On May 2, 2019 Novocure (NASDAQ: NVCR) reported financial results for the quarter ended March 31, 2019, highlighting continued revenue growth, an advancing clinical pipeline and a strong cash position (Press release, NovoCure, MAY 2, 2019, Novocure Reports First Quarter 2019 Financial Results and Provides Company Update [SID1234535580]). Novocure is a global oncology company working to extend survival in some of the most aggressive forms of cancer through the development and commercialization of its innovative therapy, Tumor Treating Fields.

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Novocure reports first quarter 2019 financial results and provides company update

(1)An "active patient" is a patient who is on Optune under a commercial prescription order as of the measurement date, including patients who may be on a temporary break from treatment and who plan to resume treatment in less than 60 days.

(2)A "prescription received" is a commercial order for Optune that is received from a physician certified to treat patients with Optune for a patient not previously on Optune. Orders to renew or extend treatment are not included in this total.

"With more than 2,600 patients on Optune as of March 31, 2019, we delivered another quarter of strong financial performance. We posted $73.3 million in net revenues in the first quarter 2019 with year-over-year revenue growth of 41 percent," said Asaf Danziger, Novocure’s Chief Executive Officer. "We also strengthened our balance sheet, adding more than $10 million in cash, cash equivalents and short-term investments in the first quarter. We continued to fund our increased investments in clinical trials and Optune technology improvements with cash flow from the GBM business."

"Our clinical pipeline continues to advance. Our HDE application for malignant pleural mesothelioma is under review at the FDA and, with the first patient enrolled in our INNOVATE-3 trial in March, enrollment is now ongoing in four phase 3 pivotal trials, creating a significant market expansion opportunity," added William Doyle, Novocure’s Executive Chairman. "We believe we are at an important inflection point, transitioning to cash generation while expanding globally, driving clinical trials and investing in technology improvements as we work to extend survival in some of the most aggressive forms of cancer."

First quarter 2019 operating statistics and financial update

There were 2,631 active patients on Optune at March 31, 2019, representing 31 percent growth versus March 31, 2018, and 10 percent growth versus December 31, 2018. The increase in active patients was driven primarily by prescription growth in EMEA and Japan and the ongoing benefit from continued growth in prescriptions for patients with newly diagnosed GBM globally.

In the United States, there were 1,778 active patients on Optune at March 31, 2019, representing 23 percent growth versus March 31, 2018.
In Germany and other EMEA markets, there were 735 active patients on Optune at March 31, 2019, representing 35 percent growth versus March 31, 2018.
In Japan, there were 118 active patients on Optune at March 31, 2019, representing 490 percent growth versus March 31, 2018.
Additionally, 1,310 prescriptions were received in the three months ended March 31, 2019, representing four percent growth compared to the same period in 2018, and flat versus the three months ended December 31, 2018.

In the United States, 925 prescriptions were received in the three months ended March 31, 2019, representing a two percent decline compared to the same period in 2018.
In Germany and other EMEA markets, 330 prescriptions were received in the three months ended March 31, 2019, representing 17 percent growth compared to the same period in 2018.
In Japan, 55 prescriptions were received in the three months ended March 31, 2019, representing 83 percent growth compared to the same period in 2018.
For the three months ended March 31, 2019, net revenues were $73.3 million, representing 41 percent growth versus the same period in 2018. Revenue growth was primarily driven by an increase of 622 active patients in our currently active markets, representing 31 percent growth, and an increase in net revenues per active patient. The increase in net revenues per active patient was primarily driven by improving reimbursement approval rates in Germany and by growth in Austria and Japan.

For the three months ended March 31, 2019, cost of revenues was $19.8 million compared to $18.2 million for the same period in 2018, representing an increase of 9 percent. The increase in cost of revenues was primarily due to the cost of shipping transducer arrays to a higher volume of active patients. Gross margin was 73% for the three months ended March 31, 2019 compared to 65% for the three months ended March 31, 2018.

Research, development and clinical trials expenses for the three months ended March 31, 2019, were $17.0 million compared to $11.1 million for the same period in 2018, representing an increase of 53 percent. This was primarily due to an increase in clinical trial and personnel expenses for our INNOVATE-3, LUNAR, METIS and PANOVA-3 trials and an increase in costs associated with medical affairs, regulatory and engineering.

Sales and marketing expenses for the three months ended March 31, 2019, were $22.3 million compared to $18.1 million for the same period in 2018, representing an increase of 23 percent. This was primarily due to increased marketing expenses and increased personnel costs associated with a larger sales force globally.

General and administrative expenses for the three months ended March 31, 2019, were $20.2 million compared to $17.3 million for the same period in 2018, representing an increase of 17 percent. This was primarily due to an increase in personnel costs and an increase in professional services.

Personnel costs for the three months ended March 31, 2019, included $9.7 million in non-cash share-based compensation expenses, comprised of $0.4 million in cost of revenues; $1.2 million in research, development and clinical trials; $2.0 million in sales and marketing; and $6.1 million in general and administrative expenses. Total non-cash share-based compensation expenses for the first quarter 2018 were $8.5 million.

Net loss for the three months ended March 31, 2019, was $12.2 million, or $0.13 per share, compared to net loss of $20.7 million for the same period in 2018, or $0.23 per share, representing an improvement of 41 percent.

At March 31, 2019, we had $152.1 million in cash and cash equivalents and $104.5 million in short-term investments, for a total balance of $256.6 million in cash, cash equivalents and short-term investments.

Anticipated clinical and regulatory milestones

FDA approval for unresectable malignant pleural mesothelioma (2019)
Zai Lab initiation of phase 2 pilot trial in gastric cancer (2019)
Data from phase 2 pilot HEPANOVA trial in advanced liver cancer (2020)
Interim analysis of phase 3 pivotal LUNAR trial in non-small cell lung cancer (2020)
Data from phase 3 pivotal METIS trial in brain metastases (2021)
Interim analysis of phase 3 pivotal PANOVA-3 trial in locally advanced pancreatic cancer (2021)
Final data from phase 3 pivotal LUNAR trial in non-small cell lung cancer (2021)
Interim analysis of phase 3 pivotal INNOVATE-3 trial in recurrent ovarian cancer (2022)
Final data from phase 3 pivotal PANOVA-3 trial in locally advanced pancreatic cancer (2022)
Final data from phase 3 pivotal INNOVATE-3 trial in recurrent ovarian cancer (2024)
Conference call details

Novocure will host a conference call and webcast to discuss first quarter 2018 financial results today, Thursday, May 2, 2019, at 8 a.m. EDT. Analysts and investors can participate in the conference call by dialing 855-442-6895 for domestic callers and 509-960-9037 for international callers, using the conference ID 8956998.

The webcast, earnings slides presented during the webcast and the corporate presentation can be accessed live from the Investor Relations page of Novocure’s website, www.novocure.com/investor-relations, and will be available for at least 14 days following the call.

On May 2, 2019 Conatus Pharmaceuticals Inc. (Nasdaq:CNAT) reported financial results for the first quarter ended March 31, 2019, and provided updates on its development programs (Press release, Conatus Pharmaceuticals, MAY 2, 2019, View Source [SID1234535611]).

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Program Updates
The company is currently conducting two double-blind, placebo-controlled Phase 2b clinical trials in collaboration with Novartis – the EmricasaN, a Caspase inhibitOR, for Evaluation (ENCORE) trials, designed to evaluate emricasan, a first-in-class pan-caspase inhibitor, in patients with liver cirrhosis caused by nonalcoholic steatohepatitis (NASH).

The ENCORE-LF (for Liver Function) clinical trial, initiated in the second quarter of 2017, has enrolled approximately 210 patients with stable decompensated NASH cirrhosis. The primary endpoint is event-free survival, which is a composite of all-cause mortality, new decompensation events, or ≥4 points progression in Model for End-stage Liver Disease (MELD) score. Enrollment was completed in the first quarter of 2019. Top-line results triggered by reaching a prespecified number of events are expected in mid-2019.

The ENCORE-PH (for Portal Hypertension) clinical trial, initiated in the fourth quarter of 2016, enrolled 263 patients with compensated or early decompensated NASH cirrhosis and severe portal hypertension. The trial’s primary endpoint was change in mean hepatic venous pressure gradient (HVPG) from baseline to Week 24 in any of three emricasan dosing groups compared with placebo. Top-line results were reported in December 2018 showing HVPG trends consistently favoring emricasan compared with placebo in the overall population but not meeting the primary endpoint. The greatest improvement was observed in patients with a baseline HVPG of 16 mmHg or higher.

Week 24 results from the ENCORE-PH clinical trial were detailed in a late-breaker oral presentation at The International Liver Congress 2019, the Annual Meeting of the European Association for the Study of the Liver (EASL) in Vienna, Austria, on April 13, 2019. The associated abstract was also selected by EASL for inclusion in the "Best of ILC" summary slide deck highlighting the most noteworthy contributions to the scientific program at this year’s meeting. A copy of the presentation is available in the Investors section of the Conatus website at www.conatuspharma.com.

Patients had the option to continue on their assigned doses of treatment or placebo in a double-blind 24-week extension period. Results following the extension period are expected in mid-2019 and will include longer term safety, liver function and clinical outcomes, but there will be no additional HVPG measurements.
During the first quarter of 2019, the company announced top-line results from a third double-blind, placebo-controlled Phase 2b clinical trial, the ENCORE-NF (for NASH Fibrosis) clinical trial in patients with biopsy-confirmed NASH and liver fibrosis. The trial’s primary endpoint was a ≥1 CRN fibrosis stage improvement with no worsening of steatohepatitis compared with placebo at week 72. The trial did not meet the primary endpoint.

The company announced in March 2019 the selection of its first internally developed product candidate, CTS-2090, an orally active inhibitor of caspase 1. Caspase 1 occupies a uniquely central position in the NLRP3 inflammasome pathway and blocks activation of the potent inflammatory cytokine IL-1β. Blocking IL-1β is a clinically validated approach to treating inflammatory diseases, with several injectable biologic products using that mechanism of action already on the market. CTS-2090 is currently in preclinical development and IND-enabling studies, with an initial clinical trial planned to begin by the first half of 2020. The company plans to pursue rare autoinflammatory diseases as initial clinical targets for CTS-2090.

Financial Results
The net loss was $4.7 million for the first quarter of 2019 compared with a net loss of $5.0 million for the first quarter of 2018.

Total revenues were $7.0 million for the first quarter of 2019 compared with $9.7 million for the first quarter of 2018. Total revenues consisted of collaboration revenues related to the Novartis agreement. The decrease in total revenues was primarily due to lower emricasan-related research and development expenses resulting in corresponding lower revenues related to the Novartis agreement.

Research and development expenses were $9.4 million for the first quarter of 2019 compared with $12.1 million for the first quarter of 2018. The decrease in research and development expenses was primarily due to lower spending related to the ENCORE-PH clinical trial and manufacturing activities, partially offset by higher spending related to the ENCORE-LF clinical trial.

General and administrative expenses were $2.6 million for the first quarter of 2019 compared with $2.7 million for the first quarter of 2018.

Cash, cash equivalents and marketable securities were $33.8 million at March 31, 2019, compared with $40.7 million at December 31, 2018, and a projected year-end 2019 balance, without including any potential milestone payments under the Novartis collaboration, of between $10 million and $15 million.

On May 2, 2019 Evelo Biosciences, Inc. (Nasdaq: EVLO) ("Evelo"), a clinical stage biotechnology company developing oral biologics that act on cells in the small intestine with striking therapeutic effects throughout the body, reported financial results and provided a business update for the first quarter of 2019 (Press release, Evelo Biosciences, MAY 2, 2019, View Source [SID1234535675]).

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"We continue to progress therapies targeting cells in the small intestine to drive systemic effects to treat major diseases. We look forward to clinical data from our first inflammatory disease trial of EDP1066 in healthy volunteers and psoriasis patients early in the third quarter and in atopic dermatitis patients shortly thereafter," said Simba Gill, Ph.D., chief executive officer of Evelo. "In addition, we have discovered novel formulations of monoclonal microbials which significantly improve potency in preclinical models. In parallel with completion of the current patient cohorts, we are advancing a novel formulation into our ongoing clinical studies, providing us with the opportunity for additional clinical readouts in the near term."

Business Highlights:

Platform Discovery: Novel Formulations with Increased Potency

Evelo has discovered a new formulation that enhances the pharmacological potency of monoclonal microbials by up to 30-fold in preclinical in vivo models.

This proprietary formulation enhances the probability of translating preclinical effects into patients and can be commercialized cost effectively.

Evelo plans to introduce this formulation into ongoing and new clinical trials beginning in the second half of 2019 across multiple monoclonal microbials.

Evelo continues to invest in enhanced forms and formulations of oral biologics.

Ongoing Clinical Studies and Anticipated Milestones

Inflammation:

EDP1066 – Phase 1b

Healthy volunteers and psoriasis patients – Evelo expects to complete dosing this quarter and to report initial clinical data early in the third quarter of 2019.

Atopic dermatitis patients – Following the recent addition of a new cohort of patients, Evelo expects to report initial clinical data in the third quarter of 2019.

New formulation – Evelo expects to report initial clinical data from cohorts of psoriasis and atopic dermatitis patients during the fourth quarter of 2019 and the first quarter of 2020, respectively.

EDP1815 – Phase 1b

Evelo completed dosing of EDP1815 in two dose-ascending healthy volunteer cohorts. Based on the data reviewed by the trial’s safety committee, the trial proceeded as planned into patients.

Following the addition of a new formulation into the trial, Evelo expects to report initial clinical data from psoriasis and atopic dermatitis patients in early 2020.

Anticipated Additional Studies

Evelo expects to continue to conduct immuno-pharmacology studies in healthy volunteers with EDP1066 and EDP1815 to explore additional doses and formulations.

Subject to data from ongoing trials, Evelo expects to initiate clinical trials in additional inflammatory disease indications in the second half of 2019.

Oncology:

EDP1503 – Phase 1/2

Evelo is conducting a Phase 1/2 clinical trial of EDP1503 in combination with KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy, in microsatellite stable colorectal cancer, triple-negative breast cancer, and patients with other tumor types that have relapsed on prior PD-1/L1 inhibitor treatment. Initial clinical data is expected in the first half of 2020.

EDP1503 – Phase 2a

The University of Chicago is conducting a Phase 2a investigator-sponsored clinical trial of EDP1503 in combination with KEYTRUDA in naive melanoma patients and melanoma patients who have relapsed on prior PD-1/L1 inhibitor treatment. Initial clinical data expected in second half of 2020.

First Quarter 2019 Financial Results

Cash Position: As of March 31, 2019, cash, cash equivalents and investments were $129.4 million, as compared to cash and cash equivalents of $147.9 million as of December 31, 2018. This decrease was due to cash used to fund operating activities and capital expenditures for the first quarter of 2019. Evelo expects that its cash, cash equivalents and investments will enable it to fund its planned operating expenses and capital expenditure requirements into the second half of 2020.

Research and Development Expenses: R&D expenses were $15.7 million for the three months ended March 31, 2019, compared to $7.1 million for the three months ended March 31, 2018. The increase of $8.6 million was due primarily to increases in costs related to Evelo’s inflammation and oncology clinical development programs, and research platform expenses, as well as increased personnel costs.

General and Administrative Expenses: G&A expenses were $5.1 million for the three months ended March 31, 2019, compared to $3.3 million for the three months ended March 31, 2018. The increase of $1.8 million was due primarily to increased general and administrative personnel costs, professional and consulting fees, and facility expenses supporting Evelo’s growing R&D organization and public company infrastructure.

Net Loss Attributable to Common Stockholders: Net loss attributable to common stockholders was $20.3 million for the three months ended March 31, 2019, or $(0.64) per basic and diluted share, as compared to a net loss attributable to common stockholders of $12.9 million for the three months ended March 31, 2018, or $(3.29) per basic and diluted share.

Conference Call
Evelo will host a conference call and webcast today at 8:30a.m. ET. To access the call please dial (866) 795-3242 (domestic) and (409) 937-8909 (international) and provide the passcode 1838168. A live webcast of the call will be available on the Investors sections of the Evelo website at www.evelobio.com. The archived webcast will be available approximately two hours after the conference call and will be available for 30 days following the call.

On May 2, 2019 Novavax, Inc., (Nasdaq: NVAX) reported its financial results and operational highlights for the first quarter ended March 31, 2019 (Press release, Novavax, MAY 2, 2019, View Source [SID1234535701]).

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First Quarter 2019 and Subsequent Operational Highlights

ResVax Program

In February 2019, Novavax announced top-line data from the Prepare trial, which was designed to determine the efficacy of ResVax against medically significant respiratory syncytial virus (RSV)-positive lower respiratory tract infection (LRTI) in infants. ResVax is the first RSV vaccine to demonstrate efficacy in infants.

In April 2019, Novavax presented additional results at the World Vaccine Congress in Washington, D.C. from the Prepare trial of ResVax. Although the Prepare trial results did not meet the pre-specified primary efficacy endpoint, it demonstrated efficacy against RSV LRTI hospitalizations, a pre-specified secondary endpoint. RSV LRTI hospitalization is not only an important indication of the severity of RSV disease in infants, it also reflects a significant economic burden to global health systems.
NanoFlu Program

In January 2019, Novavax announced positive top-line results of its Phase 2 clinical trial of NanoFlu comparing various quadrivalent formulations, with or without Novavax’ Matrix-M adjuvant, with two U.S.-licensed influenza vaccines in older adults. These results show that NanoFlu with Matrix-M generated enhanced immune responses compared to the unadjuvanted formulation, and importantly, showed superior hemagglutination inhibition antibody (HAI) responses against wild-type A(H3N2) viruses, including drifted strains, when compared to Fluzone High-Dose, the leading flu vaccine in older adults.
Key Upcoming Events

Meet with the FDA, European regulatory agencies, and potentially other national regulatory agencies during the second and third quarters, to assess opportunities for submission of marketing applications for ResVax.
Reach agreement with the FDA during the third quarter of 2019 on a proposed Phase 3 clinical trial design for NanoFlu utilizing accelerated approval criteria for licensure.
Present ResVax Phase 3 clinical trial data at the 37th Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID) on May 7, 2019.
Financial Results for the First Quarter Ended March 31, 2019

Novavax reported a net loss of $43.2 million, or $0.11 per share, for the first quarter of 2019, compared to a net loss of $46.4 million, or $0.14 per share, for the first quarter of 2018.

Novavax revenue in the first quarter of 2019 was $4.0 million, compared to $9.7 million in the same period in 2018. This 59% decrease was driven by the completion of enrollment of the Prepare trial in the second quarter of 2018.

Research and development expenses decreased 20% to $35.5 million in the first quarter of 2019, compared to $44.5 million for the same period in 2018. This decrease was primarily due to decreased development activities, including lower clinical trial costs, of ResVax.

General and administrative expenses were flat at $8.7 million in the first quarter of 2019, compared to the same period of 2018.

Interest income (expense), net was ($3.0) million in the first quarter of 2019, compared to ($2.9) million for the same period of 2018.

As of March 31, 2019, Novavax had $108.7 million in cash, cash equivalents, marketable securities and restricted cash, compared to $103.9 million as of December 31, 2018. Net cash used in operating activities for the first quarter of 2019 was $50.6 million, compared to $66.1 million for same period in 2018.

Conference Call

Novavax will host its quarterly conference call today at 4:30 p.m. ET. The dial-in numbers for the conference call are (877) 212-6076 (Domestic) or (707) 287-9331 (International), passcode 5394082. A replay of the conference call will be available starting at 7:30 p.m. ET on May 2, 2019 until 7:30 p.m. ET on May 9, 2019. To access the replay by telephone, dial (855) 859-2056 (Domestic) or (404) 537-3406 (International) and use passcode 5394082.

A webcast of the conference call can also be accessed via a link on the home page of the Novavax website (novavax.com) or through the "Investor Info"/"Events" tab on the Novavax website. A replay of the webcast will be available on the Novavax website until August 2, 2019.

About RSV in Infants

Globally, RSV (respiratory syncytial virus) is the leading viral cause of severe lower respiratory tract disease in infants and young children. It is the second leading cause of death in children under one year of age. Estimated annual hospitalizations of 1.4 million and an estimated 27,300 in-hospital deaths were due to RSV acute lower respiratory infection in children under six months of age. RSV results in a total global economic burden of $6.2 billion annually.

In the U.S., RSV is the leading cause of hospitalization of infants. Estimated annual hospitalizations are up to 76,000. While RSV can impact all infants, babies under six months of age are among those at highest risk, as approximately 77% of all first-year RSV infections occur before six months. In the U.S., the total economic burden is $2.7 billion annually.

About ResVax

ResVax is an RSV fusion (F) protein recombinant nanoparticle vaccine with aluminum phosphate as an adjuvant. It is being developed to protect infants from RSV disease via maternal immunization, which may offer the best method of protection from RSV disease in infants through the first months of life. In February 2019, Novavax announced top-line data from Prepare, a global Phase 3 clinical trial in 4,636 pregnant women, at least 3,000 of whom have received the vaccine, and their infants. Prepare is supported by an $89.1 million grant from the Bill & Melinda Gates Foundation (BMGF).

About Influenza

Influenza is a world-wide infectious disease that causes illness in humans with symptoms ranging from mild to life-threatening or even death. Serious illness occurs not only in susceptible populations such as infants, young children and older adults, but also in the general population largely because of infection by continuously evolving strains of influenza which can evade the existing protective antibodies in humans. An estimated one million deaths globally each year are attributed to influenza. Current estimates for seasonal influenza vaccine growth in the top seven markets (U.S., Japan, France, Germany, Italy, Spain and UK), show a potential increase from approximately $3.2 billion in 2012-13 season to $5.3 billion by the 2021-22 season.

About NanoFlu and Matrix M

NanoFlu is a recombinant hemagglutinin (HA) protein nanoparticle influenza vaccine produced by Novavax in its SF9 insect cell baculovirus system. NanoFlu uses HA protein amino acid sequences that are the same as the recommended wild-type circulating virus HA sequences. NanoFlu contains Novavax’ patented saponin-based Matrix-M adjuvant, which is potent and well- stimulates both high quality and durable antibody responses as well as multifunctional CD4 and CD8 T-cell responses. In January 2019, Novavax announced positive top-line data from its Phase 2 clinical trial in older adults of quadrivalent formulations of NanoFlu in 1,375 healthy older adults across clinical sites in the U.S.

About Accelerated Approval

Accelerated approval may be granted for certain biological products that have been studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit over existing treatments. Such an approval will be based on adequate and well-controlled clinical trials establishing that the biological product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit. For seasonal influenza vaccines, the hemagglutination inhibition (HAI) antibody response may be an acceptable surrogate marker of activity that is reasonably likely to predict clinical benefit. To be considered for accelerated approval, a biologics license application for a new seasonal influenza vaccine should include results from one or more well-controlled studies designed to meet immunogenicity endpoints and a commitment to conduct confirmatory post-marketing studies of clinical effectiveness in preventing influenza.

On May 2, 2019 Medigene AG (FSE: MDG1, Prime Standard), a clinical stage immuno-oncology company focusing on the development of T cell immunotherapies, reported that Dr. Maja Buerdek, Director Cellular Tools, gave an oral presentation on in vitro assays to evaluate potential TCR-mediated toxicity against neuronal cells at the American Society of Gene & Cell Therapy (ASGCT) (Free ASGCT Whitepaper) Annual Meeting in Washington, DC (Press release, MediGene, MAY 2, 2019, View Source [SID1234535565]).

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Before TCR-transgenic T cells (TCR-Ts) enter clinical studies for adoptive immunotherapy of cancer, they need to be systematically tested for possible toxic effects against healthy tissues. Toxicity can be due either to on-target/off-tumor or off-target recognition by TCR-Ts.

Medigene has developed physiologically relevant 2-dimensional and 3-dimensional in vitro models to assess potential TCR-T-mediated toxicities against a variety of healthy tissues, whereby neuronal toxicity represents a special case due to paucity of non-malignant cell lines and fresh brain tissue samples. Therefore, assessments for neurotoxicity were made using inhibitory GABA neurons and astrocytes derived from induced pluripotent stem cells (iPSCs). Neither neuronal cell type was found to express PRAME antigen as determined by direct qPCR studies in vitro. Furthermore, extensive in silico data of PRAME RNA and protein expression as well as in vitro studies of RNA in a specialized panel of 24 brain tissues failed to detect PRAME expression. Thereby, these cell types theoretically should not represent direct targets for PRAME-specific TCR-Ts through on-target/off-tumor recognition since they lack specific endogenous PRAME expression. Nevertheless, neuronal cells could potentially still be recognized via PRAME-specific TCR-Ts due to off-target toxicity, based on TCR cross-reactivity for an undefined target.

Importantly, cell surface expression of HLA-A2 on neurons, a precondition for recognition by HLA-A2-restricted PRAME-specific TCR-Ts, could only be measured after treatment with interferon gamma, mimicking a pro-inflammatory environment. Therefore, to demonstrate general susceptibility to recognition and killing via TCR-Ts, and to directly assess both on target/off-tumor and off-target toxicity, the neuronal cells were pre-treated with interferon gamma and loaded exogenously with PRAME peptide and then tested with PRAME-specific TCR-Ts. The neuronal cells were recognized and killed, demonstrating that specific recognition could be detected in this 2D assay system. Importantly, non-peptide-loaded neuronal cells survived in the presence of PRAME-specific TCR-Ts in 2D co-cultures assaying for specific cytokine release and killing. Thus, both cell types were not found to be susceptible to on-target/off-tumor toxicity, as predicted, nor were they susceptible to off-target toxicity.

Since neuronal cells could show different characteristics in vivo based on tissue-like structures, 3D neuro-spheroids were generated and utilized in co-culture assays with PRAME-specific TCR-Ts. The results confirmed those described for the 2D system, whereby 3D neuro-spheroids were not killed by the PRAME-specific TCR-Ts, whereas exogenous loading of 3D neuro-spheroids with PRAME peptide led to an efficient killing of the neurons by the PRAME-specific TCR-Ts.

Dr Maja Buerdek, Director Cellular Tools at Medigene, commented: "Medigene has added these new functional in vitro assays for evaluation of TCR-T toxicity against neuronal cells to enlarge our extensive preclinical toolbox that allows for systematic assessment of TCR-T specificity, safety and pre-clinical efficacy in vitro. The PRAME-specific TCR-Ts analyzed in these studies showed a favorable safety pattern against both iPSC-derived astrocytes and GABA neurons in vitro using 2D and 3D co-culture models."