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Item 1. Business

2023-03-09 compared with 2022-03-17 · 242 added, 717 removed, 495 unchanged (66% of the section changed)

We are a biopharmaceutical company focused on the discovery, development, and commercialization of patient-, physician-, caregiver- and societal-friendly medicinal therapies intended to improve quality of life, increase life expectancy, and resolve serious unmet needs.

Our novel mechanism pipeline of product candidates is designed with the goal to become the patient-friendly, new-era standard-of-care medicines, and to work in harmony with the human microbiome.

Summit’s lead product candidate, ridinilazole, is a novel first-in-class drug that is engaged in a global Phase III clinical trial program.

On December 20, 2021, we announced topline results for the Phase III Ri-CoDIFy study evaluating ridinilazole for treating patients suffering from Clostridioides difficile infection, also known as C.

difficile infection, or CDI.

Our second product candidate, SMT-738, was announced in May 2021 for combating multidrug resistant infections, specifically Carbapenem-resistant Enterobacteriaceae (“CRE”) infections.

SMT-738 is the first of a novel class of precision antibiotics that has entered into preclinical development.

We intend to expand our portfolio by developing further new mechanism, new era product offerings that are designed to work in harmony with the human gut microbiome in the therapeutic areas of oncology and infectious diseases.

Throughout the process of our clinical development of ridinilazole, we have learned a substantial amount regarding the importance of the microbiome as we have sought to reduce C.

difficile infection recurrence to the lowest practical levels.

Importantly, as we have continued to intensify our focus on the microbiome, we believe that the focus on the health of the microbiome will become one of the most important developments in human health over the next decade.

As a result, we intend to implement a strategy that primarily centers on microbiome-focused therapeutics that could benefit treatments in the areas of oncology and anti-infectives.

We will enact this focus through business development activities, including possible acquisitions of and/or collaborations with existing entities.

For ridinilazole, we are in the process of evaluating the future path forward, including potential partnership opportunities.

Ridinilazole for Clostridioides difficile Infection

Our lead CDI product candidate is ridinilazole (formerly SMT19969), an orally administered, novel mechanism, small molecule antibiotic.

The first patient in our Phase III clinical program was dosed ridinilazole in February 2019.

The Phase III clinical program consists of two Phase III pivotal clinical trials (“Ri-CoDIFy 1” and “Ri-CoDIFy 2”) which were combined into a single study (“Ri-CoDIFy”).

The Phase III clinical program also consists of a pediatrics study (“Ri-CoDIFy 3”).

The Phase III Ri-CoDIFy pivotal trial was designed to assess, as the primary endpoint, the superiority of ridinilazole compared to vancomycin in Sustained Clinical Response (“SCR”), which was defined as Clinical Response of the treated episode of CDI and no recurrence of CDI through 30 days after the end of treatment.

Additional endpoints included Clinical Response ("CR"), recurrence rate, safety and tolerability, analyses of the gut microbiome and metabolome, in addition to quality of life and health economic outcome measures.

The top-line results of the Ri-CoDIFy study showed that ridinilazole resulted in a numerically higher SCR rate than vancomycin but did not meet the study’s primary endpoint threshold for superiority.

Patients treated with ridinilazole, a precision antibiotic, experienced substantially less recurrence of C.

difficile infection as compared to patients administered vancomycin (nominal p-value = 0.0002).

It further showed that ridinilazole was well tolerated, and the overall safety profile remained unchanged.

We are in the process of evaluating the future path forward with respect to ridinilazole, including potential partnership opportunities.

Ridinilazole is designed to selectively target the bacterium Clostridioides difficile (previously known as Clostridium difficile ) or C.

difficile while preserving the commensal microbes of the gut microbiome, thus allowing more rapid restoration of the microbiome to a healthy state.

A healthy, diverse microbiome is associated with decreased CDI recurrence rates.

CDI is a bacterial infection of the colon caused by the bacterium C.

difficile which produces toxins that cause inflammation of the colon resulting in severe watery diarrhea, painful abdominal cramping, nausea, fever, and dehydration.

CDI can also result in more serious disease complications, including bowel perforation, sepsis, and death.

CDI typically develops following the use of antibiotics that can cause widespread damage to the microbiome, or the natural gut flora, and allow overgrowth of C.

difficile bacteria.

CDI represents a serious healthcare issue in hospitals, long-term care homes, and in the wider community.

CDI is the most common healthcare-associated infection.

Ridinilazole’s Phase III clinical program has been funded in part with federal funds from the Biomedical Advanced Research and Development Authority (“BARDA”), part of the Office of the Assistant Secretary for Preparedness and Response at the U.S.

Department of Health and Human Services.

The awarded contract was originally worth up to $62.0 million.

In June 2019 and again in January 2020, BARDA increased the value of the contract such that it is now worth up to $72.5 million.

remaining federal government funding is dependent on BARDA at its sole discretion exercising the final independent option work segment, under our achievement of certain agreed-upon milestones for ridinilazole.

As of December 31, 2021, an aggregate of $56.5 million of the total committed BARDA funding has been received.

We have also entered into a license and commercialization agreement with Eurofarma Laboratórios S.A., or Eurofarma, pursuant to which we granted Eurofarma exclusive rights to commercialize ridinilazole in specified countries in South America, Central America and the Caribbean.

We have retained commercial rights to ridinilazole for the treatment of CDI across Rest of World territories.

Other Pipeline Product Candidates

Our pipeline of product candidates is designed with the goal to become the patient-friendly, new-era standard-of-care medicines, in the therapeutic area of oncology.

On December 5, 2022, we entered into a Collaboration and License Agreement (the “License Agreement”) with Akeso, Inc.

and its affiliates (“Akeso”) pursuant to which we are partnering with Akeso to in-license its breakthrough bispecific antibody, ivonescimab.

Ivonescimab, known as AK112 in China and Australia, and also as SMT112 in the United States, Canada, Europe, and Japan, is a novel, potential first-in-class bispecific antibody intending to combine the benefits of immunotherapy via a blockade of PD-1 with the anti-angiogenesis benefits of an anti-VEGF into a single molecule.

Ivonescimab was engineered to bring two well established oncology targeted mechanisms together.

Through the License Agreement, we obtained the rights to develop and commercialize SMT112 in the United States, Canada, Europe, and Japan (the “Licensed Territory”).

The License Agreement and transaction closed on January 17, 2023 following customary waiting periods.

The entry into the License Agreement represents a significant change in the Company’s strategy.

All prior development and marketing activities relating to ridinilazole are being terminated.

All business activities related to anti-infectives are being reviewed for partnership opportunities for potential further development.

Our future operations will be focused on the development of ivonescimab and other future activities as the Company determines.

On September 28, 2022, we determined that we would seek partners or a divestiture of ridinilazole, our lead product candidate for treating patients suffering from Clostridioides difficile infection, also known as C.

difficile infection, or CDI, as the path forward for the clinical development of the asset.

As a result of this determination, we discontinued our only active study for ridinilazole, a pediatric clinical trial evaluating ridinilazole for treating adolescent patients with CDI.

We are currently involved in activities related to closeout of ridinilazole clinical trials.

Our other product candidate, SMT-738, has been in development for combating multidrug resistant infections, specifically carbapenem-resistant Enterobacteriaceae (“CRE”) infections.

SMT-738 is the first of a novel class of precision antibiotics that has been in preclinical development and has been undergoing investigational new drug (“IND”) enabling activities.

We will continue to pursue partnerships for further development of SMT-738.

Akeso Collaboration and License Agreement

Our License Agreement with Akeso, as referred to above, calls for Summit to receive the rights to develop and commercialize ivonescimab in the United States, Canada, Europe, and Japan (the “Licensed Territory”).

Akeso will retain development and commercialization rights for the rest of the regions including China.

In exchange for these rights, Summit made an upfront payment during the first quarter of 2023 comprising of $474.9 million cash and the issuance of 10 million shares of Company common stock in lieu of $25.1 million cash pursuant to the a share transfer agreement.

In connection with the License Agreement, the Company has also agreed to enter into a Supply Agreement with Akeso, pursuant to which Summit agreed to purchase a certain portion of drug substance for clinical and commercial supply (the “Supply Agreement”).

Pursuant to the terms of the License Agreement, Summit will have final decision-making authority with respect to commercial strategy, pricing and reimbursement and other commercialization matters in the Licensed Territory.

Summit has not assumed any liabilities (including contingent liabilities), nor acquired any physical assets or trade names, or hired or acquired any employees from Akeso in connection with the License Agreement.

Ivonescimab is a novel potential first-in-class PD-1 / VEGF bispecific antibody, believed to be the most advanced in clinical development.

Engineered with Akeso's unique Tetrabody technology, ivonescimab, as a single molecule, blocks programmed cell death protein 1 (“PD-1”) from binding to PD-L1 and PD-L2, and blocks vascular endothelial growth factor (“VEGF”) from binding to VEGF receptors.

In view of the co-expression of VEGF and PD-1 in the tumor microenvironment, ivonescimab, may block these two pathways more effectively and enhance the antitumor activity, as compared to combination therapy.

Ivonescimab has received Breakthrough Therapy Designation status in China from the National Medical Products Administration (“NMPA”) for three indications:

a) ivonescimab combined with chemotherapy for the treatment of EGFR-mutated locally advanced or metastatic NSCLC patients who have progressed after taking an EGFR-TKI treatment

b) ivonescimab as the first-line treatment for locally advanced or metastatic NSCLC patients with positive PD-L1 expression

c) ivonescimab combined with docetaxel for the treatment of locally advanced or metastatic NSCLC patients who have progressed after taking a prior PD-(L)1 inhibitor combined with platinum-based doublet chemotherapy .

Ivonescimab is currently being developed in China and Australia in multiple solid tumors and has been dosed in more than 500 patients.

Akeso is currently conducting, in China, a Phase III clinical trial in patients with NSCLC who are positive for an epidermal growth factor receptor (“EGFR”) mutation and whose disease has progressed after treatment with an EGFR tyrosine-kinase inhibitor (“TKI”).

As presented at ASCO 2022, ivonescimab treatment was associated with an overall response rate (ORR) in a Phase II study in patients with NSCLC who have failed EGFR-TKI’s of 68.4% and a median Progression-Free Survival (“mPFS”) time period of 8.2 months when combined with combination chemotherapy (pemetrexed and carboplatin).

The phase II study, which similarly had patients receiving ivonescimab plus chemotherapy as their first line therapy for metastatic disease, was considered to have demonstrated a tolerable safety profile and a low discontinuation rate for adverse events.

In a separate cohort, in the same phase II study, ivonescimab, combined with docetaxel in patients who have failed PD-(L)1 and chemotherapies, demonstrated a mPFS of 6.6 months.

Akeso is currently conducting, in China, a phase III clinical trial of ivonescimab monotherapy versus pembrolizumab monotherapy as the first-line treatment for NSCLC patients with positive PD-L1 expression.

Summit has clinical development and commercialization rights for SMT112 in its Licensed Territory (United States, Canada, Europe, and Japan).

Summit plans to design and conduct the clinical trial activities for SMT112 in its Licensed Territory, to support and submit relevant regulatory filings.

Summit is initiating development activities for ivonescimab and will do so first in NSCLC indications.

Product Pipeline

Status of Anti-Infectives Pipeline

Discuva Platform

2 unchanged sentences

Our Discuva Platform can be used to identify new bacterial targets for drug discovery, understand the mechanism of action of small molecules targeting varying types of bacteria and select the most optimal preclinical candidates, including those with the least propensity to develop bacterial resistance.

In addition to discovery project support, our deep biology and microbiology expertise has been utilized over the past year to provide further insights into the mechanism of action of ridinilazole and to characterize the preclinical microbiology of ridinilazole in greater detail.

The mechanism of action and microbiology studies may be an important component of any regulatory filings and communications with regulatory agencies for ridinilazole.

Enterobacteriaceae Program

We continue to advance our highly innovative program targeting infections caused by Enterobacteriaceae.

We have used our Discuva Platform to identify our DDS-04 series, a novel chemotype active against a clinically unexploited bacterial target that has the potential to treat Enterobacteriaceae infections.

Enterobacteriaceae are a family of bacteria responsible for serious infections across a number of conditions including bloodstream infections, urinary tract infections (“UTI”) and hospital-acquired pneumonias.

Multi-drug resistant (“MDR”) Enterobacteriaceae are resistant to treatment by most or occasionally all existing antibiotics.

The most difficult to treat among them are the Extended Spectrum Beta-Lactamase (“ESBL”)-producing and the Carbapenem-resistant Enterobacteriaceae (“CRE”).

According to the Center for Disease Control and Prevention (“CDC”), ESBL-producing and CRE Enterobacteriaceae have collectively caused an estimated 197,400 infections and 9,100 deaths in hospitalized patients in the United States in 2019.

Our DDS-04 series continues to build on highly promising preclinical in vivo efficacy data with an immediate focus on a new antibiotic agent for the treatment of complicated urinary tract infections, pneumonia and the associated bacteremia.

Our lead preclinical candidate for the Enterobacteriaceae program from the DDS-04 series is SMT026738 (formerly “DIS-0104145” and referred to as “SMT-738”).

SMT-738 is a novel small molecule inhibitor of the essential bacterial lipoprotein transport system (LolCDE) in Gram-negative bacteria, which displays a narrow spectrum of activity towards Enterobacteriaceae.

SMT-738 has demonstrated potent in vitro activity against global MDR isolates of E.

pneumoniae, including the clinically challenging NDM-carrying CRE isolates where many currently available treatment options have succumbed to clinical resistance including colistin, an antibiotic of last resort.

Most importantly, SMT-738 has also shown robust in vivo efficacy in relevant murine models of UTI, pneumonia and sepsis.

A preliminary rodent toxicity study has been concluded and the data supports the continued clinical development of SMT-738.

SMT-738 has the potential to become a first in class antibiotic to treat life-threatening infections.

Summit has received a sub-award from CARB-X to progress SMT-738 through preclinical development and an option to continue into Phase Ia clinical studies.

The award commits initial non-dilutive funding of up to $4.1 million for the preclinical phase, with the potential for a further $3.7 million available for the continued clinical development upon successfully achieving key preclinical development milestones.

We have been and plan to continue to perform IND-enabling activities.

Our Product Development Pipeline

The following table summarizes our product development pipeline.

(1) We have granted Eurofarma (see further discussion below of funding arrangement) an exclusive license to the commercial rights for ridinilazole in specified countries in South America, Central America and the Caribbean.

We retain commercialization rights across Rest of World territories.

(2) Currently supported by funding from CARB-X (see further discussion below of funding arrangement).

Our goal is to become a fully integrated biopharmaceutical company focused on the discovery, development, and, commercialization of patient-, provider-, novel mechanism of action and/or new era products that work in harmony with the human gut microbiome, including innovative therapeutics for the treatment of certain cancers and infectious diseases.

We have announced our intention to continue to expand our pipeline with therapeutics that work in conjunction with the human gut microbiome for the treatment of certain cancers and infectious diseases through business development activities including, but not limited to, partnerships with, collaborations with, and/or acquisitions of existing entities.

The key elements of our strategy to achieve this goal are to:

Evaluating the future path forward for our existing pipeline product candidates, including potential partnership opportunities, as applicable.

For ridinilazole, we are in the process of evaluating the future path forward, including potential partnership opportunities.

Expand our product portfolio of patient-friendly, new-era standards-of-care through our Summit Therapeutics Innovation Engine, including expanding our pipeline to potentially include patient-friendly oncology treatments.

We intend to expand our product portfolio through the identification of new-era standards-of-care therapies that work in harmony with the human gut microbiome.

Our therapeutic areas of focus, incorporating the gut microbiome, include oncology and anti-infectives.

We intend to expand our pipeline through our Summit Therapeutics Innovation Engine which is our research and discovery capabilities.

In addition, business development activities are planned to potentially further expand our pipeline through strategic collaborations with, or acquisitions of, target opportunities that elucidate our mission.

Clostridioides difficile Infection Overview

Clostridioides difficile infection (“ C.

difficile infection” or "CDI") is a bacterial infection of the colon caused by the bacterium C.

difficile which produces toxins that cause inflammation of the colon resulting in severe watery diarrhea, painful abdominal cramping, nausea, fever and dehydration.

CDI can also result in more serious disease complications, including bowel perforation, sepsis and death.

CDI represents a serious healthcare issue in hospitals as the most common hospital-acquired infection, in long-term care homes and in the wider community.

We estimate that there are approximately half a million cases of CDI each year across the United States based on a meta-analysis published in the Journal of Global Health in June 2019.

CDI originates from a bacterium known as Clostridioides difficile, Clostridium difficile or C.

difficile sometimes can be a harmless resident of the gastrointestinal tract.

The complex community of microorganisms that make up the gut microbiome usually moderates levels of C.

The gut microbiome, which includes natural gut flora, is an essential part of the normal function of the gastrointestinal tract and also has wide implications in human health, such as the proper function of the immune system.

CDI typically develops following the use of broad-spectrum antibiotic agents that can cause widespread damage to the gut microbiome and allow overgrowth of C.

Hypervirulent C.

difficile strains have also emerged and are frequently associated with more severe diseases.

A paper published in 2018 in the peer-reviewed journal, American Journal of Infection Control , reported that in the United States, the hypervirulent strain, ribotype 027, accounts for approximately one-fifth of all CDI cases.

The primary clinical issue with CDI is disease recurrence.

This is in contrast to other bacterial threats for which drug resistance is the principal concern.

According to an article published in 2012 in the peer reviewed journal Clinical Microbiology and Infection , up to 25% of patients with CDI suffer a second episode of the infection.

The risk of further recurrence rises to 65% after a patient suffers a third episode of CDI.

In addition, each episode of recurrent disease is associated with greater disease severity and higher mortality rates.

Recurrent disease is associated with an increased burden on the healthcare system.

In 2013, the CDC highlighted CDI as one of three pathogens that pose an immediate public health threat and require urgent and aggressive action.

In 2019, the CDC published an updated report that continued to highlight the threat posed by CDI, with this infection classified as one of four bacterial pathogens that poses an immediate public health threat and requires urgent and aggressive action.

In 2012, the Generating Antibiotics Incentives Now Act provisions of the FDA Safety and Innovation Act, or GAIN, became law.

The goal of GAIN is to encourage the development of new antibiotics that treat specific pathogens, including C.

difficile , which cause serious and life-threatening infections.

Current CDI Treatments

Existing treatment options for CDI are limited.

Currently, the most commonly used treatments for CDI is vancomycin, which is a broad-spectrum antibiotic.

A broad-spectrum antibiotic may not be the most appropriate treatment for CDI because although the antibiotics reduce levels of C.

difficile , they cause significant collateral damage to the gut microbiome by killing bacteria that contribute to a healthy microbiome.

This collateral damage to the gut microbiome leaves patients vulnerable to recurrent CDI.

According to the Infectious Disease Society of America (“IDSA”) guidelines, the current standard-of-care for primary CDI is to treat with antibiotics, such as fidaxomicin or vancomycin.

Both are recommended to treat primary CDI, and they do not have a label claim to reduce or prevent CDI recurrence.

No antibiotic therapeutics are currently approved for the treatment of recurrent CDI.

In October 2016, the FDA approved bezlotoxumab, a monoclonal antibody, in conjunction with an antibiotic to reduce the recurrence of CDI in patients who have a high risk of recurrence.

For patients with a recurrent CDI episode within the last 6 months, IDSA suggests using bezlotoxumab as a co-intervention along with standard-of-care (SOC) antibiotics rather than SOC antibiotics alone (conditional recommendation, very low certainty of evidence).

Bezlotoxumab binds to toxin B, one of the toxins produced by the C.

difficile bacteria, to neutralize its effects.

Bezlotoxumab does not treat CDI and has no direct antimicrobial activity.

Ridinilazole for the Treatment of CDI

We have been developing ridinilazole as an orally-administered, small molecule targeted antibiotic for the treatment of CDI.

Ridinilazole is designed to selectively target C.

difficile bacteria while preserving the microbiome and thereby treat the initial infection and reduce CDI recurrence rates.

Ridinilazole is aligned with good antibiotic stewardship through its targeted spectrum of activity and the potential to reduce disease recurrence.

Ridinilazole comprises of a symmetrical bis-benzimidazole scaffold which forms its core structure.

We believe, based on preclinical studies conducted to date, that ridinilazole is part of a novel structural class of antibiotics that is distinct from the major classes of marketed antibiotics.

We conducted a Phase III clinical study that evaluated the benefits of ridinilazole compared to the current standard-of-care antibiotic, vancomycin, in patients with CDI.

The Phase III Ri-CoDIFy trial had the primary endpoint that was testing for superiority in SCR, which is defined as Clinical Response and no recurrence of CDI within 30 days after the end of treatment.

Due to the uncertainties surrounding COVID-19 and the desire of Summit to not delay the understanding of potential clinical practice-changing data, Summit combined the two trials, formerly known as “Ri-CoDIFy 1” and "Ri-CoDIFy 2,” into a single study.

We refer to this Phase III clinical trial as "Ri-CoDIFy." We dosed the first patient in our Phase III clinical trials in February 2019.

We enrolled 759 patients in the combined Ri-CoDIFy clinical trial.

On December 20, 2021, we announced topline results for the Phase III Ri-CoDIFy study.

The study showed that ridinilazole resulted in a numerically higher SCR rate than vancomycin but did not meet the study’s primary endpoint for superiority.

We will continue to evaluate the underlying data and perform additional analyses, including analyses specific to the microbiome.

In November 2015, we reported top-line results from our double blind, randomized, active controlled Phase II clinical trial that evaluated ridinilazole compared to the current standard-of-care, vancomycin, for the treatment of CDI.

The Phase II clinical trial showed its primary endpoint of non-inferiority, with ridinilazole achieving statistical significance in testing the non-inferiority hypothesis to vancomycin in SCR.

We subsequently reported that data from our Phase II clinical trial also showed ridinilazole to be highly preserving of the gut microbiome and secondary bile acids compared to patients who received vancomycin and experienced substantial damage to the gut microbiome, which for many patients persisted during the 30-day post-treatment period.

In September 2017, we reported top-line data from our exploratory, open label, active controlled Phase II clinical trial evaluating ridinilazole compared to fidaxomicin for the treatment of CDI.

In the trial, ridinilazole preserved the gut microbiome of CDI patients to a greater extent than fidaxomicin, achieving a key secondary endpoint.

The overall safety profile of ridinilazole remains unchanged.

Ridinilazole Clinical Development

Phase III Clinical Trial Program

In the Ri-CoDIFy trial, we randomized patients in a one-to-one ratio to receive either a 200 mg dose of ridinilazole tetrahydrate administered twice per day for ten days or a 125 mg dose of vancomycin administered four times per day for ten days.

Due to the different treatment regimens, we developed dummy placebos that are administered to the patients in the Phase III clinical trials according to a schedule designed to maintain the blind within each trial.

Enrolled patients in Ri-CoDIFy were required to be at least 18 years of age or older, have a confirmed diagnosis of CDI as measured by the presence of toxin A and/or toxin B of C.

difficile in the stool as confirmed by a positive free toxin test, and must not have had more than one prior episode of CDI in the previous three months, or more than three episodes in the prior 12 months.

The Ri-CoDIFy Phase III clinical trial was designed to assess, as its primary endpoint, the superiority of ridinilazole compared to vancomycin in Sustained Clinical Response, or SCR, which was defined as Clinical Response of the treated episode of CDI and no recurrence of CDI through 30 days after the end of treatment.

On December 20, 2021, we announced topline results for the Phase III Ri-CoDIFy study evaluating ridinilazole for the treatment of and Sustained Clinical Response for patients suffering from C.

difficile infection.

The study showed that ridinilazole resulted in a numerically higher SCR rate than vancomycin but did not meet the study’s primary endpoint for superiority.

We will continue to evaluate the underlying data, including analyses specific to the microbiome.

Phase II Clinical Trial in Patients with CDI

In November 2015, we reported top-line results from our randomized, double blind, active controlled, multicenter, Phase II clinical trial of ridinilazole in patients with CDI, and we subsequently presented additional data.

We referred to this as our Phase II proof of concept clinical trial and as the "CoDIFy" study.

We conducted this clinical trial at approximately 35 sites in the United States and Canada.

The trial was conducted under an Investigational New Drug Application, or IND, that we submitted to the FDA in January 2014.

We enrolled a total of 100 patients between 18 to 90 years of age.

The trial randomized patients in a one-to-one ratio to receive either a 200 mg dose of ridinilazole tetrahydrate administered twice per day for ten days or a 125 mg dose of vancomycin administered four times per day for ten days.

The primary objective of this clinical trial was to evaluate the efficacy of ten days of dosing with ridinilazole compared to treatment with vancomycin.

The primary efficacy endpoint was non-inferiority on sustained clinical response, or SCR, which was defined as clinical cure based on the resolution of diarrhea at the test of cure, or TOC, visit on day 12 and no recurrence of CDI within 30 days after the end of treatment.

The secondary efficacy endpoints were investigator assessed clinical response at the TOC visit and rate of recurrence of CDI within 30 days after the end of treatment.

Secondary objectives of this clinical trial were the assessment of the safety and tolerability of ten days of dosing of ridinilazole compared to vancomycin, the plasma and fecal concentrations of ridinilazole in patients with CDI who received ridinilazole and the health status of CDI patients who received ten days of treatment of ridinilazole compared to patients who received ten days of treatment of vancomycin.

We also assessed the impact of vancomycin or ridinilazole on the gut microbiome of patients in the clinical trial as one of a number of exploratory objectives.

Analysis of Results

We observed the following results in our Phase II proof of concept trial:

• Ridinilazole Demonstrated Statistical Superiority Over Vancomycin for the Primary Endpoint.

Our Phase II proof of concept trial met its primary endpoint with ridinilazole achieving a SCR rate of 66.7% compared to 42.4% for vancomycin (non-inferiority margin of 15%, p=0.0004 for testing non-inferiority).

At the pre-specified 2-sided alpha level of 0.10, ridinilazole was statistically superior to vancomycin.

The primary analysis was conducted on the modified intent-to-treat, or mITT, population (36 patients dosed with ridinilazole, 33 patients dosed with vancomycin) that comprised patients with CDI confirmed by the presence of free toxin in feces.

We also observed a generally consistent trend of improved SCR with ridinilazole across subgroups at higher risk of recurrence, including the elderly, patients who were on concomitant antibiotics at the start of treatment and patients with a prior history of CDI.

• Ridinilazole Demonstrated a Large Reduction in Rates of Recurrence Compared to Vancomycin.

We observed that the statistical superiority at 2-sided alpha of 0.10 (which was prespecified in the protocol) in SCR with ridinilazole compared to vancomycin was driven by a large numerical reduction in rates of disease recurrence.

Clinical cure rates at the end of ten days of treatment were similar, with ridinilazole achieving a rate of 77.8% compared to 69.7% for

vancomycin, but ridinilazole achieved a recurrence rate of 14.3% compared to 34.8% for vancomycin during the 30-day post-treatment period.

• Ridinilazole had Minimal Impact on the Gut Microbiome.

The microbiome primary analysis of the Phase II study was performed on fecal samples collected from CDI patients at baseline, and at end of therapy (EOT, Day 10).

This analysis showed that ridinilazole had minimal impact on the gut microbiome diversity and composition compared to vancomycin indicating a smaller impact on microbiota health and preservation of resistance to infections.

No or minimal loss in alpha-diversity was observed following 10 days treatment with ridinilazole, whereas a significant loss in diversity was observed with vancomycin.

Ridinilazole also showed minimal impact on the gut microbiome composition with significant reductions in relative abundance limited to only a few taxa from the Firmicutes:

36-fold reduction of the Peptostreptococcaceae family that contains C.

difficil e, and 15-fold and 10-fold reductions of the Ruminococacceae and Clostridiaceae, respectively.

In contrast, vancomycin resulted in significant reductions in the relative abundance of several families in the Firmicutes (e.g.

>1000-fold for Lachnospiraceae and >500-fold for Ruminococcaceae), in the Bacteroidetes (>1000- fold) and in the Actinobacteria (5-fold) phyla.

These impacts are demonstrated in the illustraiont below.

These reductions were associated with a >20-fold increase in the Proteobacteria and, in particular, a >200-fold increase in Enterobacteriaceae and >1000-fold increase in Klebsiella spp .

This further gut dysbiosis with the expansion of Enterobacteriaceae pathogens may put patients at risk for subsequent infections, including multi-drug resistant pathogens such as the carbapenem-resistant K.

Differential impact of ridinilazole and vancomycin on the gut microbiota

Changes in relative abundance of bacterial taxa in CDI patients after 10 day-treatment with ridinilazole or vancomycin

l ower abundance at the end of treatment Green:

higher abundance at the end of treatment

• Ridinilazole Preserved the Gut Bile Acid Composition.

Bile acids are metabolized by bacteria within the gut.

These bile acids exist in different forms that can either favor or block the growth of C.

As expected, in healthy controls, bile acids that can block C.

difficile growth, i.e., the protective bile acids were predominant while in Phase II CDI patients bile acids that can promote C.

difficile growth were predominant.

Ridinilazole treatment preserved the gut bile acid composition and allowed a gradual normalization post-treatment.

At 30 days post-EOT, the bile acid composition of ridinilazole-treated patients trended towards that of healthy subjects showing a predominance of the protective bile acids.

In contrast, vancomycin treatment resulted in further alteration of the bile acid composition and a significant decrease of the protective bile acids to < 1% of the total bile acids at EOT.

At 30 days post-EOT, their bile acid profile was similar to that observed in the CDI patients prior to therapy, potentially predisposing vancomycin- treated patients to recurrence of the infection.

Differential impact of ridinilazole and vancomycin on gut bile acids

Fecal bile acid composition in healthy control subjects,

ridinilazole- and vancomycin-treated subjects

Day 10, end-of-treatment;

Day 40 or 30 days post-EOT

• Ridinilazole was Retained in the Gastrointestinal Tract.

Ridinilazole was restricted to the gastrointestinal tract, which is the site where CDI occurs in the body.

Systemic exposure was close to or below the level of detection in patients with CDI, with plasma concentrations very similar to those observed in our Phase I clinical trial in healthy volunteers.

• Ridinilazole Reduced Biomarkers of Inflammation.

We measured levels of two key markers of inflammation, calprotectin and lactoferrin, in feces collected from the 69 patients who comprised the mITT group.

The samples analyzed were collected at the time of randomization (prior to initiation of treatment), at day five and at day ten.

We observed that ridinilazole and vancomycin reduced concentrations of calprotectin and lactoferrin by similar levels when analyzing the results for all patients.

We also observed that a subset of patients with severe CDI had a greater reduction in levels of calprotectin and lactoferrin when treated with ridinilazole compared to vancomycin.

We believe these data indicate that ridinilazole is associated with a greater reduction in inflammatory markers compared to vancomycin in patients with severe CDI.

• Ridinilazole Significantly Improved Short- and Longer-Term Quality of Life Measures.

Patients completed the EuroQol 5-Dimension questionnaire (three level version;

EQ-5D-3L) at baseline, day 5, day 10, day 12 and day 40 to assess the impact of treatment with ridinilazole and vancomycin on five dimensions of physical and mental health:

mobility, self-care, usual activities, pain/discomfort and anxiety/depression.

As early as day 5, ridinilazole-treated patients reported improvements in index scores (p=0.008), a measure that combines scores from the five domains and visual analogue scale, or VAS, scores (p=0.01), which is a self-reported score of overall health.

More specifically, by day 40, patients treated with ridinilazole had improved significantly more than patients treated with vancomycin in anxiety and depression measures.

In addition, while both treatment arms showed significant improvements in pain and discomfort with treatment, by day 10, fewer patients treated with ridinilazole reported issues than did those treated with vancomycin.

We believe these findings support the potential for the benefits of treatment with ridinilazole to extend beyond clinical benefits to the overall wellbeing of the patient.

• Ridinilazole was Well Tolerated.

Ridinilazole was generally well tolerated.

The overall rate of adverse events and serious adverse events reported in the ridinilazole and vancomycin treatment arms were comparable.

Phase II Exploratory Clinical Trial of Ridinilazole Compared to Fidaxomicin

In September 2017, we reported top-line data from our randomized, open label, active controlled, multicenter Phase II clinical trial evaluating ridinilazole compared to fidaxomicin for the treatment of CDI.

This exploratory clinical trial was designed to generate data comparing ridinilazole to fidaxomicin, a CDI antibiotic launched in 2011, and the results of this clinical trial are expected to help to inform the commercial positioning of ridinilazole.

We conducted this clinical trial at sites in the United Kingdom, Europe and the United States, enrolling 27 patients between 18 and 90 years of age.

We randomized patients in a one-to-one ratio to receive either a 200 mg dose of ridinilazole tetrahydrate administered twice per day for ten days or a 200 mg dose of fidaxomicin administered twice per day for ten days.

The trial population was unbalanced with more patients randomized to ridinilazole having predisposing factors for recurrent CDI, and at a higher risk of poorer clinical outcomes as measured by ATLAS score, a tool for evaluating CDI in patients by age, temperature, leukocytes and albumin levels, and use of systemic antibiotics.

The primary efficacy objective of this clinical trial was to determine the safety and tolerability of ten days of dosing with 200 mg BID of ridinilazole tetrahydrate compared to dosing with 200 mg BID of fidaxomicin.

The secondary objectives of the clinical trial were to assess the following:

• the plasma pharmacokinetics of ridinilazole in patients with CDI;

• the qualitative and quantitative effect of ridinilazole and fidaxomicin on the gut microbiome;

• the plasma, urine and fecal concentrations of ridinilazole and its metabolites;

• the efficacy of ten days of dosing with ridinilazole compared to fidaxomicin for the treatment of CDI.

The measurement of efficacy was based on investigator assessed clinical response at the test of cure, or TOC, visit, with clinical cure defined as resolution of diarrhea while on treatment and maintained at the TOC visit, and sustained clinical response, defined as clinical cure at the TOC visit and no recurrence of CDI within 30 days after the end of treatment.

We reported the following findings:

• Ridinilazole Preserved the Microbiome to a Greater Extent than Fidaxomicin.

We observed that the ten days treatment with ridinilazole had markedly less of an impact on the gut microbiome of trial patients by measures of overall diversity and changes in key bacterial groups when compared to those trial patients dosed with fidaxomicin.

We observed that while ridinilazole and fidaxomicin both reduced the abundance of C.

difficile , fidaxomicin treated patients had reduced abundance of other bacterial families, including the Ruminococcaceae family from the Firmicutes, that are thought to have direct functional roles in protecting against CDI.

We observed that for a number of these bacterial families, the difference between the two treatments reached statistical significance.

We also reported alpha diversity, as measured by the Simpson's Diversity Index, as another measure of microbiome health.

We observed a greater reduction in alpha-diversity during fidaxomicin treatment compared with ridinilazole treatment.

These measures were a key secondary endpoint of the trial.

We believe that these measures provide further evidence of ridinilazole's precision in killing C.

difficile while preserving the gut.

• Ridinilazole was Well Tolerated.

The primary endpoint of the trial was safety, as measured by the number of treatment emergent adverse events and serious adverse events.

During the trial, no new or unexpected safety signals were identified and ridinilazole was well tolerated.

• Comparable Rates of Sustained Clinical Response.

We observed that seven of the 14 ridinilazole-treated patients and six of the 13 fidaxomicin-treated patients were cured at the end of treatment and did not have a recurrence of CDI within the following 30 days to achieve a sustained clinical response.

The trial was however not designed for efficacy comparisons due to the small number of patients enrolled, and so we believe no conclusions on efficacy should be made based solely on these data.

Phase I Clinical Trial in Healthy Volunteers

In 2013, we completed a randomized, partially blind, placebo-controlled Phase I clinical trial of ridinilazole in healthy volunteers.

We conducted this clinical trial at a single site in the United Kingdom under approval from the U.K.

Medicines and Healthcare products Regulatory Agency, or MHRA, and the Ethics Review Committee.

We enrolled 56 healthy male subjects in the clinical trial who were between 18 and 55 years of age.

The primary objective of the clinical trial was to determine the safety and tolerability of single and multiple ascending oral doses of ridinilazole.

The secondary objectives included determining the single and multiple oral dose pharmacokinetics of ridinilazole, assessing the effect of food on systemic exposure of ridinilazole and assessing the effect of multiple oral doses of ridinilazole on gut flora.

We conducted the clinical trial in two parts.

Part 1 consisted of an ascending single dose study and a food effect evaluation study.

In Part 1, we evaluated a total of 40 subjects, divided into the following six cohorts:

• four fasted subjects, randomized for three subjects to receive a single 2 mg dose of ridinilazole and one subject to receive placebo;

• four fasted subjects, randomized for three subjects to receive a single 20 mg dose of ridinilazole and one subject to receive placebo;

• eight fasted subjects, randomized for six subjects to receive a single 100 mg dose of ridinilazole and two subjects to receive placebo;

• eight fasted subjects, randomized for six subjects to receive a single 400 mg dose of ridinilazole and two subjects to receive placebo;

• eight fasted subjects, randomized for six subjects to receive a single 2,000 mg dose of ridinilazole and two subjects to receive placebo;

• eight subjects, randomized for six subjects to receive a single 1,000 mg dose of ridinilazole under fasted conditions and a single 1,000 mg dose under fed conditions, and two subjects to receive two single doses of placebo on the same dosing schedule.

The doses under fed and fasted conditions were separated by a minimum of six days.

Part 2 of the clinical trial consisted of a multiple dose study.

In Part 2, we evaluated a total of 16 subjects, who were divided into the following two cohorts:

• eight subjects randomized for six subjects to receive 200 mg doses of ridinilazole twice per day for nine days with a single final dose on day ten and two subjects to receive placebo on the same dosing schedule;

• eight subjects randomized for six subjects to receive 500 mg doses of ridinilazole twice per day for nine days with a single final dose on day ten and two subjects to receive placebo on the same dosing schedule.

Analysis of Trial Results

We observed the following results in this clinical trial:

• Ridinilazole was Well Tolerated.

Ridinilazole was well tolerated at all doses tested in the clinical trial.

The incidence of adverse events in the clinical trial was low for patients treated with ridinilazole and comparable to the incidence of adverse events for patients receiving placebo.

The majority of the adverse events that were considered to be possibly related to ridinilazole were classified as gastrointestinal disorders and were mild in severity and resolved without intervention.

One patient withdrew from the clinical trial after suffering from appendicitis on day one.

The trial investigator determined this serious adverse event was unlikely to be related to treatment with ridinilazole.

• Ridinilazole was Retained in the Gastrointestinal Tract.

Ridinilazole was targeted to the gastrointestinal tract, which is the site where CDI occurs in the body.

Systemic exposure was close to or below the level of detection in both fed and fasted subjects.

• Ridinilazole was Highly Selective for Total Clostridia Bacteria with Minimal Impact on Other Natural Gut Flora.

We measured levels of bacteria in fecal samples from Part 2 of the clinical trial for gut microbiome composition on the day prior to commencement of dosing and on days four and nine of the 10-day treatment.

In both the 200 mg BID and 500 mg BID dose cohorts, median levels of key bacteria groups that comprise the natural gut microbiome remained relatively constant during this period and did not fluctuate substantially from baseline.

The one exception was the total clostridia bacterial group which decreased from the baseline level to zero by day four of dosing and remained at zero on day nine of dosing.

We did not detect any C.

difficile viable cells or spores in the fecal samples of any of the healthy volunteer subjects at any point during the clinical trial.

Thus, ridinilazole affected the count of clostridia other than C.

difficile but not of any other bacteria groups that comprise the gut microbiome.

CDI Preclinical Data

In a range of preclinical studies, ridinilazole demonstrated an encouraging profile as a potential antibiotic for the treatment of initial CDI and reduction of CDI recurrence.

The following is a summary of key observations from these studies:

• Potency Against C.

We screened the in vitro activity of ridinilazole and a range of different comparators including fidaxomicin, metronidazole and vancomycin against nearly 700 C.

difficile clinical isolates.

Clinical isolates have been collected in Europe, U.S.

and Asia-Pacific and included a range of ribotypes including the hypervirulent ribotype RT 027 and most common ribotypes in Europe and U.S.

In these studies, ridinilazole was highly potent against all C.

difficile clinical isolates, either equally potent to, or more potent than, fidaxomicin and more potent than both vancomycin and metronidazole.

Ridinilazole did not display evidence of cross resistance with other classes of key antibiotics in common use.

• Targeted Spectrum of Activity .

We conducted in vitro testing of ridinilazole, vancomycin, metronidazole and fidaxomicin against a wide panel of bacteria that are commonly found in the gut microbiome and are necessary for normal function of the gastrointestinal tract and also have wide implications on human health, such as the proper function of the immune system.

As illustrated in the figure below, in this study ridinilazole had minimal activity against these beneficial bacterial groups.

Ridinilazole also displayed higher selectivity for C.

difficile in this study as compared to vancomycin, metronidazole and fidaxomicin.

In vitro potency is measured by determining the concentration of a drug (in micrograms per milliliter) needed to inhibit the growth of 90% of the bacterial strains being tested, referred to as a MIC90 measurement.

A high number, typically higher than 256, indicates a weak antimicrobial effect, and a low number, typically less than eight, indicates a potent antimicrobial effect.

We believe that the targeted spectrum of activity for ridinilazole seen in this study compared to the relatively broad-spectrum of activity of other antibiotics indicates the potential for ridinilazole to selectively target C.

difficile bacteria while preserving the microbiome and thereby reduce CDI recurrence rates.

Profile of Selectivity of Ridinilazole vs.

Other CDI Antibiotics

• Novel Mechanism of Action (MOA) .

Ridinilazole is believed to drive its bactericidal effect through a novel MoA that results in lethal perturbation of cell division.

We have conducted further studies to characterize the MoA.

It has now been demonstrated that ridinilizole is able to bind, with high affinity, to the minor groove of double-stranded DNA substrates, including C.

difficile genomic DNA.

Cell imaging using fluorescence confocal microscopy has revealed that ridinilazole exclusively co-localizes with genomic DNA in C.

DNA binding is believed to be the primary mechanism through which ridinilazole exerts its bactericidal activity in C.

Further studies will be conducted to determine the biological consequences of ridinilazole binding to genomic DNA in C.

• Protection Against CDI Recurrence .

In a hamster model, we infected one group of hamsters with a C.

difficile strain from the hypervirulent ribotype 027 and a second group of hamsters with the C.

difficile virulent reference strain 630, ribotype 012.

Hamsters from each group were treated for 5 days with different doses of ridinilazole, vancomycin and fidaxomicin and recurrence of the infection was evaluated over the 21 days following treatment.

In this hamster model, a hamster fatality within the first five days is a result of initial C.

difficile infection, while a fatality from day six to day 25 is a result of recurrent disease.

As illustrated in the figure below, the hamsters treated with two different doses of ridinilazole had survival rates of 90% to 100% against strain ribotype 027 and 80% to 100% against strain ribotype 012.

These survival rates were higher than hamsters treated with vancomycin (0% to 10% survival rates) for both CDI strains, comparable to hamsters treated with two different doses of fidaxomicin against strain ribotype 027 (90% to 100% survival rates) and higher than hamsters treated with two different doses of fidaxomicin against strain ribotype 012 (0% to 40% survival rates).

All infection control hamsters received placebo and died by the second day following infection.

• Ridinilazole Arrests Cell Division.

In in vitro studies, treatment of C.

difficile bacteria prevented bacterial replication, eventually resulting in death of the bacterial cells.

We have also observed significant increases in the length of C.

difficile cells and an absence of division septum formation, suggesting replication is halted by prevention of bacterial division.

• Inhibition of Sporulation.

difficile can form spores – a dormant, protected form of the bacterium which contributes to infection recurrence, is highly resistant to standard cleaning practices and leads to environmental persistence and disease transmission.

During in vitro studies, we found that treatment of C.

difficile with ridinilazole at concentrations which prevent bacterial replication also prevents sporulation.

We believe that inhibition of sporulation may help reduce the incidence of recurrent disease.

• Reduction in Toxin Levels in vitro.

difficile produces toxins A and B to elicit an inflammatory response in the host, resulting in the symptoms of the disease including severe diarrhea.

We found during in vitro studies that treatment of C.

difficile with ridinilazole at concentrations which prevent bacterial replication reduce toxin A and B production.

• Low Propensity for Resistance.

In vitro studies exposing C.

difficile to ridinilazole have shown that the frequency of spontaneous resistance to ridinilazole is low.

Resistant mutants that do arise, or are forcefully selected for by passaging in the presence of sub-inhibitory levels of ridinilazole, importantly showed no cross-resistance to other standard-of- care antibiotics.

• Concomitant Antibiotic Use.

In an in vitro bacterial culture study, we exposed C.

difficile to ridinilazole in combination with selected other antibiotics.

In this study, concomitant use of antibiotics had neither a synergistic nor an antagonistic effect on the minimal inhibitory concentration of ridinilazole, with the exception of lincosamide antibiotics (clindamycin and lincomycin).

For these compounds, an additive (nearly synergistic) interaction was observed.

We believe these results indicate that concomitant use of other antibiotics will not diminish the potency of ridinilazole.

This is an important finding because a significant portion of CDI patients receive antibiotic treatment for persistent or new infections.

Other Pipeline Product Candidates

Discuva Platform

Our Discuva Platform is a genetics-based technology that can be used throughout the stages of drug discovery from hit-to-lead through candidate selection.

Our Discuva Platform aligns modified bacterial transposon mutagenesis with next generation sequencing and a proprietary end user interface.

The Discuva Platform uses pathogen specific transposons.

Our Discuva Platform uses pathogen specific transposons and aligns modified bacterial transposon mutagenesis with next generation sequencing and a proprietary end user interface.

Transposons are small segments of DNA that are capable of replicating and inserting copies of DNA at random sites in the same or a different chromosome.

4 unchanged sentences

i) Identifying Essential Genes in Bacteria.

We are able to use our Discuva Platform to identify genes within bacteria

that are essential for their survival.

This allows us to identify new bacterial targets against which to develop new

antibiotic drugs.

We are able to use our Discuva Platform to identify genes within bacteria that are essential for their survival.

This allows us to identify new bacterial targets against which to develop new antibiotic drugs.

ii) Elucidating Mechanism of Action.

We are able to use our Discuva Platform to elucidate the mechanism of action of

a compound to be inferred by the genes that are upregulated during experiments when in the presence of a drug.

are able to rapidly identify the mechanism of action of a potential drug and this represents an important capability of

our Discuva Platform.

We have been able to validate the ability of our Discuva Platform to elucidate mechanisms of

action by testing antibiotic compounds representative of known classes whose mechanisms of action are known.

We are able to use our Discuva Platform to elucidate the mechanism of action of a compound to be inferred by the genes that are upregulated during experiments when in the presence of a drug.

We are able to rapidly identify the mechanism of action of a potential drug and this represents an important capability of our Discuva Platform.

We have been able to validate the ability of our Discuva Platform to elucidate mechanisms of action by testing antibiotic compounds representative of known classes whose mechanisms of action are known.

iii) Understanding Emergent Mechanisms of Resistance.

We are able to use our Discuva Platform to test a

compound’s susceptibility towards known mechanisms of antibiotic resistance to allow us to select potential drug

candidates with what we believe will be much better resistance profiles.

We believe the importance of understanding

patients prior to the development of widespread resistance.

We are able to use our Discuva Platform to test a compound’s susceptibility towards known mechanisms of antibiotic resistance to allow us to select potential drug candidates with what we believe will be much better resistance profiles.

We believe the importance of understanding patients prior to the development of widespread resistance.

On January 20, 2023, we announced that, given the License Agreement that we entered into in December 2022 and the shift in Company’s focus to oncology, we will cease further investment in the Discuva platform and evaluate further options for the use of the Discuva Platform.

Based on the evaluation of further options for the use of the Discuva Platform, management concluded that this indicated the carrying amount of the acquired Discuva Platform intangible asset may not be recoverable and therefore, performed an impairment assessment to evaluate whether the fair value of the intangible asset was less than its carrying amount.

Based on this assessment, an impairment charge of $8.5 million was recognized during the year ended December 31, 2022, representing the aggregate carrying value of the intangible asset.

See Note 12 to our consolidated financial statements contained in this Annual Report on Form 10-K for further details.

Enterobacteriaceae Program

We are developing a new mechanism novel small molecule antibiotic (SMT-738 which has originated from our DDS-04 series) for the potential treatment of infections caused by the Enterobacteriaceae, a family of Gram-negative bacteria which includes E.

coli and Klebsiella species.

Enterobacteriaceae are responsible for causing serious infections across multiple indications, for example bloodstream infections, urinary tract infections and hospital-acquired pneumonias.

Multi-Drug Resistant (“MDR”) Enterobacteriaceae are resistant to treatment by most or occasionally all existing classes of known antibiotics.

The most difficult to treat infections are those caused by the Extended Spectrum Beta-Lactamase (“ESBL”)-producing Enterobacteriaceae and the Carbapenem-resistant Enterobacteriaceae (“CRE”).

According to the CDC, ESBL-producing and CRE Enterobacteriaceae have collectively caused an estimated 197,400 infections and 9,100 deaths in hospitalized patients in the United States in 2019.

We identified the novel DDS-04 series using our Discuva Platform and, like ridinilazole, the DDS-04 series has a targeted- spectrum of activity, in this case highly specific for Enterobacteriaceae.

The DDS-04 series act via a clinically unexploited target, LolCDE, which is involved in the transport of lipoproteins from the inner to outer membrane in Gram-negative bacteria.

The cell membrane is crucial for cell viability and the lol genes are essential in bacteria such as E.coli .

In April 2019, we

reported data that showed our DDS-04 series to be rapidly bactericidal and highly potent across globally diverse Enterobacteriaceae strains, including multi-drug resistant isolates.

In April 2019, we reported data that showed our DDS-04 series to be rapidly bactericidal and highly potent across globally diverse Enterobacteriaceae strains, including multi-drug resistant isolates.

Importantly, our DDS-04 series has a low propensity for resistance development and displays no cross resistance with existing classes of antibiotics.

In July 2019, we reported initial, positive proof of concept data on an exemplar compound from our DDS-04 series across in vivo rodent models of sepsis, urinary tract infection, and pneumonia with further data presented in September 2019.

On May 18, 2021, we announced SMT026738 (“SMT-738”) as our preclinical candidate to combat multidrug resistant infections, specifically Carbapenem-resistant Enterobacteriaceae (“CRE”) infections.

SMT-738 is the first of a novel class of precision antibiotics.

Combining a novel antibiotic class (SMT-738) with a clinically unexploited target (LolCDE) mitigates the risk of pre-existing resistance, potentially allowing for the effective treatment of infections caused by Enterobacteriaceae that currently have very limited and failing treatment options due to resistance to existing antibiotic classes.

Our lead preclinical candidate for the Enterobacteriaceae program from the DDS-04 series is SMT026738 (formerly “DIS-0104145” and referred to as “SMT-738”).

SMT-738 is a novel small molecule inhibitor of the essential bacterial lipoprotein transport system (“LolCDE”) in Gram-negative bacteria, which displays a narrow spectrum of activity towards Enterobacteriaceae, that currently have very limited and failing treatment options due to resistance to existing antibiotic classes.

SMT-738 has demonstrated potent in vitro activity against global MDR isolates of E.

pneumoniae , including the clinically challenging NDM-carrying CRE isolates where many currently available treatment options have succumbed to clinical resistance including colistin, an antibiotic of last resort.

Most importantly, SMT-738 has also shown robust in vivo efficacy in relevant murine models of UTI, pneumonia and sepsis.

Preliminary toxicity studies have been conducted, and the data supports the continued clinical development of SMT-738.

SMT-738 has the potential to become a first in class antibiotic to treat life-threatening infections.

We retain worldwide clinical development and commercial rights to SMT-738.

We have been and plan to continue to perform IND-enabling activities.

Our Collaborations and Funding Arrangements

In September 2017, we were awarded a contract from the Biomedical Advanced Research and Development Authority, or BARDA, to fund, in part, the clinical and regulatory development of ridinilazole for the treatment of infections caused by C.

The contract includes a base period with federal government funding of approximately $32.0 million.

In addition, there are three option work segments that, if exercised in full by BARDA, would increase the total federal government funding under the contract to approximately $62.0 million.

In August 2018, BARDA exercised one of the option work segments worth $12 million.

In June 2019, BARDA increased the total value of the funding contract to up to $63.7 million and also exercised a second option work segment worth $9.6 million.

In January 2020, BARDA increased the contract by a further $8.8 million.

This increased the total value of the funding contract to $72.5 million and brought the total amount of committed BARDA funding to $62.4 million.

We will continue to pursue partnerships for further development of SMT-738.

Other Material Agreements

The following material agreements relate to our commitments and obligations with respect to ridinilazole and SMT-738 only.

The entry into the License Agreement represents a significant change in the Company’s strategy.

All prior development and marketing activities relating to ridinilazole are being terminated and all business activities related to anti-infectives are being reviewed for partnership opportunities for potential further development.

In September 2017, we were awarded a contract from the Biomedical Advanced Research and Development Authority ("BARDA"), part of the Office of the Assistant Secretary for Preparedness and Response at the United States Department of Health and Human Services, to fund, in part, the clinical and regulatory development of ridinilazole for the treatment of infections caused by C.

The awarded contract was originally worth up to $62.0 million.

In June 2019 and again in January 2020, BARDA increased the value of the contract such that it is now worth up to $72.5 million and brought the total amount of committed funding to $62.4 million.

As of December 31, 2022, based on translation of historical foreign currency amounts in the period, the Company has recognized $59.2 million of cumulative income since contract inception.

The contract provides for a cost-sharing arrangement under which BARDA funded a specified portion of estimated costs for the continued clinical and regulatory development of ridinilazole for CDI.

Under this cost sharing arrangement, we were responsible for a portion of the costs associated with each segment of work, including any costs in excess of the estimated amounts.

The remaining federal government funding is dependent on BARDA in its sole discretion exercising the final independent option work segment, upon the achievement by the Company of certain agreed-upon milestones for ridinilazole.

As of December 31, 2021, an aggregate of $56.5 million of the total committed BARDA funding has been received and the Company has recognized $50.3 million of cumulative income since contract inception.

The contract provides for a cost-sharing arrangement under which BARDA funds a specified portion of estimated costs for the continued clinical and regulatory development of ridinilazole for CDI.

Under this cost sharing arrangement, we are responsible for a portion of the costs associated with each segment of work, including any costs in excess of the estimated amounts.

During the base period of the contract, BARDA agreed to fund, in part, activities for our two Phase III clinical trials of ridinilazole, which were later combined into one trial (Ri-CoDIFy), and included obtaining requisite regulatory approvals for the opening of trial sites, arranging for the manufacture of clinical supply of ridinilazole and engaging third-party contract research organizations to conduct the clinical trials including initial patient enrollment and treatment.

Under the original terms of the award, the three option work segments, if exercised in full, provided for up to an additional $30 million of funding from BARDA to support the development of ridinilazole through to potential submission of applications for marketing approval.

As described above, the award was amended twice, bringing the total of additional funding available beyond the base period to $40.5 million.

In August 2018, one of the three option work segments was exercised by BARDA with the $12.0 million in funding to be drawn down to specifically support drug manufacturing activities required for the submission of marketing approval applications and other regulatory activities.

In June 2019, a second of the three option work segments was exercised by BARDA with the $9.6 million in funding to be drawn down to support patient enrollment and dosing in the Phase III clinical trials of ridinilazole.

In January 2020, BARDA increased its award by $8.8 million, with this additional funding to support a new clinical trial in adolescent patients.

Activities to be covered by the remaining option work segment include the preparation, submission and review of applications for marketing approvals of ridinilazole for CDI in the United States.

The remaining option work segment is an independent, discrete work segment that is eligible to be exercised, in BARDA’s sole discretion, upon the completion of agreed-upon milestones and deliverables.

If this option work segment is exercised by BARDA, the contract will run through April 2022, unless extended by us and BARDA.

The contract specifies the plan of activities to be conducted under the contract.

In addition to our obligations to conduct the activities provided for by the plan, we are obligated to satisfy various federal reporting requirements, addressing clinical progress, technical issues, and intellectual property and financial matters.

Payments to us under the contract are expected to be made monthly after we invoice BARDA for allowable costs that have been incurred.

BARDA may terminate this agreement upon our uncured default in our performance of the agreement or at any time if the contracting officer determines that it is in the U.S.

government’s interest to terminate the agreement.

Under standard U.S.

government contracting terms, the U.S.

government receives only limited rights for government use of certain of our pre-existing data and certain data produced with non-federal funding, to the extent such data are required for delivery to BARDA under the contract.

government receives unlimited rights to use and disclose new data first produced under the contract with BARDA.

Except for commercialization rights to ridinilazole in South America, Central America and the Caribbean, we currently have exclusive worldwide commercialization rights to ridinilazole and retain these rights under the BARDA contract.

However, the U.S.

government is entitled to a nonexclusive, nontransferable, worldwide, royalty-free license to practice or have practiced any patent on an invention that is conceived or first reduced to practice under the contract, which is referred to as a subject invention.

In addition, the U.S.

government may obtain additional rights if we do not elect to retain ownership of a subject invention or if we do not satisfy certain disclosure and patent prosecution obligations with respect to a subject invention.

Furthermore, the government is entitled to march-in rights under our contract with BARDA.

March-in rights permit the U.S.

government to require that we grant a license to a subject invention to a third party if we have not taken effective steps to achieve practical application of the invention within a reasonable time;

if such action is necessary to meet health and safety needs and/or requirements for public use that we are not meeting;

or if we have not obtained from any exclusive licensee the required agreement for manufacturing such invention substantially in the United States or a waiver of this requirement.

This option work segment was never exercised by BARDA.

The contract ran through April 2022 and was extended through December 2022 as a no cost contract, solely to close out open activities.

As a result of the Company's decision to not pursue further internal

clinical development of ridinilazole and seek partners or a divestiture related to ridinilazole as a path forward for the clinical development of the asset, the Company recorded expenses for the remaining clinical trial costs associated with the close out activities of ridinilazole and recognized the remainder of the deferred income that had been received from BARDA prior to the expenses being recognized during the third quarter of 2022.

Wellcome Trust

In October 2012, we entered into a translation award funding agreement with the Wellcome Trust Limited, as trustee of the Wellcome Trust, in order to support a Phase I and a Phase II clinical trial of ridinilazole for the treatment of CDI.

We refer to the translation award funding agreement as the translation award agreement.

Under the translation award agreement, we were eligible to receive up to $6.3 million from the Wellcome Trust, of which we received the entire $6.3 million.

The translation award agreement followed a funding agreement we and the Wellcome Trust entered in October 2009, which we refer to as the discovery award agreement, under which we received $3.7 million for preclinical development of CDI antibiotics.

We refer to any compound or product that is covered by intellectual property rights created under the discovery award agreement or the translation award agreement, or that is covered by intellectual property rights that we created or to which we had rights prior to October 2009 and that relate to the activities under the discovery award agreement or the translation award agreement, as the award products.

We agreed to use commercially reasonable efforts to achieve certain development milestones by specified dates.

We would be required to make a full or partial repayment to the Wellcome Trust of the funding we received under the translation award agreement, plus accrued interest, under specified conditions, including our unauthorized use of the award amount, our fraudulent or willful misconduct, our knowingly withholding material information from the Wellcome Trust, or an acquisition by certain third parties of all or a material part of our business or assets or of a majority of our equity.

Upon such a full repayment, our obligation to share a portion of net revenue with the Wellcome Trust would terminate.

Unless earlier terminated by the Wellcome Trust, the translation award agreement will terminate on the earlier of our full repayment of the award amount, plus accrued interest, to the Wellcome Trust following its request for repayment, or the expiration of all payment obligations under the translation award agreement and the revenue sharing agreement.

The Wellcome Trust may terminate the translation award agreement for specified reasons, including our material breach or insolvency related events or the Wellcome Trust’s determination that the clinical trials should be terminated due to a serious failure in the progress, management or conduct of the clinical trials, if we do not remedy such condition within a specified period after receiving notice.

We may not, without the Wellcome Trust’s prior consent, assign, transfer or declare a trust over the translation award agreement or otherwise dispose of any of our rights or obligations under the translation award agreement, with such consent not being unreasonably withheld, delayed or conditioned, other than an assignment to our affiliates.

Revenue Sharing Agreement

The terms of the translation award agreement required us to enter into a revenue sharing agreement with the Wellcome Trust prior to the further development (beyond the Phase II trial supported by the 2012 translational award agreement) and commercialization, which together we refer to as the "Exploitation" of any compound or product that is covered by the intellectual property rights created under the translational award agreement or the discovery award agreement, or that is covered by background intellectual property rights.

Under such revenue sharing agreement, the Wellcome Trust would be entitled to a share of the net revenue that we, our affiliates, licensees or third-party collaborators receive under the Exploitation of the award products or any intellectual property associated with such Exploitation.

The translation award funding agreement followed an initial funding agreement we and the Wellcome Trust entered into in October 2009, under which we received $3.7 million for preclinical development of CDI antibiotics.

In October 2017, we entered into a revenue sharing agreement with the Wellcome Trust.

Under the terms of the revenue sharing agreement:

(i) if we commercialize ridinilazole, the Wellcome Trust is eligible to receive a low-single digit percentage of net revenue (as defined in the translation award agreement), and a one-time milestone payment of a specified amount if cumulative net revenues exceed a specified amount;

(ii) if a third party commercializes ridinilazole, the Wellcome Trust is eligible to receive a mid-single digit percentage of the net revenues we receive from commercial sales by such third party, and a one-time milestone payment of a specified amount if cumulative net revenues we receive exceed a specified amount.

In addition, following the first commercial sale by such third party, the Wellcome Trust is eligible to receive a one-time milestone payment equal to a low-single digit percentage of the aggregate amount of any pre-commercial payments we receive from third-party licensees prior to such commercial sale;

and (iii) in the event of an assignment or sale of the assets or intellectual property pertaining to ridinilazole, the net proceeds we receive from such assignment or sale would be treated as net revenue under the revenue sharing agreement.

Under the revenue sharing agreement, it was agreed that any development funding or grant funding we receive from BARDA or other third parties, including licensees, would not be classified as net revenue or as a pre-commercial payment.

In addition, under the revenue sharing agreement, the Wellcome Trust agreed to terminate all of its rights under the translation award agreement to develop or commercialize the award products or the related intellectual property in specified markets and in

specified indications, in the event that we were not developing or commercializing the award products or such intellectual property for such markets or in such indications.

Unless earlier terminated, the revenue sharing agreement will expire upon the later of the expiration of the last patent or patent application covering ridinilazole;

the expiration of any agreement or payment obligations that we have entered into with a third party relating to the Exploitation of ridinilazole;

or the expiration of any payment obligations owed to the Wellcome Trust relating to the Exploitation of ridinilazole.

In addition, each party has the right to terminate the revenue sharing agreement if the other party materially breaches the agreement, and the breach remains uncured for a specified period or the breach is uncurable, or if the other party experiences specified insolvency related events.

Under the terms of the revenue sharing agreement upon commercialization of ridinilazole the Wellcome Trust is eligible to receive a share of the net revenues that we, our affiliates, licensees or third-party collaborators receive from commercial sales, and a one-time milestone payment of a specified amount if cumulative net revenues that we our affiliates, licensees or third-party collaborators receive exceed a specified amount.

In addition, if a third party commercializes ridinilazole following the first commercial sale by such third party, the Wellcome Trust is eligible to receive a one-time milestone payment of a share of the aggregate amount of any pre-commercial payments we receive from third-party licensees prior to such commercial sale and in the event of an assignment or sale of the assets or intellectual property pertaining to ridinilazole, the net proceeds we receive from such assignment or sale would be treated as net revenue under the revenue sharing agreement.

Eurofarma Laboratórios S.A.

In December 2017, we entered into an exclusive license and commercialization agreement with Eurofarma, pursuant to which we granted Eurofarma the exclusive right to commercialize ridinilazole in Argentina, Belize, Bolivia, Brazil, Chile, Colombia, Costa Rica, Ecuador, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Panama, Paraguay, Peru, Suriname, Dominican Republic, Uruguay and Venezuela, which we refer to as the licensed territory.

We have retained commercialization rights in the rest of the world.

Financial Terms

Under the terms of the license agreement, we received an upfront payment of $2.5 million and are entitled to receive additional development milestones upon the achievement of staged patient enrollment targets in the licensed territory in our Ri-CoDIFy 1 and Ri-CoDIFy 2 Phase III clinical trials for ridinilazole.

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In September 2021, we reached the second enrollment milestone and earned $1.25 million.

In addition, we could receive an additional $1.5 million in various development milestones.

We are eligible to receive a further $1.0 million in development milestones, $2.4 million in commercial milestones and up to $18.0 million in sales milestones when cumulative net sales equal or exceed $100.0 million in the Eurofarma licensed territory.

Each subsequent achievement of an additional $100.0 million in cumulative net sales will result in Summit receiving additional milestone payments, which, when combined with anticipated product supply transfer payments from Eurofarma paid to us in connection with a commercial supply agreement to be entered into between the two parties, will provide payments estimated to range from a mid-teens to high-teens percentage of cumulative net sales in the Eurofarma licensed territory.

We estimate such product supply transfer payments from Eurofarma will range from a high single-digit to low double-digit percentage of cumulative net sales in the licensed territory.

Regulatory and Commercial

In addition, we are eligible to receive an additional $2.5 million in various development milestones, $2.4 million in commercial milestones and up to $18.0 million in sales milestones when cumulative net sales equal or exceed $100.0 million in the Eurofarma licensed territory.

Each subsequent achievement of an additional $100.0 million in cumulative net sales will result in Summit receiving additional milestone payments, which, when combined with anticipated product supply transfer payments from Eurofarma paid to us in connection with a commercial supply agreement to be entered into between the two parties, would provide payments estimated to range from a mid-teens to high-teens percentage of cumulative net sales in the Eurofarma licensed territory.

We estimate such product supply transfer payments from Eurofarma would range from a high single-digit to low double-digit percentage of cumulative net sales in the licensed territory.

With the closeout of ridinilazole clinical trials, at this time, we are not anticipating any future payments from Eurofarma under this agreement.

Under the license agreement, Eurofarma is responsible for all costs related to obtaining regulatory approval of ridinilazole in the licensed territory and is obligated to use commercially reasonable efforts to file applications for regulatory approval in specified countries in the licensed territory within a specified time period after we have filed an application for regulatory approval, or obtained regulatory approval, for ridinilazole in a jurisdiction where we retain commercial rights.

We retain sole responsibility for the clinical development of ridinilazole in all countries and are responsible for all costs related to obtaining regulatory approval for ridinilazole outside of the licensed territory.

We are obligated to use commercially reasonable efforts to supply or cause to be supplied to Eurofarma sufficient commercial supply of ridinilazole, and Eurofarma has agreed to purchase its supply of ridinilazole exclusively from us.

If we are unable to supply Eurofarma with commercial supply of ridinilazole during the term of the agreement, we are obligated to transfer to

Eurofarma or its third-party suppliers’ know-how that would be needed for Eurofarma or its third-party suppliers to manufacture the product for commercial sale in the licensed territory.

In July 2018, we were granted a sub-award of up to $4.5 million from the Trustees of Boston University under the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator program (“CARB-X”) to fund, in part, the development of new mechanism antibiotics for the potential treatment of infections caused by gonorrhea.

Under our CARB-X award, we received an initial $2.0 million in funding from CARB-X in July 2018.

In February 2020, CARB-X increased the value of the initial funding by $1.2 million.

The remaining $2.5 million was split into two option segments.

In the third quarter of 2020, we made the decision not to advance the DDS-01 series of antibiotics and to cease work on the gonorrhoeae program based on toxicology data from preclinical studies.

Given we have ceased work on the DDS-01 series in 2020, no additional funding has been received by CARB-X in 2021 pursuant to this sub-award.

In May 2021, we announced the selection of a new preclinical candidate, SMT-738, which originated from the DDS-04 series.

SMT-738 is being developed to combat multi-drug resistant infections, specifically Carbapenem-resistant Enterobacteriaceae ("CRE") infections.

Simultaneously, Summit has received a sub-award from CARB-X to progress SMT-738 through preclinical development and an option to continue into Phase Ia clinical studies.

The award commits initial non-dilutive funding of up to $4.1 million for the preclinical phase, with the potential for a further $3.7 million available for the Phase Ia clinical phase upon successfully achieving key preclinical development milestones.

As of December 31, 2021, $0.5 million of grant funding from CARB-X has been received, $0.1 million is in accounts receivable for amounts billed, $0.6 million is in other current assets as a contract asset and we have recognized $1.2 million of cumulative income since contract inception.

University College London

On March 23, 2010, we entered into a collaborative research agreement with the School of Pharmacy, University of London which was later novated on November 28, 2011, by the School of Pharmacy to University College London.

As part of this agreement, and in consideration of their role in the development of the initial compound series from which ridinilazole was later identified, we agreed to pay the School of Pharmacy (now University College London) a low single-digit share of all revenue received by us in respect of ridinilazole, including any pre-commercial licensing revenue, up to a maximum of £1.0 million.

As part of this agreement, and in consideration of their role in the development of the initial compound series from which ridinilazole was later identified, we agreed to pay the School of Pharmacy (now University College London) a low single-digit share of all revenue received by us with respect to ridinilazole, including any pre-commercial licensing revenue, up to a maximum of $1.2 million.

To date, we have paid $0.1 million under this agreement.

In May 2021, we announced the selection of a new preclinical candidate, SMT-738, which originated from the DDS-04 series.

SMT-738 has been under development to combat multi-drug resistant infections, specifically Carbapenem-resistant Enterobacteriaceae ("CRE") infections.

Simultaneously, Summit has received a sub-award from CARB-X to progress SMT-738 through preclinical development and an option to continue into Phase Ia clinical studies.

During the quarter ended September 30, 2022, CARB-X announced changes to its funding arrangements and terms and conditions.

As a result, the current arrangement concluded as of June 30, 2022 however, we have the ability to recognize revenue for any milestone payments related to work incurred subsequent to this date in accordance with this agreement.

Discuva Limited Acquisition

Share Purchase Agreement

In December 2017, we entered into a share purchase agreement with the shareholders of Discuva, a private limited company organized under the laws of England and Wales pursuant to which we acquired all of the outstanding share capital of Discuva.

Discuva was a discovery-stage company with a bacterial genetics-based platform that facilitates the discovery and development of new mechanism antibiotics.

Under the terms of the share purchase agreement, we paid the Discuva shareholders a total upfront consideration comprised of (A) $6.7 million in cash plus an amount equal to the cash and cash equivalents of Discuva minus (i) indebtedness, (ii) any other liabilities of Discuva at the closing of the transaction that had arisen outside of the ordinary course of business and (iii) funds to be held in escrow and (B) $6.7 million of shares of common stock, satisfied by the issue of 586,685 of our fully-paid shares of common stock at a price per share of $11.41.

We made payment of the amount held in escrow, and an additional balancing amount in respect of the closing cash position was made to the Discuva shareholders in December 2018.

In addition, the Discuva shareholders will be entitled to receive contingent payments from us based on (i) the receipt of potential research and development tax credits to which Discuva may be entitled for the period from April 1, 2015, to the date of the share purchase agreement and (ii) approximately one-half of the economic benefit from any amounts received in connection with certain payments made to us under an existing collaboration agreement between Discuva and F.

Under the terms of the share purchase agreement, we paid the Discuva shareholders a total upfront consideration comprised of (A) $6.7 million in cash , (B) $6.7 million of shares of common stock, satisfied by the issue of 586,685 of our fully-paid shares of common stock at a price per share of $11.41 and (C) an additional balancing amount in respect of the closing cash position.

In addition, the Discuva shareholders are entitled to receive contingent payments from us based on (i) the receipt of potential research and development tax credits to which Discuva may be entitled for the period from April 1, 2015, to the date of the share purchase agreement and (ii) approximately one-half of the economic benefit from any amounts received in connection with certain payments made to us under an existing collaboration agreement between Discuva and F.

Hoffman - La Roche Limited, or Roche.

We made two contingent payments to the Discuva shareholders in December 2018 and May 2019 totaling $1.0 million in respect of research and development tax credits for the period from April 2015 to December 2017 (when the acquisition occurred).

We made two contingent payments to the Discuva shareholders in December 2018 and May 2019 totaling $1.0 million with respect to research and development tax credits for the period from April 2015 to December 2017 (when the acquisition occurred).

Separately, certain employees, former employees and former directors of Discuva are eligible for further payments from Discuva of up to $10.9 million based on specified development and clinical milestones related to proprietary product candidates developed under the platform.

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The assertions embodied in those representations and warranties were made solely for purposes of the share purchase agreement and may be subject to important qualifications and limitations agreed to by us and the Discuva shareholders in connection with negotiating its terms.

Moreover, the representations and warranties may be subject to a contractual standard of materiality that may be different from what may be viewed as material to shareholders or may have been

used for the purpose of allocating risk between us and the Discuva shareholders rather than establishing matters as facts.

Moreover, the representations and warranties may be subject to a contractual standard of materiality that may be different from what may be viewed as material to shareholders or may have been used for the purpose of allocating risk between us and the Discuva shareholders rather than establishing matters as facts.

For the foregoing reasons, no person should rely on such representations and warranties as statements of factual information at the time they were made or otherwise.

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Many of our competitors may have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals, and marketing approved products than we do.

These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.

Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are more convenient, or are less expensive than any products that we may develop.

Our competitors also may obtain marketing approvals for their products more rapidly than we obtain approval for ours.

In addition, our ability to compete may be affected because in some cases insurers or other third-party payors seek to encourage the use of generic products.

This may have the effect of making branded products less attractive from a cost perspective to buyers.

The key competitive factors affecting the success of our product candidates are likely to be their efficacy, safety, convenience, price and the availability of coverage, and reimbursement from government and other third-party payors.

The competition for ridinilazole includes the following:

Several pharmaceutical and biotechnology companies have established themselves in the market for the treatment of CDI, and several additional companies are developing products for the treatment of CDI.

We expect that these products will compete with ridinilazole.

Currently, the most commonly used treatments for CDI are the broad-spectrum antibiotics vancomycin and metronidazole, both of which are available in generic form in the United States.

Generic antibiotic therapies typically are sold at lower prices than branded antibiotics and generally are preferred by managed care providers of health services.

The antibiotic fidaxomicin (Dificid™ in the United States, Dificlir™ in Europe) is approved for the treatment of CDI in the United States, Japan and the European Union.

Fidaxomicin was originally developed by Optimer Pharmaceuticals, Inc., which was later acquired by Cubist Pharmaceuticals, Inc., or Cubist.

Cubist was subsequently acquired by Merck & Co., Inc., or Merck.

MGB Biopharma Limited is developing MGB-BP-3, a novel antibiotic.

In May 2020, top-line results were announced that MGB-BP-3 met endpoints of safety, efficacy and dose selection in an open label, exploratory Phase IIa clinical trial.

In January 2021, the company announced a successful end-of-phase II meeting with the FDA, noting the FDA confirmed that the design and the endpoints of their two prospective Phase III studies were appropriate.

Acurx Pharmaceuticals Inc.

is developing ibezopolstat, a novel antibiotic.

In November 2020, top-line results were announced that ibezopolstat met endpoints for efficacy and was reported to be well tolerated with no serious adverse events in an open label, exploratory Phase IIa clinical trial, and ibezopolstat is currently enrolling in a Phase IIb clinical trial.

Other CDI approaches.

A number of other approaches for the reduction of recurrence of or prevention of CDI are recently approved or in development.

One product, bezlotoxumab, has been approved with the indication of reduction of recurrence of CDI.

Merck received FDA approval for the monoclonal antibody bezlotoxumab (Zinplava™) in October 2016 and EMA approval in January 2017.

Bezlotoxumab is an antibody that neutralizes certain toxins that are produced by C.

difficile bacteria and is indicated to reduce recurrence of CDI in patients who are receiving CDI drug treatment and are at high risk of CDI recurrence.

An alternative approach to reduce the rate of CDI recurrence is fecal biotherapy, in which products aim to recolonize the bacteria that comprise the natural gut microbiome.

These products would be adjunctive therapy to antibiotics used to treat the episode of CDI.

Fecal biotherapy approaches in development include SER-109, which is being developed by Seres Therapeutics Inc., formerly Seres Health, Inc., RBX2660, and enema formulation, and RBX7455, an oral formulation, which were originally being developed by Rebiotix Inc., prior to Rebiotix being acquired by Ferring Pharmaceuticals in April 2018, and CP101, which is being developed by Finch Therapeutics.

Seres reported top-line results from a Phase III clinical trial

of SER-109 in August 2020.

The trial met its primary endpoint and Seres expects to meet with the FDA to discuss a potential filing for regulatory approval based on the Phase III data.

In May 2020, Rebiotix reported positive preliminary results on the primary efficacy measure from one of its two scheduled Phase III clinical trials of RBX2660;

its second Phase III trial is currently enrolling patients.

Finch Therapeutics announced positive top-line data from its Phase II clinical trial of CP101 related to the reduction of recurrent episodes of CDI.

Several organizations are exploring compounds for the prevention of CDI.

Pfizer is developing a vaccine, PF-06425090, that aims to induce a functional antibody response to neutralize the C.

difficile bacterial toxins.

Pfizer reported positive top-line Phase II results in January 2017.

Pfizer entered Phase III testing in 2017, and recently announced results in March 2022.

The Phase III trial did not meet its pre-specified primary endpoint of prevention of primary CDI, but two secondary endpoints indicate a highly favorable benefit in reducing CDI severity.

Synthetic Biologics, Inc., is developing ribaxamase, an oral enzyme designed to degrade certain IV beta-lactam antibiotics within the GI tract to preserve the natural balance of the microbiome and reduce the risk of colonization by bacteria, including C.

difficile, in order to prevent CDI.

In January 2017, it was reported that ribaxamase met its primary endpoint in a Phase IIb clinical trial and in November 2018, it announced that it has successfully completed an end-of-Phase II meeting with the FDA to discuss the development of ribaxamase.

Pursuant to the meeting, the FDA has proposed criteria for Phase III clinical efficacy and safety which, if achieved, may support submission for marketing approval of ribaxamase on the basis of a single Phase III clinical efficacy and safety, which if achieved, may support submission for marketing approval of ribaxamase on the basis of a single Phase III clinical trial.

Da Volterra is developing DAV132, a colon-targeted adsorbent designed to protect the gut microbiome of patients against antibiotic-induced disruption, thus seeking to prevent CDI.

DAV132 met its primary endpoint related to safety of DAV132 in a Phase II clinical trial, announced in February 2020.

A Phase III trial has commenced with the first patient randomized in July 2021.

In November 2020 Destiny Pharma acquired global rights to NTCD-M3, a naturally occurring, non-toxigenic strain of C.

difficile bacteria, which lacks the genes that can express C.

difficile toxins, for the prevention of recurring CDI.

Phase III studies are planned to start in 2022.

Our commercial opportunity could also be reduced or eliminated if the results of our clinical trials, both safety and efficacy, combined with other factors, do not lead to significant adoption of our product.

The key competitive factors affecting the success of our product candidates are likely to be their efficacy, safety, convenience, price and availability of coverage and reimbursement from government and other third-party payors.

Competition for ivonescimab (SMT112)

Ivonescimab is a novel, potential first-in-class bispecific antibody combining the effects of immunotherapy via a blockade of PD-1 with the anti-angiogenesis effects associated with blocking of VEGF into a single molecule.

Ivonescimab is the most advanced PD-1/VEGF bispecific antibody in clinical development and received Breakthrough Therapy Designation status in China for three indications:

a) ivonescimab combined with chemotherapy for the treatment of EGFR-mutated locally advanced or metastatic NSCLC patients who have progressed after taking an EGFR-TKI treatment

b) ivonescimab as the first-line treatment for locally advanced or metastatic NSCLC patients with positive PD-L1 expression

Ivonescimab is currently being investigated in Phase III clinical trials in China.

Summit is initiating development activities for SMT112 and will do so first in NSCLC indications.

Summit plans to start treating patients in clinical studies by the second quarter of 2023.

There are no known approved PD-(L)1/VEGF bispecific antibodies that are further advanced in clinical trial development or approved in the territories in which we have licensed ivonescimab.

There are also no known PD-1-based bispecific antibodies approved by the US Food and Drug Administration (“FDA”) or the European Medicines Agency (“EMA”).

Several pharmaceutical and biotechnology companies have established themselves in the market for the treatment of NSCLC, and several additional companies are developing products for the treatment of NSCLC.

Currently, the most commonly used treatments for NSCLC are several immuno-oncology drugs and chemotherapies, administered either as monotherapy or in combination with other approved therapeutics.

NSCLC treatment regimens vary due to several factors, including genetic mutations and progression of disease.

Several medications have been approved by the FDA for these treatments, including, but not limited to pembrolizumab, atezolizumab, nivolumab and durvalumab.

In addition, several potential therapeutics are in various stages of development and clinical trials for the treatment of NSCLC, including Daiichi Sankyo with patritumab deruxtecan, Merck with pembrolizumab and Janssen Research & Development, LLC with their drugs lazertinib and amivantamab.

Manufacturing

We do not own or operate, and currently have no plans to establish, manufacturing facilities for the production of clinical or commercial quantities of ridinilazole or for the other compounds that we are evaluating in our infectious disease programs.

We do not own or operate, and currently have no plans to establish, manufacturing facilities for the production of clinical or commercial quantities of ivonescimab, ridinilazole or SMT-738.

We currently rely, and expect to continue to rely, on third parties for the manufacture of our product candidates and any products that we may develop.

We currently engage a third-party manufacturer to provide clinical material of the API of ridinilazole with a different supplier responsible for drug product manufacturing services that has supplied the final drug product for use in the Phase III clinical program.

We believe these suppliers are suitable for commercial manufacture.

We are using a different third-party supplier for clinical packaging, labeling and distribution of the finalized ridinilazole drug product.

In connection with the License Agreement, we have also agreed to enter into a supply agreement with Akeso, pursuant to which we agree to purchase a certain portion of drug substance for clinical and commercial supply (the “Supply Agreement”).

Akeso shall initially be solely responsible for the manufacture of our requirements of clinical and commercial drug substance for use in the Licensed Territory until such time that we are able to establish second source suppliers or are able to manufacture the drug substance independently.

We are using a different third-party supplier for clinical packaging, labeling and distribution of the finalized drug product.

We engaged a third-party manufacturer to provide clinical material of the active pharmaceutical ingredient ("API") of ridinilazole with a different supplier responsible for drug product manufacturing services that supplied the final drug product for use in the Phase III clinical program.

We used a different third-party supplier for clinical packaging, labeling and distribution of the finalized ridinilazole drug product.

We obtain the supplies of our API and drug products from these manufacturers pursuant to agreements that include specific supply timelines and volume expectations.

We obtain the supplies of our product candidates from these manufacturers under master services contracts and specific work orders.

We do not currently have arrangements in place for redundant supply or a second source for API for ridinilazole.

If any of our current manufacturers should become unavailable to us for any reason, we believe that there are a number of potential replacements, although we might incur some delay in identifying and qualifying such replacements.

All of our product candidates are organic compounds of low molecular weight and are referred to as small molecules.

We have selected these compounds based on their potential efficacy and safety, although they are also associated with reasonable cost of goods, ready availability of starting materials and ease of synthesis.

We believe that the chemistry for ridinilazole is amenable to scale-up.

We expect to continue to develop product candidates that can be produced cost-effectively at contract manufacturing facilities.

Intellectual Property

Our success depends in large part on our ability to obtain and maintain proprietary protection for our product candidates, technology and know-how, to operate without infringing the proprietary rights of others and to prevent others from infringing our proprietary rights.

We strive to protect the proprietary technology that we believe is important to our business by, among other methods, seeking and maintaining patents, where available, that are intended to cover our product candidates, compositions and formulations, their methods of use and processes for their manufacture and any other inventions that are commercially important to the development of our business.

We have obtained and maintain proprietary protection for our antibiotic product candidates, technology and know-how, to operate without infringing the proprietary rights of others and to prevent others from infringing our proprietary rights.

We strive to protect the proprietary technology by, among other methods, seeking and maintaining patents, where available, that are intended to cover our product candidates, compositions and formulations, their methods of use and processes for their manufacture and any other inventions that are commercially important to the development of our business.

We also rely on trade secrets, know-how, continuing technological innovation and in-licensing opportunities to develop and maintain our proprietary and competitive position.

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patents, 3 U.S.

patent applications, 5 European patents and 4 European patent applications, including original filings, continuations and divisional applications, as well as numerous other foreign counterparts to these U.S.

patent applications, 3 European patents and 2 European patent applications, including original filings, continuations, divisional and validation applications, as well as numerous other foreign counterparts to these U.S.

and European patents and patent applications.

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Discuva Platform Technology.

Our Discuva platform technology is currently protected by 12 U.S.

and foreign patents, and two pending patent applications.

Our Discuva Platform technology is currently protected by 14 granted U.S.

and foreign patents.

We expect patent protection for this portfolio to expire in 2032.

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and foreign patents, with 22 pending patent applications.

The patent portfolio directed to ridinilazole includes patents and patent applications directed to composition of matter, polymorphic forms, methods of manufacture and use, and formulation subject matter.

Our patent portfolio for ridinilazole includes patents and patent applications directed to composition of matter, polymorphic forms, methods of manufacture and use and formulation subject matter.

We expect that our existing patents and patent applications (assuming the applications proceed to grant) will provide patent coverage for our ridinilazole program until 2043.

SMT-738 Program .

Our SMT738 program currently has 30 patent applications pending worldwide, directed to the composition of matter.

Our SMT738 program currently has 4 granted patents and 23 patent applications pending worldwide, directed to the composition of matter.

We anticipate that our existing portfolio (assuming the applications proceed to grant) will provide patent coverage for our SMT738 program until 2042.

In addition to the intellectual property patents and applications owned by the Company, following the completion of the License and Collaboration Agreement with Akeso, Summit has in-licensed the rights to various Akeso patent applications in the Licensed Territory and has rights to control prosecution of such in-licensed intellection property in the Licensed Territory in collaboration with Akeso.

Patent Term Extension .

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This extension may provide up to an additional five years of patent term.

Similarly, patent extensions called supplementary protection certificates or “SPCs” may be obtained in some foreign countries for patents granted in advance of obtaining market authorization.

Similarly, patent extensions called supplementary protection certificates (“SPCs”) may be obtained in some foreign countries for patents granted in advance of obtaining market authorization.

SPCs may also provide up to an additional five years of patent term.

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This six-month exclusivity may be granted if an NDA sponsor submits pediatric data that fairly respond to a written request from the FDA for such data.

The data do not need to show the product to be effective in the pediatric population studied;

does not need to show the product to be effective in the pediatric population studied;

rather if the pediatric clinical trial is deemed to fairly respond to the FDA’s request, and reports of the requested pediatric studies are submitted to and accepted by the FDA within the statutory time limits, the additional six months exclusivity is granted.

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We also seek to preserve the integrity and confidentiality of our data, trade secrets and know-how by maintaining physical security of our premises and physical and electronic security of our information technology systems.

Summit is in the process of selecting a name for our ridinilazole product, which we will pursue protection for as a trademark in the U.S.

and foreign jurisdictions around the world.

Summit, in working with Akeso, is in the process of selecting a name for ivonescimab, which we will pursue protection for as a trademark in Licensed Territories.

In connection with the development of our product pipeline, we will seek protection for marks we currently use and future marks when appropriate.

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For more information, please see the section on “Risk Factors – Risks Related to Intellectual Property”.

Clinical Affairs

We have robust engagements with nationally and internationally recognized key opinions leaders (“KOLs”) in research and clinical management of CDI.

These KOLs are important in professional societies, peer education, and research and evidence generation, and are assisting us with educational initiatives and clinical development plans.

We have a strong publication track record and anticipate multiple presentations at scientific conferences this year to establish ourselves as leaders in C.

difficile and the gut microbiome.

Sales, Marketing and Market Access

At the present time, we in the process of evaluating the future path forward for our Phase III product candidate, including potential partnership opportunities.

In light of this, we believe that our current capabilities with respect to building out a commercial team are adequate for ridinilazole and SMT-738.

Government Regulation

As a biopharmaceutical company focused on the discovery, development, and commercialization of novel antibiotics for serious infectious diseases, we are subject to extensive and ongoing regulation by the FDA under the Federal Food, Drug, and Cosmetic Act and its implementing regulations, as well as other regulatory bodies in the United States and Europe.

As a biopharmaceutical company focused on the discovery, development, and commercialization of novel therapeutics for serious diseases, we are subject to extensive and ongoing regulation by the FDA under the Federal Food, Drug, and Cosmetic Act ("FDCA") and its implementing regulations, as well as other regulatory bodies in the United States, Europe and other countries.

Government authorities in the United States, at the federal, state and local level, and in other countries and jurisdictions, including the European Union, extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, packaging, storage, record keeping, labeling, pricing, reimbursement, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, and import and export of pharmaceutical products.

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Review and Approval of Drugs in the United States

In the United States, the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act, or FDCA, and implementing regulations.

In the United States, the FDA regulates drugs under the FDCA, and implementing regulations.

The failure to comply with the FDCA and applicable U.S.

requirements at any time during the product development process, approval process or after approval may subject an applicant or sponsor to a variety of administrative or judicial sanctions, including refusal by the FDA to approve pending applications, withdrawal of an approval, imposition of a clinical hold, issuance of warning letters and other types of letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement of profits, or civil or criminal investigations and penalties brought by the FDA and the Department of Justice, or DOJ, or other federal and state governmental entities.

requirements at any time during the product development process, approval process or after approval may subject an applicant or sponsor to a variety of administrative or judicial sanctions, including refusal by the FDA to approve pending applications, withdrawal of an approval, imposition of a clinical hold, issuance of warning letters and other types of letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement of profits, or civil or criminal investigations and penalties brought by the FDA and the Department of Justice ("DOJ"), or other federal and state governmental entities.

An applicant seeking approval to market and distribute a new drug product in the United States must typically undertake the following:

• completion of preclinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s good laboratory practice, or GLP, regulations;

• submission to the FDA of an IND, which must take effect before human clinical trials may begin;

• approval by an independent institutional review board, or IRB, representing each clinical site before each clinical trial may be initiated;

• performance of adequate and well-controlled human clinical trials in accordance with current good clinical practices, or GCP, to establish the safety and efficacy of the proposed drug product for each indication;

• preparation and submission to the FDA of a new drug application, or NDA;

• completion of preclinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s good laboratory practice ("GLP regulations");

• submission to the FDA of an Investigational New Drug ("IND"), which must take effect before human clinical trials may begin;

• approval by an independent institutional review board, or IRB, approving each clinical study before each clinical trial may be initiated;

• performance of adequate and well-controlled human clinical trials in accordance with current good clinical practices ("GCP"), to establish the safety and efficacy of the proposed drug product for each indication;

• preparation and submission to the FDA of a new drug application ("NDA") or Biologic Licensing Application ("BLA");

• review of the product candidate by an FDA advisory committee, where appropriate or if applicable;

• satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities at which the product, or components thereof, are produced to assess compliance with current Good Manufacturing Practices, or cGMP, requirements and to assure that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity;

• satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities at which the product, or components thereof, are produced to assess compliance with current Good Manufacturing Practices ("cGMP"), requirements and to assure that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity;

• satisfactory completion of FDA audits of clinical trial sites to assure compliance with GCPs and the integrity of the clinical data;

• payment of user fees and securing FDA approval of the NDA;

• compliance with any post-approval requirements, including Risk Evaluation and Mitigation Strategies, or REMS, where applicable, and any post-approval studies required by the FDA.

• payment of user fees and securing FDA approval of the NDA/BLA;

• compliance with any post-approval requirements, including Risk Evaluation and Mitigation Strategies ("REMS"), where applicable, and any post-approval studies required by the FDA.

Preclinical Studies

Before an applicant begins testing a compound with potential therapeutic value in humans, the product candidate enters the preclinical testing stage.

Preclinical studies include laboratory evaluation of the purity and stability of the active pharmaceutical ingredient, or API, and the formulated drug or drug product, as well as in vitro and animal studies to assess the safety and activity of the drug for initial testing in humans and to establish a rationale for therapeutic use.

Preclinical studies include laboratory evaluation of the purity and stability of the API, and the formulated drug or drug product, as well as in vitro and animal studies to assess the safety and activity of the drug for initial testing in humans and to establish a rationale for therapeutic use.

The conduct of preclinical studies is subject to federal regulations and requirements, including GLP regulations.

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Some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, may continue after the IND is submitted.

Companies usually must complete some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, and must also develop additional information about the chemistry and physical characteristics of the investigational product and finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.

Companies usually must complete some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, and must also develop additional information about the synthesis and physical characteristics of the investigational product and finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.

The manufacturing process must be capable of consistently producing quality batches of the candidate product and, among other things, the manufacturer must develop methods for testing the identity, strength, quality and purity of the final product.

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Stability studies must be conducted to demonstrate that the candidate product does not undergo unacceptable deterioration over its shelf-life.

The IND and IRB Processes

The IND and Institutional Review Board ("IRB") Processes

An IND is an exemption from the FDCA that allows an unapproved drug to be shipped in interstate commerce for use in an investigational clinical trial and a request for FDA authorization to administer an investigational drug to humans.

Such authorization must be secured prior to interstate shipment and administration of any new drug that is not the subject of an approved NDA.

In support of a request for an IND, applicants must submit a protocol for each clinical trial and any subsequent

protocol amendments must be submitted to the FDA as part of the IND.

Such authorization must be secured prior to interstate shipment and administration of any new drug that is not the subject of an approved NDA/BLA.

In support of a request for an IND, applicants must submit a protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of the IND.

In addition, the results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and plans for clinical trials, among other things, are submitted to the FDA as part of an IND.

The FDA requires a 30-day waiting period after the filing of each IND before clinical trials may begin.

The FDA requires a 30-day waiting period after the filing of each new IND before clinical trials may begin.

This waiting period is designed to allow the FDA to review the IND to determine whether human research subjects will be exposed to unreasonable health risks.

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A partial clinical hold is a delay or suspension of only part of the clinical work requested under the IND.

For example, a specific protocol or part of a protocol is not allowed to proceed, while other protocols may do so.

No more than 30 days after imposition of a clinical hold or partial clinical hold, the FDA will provide the sponsor a written explanation of the basis for the hold.

For example, a specific protocol or part of a protocol or new patient enrollment is not allowed to proceed, while other protocols or already enrolled patients may continue.

Following issuance of a clinical hold or partial clinical hold, an investigation may only resume after the FDA has notified the sponsor that the investigation may proceed.

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When a foreign clinical study is conducted under an IND, all FDA IND requirements must be met unless waived.

When the foreign clinical study is not conducted under an IND, the sponsor must ensure that the study complies with certain regulatory requirements of the FDA in order to use the study as support for an IND or application for marketing approval.

When the foreign clinical study is not

conducted under an IND, the sponsor must ensure that the study complies with certain regulatory requirements of the FDA in order to use the study as support for an IND or application for marketing approval.

Specifically, on April 28, 2008, the FDA amended its regulations governing the acceptance of foreign clinical studies not conducted under an investigational new drug application as support for an IND or a new drug application.

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They further help ensure that non-IND foreign studies are conducted in a manner comparable to that required for IND studies.

In addition to the foregoing IND requirements, an IRB representing each institution participating in the clinical trial must review and approve the plan for any clinical trial before it commences at that institution, and the IRB must conduct continuing review and reapprove the study at least annually.

The IRB must review and approve, among other things, the study protocol and informed consent information to be provided to study subjects.

An IRB must operate in compliance with FDA regulations.

An IRB can suspend or terminate approval of a clinical trial at its institution, or an institution it represents, if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the product candidate has been associated with unexpected serious harm to patients.

In addition to the foregoing IND requirements, an IRB/Ethics Committee ("EC") representing each institution participating in the clinical trial must review and approve the plan for any clinical trial before it commences at that institution, and the IRB must conduct continuing review and reapprove the study at least annually.

The IRB/EC must review and approve, among other things, the study protocol and informed consent information to be provided to study subjects.

An IRB/EC must operate in compliance with FDA/HA ("Health Authority") regulations.

An IRB/EC can suspend or terminate approval of a clinical trial at its institution, or an institution it represents, if the clinical trial is not being conducted in accordance with the IRB’s/EC's requirements or if the product candidate has been associated with unexpected serious harm to patients.

Additionally, some trials are overseen by an independent group of qualified experts organized by the trial sponsor, known as a data safety monitoring board or committee.

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Other reasons for suspension or termination may be made by us based on evolving business objectives and/or competitive climate.

Information about clinical trials must be submitted within specific timeframes to the National Institutes of Health, or NIH, for public dissemination on its ClinicalTrials.gov website.

Information about clinical trials must be submitted within specific timeframes to the National Institutes of Health ("NIH"), for public dissemination on its ClinicalTrials.gov website.

Similar requirements for posting clinical trial information are present in the European Union (EudraCT) website:

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or 15 days after the drug or biologic receives designation as a breakthrough therapy, fast track product, or regenerative medicine advanced therapy.

Running clinical trials that can support regulatory approvals is the best way to ultimately ensure wide access for patients to our product candidates.

At this point in the development, we cannot support any use of our product candidates outside of our clinical trials.

Running clinical trials that can support regulatory approvals is

the best way to ultimately ensure wide access for patients to our product candidates.

At this point in the development, we cannot support any use of our product candidates outside of clinical trials.

In addition, on May 30, 2018, the Right to Try Act was signed into law.

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There is no obligation for a drug manufacturer to make its drug products available to eligible patients as a result of the Right to Try Act, but the manufacturer must develop an internal policy and respond to patient requests according to that policy.

Human Clinical Trials in Support of an NDA

Human Clinical Trials in Support of an NDA/BLA

Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in accordance with GCP requirements, which include, among other things, the requirement that all research subjects provide their informed consent in writing before their participation in any clinical trial.

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Phase I, Phase II and Phase III clinical trials may not be completed successfully within any specified period, or at all.

Furthermore, the FDA or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects are being exposed to an unacceptable health risk.

Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution, or an institution it represents, if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug has been associated with unexpected serious harm to patients.

The FDA will typically inspect one or more clinical sites to assure compliance with GCP and the integrity of the clinical data submitted.

Concurrent with clinical trials, companies often complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the drug as well as finalize a process for manufacturing the

product in commercial quantities in accordance with cGMP requirements.

The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, must develop methods for testing the identity, strength, quality, purity, and potency of the final drug.

Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.

Furthermore, the FDA/HA or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects are being exposed to an unacceptable health risk.

Similarly, an IRB/EC can suspend or terminate approval of a clinical trial at its institution, or an institution it represents, if the clinical trial is not being conducted in accordance with the IRB’s/EC’s requirements or if the drug has been associated with unexpected serious harm to patients.

The FDA/HA will typically inspect one or more clinical sites to assure compliance with GCP and the integrity of the clinical data submitted.

Under the Pediatric Research Equity Act ("PREA") of 2003, an NDA or supplement thereto must contain data that are adequate to assess the safety and effectiveness of the drug product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

With enactment of the Food and Drug Administration Safety and Innovation Act, or FDASIA, in 2012, sponsors must also submit pediatric study plans prior to the assessment data.

With enactment of the Food and Drug Administration Safety and Innovation Act ("FDASIA"), in 2012, sponsors must also submit pediatric study plans prior to the assessment data.

Those plans must contain an outline of the proposed pediatric study or studies the applicant plans to conduct, including study objectives and design, any deferral or waiver requests and other information required by regulation.

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The FDA or the applicant may request an amendment to the plan at any time.

For drugs intended to treat a serious or life-threatening disease or condition, FDA is to provide sponsors with its best judgment on whether pediatric studies would be required and whether their submission would be deferred until after approval.

This input is to be given by the FDA at the end-of-phase I meeting, for drugs for life-threatening diseases, and at the end-of-phase II meeting, for other drugs.

A sponsor must submit an initial pediatric study plan, if required under PREA, no later than either 60 calendar days after the date of the end-of-phase II meeting or such other time as agreed upon between FDA and the sponsor.

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Additional requirements and procedures relating to deferral requests and requests for extension of deferrals are contained in FDASIA.

Unless otherwise required by regulation, the pediatric data requirements do not apply to products with orphan designation.

The FDA Reauthorization Act of 2017 established new requirements to govern certain molecularly targeted cancer indications.

Any company that submits an NDA three years after the date of enactment of that statute must submit pediatric assessments with the NDA if the drug is intended for the treatment of an adult cancer and is directed at a molecular target that the FDA determines to be substantially relevant to the growth or progression of a pediatric cancer.

Any company that submits an NDA/BLA three years after the date of enactment of that statute must submit pediatric assessments with the NDA/BLA if the drug is intended for the treatment of an adult cancer and is directed at a molecular target that the FDA determines to be substantially relevant to the growth or progression of a pediatric cancer.

The investigation must be designed to yield clinically meaningful pediatric study data regarding the dosing, safety and preliminary efficacy to inform pediatric labeling for the product.

Submission of an NDA to the FDA

Assuming successful completion of required clinical testing and other requirements, the results of the preclinical studies and clinical trials, together with detailed information relating to the product’s chemistry, manufacture, controls and proposed labeling, among other things, are submitted to the FDA as part of an NDA requesting approval to market the drug product for one or more indications.

Under federal law, the submission of most NDAs is subject to an application user fee, which for federal fiscal year 2022 is $3,117,218 for an application requiring clinical data.

The sponsor of the approved NDA is also subject to an annual program fee, which for the fiscal year 2022 is $369,413.

Submission of an NDA/BLA to the FDA

Assuming successful completion of required clinical testing and other requirements, the results of the preclinical studies and clinical trials, together with detailed information relating to the product’s chemistry, manufacture, controls and proposed labeling, among other things, are submitted to the FDA as part of an NDA/BLA requesting approval to market the drug product for one or more indications.

Under federal law, the submission of most NDAs/BLAs is subject to an application user fee, which for federal fiscal year 2022 is $3,117,218 for an application requiring clinical data.

The sponsor of the approved NDA/BLA is also subject to an annual program fee, which for the fiscal year 2022 is $369,413.

Certain exceptions and waivers are available for some of these fees, such as an exception from the application fee for products with orphan designation and a waiver for certain small businesses.

Following submission of an application, the FDA conducts a filing review of an NDA within 60 calendar days of its receipt and strives to inform the sponsor by the 74th day after the FDA’s receipt of the submission whether the application is sufficiently complete to permit substantive review.

The FDA may request additional information rather than accept an NDA for filing.

Following submission of an application, the FDA conducts a filing review of an NDA/BLA within 60 calendar days of its receipt and strives to inform the sponsor by the 74th day after the FDA’s receipt of the submission whether the application is sufficiently complete to permit substantive review.

The FDA may request additional information rather than accept an NDA/BLA for filing.

In this event, the application must be resubmitted with the additional information.

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Once the submission is accepted for filing, the FDA begins an in-depth substantive review.

The FDA has agreed to certain performance goals in the review process of NDAs.

Under that agreement, 90% of applications seeking approval of new molecular entities, or NMEs, are meant to be reviewed within ten months from the date on which FDA accepts the NDA for filing, and 90% of applications for NMEs that have been designated for “priority review” are meant to be reviewed within six months of the filing date.

For applications seeking approval of drugs that are not NMEs, the ten-month and six-month review periods run from the date that FDA receives the application.

The FDA has agreed to certain performance goals in the review process of NDAs/BLAs.

Under that agreement, 90% of applications seeking approval of new molecular entities ("NMEs"), are meant to be reviewed within ten months from the date on which FDA accepts the NDA for filing, and 90% of applications for NMEs that have been designated for “priority review” are meant to be reviewed within six months of the acceptance date.

The review process may be extended by the FDA for three additional months to consider new information or clarification provided by the applicant to address an outstanding deficiency identified by the FDA following the original submission.

Before approving an NDA, the FDA typically will inspect the facility or facilities where the product is or will be manufactured.

These pre-approval inspections cover all facilities associated with an NDA submission, including drug component manufacturing (such as active pharmaceutical ingredients), finished drug product manufacturing, and control testing laboratories.

Before approving an NDA/BLA, the FDA typically will inspect the facility or facilities where the product is or will be manufactured.

These pre-approval inspections cover all or selected facilities associated with an NDA/BLA submission, including drug component manufacturing (such as API), finished drug product manufacturing, and control testing laboratories.

The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.

Additionally, before approving an NDA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP.

Under the FDA Reauthorization Act of 2017, the FDA must implement a protocol to expedite review of responses to

inspection reports pertaining to certain applications, including applications for products in shortage or those for which approval is dependent on remediation of conditions identified in the inspection report.

Additionally, before approving an NDA/BLA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP.

Under the FDA Reauthorization Act of 2017, the FDA must implement a protocol to expedite review of responses to inspection reports pertaining to certain applications, including applications for products in shortage or those for which approval is dependent on remediation of conditions identified in the inspection report.

In addition, as a condition of approval, the FDA may require an applicant to develop a REMS.

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To determine whether a REMS is needed, the FDA will consider the size of the population likely to use the product, seriousness of the disease, expected benefit of the product, expected duration of treatment, seriousness of known or potential adverse events, and whether the product is a new molecular entity.

REMS can include medication guides, physician communication plans for healthcare professionals, and elements to assure safe use, or ETASU.

REMS can include medication guides, physician communication plans for healthcare professionals, and elements to assure safe use ("ETASU").

ETASU may include, but are not limited to, special training or certification for prescribing or dispensing, dispensing only under certain circumstances, special monitoring, and the use of patient registries.

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Specifically, the FDA may designate a product for fast-track review if it is intended, whether alone or in combination with one or more other products, for the treatment of a serious or life-threatening disease or condition, and it demonstrates the potential to address unmet medical needs for such a disease or condition.

For fast-track products, sponsors may have greater interactions with the FDA, and the FDA may initiate review of sections of a fast-track product’s application before the application is complete.

For fast-track products, sponsors may have greater interactions with the FDA, and the FDA may initiate review of sections of a fast-track product’s application before the NDA/BLA is complete.

This rolling review may be available if the FDA determines, after preliminary evaluation of clinical data submitted by the sponsor, that a fast-track product may be effective.

The sponsor must also provide, and the FDA must approve, a schedule for the submission of the remaining information and the sponsor must pay applicable user fees.

However, the FDA’s time period goal for reviewing a fast-track application does not begin until the last section of the application is submitted.

In addition, the fast-track designation may be withdrawn by the FDA if the FDA believes that the designation is no longer supported by data emerging in the clinical trial process.

However, the FDA’s time period goal for reviewing a fast-track application does not begin until the last section of the NDA/BLA is submitted.

In addition, the fast-track designation may be withdrawn by the FDA if the FDA believes that the designation is no longer supported by data emerging.

Second, a product may be designated as a breakthrough therapy if it is intended, either alone or in combination with one or more other products, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

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This targeted approach would make antibiotic development more feasible by allowing for smaller clinical development programs that are focused on the limited, high-risk populations that would use these new antibiotics, instead of on more general populations that can be treated with existing medicines.

LPAD would also make antibiotic development more feasible by enabling FDA to assess these drugs based on the unique balance of benefits they offer vs.

risks they present to the limited number of patients they are intended to treat - specifically, patients who have few or no other treatment options.

LPAD would also make antibiotic development more feasible by enabling FDA to assess these drugs based on the unique balance of benefits they offer versus risks they present to the limited number of patients they are intended to treat - specifically, patients who have few or no other treatment options.

Product candidates that qualify for LPAD review may simultaneously qualify for one or more of FDA’s expedited review programs.

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The FDA may grant accelerated approval to a drug for a serious or life-threatening condition that provides meaningful therapeutic advantage to patients over existing treatments based upon a determination that the drug has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit.

The FDA may also grant accelerated approval for such a drug when the product has an effect on an intermediate clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality, or IMM, and that is reasonably likely to predict an effect on IMM or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

The FDA may also grant accelerated approval for such a drug when

the product has an effect on an intermediate clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality ("IMM"), and that is reasonably likely to predict an effect on IMM or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

Drugs granted accelerated approval must meet the same statutory standards for safety and effectiveness as those granted traditional approval.

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Limited Population Antibacterial Drug Pathway

With passage of the Cures Act, Congress authorized the FDA to approve an antibacterial or antifungal drug, alone or in combination with one or more other drugs, as a “limited population drug.” To qualify for this approval pathway, the drug must be intended to treat a serious or life-threatening infection in a limited population of patients with unmet needs;

the standards for approval of drugs and biologics under the FDCA and the Public Health Service Act, or PHSA, must be satisfied;

With passage of the Cures Act, Congress authorized the FDA to approve an antibacterial or antifungal drug, alone or in combination with one or more other drugs, as a “limited population drug”.

To qualify for this approval pathway, the drug must be intended to treat a serious or life-threatening infection in a limited population of patients with unmet needs;

the standards for approval of drugs and biologics under the FDCA and the Public Health Service Act ("PHSA"), must be satisfied;

and the FDA must receive a written request from the sponsor to approve the drug as a limited population drug pursuant to this provision.

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Nothing in this pathway to approval of a limited population drug prevents sponsors of such products from seeking designation or approval under other provisions of the FDCA, such as accelerated approval.

The FDA’s Decision on an NDA

On the basis of the FDA’s evaluation of the NDA and accompanying information, including the results of the inspection of the manufacturing facilities, the FDA may issue an approval letter or a complete response letter.

The FDA’s Decision on an NDA/BLA

On the basis of the FDA’s evaluation of the NDA/BLA and accompanying information, including the results of the inspection of the manufacturing facilities, the FDA may issue an approval letter or a complete response letter.

An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications.

A complete response letter generally outlines the deficiencies in the submission and may require substantial additional testing or information in order for the FDA to reconsider the application.

If and when those deficiencies have been addressed to the FDA’s satisfaction in a resubmission of the NDA, the FDA will issue an approval letter.

If and when those deficiencies have been addressed to the FDA’s satisfaction in a resubmission of the NDA/BLA, the FDA will issue an approval letter.

The FDA has committed to reviewing such resubmissions in two or six months depending on the type of information included.

Even with submission of this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.

trials, be conducted to further assess the drug’s safety after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms, including REMS, which can materially affect the potential market and profitability of the product.

Even with submission of

this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.

If the FDA approves a product, it may limit the approved indications for use for the product, require that contraindications, warnings or precautions be included in the product labeling, require that post-approval studies, including Phase IV clinical trials, be conducted to further assess the drug’s safety after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms, including REMS, which can materially affect the potential market and profitability of the product.

The FDA may prevent or limit further marketing of a product based on the results of post-market studies or surveillance programs.

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However, FDA regulations impose rigorous restrictions on manufacturers’ communications, prohibiting the promotion of off-label uses.

It may be permissible, under very specific, narrow conditions, for a manufacturer to engage in nonpromotional, non-misleading communication regarding off-label information, such as distributing scientific or medical journal information.

If a company is found to have promoted off-label uses, it may become subject to adverse public relations and administrative and judicial enforcement by the FDA, the Department of Justice, or the Office of the Inspector General of the Department of Health and Human Services, as well as state authorities.

It may be permissible, under very specific, narrow conditions, for a manufacturer to engage in

nonpromotional, non-misleading communication regarding off-label information, such as distributing scientific or medical journal information.

If a company is found to have promoted off-label uses, it may become subject to adverse public relations and administrative and judicial enforcement by the FDA, the DOJ, or the Office of the Inspector General of the Department of Health and Human Services, as well as state authorities.

This could subject a company to a range of penalties that could have a significant commercial impact, including civil and criminal fines and agreements that materially restrict the manner in which a company promotes or distributes drug products.

The federal government has levied large civil and criminal fines against companies for alleged improper promotion, and has also requested that companies enter into consent decrees or permanent injunctions under which specified promotional conduct is changed or curtailed.

In addition, the distribution of prescription pharmaceutical products is subject to the Prescription Drug Marketing Act, or PDMA, and its implementing regulations, as well as the Drug Supply Chain Security Act, or DSCSA, which regulate the distribution and tracing of prescription drug samples at the federal level, and set minimum standards for the regulation of distributors by the states.

The PDMA, its implementing regulations and state laws limit the distribution of prescription

pharmaceutical product samples, and the DSCSA imposes requirements to ensure accountability in distribution and to identify and remove counterfeit and other illegitimate products from the market.

In addition, the distribution of prescription pharmaceutical products is subject to the Prescription Drug Marketing Act ("PDMA"), and its implementing regulations, as well as the Drug Supply Chain Security Act ("DSCSA"), which regulate the distribution and tracing of prescription drug samples at the federal level, and set minimum standards for the regulation of distributors by the states.

The PDMA, its implementing regulations and state laws limit the distribution of prescription pharmaceutical product samples, and the DSCSA imposes requirements to ensure accountability in distribution and to identify and remove counterfeit and other illegitimate products from the market.

Pediatric Exclusivity

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This is not a patent term extension, but it effectively extends the regulatory period during which the FDA cannot approve another application.

GAIN Exclusivity for Antibiotics

In July 2015, the FDA has designated ridinilazole as a qualified infectious disease product, or “QIDP”, under the Generating Antibiotic Incentives Now Act, or GAIN Act.

In 2019, the Centers for Disease Control and Prevention of the U.S.

Department of Health and Human Services, or CDC, published an update of its 2013 report reviewing antibiotic resistance threats to the United States.

This updated report continued to highlight that CDI poses an immediate public health threat that requires urgent and aggressive action, and C.

difficile is one of four bacterial pathogens with this urgent threat status.

Congress passed this legislation to encourage the development of antibacterial and antifungal drug products that treat pathogens that cause serious and life-threatening infections.

To that end, the GAIN Act grants an additional five years of exclusivity upon the approval of an NDA for a drug product designated by the FDA as a QIDP.

Thus, for a QIDP, the periods of five-year new chemical entity exclusivity, three-year new clinical investigation exclusivity and seven-year orphan drug exclusivity, would become ten years, eight years and 12 years, respectively.

A QIDP is defined in the GAIN Act to mean “an antibacterial or antifungal drug for human use intended to treat serious or life- threatening infections, including those caused by:

(1) an antibacterial or antifungal resistant pathogen, including novel or emerging infectious pathogens;” or (2) certain “qualifying pathogens.” A “qualifying pathogen” is a pathogen that has the potential to pose a serious threat to public health (such as resistant Gram-positive pathogens, multi-drug resistant Gram- negative bacteria, multi-drug resistant tuberculosis and Clostridioides difficile ) and that is included in a list established and maintained by the FDA.

A drug sponsor may request the FDA to designate its product as a QIDP any time before the submission of an NDA.

The FDA must make a QIDP determination within 60 days of the designation request.

A product designated as a QIDP will be granted priority review by FDA and can qualify for “fast track” status.

The additional five years of exclusivity under the GAIN Act for drug products designated by the FDA as QIDPs applies only to a drug that is first approved on or after July 9, 2012.

Additionally, the five year exclusivity extension does not apply to:

a supplement to an application under FDCA Section 505(b) for any QIDP for which an extension is in effect or has expired;

a subsequent application filed with respect to a product approved by the FDA for a change that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device or strength;

or a product that does not meet the definition of a QIDP under Section 505(g) based upon its approved uses.

Patent Term Restoration and Extension

The term of a U.S.

patent that covers a drug, biological product or medical device approved pursuant to a PMA may also be eligible for patent term extension when FDA approval is granted, provided that certain statutory and regulatory requirements are met.

patent that covers a drug, biological product or medical device approved pursuant to a premarket approval may also be eligible for patent term extension when FDA approval is granted, provided that certain statutory and regulatory requirements are met.

The length of the patent term extension is related to the length of time the drug is under regulatory review while the patent is in force.

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Similar provisions are available in Europe and certain other foreign jurisdictions to extend the term of a patent that covers an approved drug, provided that statutory and regulatory requirements are met.

The USPTO reviews and approves the application for any patent term extension or restoration in consultation with the FDA.

Patent and Trademark Office ("USPTO") reviews and approves the application for any patent term extension or restoration in consultation with the FDA.

Regulation Outside the United States

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The time required to obtain approval in other countries and jurisdictions might differ from and be longer than that required to obtain FDA approval.

Regulatory approval in one country or jurisdiction does not ensure

regulatory approval in another, but a failure or delay in obtaining regulatory approval in one country or jurisdiction may negatively impact the regulatory process in others.

Regulation and Marketing Authorization in the European Union

Regulatory approval in one country or jurisdiction does not ensure regulatory approval in another, but a failure or delay in obtaining regulatory approval in one country or jurisdiction may negatively impact the regulatory process in others.

Regulation and Marketing Authorization in the European Union ("E.U.")

Clinical Trial Approval

The Clinical Trials Directive 2001/20/EC, the Directive 2005/28/EC on Good Clinical Practice, or GCP, and the related national implementing provisions of the individual E.U.

The Clinical Trials Directive 2001/20/EC, the Directive 2005/28/EC on Good Clinical Practice ("GCP"), and the related national implementing provisions of the individual E.U.

Member States govern the system for the approval of clinical trials in the European Union.

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However, overall related timelines will be defined by the Clinical Trials Regulation.

As of January 1, 2020, the website of the European Commission reported that the implementation of the new Clinical Trials Regulation ("CTR") was dependent on the development of a fully functional clinical trials portal and database, which would be confirmed by an independent audit, and that the new legislation would come into effect six months after the European Commission publishes a notice of this confirmation.

The website indicated that the audit was expected to commence in December 2020.

The European Commission published a notice in the Official Journal of the European Union on July 31, 2021 confirming January 31, 2022 as the date of entry into application of the Clinical Trials Regulation and the go-live of its Clinical Trials Information System (“CTIS”).

As in the United States, similar requirements for posting clinical trial information are present in the European Union (EudraCT) website:

https://eudract.ema.europa.eu/ and other countries.

https://eudract.ema.europa.eu/ and in other countries.

Marketing Authorization

To obtain a marketing authorization for a product under E.U.

regulatory systems, an applicant must submit an MAA either under a centralized procedure administered by the EMA, or one of the procedures administered by competent authorities in the E.U.

regulatory systems, an applicant must submit a marketing authorization application ("MAA") either under a centralized procedure administered by the EMA, or one of the procedures administered by competent authorities in the E.U.

Member States (decentralized procedure, national procedure or mutual recognition procedure).

A marketing authorization may be granted only to an applicant established in the E.U.

Regulation (EC) No 1901/2006 provides that prior to obtaining a marketing authorization in the European Union, applicants have to demonstrate compliance with all measures included in an EMA-approved Paediatric Investigation Plan, or PIP, covering all subsets of the pediatric population, unless the EMA has granted (1) a product-specific waiver, (2) a class waiver or (3) a deferral for one or more of the measures included in the PIP.

Regulation (EC) No 1901/2006 provides that prior to obtaining a marketing authorization in the European Union, applicants have to demonstrate compliance with all measures included in an EMA-approved Paediatric Investigation Plan ("PIP"), covering all subsets of the pediatric population, unless the EMA has granted (1) a product-specific waiver, (2) a class waiver or (3) a deferral for one or more of the measures included in the PIP.

The centralized procedure provides for the grant of a single marketing authorization by the European Commission that is valid across the European Economic Area (i.e., the European Union as well as Iceland, Liechtenstein and Norway).

Pursuant to Regulation (EC) No 726/2004, the centralized procedure is compulsory for specific products, including for medicines produced by certain biotechnological processes, products designated as orphan medicinal products, ATMPs and products with a new active substance indicated for the treatment of certain diseases, including products for the treatment of cancer.

Pursuant to Regulation (EC) No 726/2004, the centralized procedure is compulsory for specific products, including for medicines produced by certain biotechnological processes, products designated as orphan medicinal products and products with a new active substance indicated for the treatment of certain diseases, including products for the treatment of cancer.

For products with a new active substance indicated for the treatment of other diseases and products that are highly innovative or for which a centralized process is in the interest of patients, the centralized procedure may be optional.

The centralized procedure may at the

request of the applicant also be used in certain other cases.

The centralized procedure may at the request of the applicant also be used in certain other cases.

We anticipate that the centralized procedure will be mandatory for the product candidates we are developing.

Under the centralized procedure, the CHMP is also responsible for several post-authorization and maintenance activities, such as the assessment of modifications or extensions to an existing marketing authorization.

Under the centralized procedure, the Committee for Medicinal Products for Human Use ("CHMP") is also responsible for several post-authorization and maintenance activities, such as the assessment of modifications or extensions to an existing marketing authorization.

Under the centralized procedure in the European Union, the maximum timeframe for the evaluation of an MAA is 210 days, excluding clock stops, when additional information or written or oral explanation is to be provided by the applicant in response to questions of the CHMP.

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Member States and chaired by a non- voting European Commission representative.

The European Parliament also has a related “droit de regard.” The European Parliament's role is to ensure that the European Commission has not exceeded its powers in deciding to grant or refuse to grant a marketing authorization.

The European Commission may grant a so-called “marketing authorization under exceptional circumstances.” Such authorization is intended for products for which the applicant can demonstrate that it is unable to provide comprehensive data on the efficacy and safety under normal conditions of use, because the indications for which the product in question is intended are encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence, or in the present state of scientific knowledge, comprehensive information cannot be provided, or it would be contrary to generally accepted principles of medical ethics to collect such information.

The European Parliament also has a related “droit de regard”.

The European Parliament's role is to ensure that the European Commission has not exceeded its powers in deciding to grant or refuse to grant a marketing authorization.

The European Commission may grant a so-called “marketing authorization under exceptional circumstances”.

Such authorization is intended for products for which the applicant can demonstrate that it is unable to provide comprehensive data on the efficacy and safety under normal conditions of use, because the indications for which the product in question is intended are encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence, or in the present state of scientific knowledge, comprehensive information cannot be provided, or it would be contrary to generally accepted principles of medical ethics to collect such information.

Consequently, marketing authorization under exceptional circumstances may be granted subject to certain specific obligations, which may include the following:

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medicines rules expressly permit the E.U.

Member States to adopt national legislation prohibiting or restricting the sale, supply or use of any medicinal product containing, consisting of or derived from a specific type of human or animal cell, such as embryonic stem cells.

such as embryonic stem cells.

While the products we have in development do not make use of embryonic stem cells, it is possible that the national laws in certain E.U.

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Member State in which the product is to be marketed.

This application is identical to the application that would be submitted to the EMA for authorization through the

centralized procedure.

This application is identical to the application that would be submitted to the EMA for authorization through the centralized procedure.

The referenced E.U.

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Pediatric Studies

Prior to obtaining a marketing authorization in the European Union, applicants have to demonstrate compliance with all measures included in an EMA-approved Paediatric Investigation Plan, or PIP, covering all subsets of the pediatric population, unless the EMA has granted a product-specific waiver, a class waiver, or a deferral for one or more of the measures included in the PIP.

Prior to obtaining a marketing authorization in the European Union, applicants have to demonstrate compliance with all measures included in an EMA-approved Paediatric Investigation Plan, covering all subsets of the pediatric population, unless the EMA has granted a product-specific waiver, a class waiver, or a deferral for one or more of the measures included in the PIP.

The respective requirements for all marketing authorization procedures are set forth in Regulation (EC) No 1901/2006, which is referred to as the Paediatric Regulation.

This requirement also applies when a company wants to add a new indication, pharmaceutical form or route of administration for a medicine that is already authorized.

The Paediatric Committee of the EMA, or PDCO, may grant deferrals for some medicines, allowing a company to delay development of the medicine in children until there is enough information to demonstrate its effectiveness and safety in adults.

The Paediatric Committee of the EMA ("PDCO") may grant deferrals for some medicines, allowing a company to delay development of the medicine in children until

there is enough information to demonstrate its effectiveness and safety in adults.

The PDCO may also grant waivers when development of a medicine in children is not needed or is not appropriate, such as for diseases that only affect the elderly population.

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Direct-to- consumer advertising of prescription medicines is prohibited across the European Union.

Brexit and the Regulatory Framework in the United Kingdom

On June 23, 2016, the electorate in the United Kingdom voted in favor of leaving the European Union, commonly referred to as Brexit.

Following protracted negotiations, the United Kingdom withdrew from the European Union on January 31, 2020.

Pursuant to the formal withdrawal arrangements agreed between the United Kingdom and the European Union, European Union rules have ceased to apply following the transition period which ended December 31, 2020.

However, in December 2020, the United Kingdom and the European Union agreed on a trade and cooperation agreement that will apply provisionally after the end of the transition period until it is ratified by the parties to the agreement.

The United Kingdom has passed legislation giving effect to the trade and cooperation agreement, with the E.U.

expected to formally adopt the agreement in early 2021.

The trade and cooperation agreement provides a general framework for the post-withdrawal relationship between the United Kingdom and the European Union.

We expect to be subject to additional and potentially duplicative regulatory requirements due to the withdrawal of the United Kingdom from the European Union, including requirements relevant to receiving marketing approval for ridinilazole.

However there remains substantial uncertainty related to the implementation of the trade and cooperation agreement and the application of its terms.

General Data Protection Regulation

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Recently, many countries in the European Union have increased the amount of discounts required on pharmaceuticals and these efforts could continue as countries attempt to manage health care expenditures, especially in light of the severe fiscal and debt crises experienced by many countries in the European Union.

The downward pressure on health care costs in general, particularly prescription products, has become intense.

The downward pressure on health care costs in general, particularly prescription products, has become

As a result, increasingly high barriers are being erected to the entry of new products.

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Patent Term Extension

In order to compensate the patentee for delays in obtaining a marketing authorization for a patented product, a supplementary certificate, or SPC, may be granted extending the exclusivity period for that specific product by up to five years.

In order to compensate the patentee for delays in obtaining a marketing authorization for a patented product, a supplementary certificate ("SPC") may be granted extending the exclusivity period for that specific product by up to five years.

Applications for SPCs must be made to the relevant patent office in each E.U.

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• expanded the types of entities eligible for the 340B drug discount program;

beneficiaries during their coverage gap period as a condition for the manufacturers’ outpatient drugs to be covered under Medicare Part D;

• established the Medicare Part D coverage gap discount program by requiring manufacturers to provide a 70% as of January 1, 2019 point-of-sale-discount off the negotiated price of applicable brand drugs to eligible beneficiaries during their coverage gap period as a condition for the manufacturers’ outpatient drugs to be covered under Medicare Part D;

• a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research.

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Our success starts and ends with having the best talent and, as a result, we are focused on attracting, developing, and engaging our employees.

In 2021, Summit has notably strengthened the team by continuing to attract a number of leading world class employees into the Company.

These new recruits have successful track records and are acknowledged leaders in their field.

In 2022, we continued to strengthen the team by attracting a number of world class leaders with successful track records into the Company, all of our executive positions are now filled with proven leaders.

As of December 31, 2022, we had 76 full-time employees and 77 total employees.

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In 2022, we once again made challenging demands of our employees and they have responded with dedication and enthusiasm.

In 2021, Summit launched an engagement survey, in which over 80% of employees responded.

The results of this survey reflected an overall positive response by employees, particularly highlighting both the enjoyment of their work and the team they work with.

In August 2022, Summit launched an engagement survey, in which 80% of employees responded.

The results of this survey showed our employees to be well engaged, with a strong team spirit and strongly aligned to the Company’s mission.

Compensation and Benefits

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We are committed to embedding a culture of diversity, equity and inclusion across our Company.

We believe that diversity of gender, race, ethnicity, sexual orientation, culture, education, background and experience fuels innovation and enables our employees to succeed.

We believe that diversity of gender, age, ethnicity, sexual orientation, culture, education, background and experience fuels innovation and enables our employees to succeed.

This includes ensuring opportunity for all and embraces the positive effect that our diverse workforce brings.

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Our performance management process includes timely performance feedback and career development discussions which are critical to each employee’s continued growth and development within the organization.

Workplace Health and Safety and Pandemic Response

Workplace Health and Safety

We are committed to the health and safety of all of our employees.

We accomplish this through strict compliance with applicable laws and regulations regarding workplace safety.

We have continued to maintain our focus on the health and safety of our employees especially as the COVID-19 pandemic has evolved, including maintaining protocols for social distancing, daily onsite health checks and allowing our employees to work remotely as necessary based upon local government health recommendations.

Our experienced teams continue to adapt quickly to the changes and have managed our business successfully during this challenging time.

We accomplish this through strict compliance with applicable workplace safety laws and regulations, continuous risk assessment and expeditious action.

We have again had no reportable health and safety issues in 2022.

Our Corporate Information

On September 18, 2020, pursuant to a scheme of arrangement under UK law, we became the parent company of the Summit Therapeutics plc group of companies, including Summit Therapeutics plc, a public limited company incorporated under the laws of England and Wales with the Registrar of Companies of England and Wales.

Pursuant to the scheme of arrangement, all outstanding ordinary shares of Summit Therapeutics plc were exchanged for shares of our common stock on a five for one basis.

In connection with the scheme of arrangement, Summit changed its corporate domicile from the United Kingdom to Delaware.

Our principal executive offices are located at One Broadway, 14 th Floor, Cambridge, MA States 02142, and our telephone number is +1 617 514 7149.

Our website address is www.summittxinc.com .

Summit Therapeutics Inc.

was incorporated in Delaware on July 17, 2020.

Our principal executive office is located at 2882 Sand Hill Road, Suite 106, Menlo Park, California and our phone number is (650) 460-8308.

Our website is https://www.smmttx.com.

The information contained on, or that can be accessed through, our website is not incorporated by reference into this Report or in any other report or document we file with the SEC, and any reference to our website address is intended to be an inactive textual reference only.

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Available Information

We are the successor to Summit Therapeutics plc for various purposes under the Exchange Act and, through the filing of a Current Report on Form 8-K filed pursuant to Rule 12g-3 under the Exchange Act, have assumed Summit Therapeutics plc's Commission file number (001-36866).

We began filing reports under the Exchange Act with the filing of that Current Report on Form 8-K.

Our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q and Current Reports on Form 8-K, and amendments to these reports filed or furnished pursuant to Section 13(a) or 15(d) of the Exchange Act will be posted on our website as soon as reasonably practicable after electronic filing with or furnishing to the Securities and Exchange Commission and the Annual Reports on Form 20-F and Reports on Form 6-K filed by Summit Therapeutics plc prior to the completion of the Redomiciliation Transaction are available on our website.

All such postings on our website can be accessed free of charge.

We maintain a website with the address https://www.smmttx.com/.

We are not including the information contained on our website as part of, or incorporating it by reference into, this Form 10-K.

Through our website, we make available free of charge our annual reports on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K, and amendments to these reports in a timely manner after we provide them to the Securities and Exchange Commission (“SEC”).

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business