On May 9, 2022 Madrigal Pharmaceuticals, Inc. (NASDAQ:MDGL), a clinical-stage biopharmaceutical company pursuing novel therapeutics for non-alcoholic steatohepatitis (NASH), reported acceptance of four abstracts for oral presentation at the European Association for the Study of the Liver’s (EASL) International Liver Congress, including a late-breaker presentation of data from the Phase 3 MAESTRO-NAFLD-1 trial, as well as other resmetirom clinical development program updates (Press release, Synta Pharmaceuticals, MAY 9, 2022, View Source [SID1234613875]). The Company also reported financial results for the first quarter of 2022, including the completion of a $250 million term loan facility to support resmetirom clinical and commercial development objectives and position Madrigal for a potential first-to-market launch in NASH. The company drew $50 million from the facility at closing and has the ability to draw a further $200 million under the agreement.

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Paul Friedman, M.D., Chief Executive Officer of Madrigal, stated, "The MAESTRO-NAFLD-1 data as described below have reinforced our confidence in the safety and potential efficacy of resmetirom in treating non-cirrhotic NASH with significant fibrosis. We look forward to sharing detailed MAESTRO-NAFLD-1 results in a late-breaking presentation at EASL followed by topline results from the MAESTRO-NASH biopsy study in Q4. Based on the totality of efficacy data generated thus far in our clinical development program, we believe resmetirom can both address the underlying drivers of NASH in the liver and also reduce the level of fibrosis that is associated with progression to more advanced disease."

Dr. Friedman added, "The term loan facility we are announcing today strengthens Madrigal’s balance sheet, providing an additional source of funding that can be drawn at the appropriate times to meet our operational needs and support our strategic priorities, including a new MAESTRO study and the ramp-up for the potential launch of resmetirom in the U.S."

Becky Taub, M.D., Chief Medical Officer and President of Research & Development of Madrigal, stated, "We are planning to expand our NASH development program by initiating a second study in the next few months to complement the clinical outcomes portion of MAESTRO-NASH; this second study, MAESTRO-NASH Outcomes, will non-invasively examine liver-related outcomes (decompensation events) in patients with early NASH cirrhosis. In contrast, MAESTRO-NASH relies primarily on serial liver biopsy to measure progression to cirrhosis. Resmetirom has been studied in over 180 patients with well-compensated NASH cirrhosis in an open label arm of MAESTRO-NAFLD-1. The safety and efficacy results that will be presented at EASL are supportive of a potential for benefit in this population. A positive outcome in this study, in a group of patients with the highest unmet need, has the potential to significantly broaden the label for resmetirom and increase the commercial opportunity. Furthermore, it is expected to accelerate the path to full approval and enhance the statistical power to assess benefit in patients with non-cirrhotic NASH. The addition of MAESTRO-NASH Outcomes does not alter our timeline for the subpart H NDA submission in non-cirrhotic NASH that is based on the results of the liver biopsy portion of MAESTRO-NASH."

Dr. Taub added, "As we have continued to gain confidence that we will achieve both the NASH resolution as well as the fibrosis improvement endpoints in the MAESTRO-NASH biopsy study we are moving one point fibrosis reduction up the hierarchy to a primary endpoint along with NASH resolution. While we expect to achieve both endpoints, dual primaries allow for a successful outcome of the study that can be filed for subpart H approval if either the NASH resolution or one point fibrosis reduction liver biopsy endpoint is met."

Stephen Harrison, M.D., Medical Director for Pinnacle Clinical Research, San Antonio, Texas, Visiting Professor of Hepatology, Oxford University, and Principal Investigator of the MAESTRO studies commented, "There is an urgent need for NASH treatments that can prevent progression to hepatic decompensation in patients at the early stages of NASH cirrhosis, but few late-stage development programs have focused on this population. The MAESTRO-NASH Outcomes study will help us determine if resmetirom can benefit patients with more advanced disease and achieve the endpoints that are valued most by healthcare providers, regulators, payers and, most importantly, patients."

Clinical Program Updates

Late-Breaking Presentation and Multiple Oral Presentations at EASL

Multiple resmetirom abstracts have been accepted at EASL’s International Liver Congress taking place June 22-26 in London:

Late-breaking presentation: "Primary data analyses of MAESTRO-NAFLD-1, a 52 week double-blind placebo-controlled phase 3 clinical trial of resmetirom in patients with NAFLD" [Saturday, June 25 at 3:00 PM. Presenter: Stephen Harrison]

Oral presentation: "Impact of resmetirom-mediated reductions in liver volume and steatosis compared with placebo on the quantification of fibrosis using second harmonic generation in a serial liver biopsy study" [Thursday, June 23 at 4:00 PM. Presenter: Dean Tai]

Oral presentation: "Utility of FIB-4 thresholds to identify patients with at-risk F2-F3 NASH based on screening data from a 2000 patient biopsy confirmed cohort of resmetirom Phase 3 clinical trial, MAESTRO-NASH" [Saturday, June 25 at 9:15 AM. Presenter: Jörn Schattenberg]

Oral presentation: "Biomarkers, imaging and safety in a well-compensated NASH cirrhotic cohort treated with resmetirom, a thyroid hormone receptor beta agonist, for 52 weeks" [Saturday, June 25 at 5:45 PM. Presenter: Stephen Harrison]

Poster: "A higher Fibrosis-4 (FIB-4) score is associated with higher healthcare costs and hospitalizations in patients with nonalcoholic steatohepatitis" [Presenter: Elliot Tapper]

Poster: "Retrospective AI-based measurement of NASH histology (AIM-NASH) analysis of biopsies from Phase 2 study of Resmetirom confirms significant treatment-induced changes in histologic features of non-alcoholic steatohepatitis" [Presenter: Janani Iyer]

Additional Phase 3 MAESTRO-NAFLD-1 Data

In January, Madrigal announced that primary and key secondary endpoints from the double-blind, placebo-controlled, 969-patient MAESTRO-NAFLD-1 safety study were achieved; resmetirom was safe and well-tolerated and provided significant reductions in liver fat, LDL-c and other atherogenic lipids vs. placebo.

Similar to what has been reported for the 100 mg open-label arm, patients in the resmetirom 80 mg and 100 mg double-blind arms achieved reductions in ALT (p=0.002; <0.0001) relative to placebo. ALT increases ≥3 times the upper limit of normal occurred in 0.61% in the resmetirom 80 mg group, 0.31% in the 100 mg group and 1.6% of patients in the placebo group.

Treatment-emergent adverse events ≥ grade 3 in severity occurred in 7.6% of patients in the resmetirom 80 mg group, 9.0% in the 100 mg group and 9.1% in the placebo group. Withdrawals due to adverse events were 2.4% in the 80 mg group, 2.8% in the 100 mg group and 1.3% in the placebo group. GI-related adverse events (diarrhea, nausea) were increased relative to placebo at the initiation of therapy but not after the first few weeks.

FibroScan CAP (controlled attenuation parameter) scores reflective of hepatic fat were statistically significantly (p<0.0001) reduced in resmetirom arms as compared with placebo. FibroScan liver stiffness reductions were similar in the 100 mg open-label and double-blind arms. Responder analyses of FibroScan vibration-controlled transient elastography (VCTE) reduction and % reduction from baseline comparing resmetirom 100 mg open-label and double-blind arms with placebo showed a significant increase in responders in resmetirom treatment arms (~44% averaged across the arms) compared with placebo (25%); magnetic resonance elastography (MRE) responders as measured by kPa reduction were significantly greater in resmetirom-treated groups compared with placebo. Mean reduction in FibroScan VCTE in resmetirom double-blind patients were greater than placebo but not statistically significant.

Detailed results of MAESTRO-NAFLD-1 are under embargo until the late-breaking presentation at EASL.

MAESTRO-NASH Outcomes Study

In the next few months, Madrigal plans to initiate a second NASH outcomes study, MAESTRO-NASH Outcomes, a randomized double-blind placebo-controlled study in approximately 700 patients with early NASH cirrhosis to allow for non-invasive monitoring of progression to liver decompensation events. Several biomarker and imaging techniques will also be employed to assess correlates with disease progression. Ongoing open-label studies of more than 180 patients with well-compensated NASH cirrhosis (MAESTRO-NAFLD-1 open-label arm) support the potential of resmetirom in this patient population.

Previously reported data from the patients with NASH cirrhosis in the open-label arm of MAESTRO-NAFLD-1 demonstrated that resmetirom reduced hepatic fat, liver volume, liver enzymes, fibrosis markers and atherogenic lipids. Madrigal will be presenting additional results from the MAESTRO-NAFLD-1 cirrhosis population in an oral presentation at EASL.

Term Loan Facility to Support Expansion of Clinical Development Program and Resmetirom Launch

Madrigal has secured a $250 million term loan facility with Hercules Capital, Inc. (NYSE: HTGC), a leader in customized specialty financing for life sciences companies. The committed capital strengthens Madrigal’s balance sheet, providing an additional source of funding both to support the expanded clinical program and ramp-up for a potential launch of resmetirom in the U.S.

Under the terms of the loan agreement, $50 million was drawn at closing. Madrigal may also draw an additional $125 million in two separate tranches upon achievement of resmetirom clinical and regulatory milestones. An additional $75 million may be drawn by Madrigal, subject to the approval of Hercules Capital. The loan facility has a floor rate of 7.45% and adjusts with future changes in the prime rate, subject to the floor rate. The loan bears initial interest at a rate of 7.95%. Madrigal will pay interest-only for a period of 30 months, which may be extended to 60 months upon the achievement of certain milestones. The loan matures in May 2026 and may be extended an additional year upon the achievement of certain milestones.

R. Bryan Jadot, Senior Managing Director and Life Sciences Group Head at Hercules Capital stated, "Hercules is pleased to provide both upfront funding and future potential funding capacity to help Madrigal deliver on its important mission to address a large unmet medical need and improve the lives of people suffering from NASH and liver disease."

Additional details of the loan agreement will be filed with the Securities and Exchange Commission on a Current Report on Form 8-K.

Financial Results for the Three Months Ended March 31, 2022

As of March 31, 2022, Madrigal had cash, cash equivalents and marketable securities of $220.0 million, compared to $270.3 million at December 31, 2021. The decrease in cash and marketable securities resulted primarily from cash used in operations of $49.9 million.

Operating expenses were $57.6 million for the three month period ended March 31, 2022, compared to $53.0 million in the comparable prior year period.

Research and development expenses for the three month period ended March 31, 2022 were $47.9 million, compared to $45.8 million in the comparable prior year period. The increase is attributable primarily to additional activities related to the Phase 3 clinical trials, and an increase in head count.

General and administrative expenses for the three month period ended March 31, 2022 were $9.7 million, compared to $7.2 million in the comparable prior year period. The increase in general and administrative expenses for the latest three month period is due primarily to increases in commercial preparation activities, including an increase in headcount.

Interest income for the three month period ended March 31, 2022 was $0.1 million, compared to $0.2 million in the comparable prior year period. The decrease in interest income was due primarily to a lower average principal balance in our investment account in 2022.

Conference Call at 8:00 am EST

Madrigal will hold a conference call and webcast at 8:00 am EST. To access the conference call, please dial (833) 660-2754 for domestic callers or (409) 350-3497 for international callers and reference conference ID: 9765409. To access the live webcast of the call with slides please visit the Investors section of Madrigal’s website or click here. An archived webcast will be available on the Madrigal website after the event.

About the Resmetirom Phase 3 Registration Program for the Treatment of NASH

Madrigal is currently conducting two Phase 3 Clinical trials, MAESTRO-NASH and MAESTRO-NAFLD-1, to demonstrate the safety and efficacy of resmetirom for the treatment of NASH.

MAESTRO-NASH is a Phase 3 multi-center, double-blind, randomized, placebo-controlled study of resmetirom in patients with liver biopsy confirmed NASH and was initiated in March 2019. The study targets enrollment of 900 patients with biopsy-proven NASH (fibrosis stage 2 or 3, at least 450 fibrosis stage 3), randomized 1:1:1 to receive resmetirom 80 mg once a day, 100 mg once a day, or placebo. After 52 weeks of treatment a second biopsy is performed. The two primary surrogate endpoints on biopsy will be NASH resolution, with at least a 2-point reduction in NAS (NASH Activity Score), and with no worsening of fibrosis OR a one point decrease in fibrosis with no worsening of NASH. A key secondary endpoint is lowering of LDL-cholesterol. The planned target enrollment was announced as completed on June 30, 2021.

The first 900 patients in the MAESTRO-NASH study will continue on therapy after the initial 52-week treatment period; up to another 1,100 patients are to be added using the same randomization plan. The study is expected to continue for up to 54 months to accrue and measure hepatic clinical outcome events including progression to cirrhosis on biopsy (52 weeks and 54 months) and hepatic decompensation events.

MAESTRO-NAFLD-1 was initiated in December 2019 and the 52-week Phase 3 multi-center, double-blind, randomized, placebo-controlled study of resmetirom in over 1,200 patients with non-alcoholic fatty liver disease (NAFLD), presumed NASH, has completed the double-blind arms and an open label 100 mg arm. An additional open label active treatment arm in patients with early (well-compensated) NASH cirrhosis is ongoing. The primary endpoint is to evaluate the safety and tolerability of resmetirom. An open-label extension study, MAESTRO-NAFLD-OLE is ongoing.

Patients in the 52-week blinded phase of MAESTRO-NAFLD-1 were randomized 1:1:1:1 to receive resmetirom 80 mg once a day, 100 mg once a day, placebo or a 100 mg resmetirom open label arm. MAESTRO-NAFLD-1 (unlike MAESTRO-NASH), did not include a liver biopsy and represents a "real-life" NASH study. NASH or presumed NASH was documented using historical liver biopsy or non-invasive techniques including FibroScan and magnetic resonance imaging, proton density fat fraction (MRI-PDFF) respectively. Using non-invasive measures, MAESTRO-NAFLD-1 was designed to provide incremental safety information to support the NASH indication as well as provide additional data regarding clinically relevant key secondary efficacy endpoints to better characterize the potential clinical benefits of resmetirom on cardiovascular and liver related endpoints. These key secondary endpoints included LDL-cholesterol, apolipoprotein B and triglyceride (TG) lowering; and reduction of liver fat as determined by MRI-PDFF. Additional secondary and exploratory endpoints were assessed including reduction in liver enzymes, FibroScan scores and other fibrosis and inflammatory biomarkers.

Data from the 52-week portion of MAESTRO-NASH, together with data from MAESTRO-NAFLD-1 and other data, including safety parameters, will form the basis for a potential subpart H submission to FDA for accelerated approval for the treatment of NASH.

On May 9, 2022 BioNTech SE (Nasdaq: BNTX, "BioNTech" or the "Company") reported financial results for the three months ended March 31, 2022 and provided an update on its corporate progress (Press release, BioNTech, MAY 9, 2022, View Source [SID1234613874]).
"During the first quarter, we demonstrated continued execution across our growth pillars in addressing infectious diseases and oncology," said Ugur Sahin, M.D., CEO and Co-Founder of BioNTech. "We have enhanced our COVID-19 vaccine leadership and reported encouraging data for our first-in-human CAR-T therapy in solid tumors. Driven by our execution in innovation, we believe we are well positioned to achieve multiple product launches in the coming years, which would facilitate significant long-term growth."

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Key First Quarter Financial Results

"We believe the global deployment of our vaccine has likely saved millions of lives and had a significant impact on humanity. As a result of an increased order volume initially placed in late 2021 following the then emerging Omicron variant, we began the year 2022 with strong revenues and earnings, leaving us well-positioned to achieve the 2022 financial guidance we issued a few months ago," said Jens Holstein, CFO of BioNTech. "This notable financial performance also helps us to invest heavily in research and development in the years to come fueling the potential to drive future waves of innovation and growth."

Outlook for the 2022 Financial Year Reiterated

The Company reiterates its prior 2022 financial year outlook, which includes the following components:

BioNTech COVID-19 Vaccine Revenues for the 2022 Financial Year:

Estimated BioNTech COVID-19 vaccine revenues for the full 2022 financial year €13 billion – €17 billion
This revenue estimate reflects expected revenues related to BioNTech’s share of gross profit from COVID-19 vaccine sales in the collaboration partners’ territories, from direct COVID-19 vaccine sales to customers in BioNTech’s territory and expected revenues generated from products manufactured by BioNTech and sold to collaboration partners.

Planned 2022 Financial Year Expenses and Capex:

R&D expenses €1,400 million – €1,500 million
SG&A expenses €450 million – €550 million
Capital expenditures €450 million – €550 million
The ranges reflect current base case projections and do not include potential effects caused by or driven from additional collaborations or potential mergers and acquisitions transactions.

Estimated 2022 Financial Year Tax Assumptions:

BioNTech Group estimated annual effective income tax rate ~28%
Capital Allocation Framework

Given BioNTech’s strong financial, scientific and operational accomplishments, BioNTech believes that it has the resources to diligently allocate its current capital to drive a multi-platform strategy and continue to strengthen BioNTech as a fully integrated global biotechnology company, allowing it to invest in research and development activities and its global development organization, mergers and acquisitions and business development opportunities, and enhance its global footprint, including commercial and manufacturing infrastructure.
In addition, BioNTech has undertaken the following steps to return capital to shareholders, as announced in March 2022.

The Company has authorized a share repurchase program of American Depositary Shares (ADSs), pursuant to which the Company may repurchase issued and outstanding ADSs in the amount of up to $1.5 billion over the next two years. The first tranche of the share repurchase program, with a value of up to $1.0 billion, commenced on May 2, 2022.
The Management Board and Supervisory Board have proposed a special cash dividend of €2.00 per ordinary share (including those held in the form of ADSs), which corresponds to an aggregate of approximately €486.0 million, based on the number of ordinary shares and ADSs outstanding as of April 30, 2022, pending approval at the Annual General Meeting to be held in June 2022, which the Company expects to serve as the record date for the dividend.
Detailed First Quarter Financial Results

Revenues: Total revenues reported were €6,374.6 million1 for the three months ended March 31, 2022, compared to €2,048.4 million1 for the comparative prior year period. The increase was mainly due to increased commercial revenues from the supply and sales of the Company’s COVID-19 vaccine worldwide.
Under the collaboration agreements, territories have been allocated between BioNTech, Pfizer and Fosun Pharma based on marketing and distribution rights. During the three months ended March 31, 2022, BioNTech’s commercial revenues included €4,586.9 million1 gross profit share (€1,504.7 million1 gross profit share and €247.2 million1 sales milestones during the comparative prior year period). BioNTech’s share of the collaboration partners’ gross profit is based on COVID-19 vaccine sales in Pfizer’s and Fosun Pharma’s territories and represents a net figure.
In addition, during the three months ended March 31, 2022, BioNTech recognized €1,163.1 million of direct COVID-19 vaccine sales to customers in BioNTech’s territory, Germany and Turkey, as well as €603.2 million sales of products manufactured by BioNTech for its collaboration partners (€199.8 million and €63.9 million, respectively during the comparative prior year period).

Cost of Sales: Cost of sales was €1,294.1 million for the three months ended March 31, 2022, compared to €233.1 million for the comparative prior year period. The increase in cost of sales resulted mainly from the recognition of costs related to BioNTech’s COVID-19 vaccine revenues which included the share of gross profit owed to its collaboration partner Pfizer. This increase in cost of sales is additionally attributed to expenses arising from inventory write-offs and for production capacities derived from contracts with Contract Manufacturing Organizations.
Research and Development Expenses: Research and development expenses were €285.8 million for the three months ended March 31, 2022, compared to €216.2 million for the comparative prior year period. The increase was mainly due to recognizing costs related to the production of pre-launch Omicron vaccine products as research and development expenses in the period incurred and an increase in headcount. The increase was partly offset by lower research and development expenses related to the Company’s COVID-19 vaccine program as compared to the prior year period.
General and Administrative Expenses: General and administrative expenses were €90.8 million for the three months ended March 31, 2022, compared to €38.9 million for the comparative prior year period. The increase was mainly due to increased expenses for purchased management consulting and legal services as well as an increase in headcount.
Income Taxes: Income taxes were accrued in an amount to €1,319.3 million of tax expenses for the three months ended March 31, 2022, compared to €514.2 million of tax income for the comparative prior year period. The derived effective income tax rate for the three months ended March 31, 2022 was 26.3%.
Net Profit: Net profit was €3,698.8 million for the three months ended March 31, 2022, compared to €1,128.1 million for the comparative prior year period.
Cash, Cash Deposits and Trade Receivables: As of March 31, 2022, cash and cash equivalents were €6,164.1 million. In addition, trade receivables remained outstanding as of March 31, 2022, mainly due to the contractual settlement of the gross profit share under the COVID-19 collaboration with Pfizer, which has a temporal offset of more than one calendar quarter. As Pfizer’s fiscal quarter for subsidiaries outside the United States differs from BioNTech’s financial reporting cycle, it creates an additional time lag between the recognition of revenues and the payment receipt. Trade receivables for example include the gross profit share for the fourth quarter of 2021 (as defined by the contract) for which the settlement payment was received subsequent to the end of the reporting period in April 2022. Of the total trade receivables of €12,695.8 million which were outstanding as of March 31, 2022, €5,243.8 million were received in cash by mid-April 2022.
Shares Outstanding: Shares outstanding as of March 31, 2022, were 243,019,216.
The full interim unaudited condensed consolidated financial statements can be found in BioNTech’s Report on Form 6-K, filed today with the SEC and available at View Source
1BioNTech’s profit share is estimated based on preliminary data shared between Pfizer and BioNTech as further described in BioNTech’s Annual Report on Form 20-F for the year ended December 31, 2021 as well as its Quarterly Report as of and for the three months ended March 31, 2022, filed as an exhibit to BioNTech’s Current Report on Form 6-K filed on May 9, 2022. Any changes in the estimated share of the collaboration partner’s gross profit will be recognized prospectively.
2Calculated applying the average foreign exchange rate for the three months ended March 31, 2022 as published by the German Central Bank (Deutsche Bundesbank).

First Quarter 2022 and Subsequent Program Updates

On March 30, 2022, BioNTech announced its Full Year 2021 Financial Results and Corporate Update as a part of the Annual Report filed on Form 20-F, also highlighting developments between January 1 and March 30, 2022 (Link to press release). A summary of these developments as well as details of subsequent developments that occurred after March 30, 2022 is provided in the sections below.

COVID-19 Vaccine Program – BNT162

BNT162b2, the first ever approved mRNA-based product, has paved the way for a new class of medicines. BioNTech and Pfizer continue to execute on plans for global COVID-19 vaccine leadership with multiple new product launches, including label expansions, pediatric dosage forms, and development of follow-on and next generation vaccine candidates.

Commercial updates

In the first quarter of 2022, BioNTech and Pfizer have invoiced approximately 750 million COVID-19 vaccine doses. As of end-April 2022, the Companies have signed orders for approximately 2.4 billion doses in 2022. As part of BioNTech’s pledge to equitable access to medicines, the Companies are on track to deliver a total of more than two billion doses of COVID-19 vaccine to low- and middle-income countries by the end of 2022.

Manufacturing updates

BioNTech and Pfizer’s global COVID-19 vaccine supply chain and manufacturing network includes 20 manufacturing facilities spanning four continents.

In February 2022, BioNTech announced its turnkey manufacturing solution, named "BioNTainer", which is designed to enable scalable mRNA vaccine production in bulk. The novel approach utilizes a modular manufacturing unit made up of state-of-the-art manufacturing containers. BioNTainers are designed and equipped to manufacture a range of mRNA-based vaccines, for example COVID-19 vaccine doses. With their scalable and modular approach, BioNTainers are intended to enable the production of high-quality mRNA vaccine manufacturing worldwide. The establishment of the first modular mRNA manufacturing facility in the African Union is expected to start in the second half of 2022.
Clinical development and regulatory updates

BioNTech and Pfizer’s COVID-19 vaccine has received multiple regulatory approvals including expansions of authorizations for booster and pediatric vaccinations, and updated storage conditions.

Label expansions achieved in the first quarter of 2022 include approvals in multiple geographies of a booster dose in individuals 12 years and older, which were supported by real-world vaccine efficacy data.

The U.S. Food and Drug Administration (FDA) also expanded the Emergency Use Authorization (EUA) in the first quarter of 2022 to include a second booster (fourth dose) for both individuals aged 50 years and older and individuals aged 12 years and older with certain kinds of immunocompromised conditions, who have previously received a booster of any authorized or approved COVID-19 vaccine.

The Companies are continuing a robust booster development program to address waning efficacy and partial escape variants and to provide continued protection by the vaccine.

Additionally, BioNTech and Pfizer continue to monitor protection offered by BNT162b2 against emerging SARS-CoV-2 variants. BNT162b2 offers a high level of protection against variants of concern, including Alpha, Beta, and Delta, and laboratory results published in Science demonstrated three doses of BNT162b2 neutralize the SARS-CoV-2 Omicron variant.

Real-world data from Israel suggest a fourth dose of BNT162b2 increases immunogenicity and lowers rates of confirmed infections and severe illness in the elderly population. A real-world study conducted by the Israeli Ministry of Health showed that in individuals over 60 years of age, confirmed infection and severe disease after a fourth dose was lower compared to individuals who did not receive a fourth dose (Bar-On YM, et al MedRxiv. Protection by 4th dose of BNT162b2 against Omicron in Israel; February 1, 2022).

BioNTech and Pfizer are evaluating follow-on COVID-19 vaccines, including an Omicron-adapted candidate and bivalent vaccines directed against the Omicron and other strains of SARS-CoV-2, as well as novel next generation vaccine concepts. The studies are part of the ongoing effort to develop next generation COVID-19 vaccines designed to provide a broad protection against emerging variants of concern.

In a recent preprint publication (bioRxiv. Omicron breakthrough infection drives cross-variant neutralization and memory B cell formation; April 1, 2022) BioNTech showed that Omicron breakthrough infection in BNT162b2 vaccinated individuals results in strong neutralizing activity against both Omicron and previous SARS-CoV-2 variants of concern. In vitro analyses of blood sera samples from individuals double- and triple-vaccinated with BNT162b2 demonstrated that Omicron breakthrough infection mediated a broad B cell recall response, primarily through expanded preformed memory B cells that recognize antigens shared broadly by different variants, rather than inducing new B cells against strictly Omicron-specific antigens. These observations suggest that a vaccine adapted to the Omicron strain spike could similarly reshape the B-cell memory repertoire and be more beneficial than an extended series of boosters with the existing vaccines directed against the ancestral strain.

In January 2022, BioNTech and Pfizer announced the initiation of clinical trials to evaluate the safety, tolerability, and immunogenicity of an Omicron-adapted vaccine in healthy adults 18 to less than 56 years of age and adults greater than 55 years of age. The study is evaluating approximately 2,150 participants across multiple cohorts examining different regimens of the current COVID-19 vaccine or an Omicron-adapted vaccine in both vaccine experienced and naive subjects. The study also includes cohorts evaluating a bivalent Omicron-adapted vaccine. A data update is now expected in the coming weeks and will be shared with regulatory agencies.
In February 2022, following a request from the U.S. FDA, BioNTech and Pfizer initiated a rolling submission seeking to amend the EUA to include children six months to less than five years of age in response to the urgent public health need in this population. The Phase 1/2/3 trial for this patient population was designed to evaluate safety, tolerability, and immunogenicity. Following study amendments, BioNTech and Pfizer are evaluating a three-dose regimen of 3 µg per dose in children six months to less than five years of age. The data are now expected in the coming weeks.
In April 2022, multiple regulatory agencies, including the EMA and U.S. FDA authorized the extension of the shelf-life of the vaccine from nine months to twelve months when stored at -90°C to -60°C.
In April 2022, BioNTech and Pfizer announced data from a Phase 2/3 clinical trial demonstrating high immune response following a booster (third) dose of BNT162b2 in 140 healthy children five through 11 years of age. Data demonstrated that a booster dose given approximately six months after the second dose of the 10 µg primary series increased neutralizing antibodies by six-fold against the SARS-CoV-2 wild-type strain compared to levels seen after two doses. Also, data from a subanalysis of 30 sera showed a 36-fold increase in SARS-CoV-2 Omicron neutralizing titers following a booster dose. The vaccine was well tolerated with no new safety signals observed. The Companies submitted these data to U.S. FDA at the end of April 2022. Additional submissions to other regulatory agencies worldwide are ongoing.
In May 2022, the European Commission approved the reduction of the interval between the primary course and booster vaccination from ​six months to three months in individuals 12 years of age and older.
Additional Infectious Disease Programs

Prevention and treatment of infectious diseases is a long-term growth pillar for BioNTech, and the Company’s objective is to be a leader in mRNA vaccines for infectious diseases. With investments in multiple programs to address diseases with major impact on global population health and on people in lower income countries, the Company is advancing its pipeline of mRNA vaccines and therapeutics to address multiple high-need indications.

BioNTech is on track to initiate four first-in-human clinical trials in the second half of 2022 that include mRNA-based product candidates designed to address shingles (in collaboration with Pfizer), malaria, tuberculosis and herpes simplex virus type 2 (HSV 2).

Influenza Vaccine Program

BioNTech is collaborating with Pfizer to develop an influenza vaccine based on the Company’s suite of mRNA platforms.

A Phase 1 trial to evaluate BNT161, an mRNA vaccine candidate, is ongoing and a dose-finding study for a self-amplifying RNA (saRNA) vaccine candidate is planned. A data update is expected in 2022.

Oncology

BioNTech’s immuno-oncology strategy is based on pioneering approaches that harness the immune response to treat cancer. BioNTech has multiple clinical stage assets across different therapeutic classes which may have the potential to tackle tumors using complementary strategies, either by targeting tumor cells directly, or by modulating the immune response against the tumor. The Company’s oncology pillars include mRNA therapeutic vaccines, CAR-T immunotherapies, cell therapies, individualized neoantigen specific immunotherapies, RiboMabs, next-generation checkpoint immunomodulators, anti-tumor antibodies and small molecules. Many product candidates have the potential to be combined with other pipeline assets or already approved therapies.

This diverse toolkit of different technologies and modes of action has the potential to address a broad range of solid tumors in different disease stages, using both off-the-shelf and individualized approaches. For its antigen-specific immune therapies, BioNTech has assembled libraries of more than 300 proprietary or known shared antigens and has developed predictive algorithms capable of efficiently identifying multiple neoantigens on an individualized basis for any patient.

BioNTech’s clinical stage oncology pipeline includes a total of 16 product candidates in 20 ongoing clinical trials including five now in randomized Phase 2 clinical trials: two FixVac programs (BNT111 and BNT113), two indications for the iNeST product candidate autogene cevumeran (BNT122/RO7198457), and the bispecific antibody checkpoint immunomodulator BNT311 (GEN1046). BioNTech’s first-in-human trial of the Company’s novel CAR-T cell therapy candidate, BNT211, is continuing to show encouraging clinical data, an important proof-point of the Company’s scientific innovation engine.

BioNTech expects continued pipeline advancement and expansion, as well as further data readouts from the ongoing trials, in 2022.

mRNA programs

FixVac

BioNTech’s off-the-shelf cancer immunotherapy approach, FixVac, leverages the Company’s proprietary uridine mRNA (uRNA) backbone that encodes cancer-specific shared antigens for intravenous administration using the proprietary RNA-LPX formulation and is optimized for induction of strong antigen-specific immune responses. FixVac product candidates may be of clinical utility in combination with anti-PD1 in patients with a lower mutational burden tumors, including those who have already experienced checkpoint inhibitor (CPI) therapy.

Two FixVac programs are in ongoing Phase 2 trials: BNT111 in PD1 inhibitor refractory/relapsed melanoma (in collaboration with Regeneron) and BNT113 in HPV16+ PDL1+ head and neck cancer.

BNT116 – The first-in-human clinical trial to evaluate the safety, tolerability and preliminary efficacy of BNT116 is expected to be initiated in the second half of 2022.
In March 2022, BioNTech announced the expansion of its strategic collaboration with Regeneron. Under the agreement, the combination of BNT116 and Libtayo is expected to be advanced into clinical development for the treatment of advanced non-small-cell lung cancer (NSCLC).
Individualized neoantigen specific immunotherapy (iNeST)

BioNTech’s individualized cancer immunotherapy approach (iNeST) is also based on pharmacologically optimized uridine mRNA (uRNA) backbone delivered in the Company’s proprietary RNA-LPX formulation.

BioNTech’s lead iNeST product candidate, autogene cevumeran (BNT122), is being developed together with Genentech as part of a co-development and co-commercialization collaboration.

Individual mRNA cancer vaccines encode the patient’s own tumor mutations, against which neoantigen specific CD4 and CD8 T cell responses are generated in vivo. BioNTech believes this modality is well-suited for use in early-stage cancers and the adjuvant setting.

A randomized Phase 2 trial of autogene cevumeran in the adjuvant treatment of circulating tumor DNA (ctDNA) positive, surgically resected Stage II (high-risk)/Stage III colorectal cancer is ongoing. The trial is expected to enroll about 200 patients to evaluate the efficacy of autogene cevumeran compared to watchful waiting after surgery and chemotherapy, the current standard of care for these high-risk patients.
A data update from the ongoing randomized Phase 2 trial of autogene cevumeran combined with pembrolizumab in patients with 1L metastatic melanoma is expected in the second half of 2022.
RiboMabs

BioNTech’s RiboMab product candidates, BNT141 and BNT142, are designed to encode cancer cell targeting antibodies. These product candidates leverage the Company’s proprietary optimized mRNA technology combining nucleoside modifications to minimize immunogenicity with modifications in the mRNA backbone to maximize protein expression. RiboMabs may address the limitations of recombinant antibodies, including avoidance of protein manufacturing challenges and short plasma half-life.

BNT141 encodes an antibody targeting Claudin-18.2, expressed in high unmet medical need tumors, including multiple epithelial solid tumors, such as gastric and pancreatic cancers.
In January 2022, the first participant was dosed in an open-label, multi-site Phase 1/2 dose escalation, safety, and pharmacokinetic trial of BNT141 followed by expansion cohorts in patients with Claudin (CLDN)-18.2-positive tumors.
BNT142 encodes a bispecific T cell engaging antibody that targets CD3, a T cell receptor component, and Claudin-6 (CLDN6), an oncofetal cell surface antigen found in solid tumors.
BioNTech plans to start a Phase 1 clinical trial for BNT142 in the first half of 2022.
Cell therapies

CAR-T cell immunotherapy

BNT211, BioNTech’s first chimeric antigen receptor, or CAR-T cell product candidate, targets CLDN6-positive solid tumors in combination with a CAR-T cell-amplifying RNA-vaccine, or CARVac, encoding CLDN6. CARVac is also based on pharmacologically optimized uridine mRNA (uRNA) backbone delivered in the Company’s proprietary RNA-LPX formulation. CLDN-6 CAR-T cells are equipped with a second-generation CAR of high sensitivity and specificity for the tumor-specific carcino-embryonic antigen CLDN6. CARVac drives in vivo expansion of transferred CAR-T cells, increasing their persistence and efficacy. BNT211 is designed to overcome CAR-T cell therapy limitations in patients with solid tumors.

BNT211 – A Phase 1/2 open-label dose escalation and dose expansion trial evaluating BNT211 in patients with CLDN6-positive solid tumors is ongoing.

Data from the ongoing trial were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Conference 2022. The presentation included data from 16 patients who received CLDN6 CAR-T cells at two dose levels alone or combined with CARVac. Tumor indications included testicular cancer (eight patients), ovarian cancer (four patients), endometrial cancer, fallopian tube cancer, sarcoma, and gastric cancer (one patient each).

The preliminary efficacy data showed encouraging signs of clinical activity with a disease control rate of 86% and an overall response rate of 43%. All 16 patients showed robust CAR-T cell engraftment with peak expansion 10 to 17 days after infusion reaching cell frequencies of 109 total cell counts or above at the higher dose level. At the first efficacy assessment six weeks post infusion, six of 14 evaluable patients showed a partial response, or PR, and five patients had stable disease, or SD, with shrinkage of target lesions. Responses were seen in four testicular and two ovarian cancer patients. At 12 weeks, four of the six patients with a PR showed deepening and durability of responses with one patient reaching a complete response 18 weeks after infusion. All four testicular cancer patients in the higher dose level had disease control and three of these patients showed objective responses. In addition, one testicular cancer patient showed partial response after infusion of the lowest CAR-T dose level in combination with CARVac. Antitumor activity tended to be higher at the higher CAR-T dose and when combined with the vaccine, with four of five patients in the CARVac combination group showing a partial response.

The results also demonstrated an encouraging safety profile as adverse events and dose limiting toxicities were manageable.

Another data update from the ongoing Phase 1/2 trial is expected in the second half of 2022.
Corporate Updates
A key component of BioNTech’s corporate strategy is strengthening the Company’s technology platforms, digital capabilities and infrastructure through select strategic partnerships and acquisitions. In the first quarter of 2022, BioNTech entered into several new collaborations and research agreements. These included a collaboration with InstaDeep Ltd. to develop an early warning system for new SARS-CoV-2 variants, a multi-target discovery collaboration with Crescendo Biologics Ltd., and an asset purchase and option agreement with MediGene AG to develop novel T cell receptor-based immunotherapies against cancer.

In April 2022, BioNTech was granted a pandemic preparedness contract by the Federal Republic of Germany. The framework agreement is aimed at pandemic preparedness including manufacturing and supply of mRNA vaccines in emergency situations in Germany. Under the preparedness agreement, which has an initial term of five years, BioNTech will reserve and maintain manufacturing capabilities to produce at least 80 million mRNA-based vaccine doses per year.
In April 2022, BioNTech entered into an exclusive research collaboration with Matinas Biopharma to evaluate the combination of mRNA formats and Matinas’ proprietary Lipid Nanocrystal, or LNC, platform technology, including a potential formulation for oral vaccines.
Environmental, Social, and Governance (ESG)

BioNTech’s commitment to social responsibility, responsible governance, environmental and climate protection, respecting human rights, and providing equitable access to medicines is intrinsic to the vision of the Company. This commitment is best demonstrated through the Company’s efforts to democratize access to innovative medicines. In addition to the COVID-19 vaccine pledge to low and middle income countries, the Company is also addressing high medical need diseases such as malaria and tuberculosis that are prevalent on the African continent.

At the beginning of April 2022, BioNTech published its second ESG report (Sustainability Report 2021), which can be found in the Investor Relations section of BioNTech’s website.

Upcoming Investor and Analyst Events

The Annual General Meeting will take place on June 1, 2022.
BioNTech plans to host a Virtual Capital Markets Day, for analysts and investors on June 29, 2022.
Conference Call and Webcast Information

BioNTech invites investors and the general public to join a conference call and webcast with investment analysts on the same day at 8.00 a.m. EDT (2.00 p.m. CEST) to report its financial results and provide a corporate update for the first quarter of 2022.

The slide presentation and audio of the webcast will be available via this link.

To participate in the conference call, please dial the following numbers ten minutes prior to the start and provide the Conference ID:

Participants may also access the slides and the webcast of the conference call via the "Events & Presentations" page of the Investor Relations section of the Company’s website at View Source A replay of the webcast will be available shortly after the conclusion of the call and archived on the Company’s website for 30 days following the call.

On May 9, 2022 MannKind Corporation (Nasdaq: MNKD), a company focused on the development and commercialization of inhaled therapeutic products for patients with endocrine and orphan lung diseases, reported that it will be participating at upcoming conferences (Press release, Mannkind, MAY 9, 2022, View Source [SID1234613873]). Presenting from the Company will be its Chief Executive Officer, Michael Castagna, PharmD.

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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2022 RBC Capital Markets Global Healthcare Conference – Tuesday, May 17, 2022 at 11:00 am (ET)
H.C. Wainwright Global Investment Conference – Tuesday, May 24, 2022 at 1:30 pm (ET)
Interested parties can access a link to the live webcast of the presentations from the Events & Presentations section of the Company’s website at View Source The webcast replay may be accessed at the same location for 14 days following the live presentation.

On May 9, 2022 Gnubiotics Sciences SA (Gnubiotics) reported a strategic partnership agreement with ADM, a global leader in human and animal nutrition (Press release, Gnubiotics Sciences, MAY 9, 2022, View Source [SID1234613872]). The strategic partnership is centered on the commercialization of innovative microbiome solutions for companion animal health and wellbeing.

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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This strategic partnership with ADM is a major accomplishment for Gnubiotics as it represents a validation of our science and technology.

"We´re excited about this partnership with Gnubiotics, and the capabilities they bring, enabling pet parents to better understand their pets’ microbiome. With this knowledge, ADM can leverage its comprehensive pantry of pet and animal well-being solutions to improve individual pet health through precise nutrition and supplementation," said Gustavo Zenaide, Vice President of ADM Pet & Animal Well-being.

The gut microbiome is essential to the health and well-being of companion animals. Study data from Gnubiotics show Animal Milk Oligosaccharides (A.M.O.s) manufactured by Gnubiotics helped protect the microbiome of dogs from the negative effects of antibiotics. In 2021, Gnubiotics also announced patents covering microbiome-based markers to predict, diagnose and treat feline obesity, a major cause of diabetes and chronic kidney disease (CKD) in felines.

"We are pleased to work with ADM, a global leader in human and animal health and nutrition," said Yemi Adesokan, CEO and Co-Founder, Gnubiotics. "We have developed products which have functional and clinically demonstrated applications for animal health and well-being. This strategic partnership with ADM is a major accomplishment for Gnubiotics as it represents validation of our science and technology. We are excited to collaborate with ADM to continue to develop and bring to market, data-driven microbiome-targeted solutions."

On MAY 9, 2022 PureTech Health plc (Nasdaq: PRTC, LSE: PRTC) ("PureTech" or the "Company"), a clinical-stage biotherapeutics company dedicated to discovering, developing and commercialising highly differentiated medicines for devastating diseases, reported that, in connection with the $50 million share buyback programme announced on 5 May 2022, it is now commencing purchases of the Company’s ordinary shares of one pence each ("Ordinary Shares") (the "Programme") (Press release, PureTech Health, MAY 9, 2022, View Source [SID1234613864]). The Programme will be carried out in tranches and is in line with the Company’s previously announced capital allocation strategy to balance investment in the continued growth of its business with potential returns of capital to shareholders.1

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PureTech plans to execute the buyback in two tranches. In respect of the first tranche, PureTech announces that it has entered into an irrevocable non-discretionary instruction with Jefferies International Limited ("Jefferies") in relation to the purchase by Jefferies, acting as principal during the period commencing on 9 May 2022 and ending on the earlier of exhaustion of funds associated with the first tranche or 8 May 2023 (subject to any regulatory objections or concerns), of Ordinary Shares for an aggregate consideration (excluding expenses) of no greater than $25 million and the simultaneous on-sale of such Ordinary Shares by Jefferies to PureTech. Jefferies will make its trading decisions in relation to the Ordinary Shares independently of, and uninfluenced by, the Company. Purchases may continue during any close period to which the Company is subject. It is anticipated that the second tranche, subject to a separate instruction, will commence promptly on completion of the first tranche, subject to renewal of the requisite authority at the 2022 AGM.

The maximum number of Ordinary Shares that can be purchased under the first tranche of the Programme is 28,589,874 Ordinary Shares (being the maximum number of shares the Company is authorised to purchase pursuant to the authority granted by shareholders at the Company’s annual general meeting held on May 27, 2021).

The purpose of the Programme is to return capital to shareholders in line with the Company’s capital allocation strategy and to enable the Company to meet obligations arising from employee share option programmes, or other allocations of shares to employees of the Company or to members of the administrative, management or supervisory bodies of the Company, or an associate of the Company. Any shares repurchased for this purpose will be held in treasury.

Any purchase of Ordinary Shares under the first tranche of the Programme will be carried out on the London Stock Exchange and any other UK recognised investment exchange which may be agreed, in accordance with pre-set parameters and in accordance with, and subject to limits, including those limits related to daily volume and price, prescribed by the Company’s general authority to repurchase Ordinary Shares granted by its shareholders at its most recent annual general meeting on May 27, 2021, Chapter 12 of the Financial Conduct Authority’s UK Listing Rules, Article 5(1) of Regulation (EU) No. 596/2014 (as incorporated into UK domestic law by the European Union (Withdrawal) Act 2018) and Commission Delegated Regulation (EU) 2016/1052 (as incorporated into UK domestic law by the European Union (Withdrawal) Act 2018).

PureTech will announce any market repurchases of Ordinary Shares no later than 7.30 a.m. BST on the business day following the calendar day on which the repurchase occurred.