On August 9, 2021 bluebird bio, Inc. (NASDAQ: BLUE) reported financial results and business highlights for the second quarter ended June 30, 2021 and provided operational updates, including the announcement that the U.S. Food and Drug Administration (FDA) placed a clinical hold on clinical studies of elivaldogene autotemcel (eli-cel, Lenti-D) gene therapy (licensed as SKYSONA in Europe) for cerebral adrenoleukodystrophy (CALD) (Press release, bluebird bio, AUG 9, 2021, View Source [SID1234586076]).

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"I’m tremendously proud of what bluebird has accomplished this quarter both operationally and strategically to ready ourselves to launch both bluebird bio and 2seventy bio," said Nick Leschly, chief bluebird. "Seven months after announcing our intent to split, and thanks to the incredibly hard work by our teams, we have created a solid foundation for both organizations. The ABECMA launch is exceeding expectations, the oncology INDs and severe genetic disease (SGD) biologics license application (BLA) filings are tracking for later this year, and we have established clear visions and leadership teams for each business. Importantly, we have made tough strategic decisions to reshape the overall cost structure to allow both companies to launch in a strong position to execute through important value-creating milestones."

BUSINESS SEPARATION

In January 2021, bluebird announced its intent to separate into two independent, publicly traded companies (bluebird bio and 2seventy bio). The company expects the separation to be completed by the end of 2021 and to be tax-free to bluebird shareholders.

Key members of the executive teams of both companies have been announced, effective upon completion of the planned separation. This includes Andrew Obenshain as CEO of bluebird and Nick Leschly as CEO of 2seventy.
The full board of directors for both companies will be announced closer to the separation date.
2seventy has confidentially filed its Form 10 Registration Statement with the U.S. Securities and Exchange Commission (SEC), in which it describes the planned tax-free spin-off of 2seventy as a publicly traded company.
bluebird plans to distribute 100% of the outstanding shares of 2seventy common stock to bluebird’s stockholders on a pro-rata basis.
Based on current cash position and the expected $110M upfront payment upon closing of the National Resilience, Inc. strategic collaboration, the Company anticipates having a cash balance of approximately $900M at the time of separation. Together with existing and emerging sources of revenue, we expect our cash balance will be sufficient to fund approximately 24 months of operations for bluebird and 2seventy under current business plans.
ELI-CEL SAFETY UPDATE

The company received a reported Suspected Unexpected Serious Adverse Reaction (SUSAR) of myelodysplastic syndrome (MDS), that is likely mediated by Lenti-D lentiviral vector (LVV) insertion, in a patient who was treated with eli-cel, or Lenti-D drug product for CALD over one year ago in the Phase 3 ALD-104 study. Evidence currently available suggests that specific design features of Lenti-D LVV likely contributed to this event. The company has shared this information with the independent data monitoring committee of the study and the FDA has placed the eli-cel program on a clinical hold. The company does not anticipate the clinical hold to impact its programs in sickle cell disease (SCD), β-thalassemia or oncology. Subject to resolution of the clinical hold, the company anticipates completing the submission of the rolling BLA for eli-cel in 2021.

"Our hearts go out to this patient and his family, who are dealing with a challenging diagnosis," said Nick Leschly, chief bluebird. "Given what we know, we remain confident that eli-cel can offer hope for patients and families impacted by this devastating disease who have very few treatment options. We are committed to working with regulators and physicians in order to resolve this hold as soon as possible and bring this important therapy to patients in need."

BLUEBIRD BIO BUSINESS UPDATE

Today, bluebird bio is announcing that the company intends to focus its SGD business on the U.S. market and on further investments in research and development to optimize its core three programs in SCD, β-thalassemia and CALD, as well as on the development of a pipeline exploring new disease indications using in vivo LVV technology. The company remains focused and is on track to complete the rolling submissions of the U.S. BLAs in β-thalassemia in 3Q 2021 and CALD in 2021, pending resolution of the eli-cel clinical hold.

In connection with the planned completion of the business separation in the fourth quarter of 2021 and pivot to U.S.-centric efforts for SGD, bluebird plans an orderly wind down of its operations in Europe and to explore how to give patients in Europe access to its gene therapies, including potentially out-licensing the ex-U.S. rights to its three lead products to a company with European experience and capabilities.

"bluebird’s decision to focus on the U.S. market is driven by the challenges of achieving appropriate value recognition and market access for ZYNTEGLO in Europe, which makes bringing its transformative gene therapies like ZYNTEGLO and SKYSONA to patients and physicians in Europe untenable for a small innovative company at this time," said Andrew Obenshain, president, severe genetic diseases, bluebird bio. "While European regulators have been innovative partners in supporting accelerated regulatory paths for these therapies, European payers have not yet evolved their approach to gene therapy in a way that can recognize the innovation and the expected life-long benefit of these products. We are committed to and hope to find a potential partner who can help us carry forward our therapies in Europe."

BLUEBIRD BIO RECENT HIGHLIGHTS

BB1111 AND ZYNTEGLO CLINICAL HOLD LIFT – On June 7, 2021, bluebird announced that the FDA has lifted the clinical holds on the Phase 1/2 HGB-206 and Phase 3 HGB-210 studies of LentiGlobin for SCD gene therapy (bb1111) for adult and pediatric patients with SCD, and the Phase 3 Northstar-2 (HGB-207) and Northstar-3 (HGB-212) studies of betibeglogene autotemcel gene therapy (beti-cel; licensed as ZYNTEGLO in the EU and the UK) for adult, adolescent and pediatric patients with transfusion-dependent β-thalassemia (TDT). The company is working closely with study investigators and clinical trial sites to resume all study activities as soon as possible.
β-THALASSEMIA

EHA DATA – On June 11, 2021, bluebird presented data from several studies of beti-cel in adult, adolescent and pediatric patients with TDT. These data were presented during EHA (Free EHA Whitepaper)2021 Virtual, the 26th Annual Congress of the European Hematology Association (EHA) (Free EHA Whitepaper). With 51 patients enrolled, data from the long-term follow-up study (LTF-303) show that all patients treated with beti-cel who achieve transfusion independence (TI) remain free from transfusions, with the longest follow-up of seven years. Across Phase 3 studies, 89% (32/36) of evaluable patients across ages and genotypes achieved TI and remain transfusion free, including 91% (20/22) of evaluable pediatric patients under the age of 18. Data from bluebird bio’s Phase 1/2 and Phase 3 clinical studies represent more than 220 patient-years of experience with beti-cel.
EU MARKETING AUTHORIZATION – On July 9, 2021, bluebird announced that the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has concluded based on the review of all available data that the benefit-risk balance of ZYNTEGLO (beti-cel) remains favorable. bluebird bio informed the EMA that the company has lifted the voluntary marketing suspension. Today, bluebird is announcing that on the basis of the PRAC decision, the EMA CHMP (Committee for Medicinal Products for Human Use) has endorsed the positive recommendation for ZYNTEGLO by the PRAC. A confirmatory decision by the European Commission (EC) is expected in 3Q 2021.
CEREBRAL ADRENOLEUKODYSTROPHY

SKYSONA EC DECISION – On July 21, 2021, bluebird announced that the EC granted marketing authorization of SKYSONA, a one-time gene therapy for the treatment of early CALD in patients less than 18 years of age with an ABCD1 genetic mutation, and for whom a human leukocyte antigen (HLA)-matched sibling hematopoietic (blood) stem cell (HSC) donor is not available.
2SEVENTY BIO RECENT HIGHLIGHTS

ABECMA LAUNCH – This quarter, bluebird and Bristol-Myers Squibb (BMS) launched ABECMA (idecabtagene vicleucel; ide-cel) in the U.S. ABECMA generated total U.S. revenues of $24 million in 2Q 2021 which bluebird shares equally with BMS. As of June 30, 2021, over 65 sites in the U.S. had been qualified to treat patients. bluebird and BMS have reported robust demand for ABECMA and are working to continue to increase manufacturing capacity over time.
STRATEGIC MANUFACTURING ALLIANCE – On July 28, 2021, bluebird and National Resilience, Inc. (Resilience) announced a strategic alliance aimed to accelerate the early research, development and delivery of cell therapies. As part of the agreement, Resilience will acquire bluebird’s Research Triangle (bRT) manufacturing facility located in North Carolina for $110 million and will retain all of the more than 100 highly skilled technical staff and administrators currently employed at the site. Resilience will continue to support vector supply for both bluebird and 2seventy. The two companies are also finalizing a definitive agreement to establish partner programs that will share expense and revenue for successful commercialized oncology products and in parallel establish a next-generation manufacturing R&D collaboration. Additionally, 2seventy plans to invest in internal drug product manufacturing capability and capacity to support its future clinical studies.
KARMMA ASCO (Free ASCO Whitepaper) DATA – On May 19, 2021, bluebird and BMS announced new data and analyses from the pivotal KarMMa study evaluating ABECMA. These data showed a 24.8-month median overall survival in triple-class exposed relapsed/refractory multiple myeloma. With more than 24-month median follow-up, results represent longest follow-up to date from a global clinical trial of a CAR T cell therapy in multiple myeloma with 73% overall response rate and responses ongoing with a median duration of response in patients achieving a ≥CR of 21.5 months. Analysis of characteristics of neurotoxicity (NT) observed in KarMMa study reinforce well-understood safety profile of ABECMA with mostly Grade 1/2 occurrences of NT having early onset and resolution.
UPCOMING ANTICIPATED MILESTONES

BLUEBIRD BIO

bluebird anticipates the separation of its SGD and oncology businesses into two independent, publicly traded companies (bluebird bio and 2seventy bio) to be completed by the end of 2021.
TDT: The company is on track to complete its rolling BLA submission to the FDA for beti-cel in 3Q 2021. This submission is anticipated to include adult, adolescent and pediatric patients with transfusion dependent β-thalassemia across all genotypes (including non-β0/β0 genotypes and β0/β0 genotypes).
CALD: Subject to resolution of the clinical hold, the company plans to complete its rolling BLA submission to the FDA for eli-cel in 2021.
SCD: The company is continuing to evaluate the impact of the recently-lifted clinical hold on bb1111 and plans to continue to work closely with the FDA in their review of these events to provide an update on the company’s development plan and timeline for submission for regulatory approval of bb1111 by year end.
SCD: The company plans to present clinical data from its ongoing HGB-206 clinical study of bb1111 by the end of 2021.
2SEVENTY BIO

Continued commercial launch of ABECMA in the U.S.
Submission of 1-2 investigational new drug (IND) applications by the end of 2021.
Presentation of clinical data from the ongoing CRB-402 study of bb21217 by the end of 2021.
SECOND QUARTER 2021 FINANCIAL RESULTS

Cash Position: Cash, cash equivalents and marketable securities as of June 30, 2021 and December 31, 2020 were $941.6 million and $1.27 billion, respectively. The decrease in cash, cash equivalents and marketable securities is primarily related to cash used in support of ordinary course operating activities.
Revenues: Total revenues were $7.5 million for the three months ended June 30, 2021 compared to $198.9 million for the three months ended June 30, 2020. Total revenues were $20.3 million for the six months ended June 30, 2021 compared to $220.8 million for the six months ended June 30, 2020. The decrease for both periods was primarily driven by a cumulative catch-up adjustment to revenue recorded in connection with the May 2020 BMS contract modification in the second quarter of 2020.
R&D Expenses: Research and development expenses were $144.3 million for the three months ended June 30, 2021 compared to $156.3 million for the three months ended June 30, 2020. Research and development expenses were $298.8 million for the six months ended June 30, 2021 compared to $310.4 million for the six months ended June 30, 2020. The decrease for both periods was primarily driven by decreased manufacturing expenses, a decrease in license and milestone fees, and a decrease in clinical costs in light of safety events in the HGB-206 study of LentiGlobin for SCD gene therapy.
SG&A Expenses: Selling, general and administrative expenses were $78.6 million for the three months ended June 30, 2021 compared to $68.6 million for the three months ended June 30, 2020. Selling, general and administrative expenses were $165.5 million for the six months ended June 30, 2021 compared to $141.9 million for the six months ended June 30, 2020. The increase for both periods was primarily driven by an increase in consulting fees associated with the ongoing project to separate the company’s severe genetic disease and oncology businesses into two independently traded companies as well as an increased employee compensation, benefit, and other headcount related expenses.
Net Loss: Net loss was $241.7 million for the three months ended June 30, 2021 compared to $21.5 million for the three months ended June 30, 2020. Net loss was $447.5 million for the six months ended June 30, 2021 compared to $224.1 million for the six months ended June 30, 2020.
Investor Conference Call Information

bluebird will hold a conference call to discuss this update on Monday, August 9 at 8:00 a.m. ET. Investors may listen to the call by dialing (844) 825-4408 from locations in the United States or +1 (315) 625-3227 from outside the United States. Please refer to conference ID number 9698691.

To access the live webcast of bluebird’s presentation, please visit the "Events & Presentations" page within the Investors & Media section of the bluebird website at View Source A replay of the webcast will be available on the bluebird website for 90 days following the event.

On August 9, 2021 INOVIO (NASDAQ:INO), a biotechnology company focused on rapidly bringing to market precisely designed DNA medicines to treat and protect people from infectious diseases, cancer, and HPV-associated diseases, teported financial results for the quarter ended June 30, 2021 (Press release, Inovio, AUG 9, 2021, View Source [SID1234586112]). INOVIO’s management will host a live conference call and webcast at 4:30 p.m. Eastern Time today to discuss financial results and provide a general business update. The business update includes INOVIO’s COVID-19 vaccine development efforts that address both current and future variants of concern ("VOC"), accompanied with recent developments associated with INOVIO’s various therapeutic programs relating to its DNA medicines platform. The live webcast and replay may be accessed by visiting INOVIO’s website at View Source

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Dr. J. Joseph Kim, President and CEO of INOVIO, said, "With COVID-19 rates surging again globally and an increasing number of breakthrough infections, INOVIO recognizes the need for additional safe and effective first-line vaccines, particularly those which could offer potential boosting capabilities, to combat the spread of the virus and emerging variants, including the rapidly spreading delta variant. INO-4800’s ability to generate CD8 T cells are important to mitigating against variants of concern, including the delta variant. Findings from a study using clinical samples showed that INO-4800 maintained a robust T cell level against the delta variant when compared to T-cell responses from the original wildtype strain. These findings further complement our previously published Phase 1 and 2 trial data for INO-4800. As a reminder, the key advantages of INOVIO’s DNA medicines platform include the ability to generate a balanced immune response that includes engagement of both T cells and B cells, coupled with a favorable transport, thermostability, and tolerability profile. These advantages continue to be integral to our ongoing discussions with countries expected to participate in the global INNOVATE Phase 3 trial for INO-4800, some of which are also considering INO-4800 for both clinical trials and the eventual emergency use authorization (EUA)."

Dr. Kim continued, "In parallel with our global INNOVATE Phase 3 trial, we continue to prepare INOVIO’s next-generation, pan-COVID vaccine candidate, INO-4802, in a Phase 1/2 trial entitled IMPACT (INOVIO INO-4802 Multi-variant Pan-COVID-19 Vaccine Trial), where the goal is to induce cross-reactive immune responses against current and emerging viral variants as either a first-line vaccine, or as a boost."

INOVIO Key Updates & Second Quarter 2021 Highlights

Key Updates

INOVIO expanded its partnership with Advaccine Biopharmaceuticals Suzhou Co., Ltd. ("Advaccine") to jointly conduct the global Phase 3 segment of the ongoing Phase 2/3 trial called INNOVATE (INOVIO INO-4800 Vaccine Trial for Efficacy) in multiple countries.

Subsequent to the quarter end, INOVIO and Advaccine received regulatory allowance to conduct two clinical trials in China investigating heterologous boosting with INO-4800 through partner and trial-sponsor Advaccine, together with Sinovac Biotechnology ("Sinovac"). The studies will evaluate the safety and efficacy of heterologous prime-boost sequential immunizations using INO-4800 and CoronaVac, an inactivated virus COVID-19 vaccine developed by Sinovac and validated by the World Health Organization (WHO) for emergency use.

INO-4800 vaccination maintained a similar level of T cell responses against the delta variant when compared to the T cell responses to the original wildtype strain and showed a similar level of reduced neutralizing antibody activity against the delta variant by the mRNA vaccines. These findings build on previously published results showing that INO-4800 provided broad, cross-reactive immune responses in humans against alpha, beta and gamma VOC.

INOVIO published pre-clinical data as a pre-print for INO-4802 demonstrating cross-reactive immune responses against current and emerging viral variants that shows the potential INOVIO’s next-generation, pan-COVID-19 vaccine candidate, as either a first-line vaccine or potentially as a booster for individuals previously immunized with various wildtype-matched vaccines. INO-4802 induced potent neutralizing antibodies, T cell responses, and protection in a pre-clinical model against the original wildtype strain as well as against the alpha, beta, gamma and, in subsequent research, the delta variant.

Subsequent to the quarter end, INOVIO dosed the first subject in its Phase 2 clinical trial for INO-4700, its DNA vaccine candidate for Middle East Respiratory Syndrome ("MERS"), a disease in the coronavirus family for which there are no approved vaccines. The study, which is sponsored by INOVIO and funded by the Coalition for Epidemic Preparedness Innovations ("CEPI"), is evaluating the safety, tolerability and immunogenicity of INO-4700 in approximately 500 healthy adult volunteers in Jordan and Lebanon.

In 2Q 2021, the University of Pennsylvania enrolled its first patient in a Phase 1b investigator-sponsored trial of INOVIO’s DNA vaccine candidate INO-5401 alone or INO-5401 in combination with INO-9012 delivered with INOVIO’s CELLECTRA smart device, in adult cancer and non-cancer patients with BRCA1 or BRCA2 mutations.

INOVIO Second Quarter 2021 Program Updates

DNA Vaccine Candidates

INO-4800: INNOVATE Phase 3 Trial

INOVIO expanded its partnership with Advaccine to jointly conduct a global Phase 3 trial for INO-4800. Under the terms of the collaboration, INOVIO and Advaccine intend to share equally, subject to specified limitations and conditions, the total cost of the planned global Phase 3 trial, which is estimated to be approximately $100 million. This is an extension of an existing relationship between the two companies, including an exclusive agreement announced in January 2021 under which Advaccine has the exclusive rights to develop, manufacture and commercialize INO-4800 within Greater China, inclusive of mainland China, Hong Kong, Macao and Taiwan. Under the expanded partnership, Advaccine obtained rights to additional Asian countries outside of Greater China. The companies intend to evaluate the safety and efficacy of INO-4800 in a two-dose regimen (2.0 mg), administered one month apart, in a two-to-one randomization in healthy men and non-pregnant women 18 years and older across several countries, with a focus on Latin America, Asia and Africa. The 2.0 mg dose was selected from the Phase 2 segment, where INO-4800 was shown to be generally well-tolerated and immunogenic across all adult age groups. In particular, the geometric mean fold rise of binding and neutralizing antibody levels was statistically significant and greater in the 2.0 mg dose group versus the 1.0 mg dose group. Notably, the T cell immune responses measured by the ELISpot assay were also higher in the 2.0 mg dose group as compared to the 1.0 mg dose group. The primary endpoint of the Phase 3 segment will be virologically confirmed COVID-19 cases, and INOVIO anticipates the first regulatory approval next month.

During the second quarter of 2021, INOVIO released as a pre-print results from a study using clinical samples showing that INO-4800 provided broad cross-reactive immune responses in humans against VOC. The study showed the T cell responses induced by INO-4800 vaccination were fully maintained against the alpha, beta, and gamma variants when compared to the T cell responses to the original wildtype strain. Despite recent reports showing a reduction in neutralizing activity against the gamma variant by the mRNA or viral vector vaccines, INO-4800 generated robust neutralizing antibodies at levels against the gamma variant that were comparable to those observed against the wildtype strain. Taken together with the data showing the maintenance of T cell activity, the results reported in this study provide a comprehensive overview of cross-reactive cellular and humoral immune responses against SARS-CoV-2 variants for INO-4800 vaccinated individuals, showing the potential of INO-4800 to combat emerging as well as future variants of concern. The study, entitled, "INO-4800 DNA Vaccine Induces T Cell Activity and Neutralizing Antibodies Against Global SARS-CoV-2 Variants," is available via pre-print in bioRxiv.

Subsequent to this published work, INO-4800 vaccination was also found to maintain a similar level of T cell responses against the delta variant when compared to the T cell responses to the original wildtype strain, while it showed a similar level of reduced neutralizing antibody activity against the delta variant by the mRNA vaccines.

INOVIO continues to evaluate and assess the impact the new circulating strains of SARS-CoV-2 have on the immune profile elicited by INO-4800, as well as assessing boosting capabilities of INO-4800.

INO-4800: Heterologous Prime-Boost Trials

This morning, INOVIO announced the regulatory allowance in China to conduct two clinical trials investigating heterologous boosting with INO-4800 through its partner and trial-sponsor Advaccine, together with Sinovac. The trials will evaluate the safety and efficacy of heterologous prime-boost sequential immunizations using INO-4800 and CoronaVac, an inactivated virus COVID-19 vaccine developed by Sinovac and validated by the WHO for emergency use. China’s Center for Drug Evaluation of the National Medical Products Administration has allowed two Advaccine-sponsored open-label, positive-control trials to evaluate the safety, tolerability and immunogenicity of mixed boosted regimens. Both studies, which will be conducted in China, are anticipated to begin this fall and will involve healthy adult subjects 18 years of age or older.

INOVIO, Advaccine, and Sinovac have completed cross prime-boost pre-clinical animal tests using INO-4800 and CoronaVac, demonstrating that the prime-boost strategy can stimulate high-level of antigen specific binding antibodies, neutralizing antibodies by both live-virus neutralization assay and hACE2 receptor blocking assay, and antigen-specific T cell immune response.

IMPACT (INOVIO INO-4802 Multi-variant Pan-COVID-19 Vaccine Trial):

In parallel with INO-4800, INOVIO is also developing a second generation, pan-COVID vaccine candidate, INO-4802, which is designed to protect against current and future VOC. INO-4802 could potentially offer boosting capabilities in addition to an initial vaccination regimen with INO-4800 and/or other first-generation vaccines, including both adenovirus and mRNA-based platforms.

In 2Q and then updated subsequent to the quarter, INOVIO released a manuscript as a preprint in bioRxiv entitled, "Design and Immunogenicity of a Pan-SARS-CoV-2 Synthetic DNA Vaccine," which demonstrated cross-reactive immune responses against current and emerging viral variants using INOVIO’s next-generation pan-COVID-19 vaccine candidate, INO-4802, as either a first-line vaccine, or potentially as a booster for individuals previously immunized with various wildtype-matched vaccines. Specifically, INO-4802 generated potent neutralizing antibodies, T cell responses, and protection in a preclinical model against the original wildtype strain as well as against the alpha, beta, gamma and delta variants.

Infectious Diseases: Middle East Respiratory Syndrome ("MERS") and Lassa Fever

INOVIO dosed the first subject in its Phase 2 clinical trial for INO-4700, its DNA vaccine candidate for MERS. MERS, which currently has no approved vaccine, is a coronavirus that is about 100 times deadlier than COVID-19 and fatal to approximately 34% of those infected.

The Phase 2 trial is being conducted at sites in Jordan and Lebanon, where MERS cases have been reported. The randomized, double-blinded, placebo-controlled, multi-center trial, which is sponsored by INOVIO and funded by CEPI, evaluates the safety, tolerability and immunogenicity of INO-4700 administered using INOVIO’s CELLECTRA smart device in approximately 500 healthy adult volunteers.

INOVIO’s pursuit of a MERS vaccine is funded by a previously announced $56 million grant from CEPI, under which INOVIO will develop vaccine candidates through Phase 2 against MERS and Lassa fever. INOVIO and CEPI plan to pursue a stockpile of MERS vaccines available for emergency use as soon as possible following Phase 2 testing.

Subsequent to the quarter end, CEPI announced in July 2021 that it is providing $10.3 million in funding to partners in Benin, Guinea, Liberia, and Sierra Leone to participate in the epidemiological research program entitled Enable, which will enroll up to 23,000 participants, including in Nigeria, which began collecting participant data in December 2020. The Enablestudy aims to better understand the rate, location, and spread of Lassa virus across the region. CEPI has supported the development of six Lassa vaccine candidates, including INOVIO’s INO-4500. INO-4500 is the first Lassa vaccine candidate to enter Phase 1 trial in the U.S., and in the first quarter INOVIO dosed the first subject in a Phase 1b clinical trial for INO-4500 in Africa. It remains INOVIO’s and CEPI’s goal to making INO-4500 available for possible emergency use as a stockpile product after successful completion of the Phase 2 trial.

HPV-related Diseases

VGX-3100: Cervical, Vulvar, and Anal HSIL

REVEAL 1 / REVEAL 2 (Cervical HSIL)

INOVIO continues to follow subjects in REVEAL 1 (Randomized Evaluation of VGX-3100 and Electroporation for the treatment of Cervical HSIL), a Phase 3 pivotal trial evaluating VGX-3100 for the treatment of cervical high-grade squamous intraepithelial lesions caused by HPV-16 and/or HPV-18, for safety and durability of response for 18 months following the last administration. INOVIO expects to present its findings at a scientific meeting later this year and anticipates full subject-level unblinding for REVEAL 1 in the second half of 2021, which is expected to facilitate better analysis of individual, patient-level data.

Additionally, INOVIO is continuing its partnership with QIAGEN to co-develop an in-vitro diagnostic based on RNA sequencing technology to guide clinical decision-making for the use of VGX-3100 in cervical HSIL. INOVIO expects to report QIAGEN’s findings later this year.

REVEAL 2 continues to enroll across 48 sites globally, with projected total enrollment of approximately 198 adult women with histologically confirmed cervical HSIL. Participants will be evaluated for evidence of cervical HSIL on histology as well as evidence of HPV-16 and/or HPV-18 in cervical samples by type-specific HPV testing at the Week 36 visit accompanied with a one-month safety follow-up.

Immuno-oncology

INO-5401

Glioblastoma Multiforme

INOVIO, along with Regeneron, continues to evaluate its findings from the Phase 1/2 novel combination trial of DNA medicines INO-5401 and INO-9012 in combination with PD-1 inhibitor Libtayo (cemiplimab) – which is being jointly developed by Regeneron and Sanofi – for the treatment of newly diagnosed Glioblastoma Multiforme ("GBM"). The companies anticipate sharing two-year (24 months) overall survival data, including correlative immunology and tissue data, at an oncology conference in the fourth quarter of 2021.

Breast Cancer

Separately, the University of Pennsylvania enrolled its first patient in a Phase 1b investigator-sponsored study of INO-5401 alone or INO-5401 in combination with INO-9012 delivered with INOVIO’s CELLECTRA smart device in adult cancer and non-cancer patients with BRCA1 or BRCA2 mutations. This study, which is being conducted at the University of Pennsylvania, will enroll approximately 44 subjects and will test INO-5401, which contains genes that are active in human cancers (hTERT, PSMA, and WT1) and are believed to be good targets for the immune system for both individuals with cancer or at increased risk of getting cancer. ClinicalTrials.gov identifier: NCT04367675

Manufacturing

Update on Global Manufacturing Consortium

Thermo Fisher, a member of INOVIO’s global manufacturing consortium, announced in July that it opened a new cGMP plasmid DNA manufacturing facility in Carlsbad, California with INOVIO as its first client. The new facility enables Thermo Fisher and its partners to meet anticipated demand for plasmid DNA and other nucleic-acid based therapies.

Second Quarter 2021 Financial Results

Total revenue was $273,000 for the three months ended June 30, 2021, compared to $267,000 for the same period in 2020. Total operating expenses were $83.5 million compared to $33.4 million for the same period in 2020.

INOVIO’s net loss for the three months ended June 30, 2021 was $82.1 million, or $0.39 per basic and diluted share, compared to net loss of $128.7 million, or $0.83 per basic and diluted share, for the three months ended June 30, 2020.

Operating Expenses

Research and development ("R&D") expenses for the three months ended June 30, 2021, were $70.8 million compared to $22.4 million for the same period in 2020. The increase in R&D expenses was primarily attributable to manufacturing scale-up activities for INO-4800. These INO-4800 activities included the acquisition and installation of manufacturing equipment, drug manufacturing, outside services and clinical study expenses. Other increases included engineering services and expensed equipment related to our CELLECTRA 3PSP device array automation project, employee and contractor compensation and drug manufacturing expenses related to our RRP trial. These increases were offset by an increase in contra-research and development expense recorded from grant agreements of $8.1 million, among other variances.

General and administrative ("G&A") expenses were $12.7 million for the three months ended June 30, 2021, compared to $11.1 million for the same period in 2020. The increase in G&A expenses was primarily related to an increase in employee compensation, including non-cash stock-based compensation, partially offset by lower expenses for work performed related to corporate marketing and communications, among other variances.

Capital Resources

As of June 30, 2021, cash and cash equivalents and short-term investments were $443.7 million compared to $411.6 million as of December 31, 2020. As of June 30, 2021, INOVIO had 210.1 million common shares outstanding and 226.7 million common shares outstanding on a fully diluted basis, after giving effect to the exercise, vesting and conversion, as applicable, of its outstanding options, restricted stock units, convertible preferred stock and convertible debt.

INOVIO’s balance sheet and statement of operations are provided below. Additional information is included in INOVIO’s quarterly report on Form 10-Q for the three months ended June 30, 2021, which can be accessed at: View Source

Conference Call / Webcast Information

INOVIO’s management will host a live conference call and webcast at 4:30 p.m. Eastern Time today to discuss INOVIO’s financial results and provide a general business update.

The live webcast and a replay may be accessed by visiting INOVIO’s website at View Source

About INOVIO’s DNA Medicines Platform

INOVIO has 15 DNA medicine clinical programs currently in development focused on HPV-associated diseases, cancer, and infectious diseases, including coronaviruses associated with COVID-19 and MERS. DNA medicines are composed of optimized DNA plasmids, which are small circles of double-stranded DNA that are synthesized or reorganized by a computer sequencing technology and designed to produce a specific immune response in the body.

INOVIO’s DNA medicines deliver optimized plasmids directly into cells intramuscularly or intradermally using INOVIO’s proprietary hand-held smart device called CELLECTRA. The CELLECTRA device uses a brief electrical pulse to reversibly open small pores in the cell to allow the plasmids to enter, which is designed to overcome a key limitation of other DNA and other nucleic acid approaches, such as mRNA. Once inside the cell, the DNA plasmids enable the cell to produce the targeted antigen. The antigen is processed naturally in the cell and triggers the desired T cell and antibody-mediated immune responses. Administration with the CELLECTRA device is designed to ensure that the DNA medicine is efficiently delivered directly into the body’s cells, where it can go to work to drive an immune response. INOVIO’s DNA medicines do not interfere with or change in any way an individual’s own DNA. The advantages of INOVIO’s DNA medicine platform are how fast DNA medicines can be designed and manufactured; the stability of the products, which do not require freezing in storage and transport; and the robust immune response, safety profile, and tolerability that have been observed in clinical trials.

With more than 3,000 patients receiving INOVIO investigational DNA medicines in more than 7,000 applications across a range of clinical trials, INOVIO has a strong track record of rapidly generating DNA medicine candidates with potential to meet urgent global health needs.

On August 9, 2021 Idera Pharmaceuticals, Inc. ("Idera" or the "Company") (Nasdaq: IDRA) reported its financial and operational results for the second quarter ended June 30, 2021 (Press release, Idera Pharmaceuticals, AUG 9, 2021, View Source [SID1234586128]).

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"Our goal is to add new development or commercial-stage assets to Idera’s portfolio, and our team is very encouraged by the high quality and quantity of opportunities we have been presented with," stated Vincent Milano, Idera’s Chief Executive Officer. "Several of these prospects continue to advance, and we remain optimistic in Idera’s future potential."

Added Mr. Milano, "We also maintain our interest in the potential of tilsotolimod. Enrollment is complete and we continue to treat patients in the second stage of ILLUMINATE-206, our Phase 2 study in combination with BMS’s nivolumab and ipilimumab for patients with microsatellite-stable colorectal cancer. We also continue to support AbbVie in the form of study drug in their trial for patients with head and neck squamous cell carcinoma."

Second Quarter Financial Results
Research and development expenses for the three months ended June 30, 2021 totaled $3.9 million, compared to $5.4 million for the same period in 2020. General and administrative expense for the three months ended June 30, 2021 totaled $2.5 million compared to $2.6 million for the same period in 2020. Restructuring costs for the three months ended June 30, 2021 totaled approximately $1.2 million and relate to a reduction in force initiated in April 2021 to better align our workforce to our ongoing operational and business development activities. No such costs were incurred during the three months ended June 30, 2020. Additionally, during the three months ended June 30, 2020, we recorded $0.9 million and $15.3 million non-cash warrant revaluation loss and non-cash future tranche right revaluation loss, respectively, related to securities issued in connection with our December 2019 private placement transaction. No such non-cash losses were recognized in the three months ended June 30, 2021.

As a result of the factors above, net loss applicable to common stockholders for the three months ended June 30, 2021 was $7.6 million or $0.15 per basic and diluted share compared to a net loss applicable to common stockholders of $24.2 million or $0.72 per basic and diluted share for the same period in 2020.
Excluding the non-cash loss of approximately $16.3 million for the three months ended June 30, 2020 related to the securities issued in connection with the December 2019 private placement transaction, net loss applicable to common stockholders was $8.0 million.

On August 9, 2021 Enlivex Therapeutics Ltd. (Nasdaq: ENLV, the "Company"), a clinical-stage macrophage reprogramming immunotherapy company, reported that financial results for the second quarter ended June 30, 2021 were filed with the SEC on August 6, 2021 and provided a business update (Press release, Enlivex Therapeutics, AUG 9, 2021, View Source [SID1234586144]).

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"We are very pleased with our recent progress, which has placed us on track to achieve a steady cadence of value creating milestones," said Oren Hershkovitz, CEO of Enlivex. "Our placebo-controlled Phase IIb sepsis trial is ongoing, with top-line data expected in the second quarter of 2022. We are also on track to initiate a Phase IIb trial evaluating AllocetraTM as a treatment for severe/critical COVID-19 patients in Israel in Q3 of this year, and we plan to expand the trial to include European sites thereafter. These trials are each supported by compelling clinical data that highlight the broad applicability of Allocetra’s immunotherapeutic mechanism of action."

Dr. Hershkovitz continued, "Alongside our clinical progress, we have also generated preclinical data highlighting Allocetra’s potential to synergistically enhance the efficacy of cancer therapies. By combining AllocetraTM with these therapies, we believe we can improve response rates and provide effective therapeutic options to patients who currently have none available. We look forward to evaluating this hypothesis through our planned Phase Ib solid tumor trial. With a strong financial position and talented leadership team, we believe we are well positioned to advance these and our other clinical studies as we work to become a leader in cell therapies for infectious, inflammatory and oncologic diseases."

Business Highlights and Upcoming Milestones

Sepsis:

Sepsis is a life-threatening disease with no FDA approved therapies and a high unmet need. Each year, more than 1.7 million adults in the United States develop sepsis, with more than 270,000 dying of the disease. Enlivex’s immunotherapy product candidate AllocetraTM is being evaluated in a placebo-controlled, randomized, dose-finding, multi-center, Phase IIb trial in patients with pneumonia-associated sepsis. The trial, which has multiple sites currently open for enrollment, is expected to include 120 to 160 patients across four cohorts receiving varying doses of AllocetraTM or placebo, all in addition to standard-of-care therapy. The trial’s two primary endpoints include both safety (number and severity of adverse events and severe adverse events), and efficacy (change from baseline in sequential organ failure (SOFA) score) assessments throughout a 28-day follow-up period. The trial is supported by previously reported positive results from a Phase Ib investigator-initiated trial showing vastly improved clinical outcomes, including SOFA scores, duration of hospitalization, and mortality, in AllocetraTM-treated sepsis patients compared to a group of matched historical controls that received standard-of-care therapy. Top-line results from the Phase IIb study are expected in Q2 2022.

COVID-19:

Enlivex believes that COVID-19 will migrate from a pandemic to an endemic, with multiple variants continuing to circulate throughout the population. Further, AllocetraTM has demonstrated the potential to address a critical unmet need for COVID-19 patients in severe or critical condition, who don’t have many effective treatment options available today. In late 2020 and early 2021, Enlivex reported positive top-line results in 21 patients from Phase Ib and Phase II investigator-initiated trials in COVID-19 patients in severe/critical condition. Aggregate data from the two trials showed a 0% (0/21) mortality rate at the end of the 28 days follow-up period and that 90.5% (19/21) of patients recovered from their respective severe/critical condition and were discharged from the hospital after an average of 5.6 days following AllocetraTM administration.
To facilitate the advancement of its COVID-19 program, Enlivex has submitted a regulatory filing with the Israeli Ministry of Health to initiate a placebo-controlled, double-blinded, randomized, multi-center Phase IIb trial in COVID-19 patients in severe/critical condition with associated acute respiratory distress syndrome (ARDS). The trial will be designed to recruit up to 152 patients (76 AllocetraTM plus standard-of-care, 76 placebo plus standard-of-care). In addition, the Company plans to add several European clinical sites as part of this study, and is in discussions with the European Medicines Agency (EMA) and certain local European regulators for this purpose. The Phase IIb clinical trial will have two primary endpoints: ventilation-free survival and recovery for each of the two sub-populations of patients in the study (severe and critical), and could potentially be sufficient for obtaining emergency or conditional marketing authorization for either patient sub-population, though no guidance as per the potential for such emergency or conditional marketing authorization has been provided by the Israeli Ministry of Health or European regulators.

Solid tumors:

Alongside some industry experts, Enlivex believes that one of the main problems with the lack of efficacy of immunotherapies targeted at patients with various solid tumor malignancies is the negative reprogramming of macrophages in the tumor microenvironment. This negative reprogramming results in proliferation of pro-tumor macrophages, contributing to drug resistance, preventing disease resolution, and promoting disease severity. Data from initial preclinical solid tumor models suggest that AllocetraTM has the potential to reprogram such macrophages back to their respective homeostatic state, and thereby may assist in disease resolution and offer patients that do not respond well to existing FDA-approved immunotherapies with an effective treatment option. Based on these and other data, Enlivex plans to initiate a Phase Ib trial evaluating AllocetraTM in combination with a chemotherapy in solid peritoneal tumors in Q4 2021, and a Phase Ib trial evaluating AllocetraTM in combination with an immune checkpoint inhibitor H1 2022.
Corporate:

Subsequent to the quarter end, Enlivex initiated the design and construction process for a new cGMP AllocetraTM manufacturing plant in Israel. The Company intends to use the additional manufacturing capacity to support ongoing clinical trials, future clinical trials and initial commercial production of AllocetraTM that may occur if it receives applicable regulatory approvals. The planned new facility will initially be approximately 17,000 square feet, and will have the ability to be expanded to approximately 21,500 square feet in the future.

Subsequent to the quarter end, Enlivex hired biotech-industry veteran Tzvi Palash as Project Lead to manage the design and construction of the Company’s new cGMP AllocetraTM manufacturing plant. Mr. Palash joined Enlivex from Gamida Cell, where he served as Chief Operating Officer.

In May 2021, Enlivex was awarded an Israel Innovation Authority (IIA) Grant of approximately $1.1 million to support the clinical development of AllocetraTM in sepsis. To date, the Company has received a total of approximately $7.6 million in non-dilutive grants from the IIA for clinical trials and product development, excluding this recently approved grant.

Throughout the second quarter, Enlivex’s global intellectual property portfolio around AllocetraTM was strengthened by the issuance of two patents. The first of these patents was granted in Canada (Canadian patent No. 2,893,962) and covers pharmaceutical compositions, manufacturing methods, and uses of AllocetraTM. The second patent, which was granted in Europe (European patent No. 3,258,943), covers therapeutic compositions of AllocetraTM and chimeric antigen receptor (CAR)-T immunotherapies for inhibition or reduction of cytokine storms associated with CAR-T therapies for cancer.
Second Quarter 2021 Financial Results

Research and development expenses were $2.539 million for the three months ended June 30, 2021, compared to $1.257 million for the same period in 2020. The increase was primarily attributable to increase in salaries, increase in expenses associated with pre-clinical studies, clinical studies and consumption of materials, and increase in stock-based compensation to employees offset by an increase in grants from the Israel Innovation Authority.

General and administrative expenses were $1.269 million for the three months ended June 30, 2021, compared to $0.976 million for the same period in 2020. The increase was primarily due to increase in stock-based compensation to employees and directors, and in insurance expenses.

Net loss for the three months ended June 30, 2021, was $3.108 million, compared to a net loss of $3.041 million for the three months ended June 30, 2020.

As of June 30, 2021, Enlivex had cash and marketable securities of $90.6 million. The Company believes that its existing cash and marketable securities will be sufficient to fund its operating expenses and capital expenditure requirements through 2023.
ABOUT ALLOCETRATM

AllocetraTM is being developed as a universal, off-the-shelf cell therapy designed to reprogram macrophages into their homeostatic state. Diseases such as solid cancers, sepsis, COVID-19 and many others reprogram macrophages out of their homeostatic state. These non-homeostatic macrophages contribute significantly to the severity of the respective diseases. By restoring macrophage homeostasis, AllocetraTM has the potential to provide a novel immunotherapeutic mechanism of action for life-threatening clinical indications that are defined as "unmet medical needs", as a stand-alone therapy or in combination with leading therapeutic agents.

On August 9, 2021 MaxCyte, Inc. (Nasdaq: MXCT) (LSE: MXCT, MXCN), a leading provider of cell-engineering platform technologies, reported the signing of a clinical and commercial license with Sana Biotechnology, Inc. (Nasdaq: SANA), a company focused on creating and delivering engineered cells as medicines (Press release, MaxCyte, AUG 9, 2021, View Source [SID1234586161]).

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Under the terms of the agreement, Sana Biotechnology obtains non-exclusive clinical and commercial rights to use MaxCyte’s Flow Electroporation technology and ExPERT platform. In return, MaxCyte is entitled to receive platform licensing fees and program-related milestone payments.

Doug Doerfler, President and CEO of MaxCyte, said: "We are delighted to support Sana’s ex vivo cell therapy programs and recognize the potential of the company’s novel hypoimmune cell platform to advance treatments for serious diseases. This agreement represents an important achievement for MaxCyte as we continue to expand the use of our next-generation technology platform to support the development of innovative treatments."

MaxCyte’s ExPERT instrument portfolio represents the next generation of leading, clinically-validated, electroporation technology for complex and scalable cell engineering. By delivering high transfection efficiency, seamless scalability and enhanced functionality, the ExPERT platform delivers the high-end performance essential to enable the next wave of biological and cellular therapeutics.