nephrology Association (IPNA), being held September 20 – 24, 2016 in Iguaçu, Brazil, in an oral presentation on Saturday, September 24, at 3:25 pm Brasília Time (2:25 pm ET).
Initial Phase 1/2 data for ALN-AAT at the 12th Annual Meeting of the Oligonucleotide Therapeutics Society (OTS), being held September 25 – 28, 2016 in Montreal, Canada;
Alnylam also announces today that it plans to host an R&D Day on the morning of Friday, December 16, 2016 at the Westin New York at Times Square in New York City.
In addition, in the second half of 2016, Alnylam plans to:
Complete enrollment in ENDEAVOUR Phase 3 study of revusiran;
Present additional clinical data from the fitusiran Phase 1 study and initial data from the Phase 1/2 OLE study;
Start a new Phase 2 trial with ALN-CC5 in inadequate eculizumab responder PNH patients;
Present additional clinical data from the ongoing Phase 1/2 trial of ALN-CC5 in PNH patients;
Present initial ALN-AS1 data in recurrent attack porphyria patients;
Present initial ALN-TTRsc02 Phase 1 data;
File a Clinical Trial Application for a new Genetic Medicine program; and
Consistent with guidance from The Medicines Company, present initial Phase 2 data for ALN-PCSsc.
Upcoming RNAi Roundtables

Alnylam plans to continue hosting its series of online "RNAi Roundtables" in August, September, and October. Upcoming events include:
Fitusiran for the treatment of hemophilia and rare bleeding disorders
Monday, August 22, 10:30 – 11:45 am ET
Akin Akinc, Ph.D., Vice President, General Manager, Fitusiran
Benny Sorensen, M.D., Ph.D., Senior Director, Clinical Research
Guest Speaker: Brian O’Mahony, Chief Executive, Irish Haemophilia Society Ltd. and person living with severe hemophilia B
ALN-CC5 for the treatment of complement-mediated diseases
Wednesday, August 31, 11:00 am – 12:00 pm ET
Jeff Miller, Vice President, General Manager, CC5 Program
Pushkal Garg, M.D., Senior Vice President, Clinical Development
Guest Speaker: Anita Hill, M.D., Ph.D., MRCP, FRCPath, Consultant Haematologist for Leeds Teaching Hospitals NHS Trust, UK, and Lead for the National PNH Service in England
ALN-AS1 for the treatment of acute hepatic porphyrias
Tuesday, September 13, 11:30 am – 12:45 pm ET
John Maraganore, Ph.D., Chief Executive Officer
William Querbes, Ph.D., Associate Director, Research
Guest Speaker: Ariel Lager, living with Acute Intermittent Porphyria
ALN-GO1 for the treatment of primary hyperoxaluria type 1 (PH1)
Tuesday, September 27, 10:00 – 11:00 am ET
Barry Greene, President and Chief Operating Officer
David Erbe, Ph.D., Director, Research
Guest Speaker: Sally-Anne Hulton, M.D., FRCPCH, MRCP, FCP, MBBCh, Consultant Paediatric Nephrologist and Clinical Lead, Birmingham Children’s Hospital NHS Trust
Guest Speaker: Jennifer Lawrence, M.D. (mother of George Tidmore, a PH1 patient)
ALN-HBV for the treatment of hepatitis B virus (HBV) infection
Tuesday, October 11, 9:00 am – 10:00 am ET
Barry Greene, President and Chief Operating Officer
Laura Sepp-Lorenzino, Ph.D., Vice President, Entrepreneur-in-Residence
Guest Speaker: Heiner Wedemeyer, M.D., Managing Senior Physician and Assistant Professor in the Department of Gastroenterology, Hepatology and Endocrinology at Hannover Medical School
Additional details for the RNAi Roundtables will be provided at www.alnylam.com/roundtables.

Financials

"Alnylam continues to maintain a strong balance sheet, ending the second quarter of 2016 with approximately $1.28 billion in cash," said Michael Mason, Vice President, Finance and Treasurer. "Our financial strength allows us to continue to invest in a broad pipeline of investigational RNAi therapeutics across our three STArs, aligned with achievement of our ‘Alnylam 2020′ goals. As for financial guidance this year, we remain on track to end 2016 with greater than $1.0 billion in cash, including $150.0 million in restricted investments."

Cash and Investments

At June 30, 2016, Alnylam had cash, cash equivalents and marketable securities, and restricted investments of $1.28 billion, as compared to $1.28 billion at December 31, 2015.

Credit Agreements

In April 2016, Alnylam entered into $150.0 million of term loan agreements, related to the build out of the Company’s new manufacturing facility, that mature in April 2021. Interest on the borrowings is calculated based on LIBOR plus 0.45 percent. The obligations under the term loan agreements are secured by cash collateral in an amount equal to, at any given time, at least 100 percent of the principal amount of all term loans outstanding under the agreements at such time.

GAAP Net Loss

The net loss according to accounting principles generally accepted in the U.S. (GAAP) for the second quarter of 2016 was $90.1 million, or $1.05 per share on both a basic and diluted basis (including $15.8 million, or $0.18 per share of non-cash stock-based compensation expense), as compared to a net loss of $71.8 million, or $0.85 per share on both a basic and diluted basis (including $10.2 million, or $0.12 per share of non-cash stock-based compensation expense), for the same period in the previous year.

Revenues

Revenues were $8.7 million in the second quarter of 2016 and 2015. Revenues for the second quarter of 2016 included $5.4 million from the company’s alliance with Sanofi Genzyme and $3.3 million from the company’s alliance with The Medicines Company. The company expects net revenues from collaborators to increase during the second half of 2016 due to an expected increase in expense reimbursement from Sanofi Genzyme.

Research and Development Expenses

Research and development (R&D) expenses were $83.2 million in the second quarter of 2016, which included $9.3 million of non-cash stock-based compensation, as compared to $67.0 million in the second quarter of 2015, which included $6.1 million of non-cash stock-based compensation. The increase in R&D expenses for the quarter ended June 30, 2016 as compared to the prior year period was due primarily to higher compensation and related expenses and non-cash stock-based compensation expenses resulting from a significant increase in headcount during the period as the company continues to advance and expand its development pipeline. In addition, clinical trial and manufacturing and external services expenses increased during the quarter ended June 30, 2016 as compared to the quarter ended June 30, 2015 as a result of the significant advancement of the company’s Genetic Medicine pipeline. The company expects that R&D expenses during the second half of 2016 will increase compared to the first half of 2016 as it continues to develop its pipeline and advance its product candidates into clinical trials, but that such expenses will be variable on a quarterly basis depending on the timing of manufacturing batches, clinical trial enrollment, and non-cash stock-based compensation expenses.

General and Administrative Expenses

General and administrative (G&A) expenses were $18.0 million in the second quarter of 2016, which included $6.5 million of non-cash stock-based compensation, as compared to $14.6 million in the second quarter of 2015, which included $4.0 million of non-cash stock-based compensation. The increase in G&A expenses for the quarter ended June 30, 2016 as compared to the prior year period was due primarily to an increase in compensation and related expenses and non-cash stock-based compensation expense due to an increase in headcount. The company expects that G&A expenses during the second half of 2016 will remain relatively consistent with the first half of 2016.

Medigene reports results of first six months 2016

On August 5, 2016 Medigene AG (MDG1, Frankfurt, Prime Standard), a clinical stage immuno-oncology company focusing on the development of T-cell immunotherapies for the treatment of cancer, reported financial results and corporate updates for the first six months of 2016 (Press release, MediGene, AUG 4, 2016, View Source [SID:1234514267]).

Major events since the beginning of 2016:

Immunotherapies:

Phase II of Phase I/II trial with DC vaccine for the treatment of acute myeloid leukaemia (AML) initiated following positive recommendation by DSMB
Collaboration started with Max Delbrück Center and The Charité in Berlin for Germany’s first investigator-initiated clinical TCR trial
DC platform and TCR platform strengthened by new patents
Additional viral vector production capacities secured for clinical TCR trials
Company:

Expansion of management team
Capital increase by contribution in kind to fund milestone payment for the beginning of Phase II of Medigene’s Phase I/II trial with DC vaccines
Key figures in the first half of 2016:

R&D expenses increased by 23% to €5,079 k (6M 2015: €4,117 k)
Total revenue increased by 62% to €5,470 k (6M 2015: €3,372 k)
EBITDA loss reduced by 6% to €4,011 k (6M 2015: €4,251 k)
Cash and cash equivalents and time deposits increased by 4% to €48,672 k (12/31/2015: €46,759 k)
Prof. Dolores Schendel, Chief Executive Officer and CSO of Medigene AG, comments: "In recent months we have made huge advances in preparations for the clinical development of TCRs and strengthened our portfolio of patents for this highly innovative therapy. In addition, our DC trial reached a meaningful milestone with progression into Phase II. I am delighted to be able to announce such significant progress in the first five months of my term as CEO of Medigene AG."

Dave Lemus, Chief Operating Officer of Medigene AG adds: "The continued improvement in our financial position in the first six months of 2016 reflects in part the successful repositioning of Medigene as a leading player in the field of immuno-oncology. Moreover, our solid financial situation allows us to increasingly exploit the full potential of our immunotherapy capabilities by funding further research and development activities."

Key figures in first half of 2016:

In € k 6M-2016

6M-2015

Change

Results of operations
Revenue 1,385 1,363 2%
Other operating income 4,085 2,009 103%
thereof gain on sale of intangible assets, net 2,365 0 -
Total revenue 5,470 3,372 62%
Cost of sales -773 -471 64%
Gross profit 4,697 2,901 62%
Selling and general administrative expenses -4,013 -3,476 15%
Research and development expenses -5,079 -4,117 23%
Operating result -4,395 -4,692 -6%
Income from the sale of financial assets 4,242 0 -
Net profit/loss for the period -401 -6,113 -93%
EBITDA -4,011 -4,251 -6%
Earnings per share (€) -0.02 -0.44 -95%
Personnel expenses -4,536 -3,581 27%

Cash flows
Net cash used in operating activities -8,818 -4,953 78%
Net cash from/used in investing activities 10,864 -159 >-200%
Net cash from financing activities -132 195 -168%

Balance sheet data as at June 30, 2016 and December 31, 2015
Cash and cash equivalents and time deposits 48,672 46,759 4%
Total assets 105,599 113,531 -7%
Current liabilities 5,244 9,664 -46%
Non-current liabilities 12,781 13,879 -8%
Shareholders’ equity 87,574 89,988 -3%
Equity ratio (%) 83 79 5%

Employees as at June 30 80 71 13%
FTE as at June 30 73 65 12%

Medigene share as at June 30
Total number of shares outstanding 20,088,260 14,051,815 43%
Total revenue of the Company increased by 62% to €5,470 k in the reporting period (6M 2015: €3,372 k) on account of non-recurring impacts related to the sale of EndoTAG in December 2015. Income of €2,365 k was generated by this sale in the first quarter of 2016. The Company generates its revenue and other operating income from its non-core business.

Research and development expenses increased by 23% in the first six months of 2016 to €5,079 k (6M 2015: €4,117 k) as expected. The increase in these expenses is mainly due to planned increases in expenses for preclinical and clinical trials for Medigene’s immunotherapies which increased significantly by 68% to €4,345 k in the first six months of 2016 (6M 2015: €2,585 k). This increase was partially offset by the decrease in development expenses for other sold products.

Despite higher research and development expenses for Medigene’s immunotherapy programs, the EBITDA loss decreased by 6% in the first half of 2016 to €4,011 k (6M-2015: €4,251 k). Medigene’s EBITDA is derived from the net profit/loss for the period; it excludes any taxes, financial results (comprising interest income, interest expense, other financial result and income the sale of financial assets), foreign exchange gains or losses, share of results of associates, or depreciation or amortization.

Due to non-recurring effects, including the sale of EndoTAG and Immunocore shares, the net loss after taxes improved in the first six months of 2016 to just €401 k (6M 2015: €6,113 k).

The net cash used in operating activities increased to €8,818 k in the first half of 2016 (6M 2015: €4,953 k). This represents an average monthly cash outflow of €1.5 m in the first six months of 2016 (6M 2015: €0.8 m). The major part of the cash used was directed at research and development, sales and administration and an increase in working capital. The current level of cash used in operating activities is not indicative of future trends as it is significantly impacted by non-recurring payments in partner arrangements and research and development expenses, which in turn are impacted by project stage/status.

Medigene recorded a cash inflow from investing activities of €10,864 k in the first six months of 2016 in contrast to a cash outflow of €159 k in the comparable period of the prior year. The cash inflow resulted primarily from the sale of shares in Immunocore Ltd. for €6 m and from the sale of Catherex, Inc. to Amgen Inc. for €4 m.

The cash and cash equivalents and time deposits of the Company amounted to €48,672 k as at the end of the reporting period (December 31, 2015: €46,759 k). Medigene generated a cash inflow of €10,672 k from the above sales.

Financial forecast 2016:
Medigene confirms its financial guidance for the fiscal year 2016. In line with previous expectations, the Company plans to expand its clinical development programs, which will significantly increase R&D expenses in the immunotherapies segment to €9 – 11 m (2015: €5.5 m). The EBITDA loss for 2016 is anticipated to come to €10 -12 m (2015: €9.5 m).

The Company expects total Veregen revenue of €3 – 4 m in 2016 (2015: €3.1 m), and stable or increasing total revenue (2015: €6.8 m). As revenue is not generated in the Company’s core business of immunotherapies, these figures are not indicative of progress in the Company’s core business.. This financial guidance also does not include any possible revenues from potential new partnership agreements, or any exchange rate fluctuation.

The detailed 6-Months Report 2016 is available online at:
View Source

Tetraphase Pharmaceuticals Reports Second Quarter 2016 Financial Results and Highlights Recent Progress

On August 4, 2016 Tetraphase Pharmaceuticals, Inc. (NASDAQ:TTPH), a clinical stage biopharmaceutical company developing novel antibiotics to treat life-threatening multidrug-resistant (MDR) infections, reported financial results for the second quarter ended June 30, 2016, and provided an overview of certain corporate achievements and plans (Press release, Tetraphase, AUG 4, 2016, View Source [SID:1234514266]).

"During the second quarter, we finalized the protocol for IGNITE4, our upcoming phase 3 clinical trial evaluating IV eravacycline in patients with complicated intra-abdominal infections (cIAI), and remain on track to initiate this trial early in the fourth quarter of 2016," said Guy Macdonald, Tetraphase’s President and Chief Executive Officer. "Based on discussions with the FDA, we have designed IGNITE4 using a 12.5% non-inferiority margin and a trial population of approximately 450 patients. We currently anticipate reporting top-line results from IGNITE4 as early as the fourth quarter of 2017. In parallel, we are also working to finalize the trial design for IGNITE3, our phase 3 clinical trial evaluating once-daily IV eravacycline in complicated urinary tract infections (cUTI), and we look forward to providing details regarding the design and timing of IGNITE3 once the protocol is completed."

Dr. Patrick Horn, Tetraphase’s Chief Medical Officer, commented, "Separately, we continue to advance development work on the oral formulation of eravacycline. Early data from this phase 1 program indicate that the oral dosing regimen used in IGNITE2 leads to lower systemic levels of eravacycline than expected. These data also suggest that administration of oral eravacycline in a fasted state results in increased drug exposure. With this information now in hand, we have commenced further clinical testing designed to evaluate several additional variables associated with optimizing the oral eravacycline dosing regimen."

"Along with the advancement of our clinical programs, we continue to build the profile of eravacycline by testing it against multidrug-resistant bacterial strains in vitro and, at ASM Microbe and ECCMID we presented data showing eravacycline’s potent activity against these difficult-to-treat pathogens, including carbapenem-resistant enterobacteriaceae and Acinetobacter baumannii," added Dr. Horn. "We also recently confirmed that in in vitro studies eravacycline retained its potent activity against colistin-resistant clinical isolates expressing the mcr-1 gene, which was just found in bacteria in the U.S. for the first time, and we look forward to presenting these data at an upcoming medical meeting."

Second Quarter 2016 Financial Results

As of June 30, 2016, Tetraphase had cash and cash equivalents of $178.3 million and 36.7 million shares outstanding. The company expects that its cash and cash equivalents, as well as expected revenue from its U.S. government awards, will be sufficient to fund operations into the middle of 2018.

Revenues during the second quarter of 2016 were $1.2 million compared to $3.3 million for the same period in 2015. Revenues for each period consisted of contract and grant revenue under the Company’s U.S. government awards for the development of Tetraphase compounds for the treatment of diseases caused by bacterial biothreat pathogens and for certain infections caused by life-threatening multidrug-resistant bacteria. The decrease in revenues was primarily due to the scope and timing of activities related to our BARDA Contract conducted during the quarter ended June 30, 2016.

Research and development (R&D) expenses for the second quarter of 2016 were $13.7 million compared to $22.9 million for the same period in 2015. The decrease in R&D expenses was primarily due to lower costs related to our Phase 3 clinical program for eravacycline.

General and administrative (G&A) expenses for the second quarter of 2016 were $4.8 million compared to $6.5 million for the same period in 2015. The decrease in G&A expenses was primarily due to a decrease in stock-based compensation expense, as well as a decrease in pre-commercialization activities for eravacycline.

For the second quarter of 2016, Tetraphase reported a net loss of $17.2 million, or $0.47 per share, compared to a net loss of $26.0 million, or $0.72 per share, for the same period in 2015.

Second Quarter and Recent Corporate Highlights

Presented data at the 26th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), including preclinical data for eravacycline and TP-6076.

Received guidance from the U.S. FDA confirming that one additional positive phase 3 clinical trial will be required to support a New Drug Application (NDA) submission for IV eravacycline. Based on the FDA’s guidance, Tetraphase plans to conduct two additional pivotal phase 3 clinical trials: one in cIAI (IGNITE4) to support the NDA filing and one in cUTI (IGNITE3) that will form the basis of a supplemental NDA for IV eravacycline.

Finalized the clinical trial design for IGNITE4 to support an NDA filing for IV eravacycline for cIAI. IGNITE4, the Company’s planned phase 3 clinical trial evaluating the efficacy and safety of twice-daily IV eravacycline compared to meropenem in patients with cIAI, is expected to enroll approximately 450 patients and the primary analysis will be conducted using a 12.5% non-inferiority margin. Tetraphase expects to initiate this clinical trial early in the fourth quarter of 2016, with top-line results expected as early as the fourth quarter of 2017.

Presented data at the American Society of Microbiology (ASM) Microbe 2016 Conference, including clinical and preclinical data for eravacycline and preclinical data for TP-271, a novel, broad-spectrum antibiotic candidate which is being developed to combat respiratory disease caused by bacterial biothreats and antibiotic-resistant public health pathogens, as well as bacterial pathogens associated with community-acquired bacterial pneumonia.

Commenced patient dosing in a phase 1 clinical trial for TP-6076, the lead candidate from the Company’s second-generation antibiotic program which has demonstrated potent preclinical activity against multidrug-resistant Gram-negative pathogens.
Continued clinical testing designed to advance the development of an oral dose formulation of eravacycline. During the second quarter, Tetraphase completed preliminary clinical testing which indicates that the overall efficacy results in IGNITE2 were likely driven by underperformance of the oral formulation due to a food effect. Preliminary clinical testing also suggests that administration of oral eravacycline in a fasted state results in increased drug exposure. Further clinical testing is now underway to evaluate several additional variables associated with increasing drug exposure and optimizing the oral eravacycline dosing regimen.
Added to the Russell Microcap Index when the Russell Investment Group reconstituted its family of U.S. indexes in late June 2016.