What changed in this filing

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Item 1A. Risk Factors

2022-03-08 compared with 2021-03-18 · 258 added, 215 removed, 1078 unchanged (30% of the section changed)

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Some of these risks are:

The outbreak of the novel strain of coronavirus, SARS-CoV-2 and its emerging variants, which causes COVID-19, has, and may continue to, adversely impact our business, including the timing of our clinical trials.

We have no source of product revenue and we have incurred significant losses since inception.

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If we are unable to commercialize our product candidates or experience significant delays in doing so, our business will be materially harmed.

The results from our global pivotal PEACE Phase 3 trial may not support marketing approval, and the FDA may require us to conduct additional clinical trials or evaluate current subjects for an additional follow-up period.

Clinical drug development involves a lengthy and expensive process with an uncertain outcome.

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Our engineered human enzyme product candidates represent a novel therapeutic approach, which could result in heightened regulatory scrutiny, delays in clinical development, or delays in our ability to achieve regulatory approval or commercialization of our product candidates.

We have only initiated clinical trials for pegzilarginase and AGLE-177 for the treatment of certain conditions and have only dosed pegzilarginase in humans.

We have only initiated clinical trials for pegzilarginase and AGLE-177 for the treatment of certain conditions and have only dosed pegzilarginase and AGLE-177 in humans.

We have not dosed any of our other product candidates in humans.

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Risks Related to Our Financial Position and Need for Additional Capital

We and our independent auditors have expressed doubt about our ability to continue as a going concern.

The independent registered public accounting firm auditors’ report accompanying our financial statements for the year ended December 31, 2021 contained an explanatory paragraph expressing substantial doubt about our ability to continue as a going concern.

In view of these matters, our ability to continue as a going concern is dependent upon our ability to raise additional capital through outside sources.

We intend to obtain funding through the sale of common stock in public offerings and/or private placements, debt financings, or through other capital sources, including collaborations with other companies or other strategic transactions.

The failure to obtain sufficient financing or strategic partnerships could adversely affect our ability to achieve our business objectives and continue as a going concern.

Our limited operating history may make it difficult for you to evaluate the success of our business to date and to assess our future viability.

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Our operations to date have been limited to organizing and staffing our company, business planning, raising capital, acquiring and developing our technology, identifying potential product candidates, undertaking nonclinical studies, and preparing for, commencing and conducting clinical trials of our most advanced product candidates, pegzilarginase and AGLE-177.

We have not yet demonstrated our ability to successfully complete a pivotal clinical trial, obtain marketing approvals, manufacture a commercial scale product or arrange for a third party to do so on our behalf, or conduct sales and marketing activities necessary for successful product commercialization.

Other than the PEACE Phase 3 trial of pegzilarginase, we have not demonstrated our ability to successfully complete a pivotal clinical trial.

We have not yet demonstrated our ability to successfully obtain marketing approvals, manufacture a commercial scale product or arrange for a third party to do so on our behalf, or conduct sales and marketing activities necessary for successful product commercialization.

Products, on average, take ten to 15 years to be developed from the time they are discovered to the time they are approved and available for treating patients.

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Our ability to generate revenue and become profitable depends upon our ability to successfully complete the development of any of our product candidates, including pegzilarginase and AGLE-177, for any of our target indications and to obtain necessary regulatory approvals.

To date, we have recognized revenue solely from a fully utilized government grant and have not generated any product revenue.

To date, we have recognized revenue from a license and supply agreement and a fully utilized government grant and have not generated any product revenue.

Even if we receive regulatory approval for any of our product candidates, we do not know when these product candidates will generate revenue for us, if at all.

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As of December 31, 2021, we had an accumulated deficit of $341.8 million.

We have financed our operations primarily through private placements of our preferred stock, the initial public offering of our common stock, follow-on public offerings of our common stock and pre-funded warrants, and collection of a research grant.

Based upon our current operating plans, we believe that we have sufficient resources to fund operations into the first quarter of 2023 with our existing cash, cash equivalents, and marketable securities.

Accordingly, based on recurring losses from operations incurred since inception, the expectation of continued operating losses, and the need to raise additional capital to finance our future operations, we determined that there is substantial doubt about our ability to continue as a going concern within twelve months of the issuance date of these financial statements.

We plan to address this condition through the sale of common stock in public offerings and/or private placements, debt financings, or through other capital sources, including collaborations with other companies or other strategic transactions.

In the past, we have financed our operations primarily through private placements of our preferred stock, the initial public offering of our common stock, follow-on public offerings of our common stock and pre-funded warrants, collection of a research grant, and the licensing of our product rights for commercialization of pegzilarginase in Europe and certain countries in the Middle East.

We have devoted substantially all of our efforts to research and development.

Currently, we are conducting clinical development for pegzilarginase for the treatment of Arginase 1 Deficiency and for AGLE-177 for the treatment of Homocystinuria.

We initiated a Phase 1/2 clinical trial of AGLE-177 for the treatment of patients with Homocystinuria in the second quarter of 2020, however, timing of first patient dosing will depend on determinations by individual sites given COVID-19.

We have not initiated clinical development of our other product candidates and none of our product candidates are ready for commercialization.

We expect to continue to incur significant expenses and increasing operating losses for the foreseeable future, and the net losses we incur may fluctuate significantly from quarter to quarter.

We expect to continue to incur

significant expenses and increasing operating losses for the foreseeable future, and the net losses we incur may fluctuate significantly from quarter to quarter.

We anticipate that our expenses will increase substantially if and as we:

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We may never succeed in these activities and, even if we do, we may never generate revenues that are significant or large enough to achieve profitability.

We are currently advancing clinical development for pegzilarginase for the treatment of Arginase 1 Deficiency and have initiated a Phase 1/2 clinical trial of AGLE-177 for the treatment of patients with Homocystinuria.

We are currently advancing clinical development for pegzilarginase for the treatment of Arginase 1 Deficiency and have also initiated dosing in our Phase 1/2 clinical trial of AGLE-177 for the treatment of patients with Homocystinuria.

We are in the nonclinical development stages for our remaining product candidates.

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Accordingly, we will need to obtain substantial additional funding to support our continuing operations.

If we are unable to raise capital when needed for any reason, including but not limited to a federal government shutdown, or on acceptable terms, we would be forced to delay, reduce or eliminate our discovery and nonclinical development programs, our ongoing clinical development, or any future clinical development or commercialization efforts.

Based upon our planned use of our cash, cash equivalents, marketable securities, and restricted cash as of December 31, 2020, we estimate such funds will be sufficient for us to (i) to advance the clinical development of pegzilarginase through our Phase 3 PEACE trial and Biologics License Application, or BLA, submission, (ii) fund completion of our ongoing open-label extension study for patients with Arginase 1 Deficiency, and (iii) to advance the clinical development of AGLE-177 through our Phase 1/2 clinical trial and preparation for a potential Phase 3 trial for the treatment of patients with Homocystinuria.

If we are unable to raise capital when needed for any reason, including but not limited to a U.S.

federal government shutdown, or on acceptable terms, we would be forced to delay, reduce or eliminate our discovery and nonclinical development programs, our ongoing clinical development, or any future clinical development or commercialization efforts.

Based upon our planned use of our cash, cash equivalents, marketable securities, and restricted cash as of December 31, 2021, we estimate such funds will be sufficient for us to (i) to advance the clinical development of pegzilarginase through our Biologics License Application, or BLA, submission, for the treatment of Arginase 1 Deficiency (ii) fund our two ongoing extension studies for patients with Arginase 1 Deficiency, (iii) advance the clinical development of AGLE-177 through our Phase 1/2 clinical trial and preparation for a potential Phase 3 trial for the treatment of patients

with Homocystinuria , and (iv) to advance AGLE-325 through IND-enabling studies .

Our future capital requirements will depend on many factors, including:

the costs associated with the scope, progress and results of compound discovery, nonclinical development, laboratory testing and clinical trials for our product candidates;

the costs related to the extent to which we enter into partnerships or other arrangements with third parties in order to further develop our product candidates;

the extent to which we enter into partnerships or other arrangements with third parties in order to further develop our product candidates;

the costs and fees associated with the discovery, acquisition or in-license of product candidates or technologies;

our ability to establish collaborations on favorable terms, if at all;

the costs of future commercialization activities, if any, including product sales, marketing, manufacturing and distribution, for any of our product candidates for which we receive marketing approval;

the costs of commercialization activities, including product sales, marketing, manufacturing and distribution, for any of our product candidates for which we receive marketing approval;

revenue, if any, received from commercial sales of our product candidates, should any of our product candidates receive marketing approval;

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Our product candidates, if approved, may not achieve commercial success.

Our commercial revenues, if any, will be derived from sales of product candidates that we do not expect to be commercially available for many years, if at all.

Our commercial revenues, if any, will be derived from sales of products, none of which have been approved to date.

Accordingly, we will continue to rely on additional financing to achieve our business objectives, which may not be available to us on acceptable terms, or at all.

Raising additional capital may cause dilution to our stockholders, restrict our operations or require us to relinquish rights to our technologies or product candidates.

Until such time, if ever, as we can generate substantial product revenues, we expect to finance our cash needs through a combination of equity or equity-linked offerings, debt financings, grants from research organizations and license and collaboration agreements.

We do not have any committed external source of funds.

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We may not be successful in advancing the clinical development of our product candidates, including pegzilarginase and AGLE-177.

In order to execute on our strategy of advancing the clinical development of our product candidates, we are conducting a global pivotal Phase 3 PEACE (Pegzilarginase Effect on Arginase 1 Deficiency Clinical Endpoints) clinical trial, an ongoing open-label extension study of our completed Phase 1/2 clinical trial for the treatment of Arginase 1 Deficiency and a Phase 1/2 clinical trial of AGLE-177 for the treatment of patients with Homocystinuria, however, the timing of first patient dosing of AGLE-177 will depend on determinations by individual sites given COVID-19.

In order to execute on our strategy of advancing the clinical development of our product candidates, we completed the double-blind placebo-controlled portion of our global pivotal PEACE Phase 3 clinical trial and are conducting two long-term extension studies in the PEACE Phase 3 clinical trial and Phase 1/2 open-label extension study for the treatment of Arginase 1 Deficiency, and a Phase 1/2 clinical trial of AGLE-177 for the treatment of patients with Homocystinuria.

If our product candidates fail to work as we expect, or if we need to conduct additional studies to better understand the relationship between our product candidates and clinical activity, our ability to assess the therapeutic effect, seek regulatory approval or otherwise begin or further clinical development, could be compromised.

For instance, we discontinued clinical development of pegzilarginase for the treatment of the hematological malignancies acute myeloid leukemia, or AML, and myelodysplastic syndrome, or MDS, in December 2017 due to lack of evidence of clinical benefit.

Although we announced topline results from the PEACE Phase 3 trial in December 2021 and plan to submit a BLA to the FDA to support approval for pegzilarginase based on the results of the trial, the FDA may not agree with the adequacy of the trial design or with our interpretation of the data from the PEACE Phase 3 trial.

For example, the study was unable to demonstrate nominal statistical significance on any prespecified clinical outcome-based endpoints, so the FDA may determine that there is insufficient direct evidence of effectiveness or inadequate justification to support approval based on the biomarker endpoint we have chosen.

The failure to demonstrate improvement on such clinical endpoints could have been due to an

insufficient duration on treatment to detect such an effect.

For example, in preliminary comments from the FDA prior to a Type B guidance meeting, the FDA indicated that the PEACE Phase 3 trial results described at a high-level do not appear to provide substantial evidence of effectiveness to support a BLA submission.

FDA has raised concerns with the selected primary endpoint and that the duration for our PEACE Phase 3 clinical trial may not be adequate to assess for clinically meaningful changes.

Similarly, our dosing duration for our PEACE Phase 3 clinical trial may not have been adequate to assess safety and immunogenicity assessment of pegzilarginase .

Therefore, while we intend to submit a BLA to the FDA, the FDA may decide not to file our BLA or approve the BLA in a timely manner , or at all.

If the FDA does not approve our BLA, we may need to conduct additional studies and our expected timing of commercialization of pegzilarginase could be delayed.

We have in the past had to cease clinical development of product candidates for other indications.

We discontinued clinical development of pegzilarginase for the treatment of the hematological malignancies acute myeloid leukemia, or AML, and myelodysplastic syndrome, or MDS, in December 2017 due to lack of evidence of clinical benefit.

Additionally, we completed our Phase 1 clinical trial of pegzilarginase for the treatment of advanced solid tumors to study small cell lung cancer, uveal melanoma, and cutaneous melanoma and our combination trial of pegzilarginase with pembrolizumab for the treatment of patients with SCLC.

We are currently exploring partnership opportunities for further development in oncology.

Also, while we have shown in our Phase 1/2 trial for the treatment of Arginase 1 Deficiency that a reduction of arginine and its metabolites appears to result in clinical benefit, the Health Authorities may not agree with our assessment.

Such an event may result in longer development times, larger trials and a greater likelihood of terminating the trial or not obtaining regulatory approval.

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We have invested a significant portion of our efforts and financial resources in the nonclinical and clinical development and testing of our most advanced product candidate, pegzilarginase, for the treatment of patients with Arginase 1 Deficiency and in certain oncology trials.

Our ability to generate product revenues, which we do not expect will occur for many years, if ever, will depend heavily on the successful development and commercialization of pegzilarginase.

Our ability to generate product revenues, if ever, will depend heavily on the successful development and commercialization of pegzilarginase.

The success of pegzilarginase, AGLE-177, and our other product candidates will depend on many factors, including the following:

successful enrollment of patients in, and the completion of, our ongoing and planned clinical trials, including our global pivotal Phase 3 PEACE clinical trial;

receiving required regulatory approvals for the development and commercialization of our product candidates as monotherapy or in combination with other products;

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If we do not achieve one or more of these factors in a timely manner or at all, we could experience significant delays or an inability to successfully commercialize our product candidates, which would materially harm our business.

The results from our global pivotal PEACE Phase 3 trial may not support marketing approval, and the FDA may require us to conduct additional clinical trials to evaluate subjects for an additional follow-up period.

We announced updated data from our ongoing PEACE Phase 3 trial in December 2021 and plan to submit a BLA to the FDA in the second quarter of 2022 seeking full approval of pegzilarginase.

Even though the PEACE Phase 3 trial achieved statistical significance on its primary endpoint and a positive trend in a secondary endpoint was observed, nominal statistical significance was not reached on any of the prespecified key secondary or secondary endpoints evaluating motor assessments.

In preliminary comments from the FDA prior to a Type B guidance meeting, the FDA indicated that the PEACE Phase 3 trial results described at a high-level do not appear to provide substantial evidence of effectiveness to support a BLA submission.

Therefore, while we intend to submit a BLA to the FDA, the FDA may decide not to file our BLA.

Further, even if the FDA files our BLA, the FDA may not conclude that the design of or results seen in the trial sufficiently demonstrate substantial evidence of effectiveness, including the demonstration of a clinically

meaningful effect.

The FDA also weighs the benefits of a product against its risks and the FDA may view the efficacy results in the context of safety as not being supportive of regulatory approval.

We cannot predict whether the BLA that we plan to submit for pegzilarginase will be filed or approved in a timely manner or at all.

The outbreak of the novel strain of coronavirus, SARS-CoV-2 and its variants, which causes COVID-19, has, and may continue to, adversely impact our business, including our clinical trials and nonclinical studies, supply chain interruptions, and delays for raw materials.

Public health crises such as pandemics or similar outbreaks could adversely impact our business.

In December 2019, a novel strain of coronavirus, SARS-CoV-2, which causes COVID-19, surfaced in Wuhan, China.

Since then, COVID-19 has spread to multiple countries, including the United States.

In response to the spread of COVID-19, we have closed our executive offices with our administrative employees continuing their work outside of our offices, restricted on-site staff to only those required to execute their job responsibilities and limited the number of staff in any given research and development laboratory.

In response to the COVID-19 pandemic and the ongoing vaccination campaign, we have reopened our executive offices and research laboratory in adherence with our COVID-19 protective protocols.

While some of our administrative employees continue their work outside of our offices, a significant portion of our employees, including laboratory personnel, have returned to the office either full- or part-time.

Timely enrollment in our clinical trials is dependent upon global clinical trial sites which may be adversely affected by global health matters, such as pandemics.

We are currently conducting clinical trials for our product candidates in many countries, including the United States, Australia, United Kingdom and throughout the European Union.

We are currently conducting clinical trials for our product candidates in many countries, including the United States, Canada, Australia, United Kingdom and throughout the European Union.

The regions in which we operate are currently being or may in the future be affected by COVID-19.

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diversion of healthcare resources away from the conduct of clinical trials, including the diversion of hospitals serving as our clinical trial sites and hospital staff supporting the conduct of our clinical trials, or restricted access to clinical trial sites for on-site monitoring activities;

interruption of key clinical trial activities, such as clinical assessments at pre-specified timepoints during the trial and clinical trial site data monitoring, due to limitations on travel imposed or recommended by federal or state governments, employers and others or interruption of clinical trial subject visits and study procedures (particularly any procedures that may be deemed non-essential), which may impact the integrity of subject data and clinical study endpoints;

interruption of key clinical trial activities, such as clinical assessments at pre-specified timepoints during the trial and clinical trial site data monitoring, due to limitations on travel imposed or recommended by federal, state, or foreign governments, employers and others or interruption of clinical trial subject visits and study procedures (particularly any procedures that may be deemed non-essential), which may impact the integrity of subject data and clinical study endpoints;

interruption or delays in the operations of the FDA and comparable foreign regulatory agencies, which may impact feedback and approval timelines;

limitations on employee resources that would otherwise be focused on the conduct of our nonclinical studies and clinical trials, including because of sickness of employees or their families, the desire of employees to avoid contact with large groups of people, an increased reliance on working from home or mass transit disruptions;

interruption of, or delays in receiving, supplies of our product candidates from our CMOs due to staffing shortages, production slowdowns or stoppages, disruptions in delivery systems and commandeering of manufacturing facilities for COVID-19 vaccines;

reduced ability to engage with the medical and investor communities due to the cancellation of conferences scheduled throughout the year.

For example, the timing of our Phase 3 PEACE trial has been impacted by COVID-19 as a result of all of our clinical trial sites temporarily suspending screening.

Due to this impact, we now expect the Phase 3 PEACE trial enrollment to close in March 2021, with completion of screening and all patients randomized by the end of April 2021.

reduced ability to engage with the scientific, medical and investor communities due to the cancellation of conferences scheduled throughout the year;

delays and interruptions to the supply chain, including the raw materials needed for manufacturing.

For example, the timing of our double-blind placebo-controlled portion of our PEACE Phase 3 trial was impacted by COVID-19 as a result of all of our clinical trial sites temporarily suspending screening.

All patients that had initially paused dosing due to COVID-19 had restarted treatment by September 2020.

However, patients may miss dosing appointments in the future, whether due to COVID-19 or other reasons.

While the Phase 3 PEACE trial protocol allows for a patient to miss a few dosing appointments without being disqualified from the trial, an excessive number of missed doses may adversely affect the usefulness of the data collected in the trial or require us to exclude a subject from the per protocol analysis.

In addition, although we have initiated our Phase 1/2 open label clinical trial of AGLE-177 for the treatment in patients with Homocystinuria, the protocol requires in-person visits to clinical trial sites.

These sites are located in areas experiencing significant impacts to their healthcare systems due to COVID-19 and consequently many have suspended patient recruitment.

While we initiated this trial in the second quarter of 2020, the timing of first patient dosing will depend on determinations by individual sites as they adjust to impacts from COVID-19.

We completed enrollment and randomization of patients in the PEACE Phase 3 trial in April 2021 and announced topline data from the trial in December 2021.

In addition, although we are conducting a Phase 1/2 open-label clinical trial of AGLE-177 for the treatment in patients with Homocystinuria, the protocol requires in-person visits to clinical trial sites.

Many of these sites are located in areas that have experienced significant impacts and may continue to experience more pronounced impacts to their healthcare

systems due to COVID-19 and consequently many previously suspended patient recruitment and may do so again in the future.

While we initiated dosing in our Phase 1/2 clinical trial investigating AGLE-177 for the treatment of Homocystinuria in June 2021, the timing of continued enrollment may be delayed in the future due to the impact of COVID-19 and local restrictions.

For example, in September 2021, we announced that we believe the emergence of the delta variant and lockdowns in Australia, which have slowed trial enrollment, will impact the availability of data for our Phase 1/2 clinical trial for AGLE-177 and, as a result, we stated that we no longer plan ned to provide a clinical update relating to this trial in 2021.

Additionally, missed doses by patients in the study may adversely affect the usefulness of the data collected in the trial.

These and other factors arising from the COVID-19 pandemic could worsen in countries that are already afflicted with COVID-19, could continue to spread to additional countries, or could return to countries where the pandemic has been partially contained, each of which could further adversely impact our ability to conduct clinical trials and our business generally, and could have a material adverse impact on our operations and financial condition and results.

In addition, the trading prices for our common stock and other biopharmaceutical companies, as well as the broader equity and debt markets, have been highly volatile as a result of the COVID-19 pandemic and the resulting impact on economic activity.

As a result, we may face difficulties raising capital when needed, and any such sales may be on

unfavorable terms to us.

As a result, we may face difficulties raising capital when needed, and any such sales may be on unfavorable terms to us.

Further, to the extent we raise additional capital through the sale of equity or convertible debt securities, the ownership interest of existing stockholders will be diluted.

The COVID-19 outbreak continues to rapidly evolve.

The extent to which the outbreak may impact our business, clinical trials and nonclinical studies will depend on future developments, which are highly uncertain and cannot be predicted with confidence, such as the ultimate geographic spread of COVID-19, the duration of the outbreak, travel restrictions and actions to contain the outbreak or treat its impact, such as social distancing and quarantines or lock-downs in the United States and other countries, business closures or business disruptions and the effectiveness of actions taken in the United States and other countries to contain and treat the disease.

The COVID-19 outbreak, including the emergence of its variants and their effects, continues to rapidly evolve.

The extent to which the outbreak may impact our business, clinical trials and nonclinical studies will depend on future developments, which are highly uncertain and cannot be predicted with confidence, such as the ultimate geographic spread of COVID-19, the duration of the outbreak, the speed and breadth of mass vaccinations and boosters for COVID-19 and the efficacy of such vaccines and treatments, travel restrictions and actions to contain the outbreak or treat its impact, such as social distancing and quarantines or lock-downs in the United States and other countries, business closures or business disruptions and the effectiveness of actions taken in the United States and other countries to contain and treat the disease.

Clinical drug development involves a lengthy and expensive process with an uncertain outcome.

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The results of nonclinical studies and early clinical trials of our product candidates may not be predictive of the results of later-stage clinical trials that will likely differ in design and size from early-stage clinical trials, and interim results of a clinical trial do not necessarily predict final results.

For example, while we have observed a reduction in blood arginine and arginine metabolite levels due to administration of pegzilarginase in patients with Arginase 1 Deficiency, and a reduction in blood arginine levels due to pegzilarginase in patients with advanced solid tumors, this data may not necessarily be predictive of the final results of all patients intended to be enrolled in our ongoing or future clinical trials, and may also not be predictive of pegzilarginase’s ability to reduce arginine or arginine metabolite levels for these patients over a longer term nor predictive of positive clinical outcomes.

For example, while we have observed a reduction in blood arginine and arginine metabolite levels due to administration of pegzilarginase in patients with Arginase 1 Deficiency, and a reduction in blood arginine levels due to pegzilarginase in patients with advanced solid tumors, these data may not necessarily be predictive of the final results of all patients intended to be enrolled in our ongoing or future clinical trials, and may also not be predictive of pegzilarginase’s ability to reduce arginine or arginine metabolite levels for these patients over a longer term nor predictive of positive clinical outcomes.

In addition, while we intend to announce interim data from our clinical trials from time to time, such reports may be based on unaudited data provided by our clinical trial investigators.

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In addition, our observations of clinical improvements, through clinician and assessor feedback or assessment tools in the Phase 1/2 clinical trial and Phase 2 open-label study of pegzilarginase in patients with Arginase 1 Deficiency after cumulative doses, may not be representative of our observations with subsequently dosed patients out to a similar or longer duration of cumulative dosing.

We have begun dosing in our single, global pivotal Phase 3 PEACE clinical trial to evaluate the safety and efficacy of pegzilarginase.

We completed enrollment in our single, global pivotal PEACE Phase 3 clinical trial to evaluate the safety and efficacy of pegzilarginase in patients with Arginase 1 Deficiency.

Due to COVID-19, all of our clinical trial sites temporarily suspended screening, limiting patient access, and resulting in some missed dosing appointments for patients.

All patients that had initially paused dosing due to COVID-19 had restarted treatment by September 2020.

However, patients may miss dosing appointments in the future, whether due to COVID-19 or other reasons.

The Phase 3 PEACE trial protocol allows for a patient to miss a few dosing appointments without being disqualified from the trial, but an excessive number of missed doses may adversely affect the usefulness of the data collected in the trial or require us to exclude a subject from the per protocol analysis.

Furthermore, while our completed Phase 1/2 clinical trial for the treatment of patients with Arginase 1 Deficiency primarily evaluated the safety of our product candidate, such nonclinical and clinical data are often susceptible to varying interpretations and analyses, and many companies that have believed their product candidates performed satisfactorily in nonclinical studies and clinical trials have nonetheless failed to obtain marketing approval of their products.

Further, while we have conducted prior clinical trials of pegzilarginase in certain oncology indications, we are currently exploring partnership opportunities for further development in oncology.

In addition, while we

initiated dosing in our Phase 1/2 clinical trial investigating AGLE-177 for the treatment of Homocystinuria in June 2021, the timing of continued enrollment may be delayed in the future due to the impact of COVID-19 and local restrictions.

Additionally, missed doses by patients in the study may adversely affect the usefulness of the data collected in the trial.

Furthermore, while we have conducted prior clinical trials of pegzilarginase in certain oncology indications, we are currently exploring partnership opportunities for further development in oncology.

It is impossible to predict when or if any of our product candidates will prove effective or safe in humans or will receive regulatory approval.

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There can be no assurance that the Health Authorities will allow us to begin clinical trials or that they will not put any of the trials for any of our product candidates that enter or have entered clinical development on clinical hold in the future.

We may experience numerous unforeseen events during, or as a result of, clinical trials that could delay or prevent our ability to receive marketing

approval or commercialize our product candidates.

We may experience numerous unforeseen events during, or as a result of, clinical trials that could delay or prevent our ability to receive marketing approval or commercialize our product candidates.

Clinical trials may be delayed, suspended or prematurely terminated because costs are greater than we anticipate or for a variety of reasons, such as:

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there may be changes in governmental regulations or administrative actions.

If we are required to modify our ongoing clinical trial protocols, conduct additional clinical trials or other testing of our product candidates beyond those that we currently contemplate, if we are unable to successfully initiate or complete clinical trials of our product candidates or other testing, if the results of these trials or tests do not demonstrate sufficient clinical benefit or if our product candidates do not have an acceptable safety profile, we may:

clinical trials of our product candidates or other testing, if the results of these trials or tests do not demonstrate sufficient clinical benefit or if our product candidates do not have an acceptable safety profile, we may:

be delayed in obtaining marketing approval for our product candidates;

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Although we reached an agreement with the FDA in November 2017 and began dosing pediatric patients, the FDA may require additional information or studies to be conducted, or impose conditions that could further delay or restrict our other planned clinical activities in the future.

We began our global pivotal Phase 3 PEACE clinical trial in which we are studying plasma arginine reduction from baseline over 24 weeks as our primary endpoint.

We began our global pivotal PEACE Phase 3 clinical trial in which we are studying plasma arginine reduction from baseline over 24 weeks as our primary endpoint.

However, evidence of stabilization or improvement of clinical signs and symptoms of Arginase 1 Deficiency, such as our secondary endpoints, consisting of clinical outcome assessments focused primarily on mobility, as well as clinician and caregiver global impressions of effectiveness, may be required in addition to the primary endpoint to support approval.

Certain of our clinical outcome secondary endpoints will be measured using motor assessments that have not been previously validated for Arginase 1 Deficiency, including the gross motor function classification system.

Certain of our clinical outcome secondary endpoints are being measured using motor assessments that have not been previously validated for Arginase 1 Deficiency, including the gross motor function classification system.

Such motor assessments have only been validated in ambulatory children with cerebral palsy.

We believe these motor functional assessments are translatable to Arginase 1 Deficiency patients given the similarities in symptoms of children with cerebral palsy and the Arginase 1 Deficiency populations, however the FDA or other Health Authorities may disagree.

If we are unable to demonstrate sufficient improvement on such clinical endpoints, the FDA may determine that there is insufficient direct evidence of effectiveness or inadequate justification to support a full approval based on the biomarker endpoint we have chosen.

The failure to demonstrate improvement on such clinical endpoints could be due to an insufficient duration on treatment to see such an effect.

For example, the FDA indicated that our dosing duration for our Phase 3 PEACE clinical trial may not be adequate to assess for clinically meaningful changes.

Similarly, our dosing duration for our Phase 3 PEACE clinical trial may not be adequate to assess safety and immunogenicity assessment of pegzilarginase.

Significant nonclinical or clinical trial delays also could shorten any periods during which we may have the exclusive right to commercialize our product candidates or allow our competitors to bring products to market before we do and impair our ability to successfully commercialize our product candidates and may materially harm our business and results of operations.

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Additionally, commencing any future clinical trials is subject to finalizing the trial design and submitting an IND, CTA or comparable submission in other jurisdictions.

We plan to advance AGLE-325 for the treatment of patients with Cystinuria through IND-enabling studies in 2022 and potential subsequent initiation of clinical development.

Even after we submit an IND, CTA or comparable submission in other jurisdictions, the Health Authorities could disagree that we have satisfied their requirements to commence our clinical trials, disagree with our study design, or may change their guidance criteria, which may require us to complete additional nonclinical studies or amend our protocols or impose stricter conditions on the commencement of clinical trials.

Failure to submit or have effective INDs, CTAs or other comparable foreign equivalents and commence clinical programs will significantly limit our opportunity to generate revenue.

Failure to submit or have effective INDs, CTAs or other comparable foreign equivalents and commence clinical programs will ultimately limit our opportunity to generate revenue.

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Because this is a relatively new and expanding area of novel therapeutic interventions, there can be no assurance as to the length of the trial period, the manufacturing and quality control standards required to be met by regulators, the number of patients the Health Authorities will require to be enrolled in the trials in order to establish the safety, efficacy, purity and potency of engineered human enzyme products, or that the data generated in these trials will be acceptable to the FDA or another applicable regulatory authority to support marketing approval.

We have only initiated clinical trials for pegzilarginase and AGLE-177 for the treatment of certain conditions and have only dosed pegzilarginase in humans.

We have only initiated clinical trials for pegzilarginase and AGLE-177 for the treatment of certain conditions.

We have not dosed any of our other product candidates in humans.

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If our product candidates are associated with undesirable side effects in nonclinical studies or clinical trials, in monotherapy or combination therapy, or have characteristics that are unexpected, we may need to interrupt, delay or abandon their development or limit development to more narrow uses or subpopulations in which the undesirable side effects or other characteristics are less prevalent, less severe or more acceptable from a risk-benefit perspective.

We are currently conducting clinical trials for pegzilarginase for the treatment of patients with Arginase 1 Deficiency and AGLE-177 for the treatment of patients with Homocystinuria.

We completed the double-blind placebo-controlled portion of our global pivotal PEACE Phase 3 trial and pegzilarginase is continuing to be evaluated in two long-term extension studies in the PEACE Phase 3 trial and a Phase 1/2 open-label extension study for the treatment of patients with Arginase 1 Deficiency.

We are also conducting a Phase 1/2 AGLE-177 for the treatment of patients with Homocystinuria.

Given the nature of the patient populations enrolled in these trials, we have observed and expect to continue to observe serious adverse events that could be related or unrelated to pegzilarginase and could impact the safety or efficacy of pegzilarginase and we may observe serious adverse events that could be related or unrelated to AGLE-177 and could impact the safety or efficacy of AGLE-177.

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In our completed combination trial of pegzilarginase and pembrolizumab in patients with previously-treated small cell lung cancer, safety observations were consistent with prior studies of pegzilarginase in patients with cancer.

In a completed Phase 1/2 clinical trial and an ongoing open-label extension study of pegzilarginase for the treatment of patients with Arginase 1 Deficiency, we have observed serious adverse events in some patients, including hypersensitivity and hyperammonemia, which were infrequent, expected and manageable.

In a completed Phase 1/2 clinical trial and an ongoing Phase 2 open-label extension study of pegzilarginase for the treatment of patients with Arginase 1 Deficiency, we have observed serious adverse events in some patients, including hypersensitivity and hyperammonemia, which were infrequent, expected and manageable.

Hyperammonemia is an important metabolic effect experienced by some patients with Arginase 1 Deficiency.

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For example, it is possible that patients’ immune systems may recognize our engineered human enzymes as foreign and trigger an immune response.

This risk is heightened in patients with many genetic enzyme deficiencies who lack the target enzyme, including patients with Arginase 1 Deficiency that we are treating in our global pivotal Phase 3 PEACE trial, our Phase 2 trial open label

extension study, and any future clinical trials we conduct for this rare genetic disease or in trials in patients with Homocystinuria with A GLE- 177.

In addition, our product candidates such as pegzilarginase and A GLE- 177 break down target amino acids, thereby releasing metabolites into the bloodstream.

heightened in patients with many genetic enzyme deficiencies who lack the target enzyme, including patients with Arginase 1 Deficiency that we are treating in our global pivotal PEACE Phase 3 trial, our Phase 2 trial open - label extension study, and any future clinical trials we conduct for this rare genetic disease or in trials in patients with Homocystinuria with AGLE-177.

In addition, our product candidates such as pegzilarginase and AGLE-177 break down target amino acids, thereby releasing metabolites into the bloodstream.

Some patients may be sensitive to these metabolites, increasing the risk of an adverse reaction due to treatment, which risk may not be able to be mitigated through dosing.

Finally, although our engineered human enzyme product candidates such as pegzilarginase and AGLE- 177 are engineered from the human genome, pegzilarginase and A GLE- 177 are produced in E.

Finally, although our engineered human enzyme product candidates such as pegzilarginase and AGLE-177 are engineered from the human genome, pegzilarginase and AGLE-177 are produced in E.

This manufacturing process could lead to the products being more likely to trigger an immune response than we expect.

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We may not be able to initiate or continue our ongoing or planned clinical trials if we are unable to locate and enroll a sufficient number of eligible patients to participate in these trials as required by the Health Authorities.

For example, the timing of our Phase 3 PEACE trial has been impacted by COVID-19.

All of our clinical trial sites temporarily suspended screening, limiting patient access, and resulting in some missed dosing appointments for patients.

For example, although we have completed the double-blind placebo-controlled portion of our PEACE Phase 3 trial and are currently enrolling in our Phase 1/2 clinical trial investigating AGLE-177 for the treatment of Homocystinuria, the timing of each trial has been impacted by COVID-19.

All of our clinical trial sites for the PEACE Phase 3 trial temporarily suspended screening, limiting patient access, and resulting in some missed dosing appointments for patients.

All patients that had initially paused dosing due to COVID-19 had restarted treatment by September 2020.

However, patients may miss dosing appointments in the future, whether due to COVID-19 or other reasons.

Furthermore, we have initiated a Phase 1/2 clinical trial of AGLE-177 for Homocystinuria in the second quarter of 2020, however, the timing of first patient dosing will depend on determinations by individual sites given COVID-19 and our priorities at this time are to avoid further overburdening hospital staff and to minimize the risk of trial participants exposure to COVID-19.

Also , many of our product candidates, including pegzilarginase and AGLE-177, initially target indications that may be characterized as orphan markets, which can prolong the clinical trial timeline if sufficient patients cannot be enrolled in a timely manner.

Additionally, while we initiated dosing in our Phase 1/2 clinical trial investigating AGLE-177 for the treatment of Homocystinuria in June 2021, the timing of continued enrollment may be delayed in the future due to the impact of COVID-19 and local restrictions.

Furthermore, many of our product candidates, including pegzilarginase and AGLE-177, initially target indications that may be characterized as orphan markets, which can prolong the clinical trial timeline if sufficient patients cannot be enrolled in a timely manner.

Arginase 1 Deficiency is a rare disorder, and there are no published reports of disease prevalence.

We commissioned a genetic prevalence analysis and based on that analysis estimate the Arginase 1 Deficiency population is greater than 2,500 patients in the global addressable markets.

We commissioned a genetic prevalence analysis and based on that analysis estimate the Arginase 1 Deficiency population is greater than 2,500 patients in the global addressable markets and greater than 1,150 patients in the territories with regulatory and launch plans underway.

The genetic prevalence-based methodology is intended to account for misdiagnosis of the disease and to address limitations in newborn screening methodology, including naturally low arginine levels in newborns and lack of geographic availability or standardization of testing.

Presently, only 34 U.S.

states and jurisdictions perform newborn screening for Arginase 1 Deficiency, and newborn screening is not currently widely performed in European countries.

D ue to screening requirements and enrollment restrictions in our clinical trial protocol, or any additional restrictions that may be imposed by regulatory agencies, not all patients may be eligible for inclusion in our planned global pivotal Phase 3 PEACE clinical trial.

As of January 2021, we have identified over 300 Arginase 1 Deficiency patients in the global addressable markets, primarily in the U.S.

and France, Germany, Italy, Spain and the United Kingdom, referred to as the EU5, representing approximately 65% and 30% of the estimated genetic prevalence populations in the U.S.

and EU5, respectively.

We estimate the patient population for Homocystinuria may exceed 30,000 in global addressable markets, but we may not be able to initiate the trial as expected or locate and enroll a sufficient number of eligible patients as required by the Health Authorities, and the necessary regulatory approvals could be delayed or prevented.

states perform newborn screening for Arginase 1 Deficiency, and newborn screening is not currently widely performed in European countries.

We estimate the patient population for Homocystinuria in global addressable markets may exceed 30,000 patients, including B6-responsive and B6-non-responsive patients, with approximately 15,000 to 18,000 estimated B6-non-responsive patients (of which approximately 6,000 to 6,600 are estimated in the key commercial markets of the United States, France, Germany, Italy, Spain, and the United Kingdom), but we may not be able to continue to enroll the trial as expected or locate and enroll a sufficient number of eligible patients as required by the Health Authorities, and the necessary regulatory approvals could be delayed or prevented.

Delays in patient enrollment could result in increased costs, delays in advancing our product development, delays in testing the effectiveness of our technology or termination of the clinical trials altogether.

Patient enrollment is affected by factors including:

the impact of COVID-19 and related local restrictions;

the severity of the disease under investigation;

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There is no assurance that we will be able to enter into such arrangements on favorable terms, or at all.

Even though we have obtained orphan drug designation for pegzilarginase in the United States and Europe for the treatment of hyperargininemia, and for AGLE-177 in the United States and Europe for the treatment of patients with Homocystinuria, we may not obtain or maintain orphan drug exclusivity for pegzilarginase or AGLE-

177 and we may not obtain orphan drug designation or exclusivity for any of our other product candidates or indications.

Even though we have obtained orphan drug designation for pegzilarginase in the United States and Europe for the treatment of Arginase 1 Deficiency (hyperargininemia), and for AGLE-177 in the United States and Europe for the treatment of patients with Homocystinuria, we may not obtain or maintain orphan drug exclusivity for pegzilarginase or AGLE-177 and we may not obtain orphan drug designation or exclusivity for any of our other product candidates or indications.

Regulatory authorities in some jurisdictions, including the United States and Europe, may designate drugs or biologics for relatively small patient populations as orphan drugs.

Under the Orphan Drug Act, the FDA may designate a product as an orphan drug if it is a drug or biologic intended to treat a rare disease or condition, which is generally defined as a patient population of fewer than 200,000 individuals in the United States.

Under the Orphan Drug Act, the FDA may designate a product as an orphan drug if it is a drug or biologic intended to treat a rare disease or condition, which is generally defined

as a patient population of fewer than 200,000 individuals in the United States.

Similarly, the European Commission may designate a product as an orphan drug under certain circumstances.

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We have also received orphan drug designation in the United States and Europe for AGLE-177 for the treatment of patients with Homocystinuria.

A company that first obtains FDA or EMA approval for a designated orphan drug for the designated rare disease or condition receives orphan drug marketing exclusivity for that drug for the designated disease for a period of seven years in the United States or ten years in the European Union, respectively.

This orphan drug exclusivity prevents the FDA or EMA from approving another application, including a Biologics License Application, or BLA, in the United States or a MAA in the European Union, to market a drug containing the same principal molecular structural features for the same orphan indication, except in very limited circumstances, including when the FDA or the EMA concludes that the later drug is safer, more effective or makes a major contribution to patient care.

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Further, even if we obtain orphan drug exclusivity for a product, that exclusivity may not effectively protect the product from competition because different drugs with different active moieties can be approved for the same condition or a drug with the same principal molecular structural features can be approved for a different indication.

Orphan drug designation neither shortens the development time or regulatory review time of a drug nor gives the drug any advantage in the regulatory review or approval process.

Orphan drug designation by FDA or EMA neither shortens the development time or regulatory review time of a drug nor gives the drug any advantage in the regulatory review or approval process.

In addition, even if we intend to seek orphan drug designation for other product candidates or indications, we may never receive such designations or obtain orphan drug exclusivity.

A Rare Pediatric Disease designation by the FDA does not guarantee that the NDA or BLA for the product will qualify for a priority review voucher upon approval, and it does not lead to a faster development or regulatory review process, or increase the likelihood that any of our product candidates will receive marketing approval.

Under the Rare Pediatric Disease Priority Review Voucher program, upon the approval of a qualifying BLA or NDA for the treatment of a rare pediatric disease, the sponsor of such an application would be awarded a rare pediatric disease priority review voucher that can be used to obtain priority review for a subsequent BLA or NDA.

Under the Rare Pediatric Disease Priority Review Voucher program, upon the approval of a qualifying BLA or NDA for the treatment of a rare pediatric disease, the sponsor of such an application would be awarded a transferable rare pediatric disease priority review voucher that can be used to obtain priority review for a subsequent BLA or NDA.

In September 2018, the FDA notified us that we obtained Rare Pediatric Disease designation for pegzilarginase for the treatment of patients with Arginase 1 Deficiency , and in November 2020, the FDA notified us that we obtained Rare Pediatric Disease designation for AGLE-177 for the treatment of Homocystinuria.

On December 27, 2020, the Creating Hope Reauthorization Act extended the Rare Pediatric Disease Priority Review Voucher Program, and after September 30, 2024, the FDA may only award a voucher for an approved rare pediatric disease product application if the sponsor has rare pediatric disease designation for the drug, and that designation was granted by September 30, 2024.

After September 30, 2026, FDA may not award any rare pediatric disease priority review vouchers.

After September 30, 2026, the FDA may not award any rare pediatric disease priority review vouchers.

However, there is no guarantee that any of our product candidates will be approved by that date, or at all, and, therefore, we may not be in a position to obtain a priority review voucher prior to expiration of the program, unless Congress further reauthorizes the program.

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We may not be able to file for marketing approvals and may not receive necessary approvals to commercialize our products in any market.

We or third parties may not be successful in developing diagnostic assays, if required for our product candidates.

In developing a product candidate for some indications, we may decide to use a biomarker-based test to identify patients for enrollment and, or, monitor patients in clinical trials.

We or third parties may not be successful in developing diagnostic assays, or enhanced biomarker approaches, if required for our product candidates.

In developing a product candidate for some indications, we may decide to use a biomarker-based test to identify patients for enrollment and, or, monitor patients in clinical trials or in the commercial environment, which could require development of new and/or modification of existing biochemical monitoring approaches.

In such case, the FDA may require the development and regulatory approval of a companion diagnostic assay as a condition to approval of the product candidate.

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Alternatively, we may also make the decision that our therapy does not require a companion diagnostic, however the Health Authorities may disagree and require the development and regulatory approval of a companion diagnostic assay as a condition of approval of the product candidate, creating additional costs and a delay in bringing our product candidate to market.

We expect to expand our development and regulatory capabilities and potentially implement sales, marketing and distribution capabilities, and, as a result, we may encounter difficulties in managing our growth, which could disrupt our operations.

We expect to experience significant growth in the number of our employees and the scope of our operations, particularly in the areas of product candidate development, regulatory affairs and, if any of our product candidates receives marketing approval, sales, marketing and distribution.

We currently do not have a marketing or sales team for the marketing, sales and distribution of any of our product candidates that are potentially able to obtain regulatory approval.

We expect to expand our development and regulatory capabilities and potentially implement commercialization capabilities, and, as a result, we may encounter difficulties in managing our growth, which could disrupt our operations.

We currently do not have a fully integrated commercial team to distribute and market our product candidates following regulatory approval, if approved.

In order to commercialize any product candidates, we must build on a territory-by-territory basis marketing, sales, distribution, managerial and other non-technical capabilities or make arrangements with third parties to perform these services, and we may not be successful in doing so.

If our product candidates receive regulatory approval, we intend to establish an internal sales or marketing team with technical expertise and supporting distribution capabilities to commercialize our product candidates, which will be expensive and time consuming and will require significant attention of our executive officers to manage.

We will also have to compete with other pharmaceutical and biotechnology companies to recruit, hire, train and retain marketing and sales personnel.

Any failure or delay in the development of our internal sales, marketing and distribution capabilities would adversely impact the commercialization of any of our product candidates that we obtain approval to market.

If our product candidates receive regulatory approval, we intend to establish a fully integrated commercial organization with technical expertise and supporting distribution capabilities to commercialize our product candidates, which will be expensive and time consuming and will require significant attention of our executive officers to manage.

We will also have to compete with other pharmaceutical and biotechnology companies to recruit, hire, train and retain commercial personnel.

Any failure or delay in the development of our internal sales, marketing, access, reimbursement, and distribution capabilities would adversely impact the commercialization of any of our product candidates that we obtain approval to market.

With respect to the commercialization of all or certain of our product candidates, we may choose to collaborate, either globally or on a territory-by-territory basis, with third parties that have direct sales forces and established distribution systems, either to augment our own sales force and distribution systems or in lieu of our own sales force and distribution systems.

In particular, we have and expect to continue to partner with third parties to commercialize pegzilarginase outside the United States.

For example, in March 2021, we entered into a licensing agreement with Immedica , in which Immedica acquired the product rights for commercialization of pegzilarginase in the European Economic Area and certain Middle East jurisdictions.

We may have little or no control over the marketing and sales efforts of such third parties and our revenue from product sales may be lower than if we had commercialized our product candidates ourselves.

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Our understanding of both the number of people who suffer from conditions such as Arginase 1 Deficiency or Homocystinuria, as well as the potential subset of those who have the potential to benefit from treatment with our product candidates, are based on estimates.

We expect our product candidates targeting rare diseases to target the smaller patient populations that suffer from the respective diseases we seek to treat.

We expect our product candidates targeting rare diseases to target a smaller subset of patient populations that suffer from the respective diseases we seek to treat.

These estimates may prove to be incorrect and new studies may reduce the estimated incidence or prevalence of these diseases.

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the strength of marketing and distribution support;

the availability of third-party coverage and adequate reimbursement for our product candidates;

the availability of third-party payor coverage and adequate reimbursement for our product candidates;

the prevalence and severity of their side effects;

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Many of our competitors have substantially greater financial, technical and other resources, such as larger research and development staff and experienced marketing and manufacturing organizations and well-established sales forces.

Competition may increase further as a result of advances in the commercial

applicability of technologies and greater availability of capital for investment in these industries.

Competition may increase further as a result of advances in the commercial applicability of technologies and greater availability of capital for investment in these industries.

Our competitors may succeed in developing, acquiring or licensing, on an exclusive basis, product candidates that are more effective or less costly than any product candidate that we are currently developing or that we may develop.

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From a clinical development perspective, Acer Therapeutics Inc.

is developing a taste-masked, immediate-release formulation of sodium phenylbutyrate for the treatment of hyperammonemia and recently announced their intent to enter a global development and commercialization agreement with Relief Therapeutics Holding AG.

is developing a taste-masked, immediate-release formulation of sodium phenylbutyrate (ACER-001) for the treatment of hyperammonemia and in 2021 announced their intent to enter a global development and commercialization agreement with Relief Therapeutics Holding AG.

In October 2021 , Acer announced that the FDA has accepted for filing the NDA for ACER-001 and has assigned a PDUFA target action date of June 5, 2022.

We anticipate a competitive landscape in Homocystinuria.

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Travere Therapeutics Inc.

recently acquired Orphan Technologies Ltd., a clinical-stage biopharmaceutical company focused on the development of OT-58 (now TVT-058) for the treatment of Classical Homocystinuria.

Travere is enrolling a Phase 1/2 study of TVT-058, an enzyme replacement therapy in patients with Homocystinuria due to cystathionine β-synthase deficiency and has stated that topline data from this study will be available in 2021.

is focused on the development of pegtibatinase, an enzyme replacement therapy in patients with Homocystinuria due to cystathionine β-synthase deficiency.

Travere released topline data in December 2021 from its Phase 1/2 study of pegtibatinase which showed a 55% reduction in homocysteine at the highest dose cohort (1.5mg/kg, 2x/week).

We are aware of three other investigational therapies in preclinical stages.

The first is Synlogic, studying SYNB1353, an oral synthetic biotic platform that consumes toxic metabolites in the GI tract.

Synlogic presented pre-clinical data on this molecule at ICIEM in November 2021.

The second is Codexis, studying CDX-6512, an oral methionine-gamma-lyase enzyme therapy.

Codexis also presented pre-clinical data on this molecule at ICIEM in November 2021.

Additionally, Erytech Pharma SA has a product candidate for Homocystinuria in preclinical development.

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Sales of any of our product candidates that receive marketing approval will depend substantially, both in the United States and internationally, on the extent to which the costs of our product candidates will be paid by health maintenance, managed care, pharmacy benefit and similar healthcare management organizations, or reimbursed by government health administration authorities, private health coverage insurers and other third-party payors.

If reimbursement is not available, or is available only to limited levels, we may not be able to successfully commercialize our product candidates.

If reimbursement is not available, or is available only to limited levels, we may not be able to successfully commercialize

our product candidates.

Even if coverage is provided, the approved reimbursement amount may not be high enough to allow us to establish or maintain pricing sufficient to realize a sufficient return on our investment.

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Outside the United States, international operations are generally subject to extensive governmental price controls and other market regulations, and we believe the increasing emphasis on cost-containment initiatives in Europe, Canada and other countries has and will continue to put pressure on the pricing and usage of therapeutics such as our product candidates.

In many countries, particularly the countries of the European Union, the prices of medical products are subject to varying price control mechanisms as part of national health systems.

In many countries, particularly the UK and the countries of the European Union, the prices of medical products are subject to varying price control mechanisms as part of national health systems.

In these countries, pricing negotiations with governmental authorities can take considerable time after the receipt of marketing approval for a product.

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As a result, increasingly high barriers are being erected to the entry of new products into the healthcare market.

In addition to CMS and private payors, professional organizations such as the National Comprehensive Cancer Network and the American Society of Clinical Oncology can influence decisions about reimbursement for new products by determining standards for care.

In addition to CMS and private payors, professional organizations can influence decisions about reimbursement for new products by determining standards for care.

In addition, many private payors contract with commercial vendors who sell software that provide guidelines that attempt to limit utilization of, and therefore reimbursement for, certain products deemed to provide limited benefit to existing alternatives.

Such organizations may set guidelines that limit reimbursement or utilization of our product candidates.

Furthermore, some of our target indications, including for Arginase 1 Deficiency for pegzilarginase and for Homocystinuria for AGLE-177, are orphan indications where patient populations are small.

Furthermore, some of our target indications, including for Arginase 1 Deficiency for pegzilarginase and Homocystinuria for AGLE-177, are orphan indications where patient populations are small.

In order for therapeutics that are designed to treat smaller patient populations to be commercially viable, the reimbursement for such therapeutics must be higher, on a relative basis, to account for the lack of volume.

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Under the BPCIA, an application for a biosimilar product cannot be approved by the FDA until 12 years after the first licensure of date of the reference product licensed under a BLA.

On March 6, 2015, the FDA approved the first biosimilar product under the BPCIA.

On March 6, 2015, the FDA approved the first biosimilar product under the BPCIA and on July 28, 2021, approved the first interchangeable biosimilar.

However, the law is complex and is still being interpreted and implemented by the FDA.

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Most states have enacted substitution laws that permit substitution of only interchangeable biosimilars.

The extent to which a highly similar biosimilar, once approved, will be substituted for any one of our reference products that may be approved in a way that is similar to traditional generic substitution for non-biological products is not yet clear, and will depend on a number of marketplace and regulatory factors that are still developing.

The extent to which a biosimilar, once approved, will be substituted for any one of our reference products that may be approved in a way that is similar to traditional generic substitution for non-biological products is not yet clear, and will depend on a number of marketplace and regulatory factors that are still developing.

If we fail to develop additional product candidates, our commercial opportunity will be limited.

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If in the future we are unable to establish U.S.

or global sales and marketing capabilities or enter into agreements with third parties to sell and market our product candidates, we may not be successful in commercializing our product candidates if they are approved and we may not be able to generate any revenue

We currently do not have a marketing or sales team for the marketing, sales and distribution of any of our product candidates that may receive regulatory approval.

We do not yet have a fully integrated commercial organization with all of the functions required to market, sell and distribute our product candidates that may receive regulatory approval.

In order to commercialize any product candidates after approval, we must build on a territory-by-territory basis marketing, sales, distribution, managerial and other non-technical capabilities or make arrangements with third parties to perform these services, and we may not be successful in doing so.

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If we are unable to enter into or maintain such arrangements when needed on acceptable terms, or at all, we may not be able to successfully commercialize any of our product candidates that receive regulatory approval or any such commercialization may experience delays or limitations.

In particular, we have and expect to continue to partner with third parties to commercialize pegzilarginase outside the United States.

In March 2021, we entered into a license and supply agreement with Immedica, in which Immedica acquired the product rights for commercialization of pegzilarginase for certain territories outside the U.S.

If we are unable to enter into or maintain such arrangements when needed on acceptable terms, or at all, we may not be able

to successfully commercialize any of our product candidates that receive regulatory approval or any such commercialization may experience delays or limitations.

If we are not successful in commercializing our product candidates, either on our own or through collaborations with one or more third parties, our future product revenue will suffer and we may incur significant additional losses.

If we obtain approval to commercialize our product candidates outside of the United States, in particular in the EU, a variety of risks associated with international operations could materially adversely affect our business.

We expect that we will be subject to additional risks in commercializing our product candidates outside the United States, including:

different regulatory requirements for approval of drugs and biologics in foreign countries;

different processes and requirements to obtain adequate reimbursement for our approved therapies;

reduced protection for intellectual property rights;

unexpected changes in tariffs, trade barriers and regulatory requirements;

economic weakness, including inflation, or political instability in particular foreign economies and markets;

compliance with tax, employment, immigration and labor laws for employees living or traveling abroad;

foreign currency fluctuations, which could result in increased operating expenses and reduced revenues, and other obligations incident to doing business in another country;

workforce uncertainty in countries where labor unrest is more common than in the United States;

production shortages resulting from any events affecting raw material supply or manufacturing capabilities abroad;

business interruptions resulting from geopolitical actions, including war and terrorism or natural disasters including earthquakes, typhoons, floods and fires.

Risks Related to Our Reliance on Third Parties

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We currently rely and will continue to rely on third parties to provide manufacturing and clinical development capabilities.

For example, we currently rely on third party contract manufacturing organizations, to manufacture and supply nonclinical and clinical trial quantities of the biological substance of our lead product candidate, pegzilarginase, AGLE-177 in Homocystinuria, and for additional pipeline product candidates.

For example, we currently rely on third party contract manufacturing organizations, to manufacture and supply nonclinical and clinical trial quantities of our lead product candidate, pegzilarginase, AGLE-177, and for additional pipeline product candidates.

We also expect to continue to rely on such third parties to manufacture and supply commercial quantities of pegzilarginase, as well as AGLE-177 for our Phase 1/2 clinical trial.

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Further, to meet the demand for COVID-19 vaccine production, manufacturers are required to prioritize rated orders issued by the Federal Emergency Management Agency pursuant to the U.S.

Defense Production Act of 1950, or the DPA.

Defense Production Act of 1950, or

The potential for manufacturing facilities and materials to be commandeered under the DPA, or equivalent foreign legislation, could make it more difficult to obtain materials or manufacturing slots for the products needed for our clinical trials or commercialization of our product candidates, which could lead to delays in these trials and successful commercialization.

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Any performance failure, including due to COVID-19, on the part of our existing or future manufacturers could delay clinical development or marketing approval.

We do not currently have arrangements in place for redundant supply or a

source for bulk drug substance.

Currently, third party manufacturers are supplying, and are expected to continue to supply, the drug substance requirements for our ongoing and planned clinical trials with pegzilarginase and A GLE- 177.

We do not currently have arrangements in place for redundant supply or a source for bulk drug substance.

If such third party manufacturers cannot supply us with sufficient amounts, pursuant to product requirements as agreed, we may be required to identify alternative manufacturers, which would lead us to incur added costs and delays in identifying and qualifying any replacement.

The formulation used in early studies is not a final formulation for commercialization.

The formulation used in early studies may not be a final formulation for commercialization.

If we are unable to demonstrate that our commercial scale product is comparable to the product used in clinical trials, we may not receive regulatory approval for that product without additional clinical trials.

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Even if we are able to establish agreements with third-party manufacturers on acceptable terms, such third-party manufacturers may have limited experience manufacturing pharmaceutical drugs for commercialization, and reliance on third-party manufacturers for the commercial supply of our products may expose us to various risks, including:

possible noncompliance by the third party with regulatory requirements and quality assurance;

the possible noncompliance by the third party with regulatory requirements and quality assurance;

the possible breach of the manufacturing agreement by the third party;

the operations of such third parties could be disrupted by conditions unrelated to our business or operations, including the bankruptcy of such party, the issuance of an FDA Form 483 notice or warning letter, or other enforcement action by the FDA or other regulatory authority;

the possible misappropriation of our proprietary information, including our trade secrets and know-how;

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Third-party manufacturers may not be able to comply with current good manufacturing practices, or cGMP, or similar regulatory requirements outside the United States.

Although we do not have day-to-day control over third-party manufacturers’ compliance with these regulations and standards, we are responsible for ensuring compliance with such regulations and standards.

Although we do not have day-to-day control over third-party

manufacturers’ compliance with these regulations and standards, we are responsible for ensuring compliance with such regulations and standards.

Our failure, or the failure of our third-party manufacturers, to comply with applicable regulations could result in sanctions being imposed on us, including clinical holds, fines, injunctions, civil penalties, delays, suspension or withdrawal of approvals, license revocation, seizures or recalls of product candidates, operating restrictions and criminal prosecutions, any of which would significantly and adversely affect supplies of our product candidates and our business.

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Our current and anticipated future dependence upon others for the manufacture of our product candidates may adversely affect our future profit margins and our ability to commercialize any product candidates that receive marketing approval on a timely and competitive basis.

Failure of any future third-party collaborators to successfully commercialize diagnostics developed for use with our therapeutic product candidates could harm our ability to commercialize these product candidates.

We do not plan to develop diagnostics internally and, as a result, we are dependent on the efforts of our third-party strategic partners to successfully commercialize any needed diagnostics or monitoring assays.

Failure of any future third-party collaborators to successfully commercialize diagnostics or monitoring assays developed for use with our therapeutic product candidates could harm our ability to commercialize these product candidates.

We do not plan to internally develop diagnostics or monitoring assays, or Assays.

As a result, we are dependent on the efforts of our third-party strategic partners to successfully commercialize any needed Assays.

Our strategic partners:

may not perform their obligations as expected;

may encounter production difficulties that could constrain the supply of the diagnostics;

may have difficulties gaining acceptance of the use of the diagnostics in the clinical community;

may not pursue commercialization of any diagnostics;

may encounter production difficulties that could constrain the supply of the Assays;

may have difficulties gaining acceptance of the use of the Assays in the clinical community;

may not pursue commercialization of any Assays;

may elect not to continue or renew commercialization programs based on changes in the strategic partners’ strategic focus or available funding, or external factors, such as an acquisition, that divert resources or create competing priorities;

may not commit sufficient resources to the marketing and distribution of such diagnostic product candidates;

may not commit sufficient resources to the marketing and distribution of such Assay product candidates;

may terminate their relationship with us.

If diagnostics needed for use with our therapeutic product candidates fail to gain market acceptance, our ability to derive revenues from sales of these therapeutic product candidates could be harmed.

If our strategic partners fail to develop and commercialize these diagnostics, it could adversely affect and delay the development or commercialization of our therapeutic product candidates.

If Assays needed for use with our therapeutic product candidates fail to gain market acceptance, our ability to derive revenues from sales of these therapeutic product candidates could be harmed.

If our strategic partners fail to develop and commercialize these Assays, it could adversely affect and delay the development or commercialization of our therapeutic product candidates.

We may not be successful in finding strategic partners for continuing development or commercialization of certain of our product candidates.

We may seek to develop strategic partnerships for developing certain of our product candidates, due to capital costs required to develop the product candidates or manufacturing constraints.

We also have entered into and expect to enter into future partnership agreements to commercialize pegzilarginase outside the United States, including through our licensing agreement with Immedica.

We may not be successful in our efforts to establish such a strategic partnership or other alternative arrangements for our product candidates because our research and development pipeline may be insufficient, our product candidates may be deemed to be at too early of a stage of development for collaborative effort or third parties may not view our product candidates as having the requisite potential to demonstrate safety and efficacy.

In addition, we may be restricted under existing collaboration agreements from entering into future agreements with potential strategic partners.

In addition, we may be restricted under existing collaboration or license and development agreements from entering into

future agreements with potential strategic partners.

We cannot be certain that, following a strategic transaction or license, we will achieve an economic benefit that justifies such transaction.

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In addition, while it is our policy to require our employees and contractors who may be involved in the development of intellectual property to execute agreements assigning such intellectual property to us, we may be unsuccessful in executing such an agreement with each party who in fact develops intellectual property that we regard as our own.

Our and their assignment agreements may not be self-executing or may be breached, and we may be forced to bring claims

against third parties, or defend claims they may bring against us, to determine the ownership of what we regard as our intellectual property.

Our and their assignment agreements may not be self-executing or may be breached, and we may be forced to bring claims against third parties, or defend claims they may bring against us, to determine the ownership of what we regard as our intellectual property.

If we fail in prosecuting or defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights or personnel.

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We have not received approval to market any of our product candidates from regulatory authorities in any jurisdiction.

We have no experience in filing and supporting the applications necessary to gain marketing approvals and expect to rely on third-party CROs to assist us in this process.

Securing marketing approval requires the submission of extensive nonclinical and clinical data and supporting information to regulatory authorities for each therapeutic indication to establish the product candidate’s safety and efficacy.

We have limited experience in filing and supporting the applications necessary to gain marketing approvals and expect to rely on third-party CROs to assist us in this process.

Securing marketing approval requires the submission of extensive nonclinical and clinical data and supporting information to regulatory authorities for each therapeutic

indication to establish the product candidate’s safety and efficacy.

Securing marketing approval also requires the submission of information about the product manufacturing process to, and inspection of manufacturing facilities by, the regulatory authorities.

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We have received Fast Track Designation from the FDA for our lead product candidate pegzilarginase for the treatment of hyperargininemia secondary to Arginase 1 Deficiency and may seek such designation for some or all of our product candidates.

If a drug or biologic is intended for the treatment of a serious or life-threatening condition and the drug or biologic demonstrates the potential to address unmet medical needs for this condition, the drug or biologic sponsor may apply for FDA Fast Track Designation.

apply for FDA Fast Track Designation.

The FDA has broad discretion whether or not to grant this designation.

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Many drugs or biologics that have received Fast Track Designation have failed to obtain approval.

We may also seek approval of our products from the FDA through the use of the accelerated approval program, but such mechanism may not lead to a faster development or regulatory review or approval process.

FDA may also consider approval of our products through the use of the accelerated approval program, but such mechanism may not lead to a faster development or regulatory review or approval process.

Even if we receive approval from the FDA under the accelerated approval program, if our confirmatory postmarketing trial does not verify clinical benefit, or if we do not comply with rigorous postmarketing requirements, the FDA may seek to withdraw the approval.

Under the FDA’s accelerated approval program, the FDA may approve a drug or biologic for a serious or life-threatening illness that provides meaningful therapeutic benefit to patients over existing treatments based upon a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that is thought to predict clinical benefit but is not itself a measure of clinical benefit, or a biomarker that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality 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 bases its decision on whether to accept the proposed surrogate or intermediate clinical endpoint on

the scientific support for that endpoint.

The FDA bases its decision on whether to accept the proposed surrogate or intermediate clinical endpoint on the scientific support for that endpoint.

Studies that demonstrate a drug’s effect on a surrogate or intermediate clinical endpoint must be adequate and well controlled as required by the FDC Act.

If we were to seek accelerated approval for pegzilarginase, AGLE-177, or any future product candidates, FDA may determine there is inadequate justification to support that our surrogate endpoint is reasonably likely to predict clinical benefit in patients.

For example, FDA may determine there is inadequate justification that a reduction in plasma arginine is reasonably likely to predict clinical benefit in patients with Arginase 1 Deficiency.

If FDA were to consider accelerated approval in the review of an application for any product candidates, the FDA may determine there is inadequate justification to support that our surrogate endpoint is reasonably likely to predict clinical benefit in patients.

For drugs or biologics granted accelerated approval, post-marketing well-controlled, adequately powered confirmatory trials of sufficient duration are typically required to describe the anticipated effect on irreversible morbidity or mortality or other clinical benefit.

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Accordingly, even if we believe, after completing early clinical trials, that one of our product candidates meets the criteria for designation as a Breakthrough Therapy, the FDA may disagree and instead determine not to make such designation.

Even though we have received Breakthrough Therapy Designation for pegzilarginase for the treatment of Arginase 1 Deficiency, or even if we receive Breakthrough Therapy Designation for other product candidates or indications in the future, we may not experience a faster development process, review or approval compared to drugs or biologics considered for approval under conventional FDA procedures and such a designation does not assure ultimate approval by the FDA.

Even though we have received

Breakthrough Therapy Designation for pegzilarginase for the treatment of Arginase 1 Deficiency, or even if we receive Breakthrough Therapy Designation for other product candidates or indications in the future, we may not experience a faster development process, review or approval compared to drugs or biologics considered for approval under conventional FDA procedures and such a designation does not assure ultimate approval by the FDA.

In addition, even though we have received Breakthrough Therapy Designation for pegzilarginase for the treatment of Arginase 1 Deficiency, or if one or more of our other product candidates qualify as Breakthrough Therapies, the FDA may later decide that such product candidates no longer meet the conditions for qualification.

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A priority review designation means that the goal for the FDA to review an application is six months, rather than the standard review period of ten months.

We may request priority review for applications for our product candidates.

We plan to request priority review of our BLA for pegzilarginase.

We may request priority review for applications for our other product candidates.

The FDA has broad discretion with respect to whether or not to grant priority review designation to an application, so even if we believe an application for a particular product candidate is eligible for such designation, the FDA may decide not to grant it.

Moreover, a priority review designation does not necessarily result in an expedited regulatory review or approval process or confer any advantage with respect to approval compared to

conventional FDA procedures.

Moreover, a priority review designation does not necessarily result in an expedited regulatory review or approval process or confer any advantage with respect to approval compared to conventional FDA procedures.

Receiving priority review from the FDA does not guarantee approval within the six-month review cycle or at all.

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The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, or collectively the ACA, is a sweeping law intended to broaden access to health insurance, reduce or constrain the growth of healthcare spending, enhance remedies against fraud and abuse, add transparency requirements for the healthcare and health insurance industries, impose new taxes and fees on the health industry and impose additional health policy reforms.

Among the provisions of the ACA of importance to our potential product candidates are the following:

an annual, nondeductible fee on any entity that manufactures, or imports specified branded prescription drugs and biologic agents;

an increase in the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program;

expansion of healthcare fraud and abuse laws, including the False Claims Act and the Anti-Kickback Statute, new government investigative powers, and enhanced penalties for noncompliance;

a Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 70% point-of-sale discounts off negotiated prices;

extension of manufacturers’ Medicaid rebate liability to managed care utilization;

expansion of eligibility criteria for Medicaid programs;

expansion of the entities eligible for discounts under the Public Health Service pharmaceutical pricing program;

requirements to report financial arrangements with physicians and teaching hospitals;

a requirement to annually report drug samples that manufacturers and distributors provide to physicians;

a Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research.

The ACA, among other things, also expanded manufacturers’ rebate liability under the Medicaid Drug Rebate Program and imposed a significant annual, nondeductible fee on companies that manufacture or import certain branded prescription drug products.

In addition, other legislative changes have been proposed and adopted since the ACA was enacted.

These changes included aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, starting in 2013.

While there was a suspension of the payment reductions as a result of the COVID-19 pandemic, the reductions are being phased back in and are currently expected to remain in effect through 2030.

In January 2013, the American Taxpayer Relief Act of 2012 was signed into law, which, among other things, reduced Medicare payments to several providers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

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More recently, the Tax Cuts and Jobs Act was signed into law, which eliminated certain requirements of the ACA, including the individual mandate.

It is unclear the impact this legislation will have on the ACA because a decision regarding the constitutionality of the ACA after the repeal of the individual mandate was ultimately appealed to the United States Supreme Court.

On November 10, 2020, oral arguments were heard in this case.

It is unclear when a decision will be made.

We cannot predict whether the challenges to the ACA will continue or whether other proposals will be made or adopted, or what impact these efforts may have on us.

On June 17, 2021, the United States Supreme Court held that plaintiffs do not have standing to challenge the constitutionality of the individual mandate.

It is unclear whether there will be additional challenges to the ACA.

Additionally, on January 28, 2021, the President of the United States issued an executive order to initiate a special enrollment p e riod from Febr ua ry 15, 2021 through May 15, 2021 for purposes of obtaining health insurance coverage through the ACA marketplace.

The executive order also instructs certain governmental agencies to review a nd reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining M ed icaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA.

It is uncertain how other such litigation or the healthcare measures of the United States adm inistration will impact the ACA and our business.

We expect that the ACA, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and in additional downward pressure on the price that we receive for any approved product.

For example, on September 9, 2021, the Biden administration published a wide-ranging list of policy proposals,

most of which would need to be carried out by Congress, to reduce drug prices and drug payment.

The Department of Health and Human Services plan includes, among other reform measures, proposals to lower prescription drug prices, including by allowing Medicare to negotiate prices and disincentivizing price increases, and to support market changes that strengthen supply chains, promote biosimilars and generic drugs, and increase price transparency.

Many similar proposals, including the plans to give Medicare Part D authority to negotiate drug prices, require drug manufacturers to pay rebates on drugs whose prices increase greater than the rate of inflation, and cap out-of-pocket costs, have already been included in policy statements and legislation currently being considered by Congress.

It is unclear to what extent these and other statutory, regulatory, and administrative initiatives will be enacted and implemented.

Any reduction in reimbursement from Medicare or other government programs may result in a similar reduction in payments from private payors.

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Comprehensive tax reform bills could increase the tax burden on our orphan drug programs and adversely affect our business and financial condition.

In December 2017, the U.S.

government enacted comprehensive tax legislation that includes significant changes to the taxation of business entities.

These changes include, among others, (i) a permanent reduction to the corporate income tax rate, (ii) a partial limitation on the deductibility of business interest expense, (iii) a shift of the U.S.

taxation of multinational corporations from a tax on worldwide income to a territorial system (along with certain rules designed to prevent erosion of the U.S.

income tax base) and (iv) a one-time tax on accumulated offshore earnings held in cash and illiquid assets, with the latter taxed at a lower rate.

Further, the comprehensive tax legislation, among other things, reduces the orphan drug credit from 50% to 25% of qualifying expenditures.

When and if we become profitable, this reduction in tax credits may result in an increased federal income tax burden on our orphan drug programs as it may cause us to pay federal income taxes earlier under the revised tax law than under the prior law and, despite being partially off-set by a reduction in the corporate tax rate from a top marginal rate of 35% to a flat rate of 21%, may increase our total federal tax liability attributable to such programs.

Notwithstanding the reduction in the corporate income tax rate, the overall impact of this tax reform is uncertain, and our business and financial condition could be adversely affected.

In addition, it is uncertain if and to what extent various states will conform to the newly enacted federal tax law.

On March 27, 2020, the Coronavirus Aid, Relief and Economic Security, or CARES, Act was enacted and signed into law in response to COVID-19.

The CARES Act includes changes to the tax provisions that benefit business entities and makes certain technical corrections to the 2017 Tax Cuts and Jobs Act.

The tax relief measures for businesses include a five-year net operating loss carryback, suspension of annual deduction limitation of 80% of taxable income from net operating losses generated in a tax year beginning after December 31, 2017 for taxable years beginning after December 31, 2017 and beginning on or prior to December 31, 2020, changes in the deductibility of interest, acceleration of alternative minimum tax credit refunds, payroll tax relief, technical corrections on net operating loss carryforwards for fiscal year taxpayers and allowing accelerated deductions for qualified improvement property.

The CARES Act also provides other non-tax benefits to assist those impacted by the pandemic.

While we have evaluated the impact of the CARES Act and to date have determined that there is no material impact to the income tax provision for the quarter, the overall impact of this tax reform is uncertain, and our business and financial condition could be adversely affected.

New income, sales, use or other tax laws, statutes, rules, regulations or ordinances could be enacted at any time, which could adversely affect our business and financial condition.

Further, existing tax laws, statutes, rules, regulations or ordinances could be interpreted, changed, modified or applied adversely to us.

For example, the 2017 Tax Cuts and Jobs Act, among others, reduced the orphan drug credit from 50% to 25% of qualifying expenditures.

When and if we become profitable, this reduction in tax credits may result in an increased federal income tax burden on our orphan drug programs.

On March 27, 2020, the Coronavirus Aid, Relief and Economic Security, or CARES Act, was enacted and modified certain portions of the 2017 Tax Cuts and Jobs Act, including with respect to the carryforward of net operating losses.

Future changes in corporate tax rates, rules relating to the realization of net deferred tax assets, and other tax legislation could have a material impact on the value of our deferred tax assets, could result in a significant one-time charges, and could increase our future U.S.

Risks Related to Our Intellectual Property

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The issuance of a patent, while given the presumption of validity under the law, is not conclusive as to its inventorship, scope, validity or enforceability, and our owned and licensed patents may be challenged in the courts or patent offices in the United States and abroad.

Such challenges may result in loss of exclusivity or freedom to operate or in patent claims being narrowed, invalidated or held unenforceable, in whole or in part, which could limit our ability to stop others from using or commercializing similar or identical technology and product candidates, or limit the duration of the patent protection of our technology and product candidates.

Such challenges may result in loss of exclusivity or in patent claims being narrowed, invalidated or held unenforceable, in whole or in part, which could limit our ability to stop others from using or commercializing similar or identical technology and product candidates, or limit the duration of the patent protection of our technology and product candidates.

In addition, patents have a limited lifespan.

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PTO and various governmental patent agencies outside the United States in several stages over the lifetime of the patents and/or applications.

We have systems in place to remind us to pay these fees, and we employ an outside firm and rely on our outside counsel to pay these fees due to non-U.S.

patent agencies.

We have systems in place to remind us to pay these fees, and we employ an outside firm and rely on our outside counsel to pay these fees.

PTO and various non-U.S.

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Third parties may assert infringement claims against us based on existing patents or patents that may be granted in the future.

We may also institute proceedings in courts or patent offices seeking decisions regarding the validity or scope of patents owned by third parties.

For example, we have filed nullity actions in the Federal Patent Court in Germany regarding two German patents relating to arginases.

It is also possible that we have failed to identify relevant third-party patents or applications.

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We are not aware of any threatened or pending claims related to these matters, but in the future litigation may be necessary to defend against such claims.

In addition, while it is our policy to require our employees, independent contractors and consultants who may be involved in the development of intellectual property to execute agreements assigning such intellectual property to us, we may be unsuccessful in timely obtaining such an agreement with each party who in fact develops intellectual property that we regard as our own.

we regard as our own.

Even if timely obtained, such agreements may be breached, and we may be forced to bring claims against third parties, or defend claims they may bring against us, to determine the ownership of what we regard as our intellectual property.

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Presently we have rights to intellectual property to develop our product candidates, including patents and patent applications we own or exclusively license from the University of Texas at Austin.

Because our programs may involve additional product candidates that may require the use of proprietary rights held by third parties, the growth of our business may depend in part on our ability to acquire, in-license or use these proprietary rights.

Because our programs may involve additional product candidates that may require the use of proprietary rights held by third parties, the growth of our

business may depend in part on our ability to acquire, in-license or use these proprietary rights.

We may be unable to acquire or in-license any compositions, methods of use, processes or other third-party intellectual property rights from third parties that we identify as necessary for our product candidates.

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However, no assurance can be given that we have entered into appropriate agreements with all parties that have had access to our trade secrets, know-how or other proprietary information, or that such agreements will provide for a meaningful protection of our trade secrets, know-how or other proprietary information in the event of any unauthorized use or disclosure of information.

Enforcing a claim that a party illegally disclosed or misappropriated a trade secret is difficult, expensive and

time-consuming, and the outcome is unpredictable.

Enforcing a claim that a party illegally disclosed or misappropriated a trade secret is difficult, expensive and time-consuming, and the outcome is unpredictable.

Even if we are successful in prosecuting such claims, any remedy awarded may be insufficient to fully compensate us for the improper disclosure or misappropriation.

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Many companies have encountered significant problems in protecting and defending intellectual property rights in foreign jurisdictions.

The legal systems of certain countries, particularly certain developing countries, do not favor the enforcement of patents and other intellectual property protection, particularly those relating to biopharmaceuticals, which could make it difficult for us to stop the infringement of our patents or marketing of competing products in violation of our proprietary rights generally.

proprietary rights generally.

Proceedings to enforce our patent rights in foreign jurisdictions could result in substantial cost and divert our efforts and attention from other aspects of our business, could put our patents at risk of being invalidated or interpreted narrowly and our patent applications at risk of not issuing and could provoke third parties to assert claims against us.

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The Restated License was amended in August 2017, December 2017, and December 2018 to revise diligence milestones and license additional patent applications, including our program candidates under the AGLE-177 and cystinuria programs.

The intellectual property licensed under the Restated License includes an invention that was made with U.S.

The intellectual property licensed under the Restated License includes inventions that were made with U.S.

government support.

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The Leahy-Smith Act and its implementation could increase the uncertainties and costs surrounding the prosecution of our patent applications and the enforcement or defense of our issued patents, all of which could have a material adverse effect on our business and financial condition.

The Leahy-Smith Act also requires an inventor to file a patent application on their invention prior to any other bone fide independent inventor.

The Leahy-Smith Act also requires an inventor to file a patent application on their invention prior to any other bona fide independent inventor.

Since patent applications in the United States and most other countries are confidential for a period of time after filing, we cannot be certain that we were the first to either (i) file any patent application related to our product candidates or (ii) invent any of the inventions claimed in our patents or patent applications.

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Depending upon the timing, duration and specifics of FDA marketing approval of our product candidates, if any, one of the U.S.

patents covering each of such approved product(s) or the use thereof may be eligible for up to five years of patent term restoration.

patents covering each of such approved product(s) or the use thereof may be eligible for up to five years of

patent term restoration.

Patent term extension allows a maximum of one patent to be extended per FDA-approved product.

Patent term extension also may be available in certain foreign countries upon regulatory approval of our product candidates.

Patent term extension also may be available in certain foreign countries upon regulatory approval of our product candidates , if any .

Nevertheless, we may not be granted patent term extension either in the United States or in any foreign country because of, for example, failing to apply within applicable deadlines, failing to apply prior to expiration of relevant patents or otherwise failing to satisfy applicable requirements.

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In addition, if a patent we wish to extend is owned by another party and licensed to us, we may need to obtain approval and cooperation from our licensor to request the extension.

If we are unable to obtain patent term extension or restoration, or the term of any such extension is less than we request, the period during which we will have the right to exclusively market our product will be shortened and our competitors may obtain approval of competing products following our patent expiration, and our revenue could be reduced, possibly materially.

If we are unable to obtain patent term extension or restoration, or the term or scope of any such extension is less than we request, the period during which we will have the right to exclusively market our product will be shortened and our competitors may obtain approval of competing products following our patent expiration, and our revenue could be reduced, possibly materially.

We have not yet registered our trademarks in all of our potential markets, and failure to secure those registrations could adversely affect our business.

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Third parties may pursue trademark infringement actions against us, potentially resulting in substantial costs and material delays.

As our industry grows, we may be subject to an increasing amount of litigation that is common in the pharmaceutical industry based on allegations of infringement or other alleged violations of trademarks.

As our activities grow, we may be subject to an increasing amount of litigation that is common in the pharmaceutical industry based on allegations of infringement or other alleged violations of trademarks.

Any claims of infringement, with or without merit, could be time consuming, costly, and difficult to defend.

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Our future success depends on our ability to retain key executives and to attract, retain and motivate qualified personnel.

We are a clinical-stage biotechnology company with a limited operating history, and, as of December 31, 2020, had 90 employees, including four executive officers.

We are a clinical-stage biotechnology company with a limited operating history, and, as of December 31, 2021, had 101 employees.

We are highly dependent on the research and development, clinical and business development expertise of our executive officers, as well as the other principal members of our management, scientific and clinical team.

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In addition, we rely on consultants and advisors, including scientific and clinical advisors such as our scientific advisory board, to assist us in formulating our discovery and nonclinical and clinical development and commercialization strategy.

Our consultants and advisors, including members of our scientific advisory board, may be employed by employers other than us and may have commitments under consulting or advisory contracts with other entities that may limit their availability to us.

Our consultants and advisors, including members of our scientific advisory board, may be employed by

employers other than us and may have commitments under consulting or advisory contracts with other entities that may limit their availability to us.

If we are unable to continue to attract and retain high quality personnel, our ability to pursue our growth strategy will be limited.

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regulatory authorities, or (v) report financial information or data accurately or disclose unauthorized activities to us.

Employee misconduct could also involve the improper use of information obtained in the course of clinical trials, which could result in regulatory sanctions and

serious harm to our reputation.

Employee misconduct could also involve the improper use of information obtained in the course of clinical trials, which could result in regulatory sanctions and serious harm to our reputation.

It is not always possible to identify and deter employee misconduct, and the precautions we take to detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to be in compliance with such laws, standards or regulations.

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Under Section 382 of the Internal Revenue Code of 1986, as amended, if a corporation undergoes an “ownership change,” generally defined as a greater than 50% change (by value) in its equity ownership over a three-year period, the corporation’s ability to use its pre-change net operating loss carryforwards, or NOLs, and other pre-change tax attributes (such as research tax credits) to offset its post-change income or taxes may be limited.

It is possible that we may have triggered an “ownership change” limitation.

It is possible that we may have

triggered an “ownership change” limitation.

We may also experience ownership changes in the future as a result of subsequent shifts in our stock ownership (some of which are outside of our control).

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Pursuant to Section 404, we have been required to furnish a report by our management on our internal control over financial reporting.

However, while we remain an emerging growth company, we will not be required to include an attestation report on internal control over financial reporting issued by our independent registered public accounting firm.

However, while we remain a non-accelerated filer, we will not be required to include an attestation report on internal control over financial reporting issued by our independent registered public accounting firm.

Internal control over financial reporting is a process designed to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements in accordance with generally accepted accounting principles in the United States.

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Moreover, we have also registered under the Securities Act shares of common stock that we may issue under our equity compensation plans.

In addition, in February 2019, our shelf registration statement on Form S-3 for the potential offering, issuance and sale by us of up to $200.0 million of our common stock, preferred stock, debt securities, warrants to purchase our common stock, preferred stock and debt securities, subscription rights to purchase our common stock, preferred stock and debt securities, and units consisting of all or some of these securities was declared effective by the SEC.

In connection with this shelf registration statement, on April 16, 2020, we entered into an “at-the-market” offering of our common stock pursuant to a sales agreement between us and JonesTrading Institutional Services LLC, or JonesTrading.

In addition, in April 2020, we entered into an “at-the-market” offering of our common stock pursuant to a sales agreement between us and JonesTrading Institutional Services LLC, or JonesTrading, under a shelf registration statement on Form S-3.

Subject to certain limitations in the sales agreement and compliance with applicable law, we have the discretion to deliver a placement notice to JonesTrading at any time throughout the term of the sales agreement, which has a term equal to the term of the registration statement on Form S-3 unless otherwise terminated earlier by us or JonesTrading pursuant to the terms of the sales agreement.

The number of shares that are sold by JonesTrading after delivering a placement notice will fluctuate based on the market price of our common stock during the sales period and limits we set with JonesTrading.

Because the price per share of each share sold will fluctuate based on the market price of our common stock during the

sales period, it is not possible at this stage to predict the number of shares that will be ultimately issued.

Because the price per share of each share sold will fluctuate based on the market price of our common stock during the sales period, it is not possible at this stage to predict the number of shares that will be ultimately issued.

Issuances of any shares sold pursuant to the sales agreement will have a dilutive effect on our existing stockholders.

In February 2022, the registration statement on Form S-3, which the at-the-market offering was registered under, expired and no sales under this registration statement will occur going forward.

In July 2020, we filed a new shelf registration statement on Form S-3 that was declared effective in July 2020 by the SEC for the potential offering, issuance and sale by us of up to $400.0 million of our common stock, preferred stock, debt securities, warrants to purchase common stock, preferred stock and debt securities, subscription rights to purchase common stock and units consisting of all or some of these securities.

If we sell common stock, preferred stock, convertible securities and other equity securities in other transactions pursuant to our shelf registration statements on Form S-3, existing investors may be materially diluted by such subsequent sales and new investors could gain rights superior to our existing stockholders.

If we sell common stock, preferred stock, convertible securities and other equity securities in other transactions pursuant to our shelf registration statements on Form S-3,

existing investors may be materially diluted by such subsequent sales and new investors could gain rights superior to our existing stockholders.

In May 2021, we filed a shelf registration statement on Form S-3, that was declared effective on June 8, 2021 by the SEC, registering up to 19,020,434 shares of our common stock held by 667, L.P., or 667, and Baker Brothers Life Sciences, L.P., or Life Sciences, and together with 667, the Baker Funds, which includes 15,610,328 shares of common stock issuable upon the exercise of pre-funded warrants held by the Baker Funds, for resale or other disposition from time to time as described in the registration statement.

In addition, in the future, we may issue additional shares of common stock or other equity or debt securities convertible into common stock in connection with a financing, acquisition, litigation settlement, employee arrangements or otherwise, including upon exercise of our pre-funded warrants.

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however, any exercise would increase the number of shares eligible for future resale in the public market and result in substantial dilution to our stockholders.

To date, we have issued pre-funded warrants to purchase a total of 17,610,328 shares of our common stock, and all such pre-funded warrants are currently outstanding.

To date, we have issued pre-funded warrants to purchase a total of 17,610,328 shares of our common stock, of which 1,000,000 have been exercised and 16,610,328 are currently outstanding.

Each pre-funded warrant is exercisable for $0.0001 per share of common stock underlying such pre-funded warrant, which may be paid by way of a cashless exercise, meaning that the holder may not pay a cash purchase price upon exercise, but instead would receive upon such exercise the net number of shares of common stock determined according to the formula set forth in the pre-funded warrant.

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Without an active market, the liquidity of the pre-funded warrants will be limited and their value may be adversely impacted.

Additionally, each holder of pre-funded warrants will not be entitled to exercise any portion of any pre-funded warrant, which, upon giving effect to such exercise, would cause (i) the aggregate number of shares of our common stock beneficially owned by the holder (together with its affiliates) to exceed 9.99% of the number of shares of our common stock outstanding immediately after giving effect to the exercise, or (ii) the combined voting power of our securities beneficially owned by the holder (together with its affiliates) to exceed 9.99% of the combined voting power of all of our securities then outstanding immediately after giving effect to the exercise.

Additionally, each holder of pre-funded warrants will not be entitled to exercise any portion of any pre-funded warrant, which, upon giving effect to such exercise, would cause (i) the aggregate number of shares of our common stock beneficially owned by the holder (together with its affiliates) to exceed 4.99%, or 9.99% for certain holders, of the number of shares of our common stock outstanding immediately after giving effect to the exercise, or (ii) the combined voting power of our securities beneficially owned by the holder (together with its affiliates) to exceed 4.99%, or 9.99% for certain holders, of the combined voting power of all of our securities then outstanding immediately after giving effect to the exercise.

However, any holder may increase or decrease such percentage to any other percentage (not in excess of 19.99% for the majority of such warrants) upon at least 61 days’ prior notice from the holder to us.

We are an “emerging growth company,” and the reduced disclosure requirements applicable to emerging growth companies may make our common stock less attractive to investors.

We are an “emerging growth company,” as defined in the Jumpstart Our Business Startups Act of 2012, or the JOBS Act, and may remain an emerging growth company through December 31, 2021.

For so long as we remain an emerging growth company, we are permitted and intend to rely on exemptions from certain disclosure requirements that are applicable to other public companies that are not emerging growth companies.

We are a “smaller reporting company,” and the reduced disclosure requirements applicable to smaller reporting companies may make our common stock less attractive to investors.

We are a “smaller reporting company,” under the Exchange Act.

For so long as we remain a smaller reporting company, we are permitted and intend to rely on exemptions from certain disclosure requirements that are applicable to other public companies that are not smaller reporting companies.

These exemptions include:

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not being required to comply with the auditor attestation requirements in the assessment of our internal control over financial reporting of Section 404(b) of the Sarbanes-Oxley Act;

not being required to comply with any requirement that may be adopted by the Public Company Accounting Oversight Board regarding mandatory audit firm rotation or a supplement to the auditor’s report providing additional information about the audit and the financial statements;

reduced disclosure obligations regarding executive compensation .

exemptions from the requirements of holding a nonbinding advisory vote on executive compensation and shareholder approval of any golden parachute payments not previously approved.

The JOBS Act provides that an emerging growth company can take advantage of an extended transition period for complying with new or revised accounting standards.

This allows an emerging growth company to delay the adoption of these accounting standards until they would otherwise apply to private companies.

We have irrevocably elected not to avail ourselves of this exemption and, therefore, we will be subject to the same new or revised accounting standards as other public companies that are not emerging growth companies.

We may continue to take advantage of these exemptions until we are no longer a smaller reporting company.

We will remain a smaller reporting company if we have either (i) less than $250 million in market value of our shares held by non-affiliates as of the last business day of our second fiscal quarter or (ii) less than $100 million of annual revenues in our most recent fiscal year and a market value of our shares held by non-affiliates less than $700 million as of the last business day of our second fiscal quarter.

We may choose to take advantage of some but not all of these scaled disclosure requirements.

Therefore, the information that we provide stockholders may be different than one might get from other public companies.

Further, if some investors find our shares of common stock less attractive as a result, there may be a less active trading market for our shares of common stock and the market price of such shares of common stock may be more volatile.

We will continue to incur increased costs as a result of operating as a public company, and our management will be required to devote substantial time to new compliance initiatives and corporate governance practices.

As a public company, and particularly after we are no longer an emerging growth company, we incur significant legal, accounting and other expenses that we did not incur as a private company.

As a public company, and particularly now that we are no longer an emerging growth company, we incur significant legal, accounting and other expenses that we did not incur as a private company.

The Sarbanes-Oxley Act of 2002, the Dodd-Frank Wall Street Reform and Consumer Protection Act, the listing requirements of The Nasdaq Global Market and other applicable securities rules and regulations impose various requirements on public companies, including establishment and maintenance of effective disclosure and financial controls and corporate governance practices.

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Pursuant to Section 404, we are required to furnish a report by our management on our internal control over financial reporting.

As discussed above, if we cease to be an emerging growth company, we will be required to include an attestation report on internal control over financial reporting issued by our independent registered public accounting firm as required by Section 404(b).

As discussed above, if we cease to be a non-accelerated filer, we will be required to include an attestation report on internal control over financial reporting issued by our independent registered public accounting firm as required by Section 404(b).

To achieve compliance with Section 404 within the prescribed period, we will be engaged in a process to document and evaluate our internal control over financial reporting, which is both costly and challenging.

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Our operations also produce hazardous waste products.

We generally contract with third parties for the disposal of these materials and wastes.

We generally contract with third parties for the disposal of these

materials and wastes.

We cannot eliminate the risk of contamination or injury from these materials.

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Furthermore, we have little or no control over the security measures and computer systems of third parties including any CROs we may work with in the future.

While we and, to our knowledge, our third-party strategic partners have not experienced any such system failure, accident or security breach to date, if such an event were to occur, it could result in material negative consequences for us including interruptions in our operations, the operations of our strategic partners, or our manufacturers or suppliers, misappropriation of confidential business information and trade secrets, disclosure of corporate strategic plans, and result in material disruptions of our product candidate development programs.

While we and, to our knowledge, our third-party strategic partners have not experienced any such material system failure, accident or security breach to date, if such an event were to occur, it could result in material negative consequences for us including interruptions in our operations, the operations of our strategic partners, or our manufacturers or suppliers, misappropriation of confidential business information and trade secrets, disclosure of corporate strategic plans, and result in material disruptions of our product candidate development programs.

Additionally, the costs to us or our CROs, third-party vendors, or other contractors or consultants we may utilize to mitigate network security problems, bugs, viruses, worms, malicious software programs and security vulnerabilities could be significant, and while we have implemented security measures to protect our data security and information technology systems, our efforts to address these problems may not be successful, and these problems could result in unexpected system failures, interruptions, delays, cessation of service and other harm to our business and our competitive position.

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Moreover, if a security breach affects our systems or results in the unauthorized access, use or disclosure of personal information, our reputation could be materially damaged.

In addition, such a breach may require notification to

governmental agencies, the media and/or affected individuals pursuant to various federal, state and international privacy and security laws, if applicable, including HIPAA or HITECH and its implementing rules and regulations, as well as regulations promulgated by the Federal Trade Commission and state breach notification laws.

In addition, such a breach may require notification to governmental agencies, the media and/or affected individuals pursuant to various federal, state and international privacy and security laws, if applicable, including HIPAA or HITECH and its implementing rules and regulations, as well as regulations promulgated by the Federal Trade Commission and state breach notification laws.

We would also be exposed to a risk of loss or litigation and potential liability under laws, regulations and contracts that protect the privacy and security of personal information.

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Any of the foregoing could have a material adverse effect on our business, reputation, results of operations, financial condition and prospects.

We depend on our information technology and infrastructure, and disruptions could compromise sensitive information related to our business or other personal information or prevent us from accessing critical information, which could adversely affect our business, reputation, results of operations, financial condition and prospects.

information, which could adversely affect our business, reputation, results of operations, financial condition and prospects.

We rely on the efficient and uninterrupted operation of information technology systems to manage our operations, to process, transmit, and store electronic and financial information, and to comply with regulatory, legal and tax requirements.

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We are subject to a variety of stringent and changing privacy and data security laws, regulations and standards, as well as contractual obligations related to data privacy and security, and our actual or perceived failure to comply with them could harm our business and reputation and subject us to significant fines and liability.

We maintain a large quantity of sensitive information, including confidential business and patient health information in connection with our clinical trials, and are subject to laws and regulations governing the privacy and security of such information.

We maintain a quantity of sensitive information, including confidential business and patient health information in connection with our clinical trials, and are subject to laws and regulations governing the privacy and security of such information.

In the United States, there are numerous federal and state privacy and data security laws and regulations governing the collection, use, disclosure and protection of personal information, including federal and state health information privacy laws, federal and state security breach notification laws, and federal and state consumer protection laws.

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Use of the data transfer mechanisms must now be assessed on a case-by-case basis taking into account the legal regime applicable in the destination country, in particular applicable surveillance laws and rights of individuals.

The European Data Protection Board, or the EDPB, issued additional guidance regarding the Court of Justice’s decision on November 11, 2020 which imposes higher burdens on the use of data transfer mechanisms, such as the SCCs, for

cross-border data transfers.

To comply with this guidance, we may need to implement additional safeguards to further enhance the security of data transferred out of the EEA, which could increase our compliance costs, expose us to further regulatory scrutiny and liability, and adversely affect our business.

Further, the European Commission published new versions of the SCCs for comment.

While the comment period ended in December 2020, the European Commission is expected to finalize and implement the new Standard Contractual Clauses in early 2021.

Further, the European Commission adopted two new sets of SCCs on June 4, 2021 and set timelines for when they became effective.

These obligations may be interpreted and applied in a manner that is inconsistent from one jurisdiction to another and may conflict with other requirements or our practices.

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For example, since the transition period for Brexit ended December 31, 2020, there remains some uncertainty regarding cross-border data transfers from the EEA to the United Kingdom.

The EU is expected to either issue an adequacy decision for such transfers in early 2021, or an adequacy mechanism such as the SCCs will be required for transfer of personal information from the EEA to the United Kingdom.

With respect to transfers of personal data from the EEA to the United Kingdom, on June 28, 2021, the European Commission issued an adequacy decision in respect of the United Kingdom’s data protection framework, enabling data transfers from EU member states to the United Kingdom to continue without requiring organizations to put in place contractual or other measures in order to lawfully transfer personal data between the territories.

While it is intended to last for at least four years, the European Commission may unilaterally revoke the

adequacy decision at any point, and if this occurs it could lead to additional costs and increase our overall risk exposure.

Additionally, the United Kingdom implemented the Data Protection Act effective in May 2018 and statutorily amended in 2019, that substantially implements the GDPR and contains provisions, including UK-specific derogations, for how GDPR is applied in the United Kingdom.

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Natural disasters could severely disrupt our operations or the operations of our third party manufacturers’ facilities and have a material adverse effect on our business, financial condition, results of operations and prospects.

If a natural disaster, power outage, global epidemic, pandemic or contagious disease, or other event occurred that prevented us from

using all or a significant portion of our headquarters or research laboratory, that damaged critical infrastructure, such as our third party manufacturers’ facilities, or that otherwise disrupted operations, it may be difficult or, in certain cases, impossible for us to continue our business for a substantial period of time.

If a natural disaster, power outage, global epidemic, pandemic or contagious disease, or other event occurred that prevented us from using all or a significant portion of our headquarters or research laboratory, that damaged critical infrastructure, such as our third party manufacturers’ facilities, or that otherwise disrupted operations, it may be difficult or, in certain cases, impossible for us to continue our business for a substantial period of time.

The disaster recovery and business continuity plans we have in place currently are limited and may not prove adequate in the event of a serious disaster or similar event.

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If one or more of these analysts cease coverage of our company or fail to regularly publish reports on us, we could lose visibility in the financial markets, which could cause our stock price or trading volume to decline.

UNRESOLVED STAFF COMMENTS

UNRESOLV ED STAFF COMMENTS

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 1A. Risk Factors