What changed in this filing

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Item 1. Business

2023-03-22 compared with 2022-02-24 · 391 added, 459 removed, 730 unchanged (54% of the section changed)

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(“Cyclerion”, the “Company”

or “we”) is a clinical-stage biopharmaceutical company on a mission to develop treatments that restore cognitive function.

Our lead asset, CY6463, is a pioneering, central nervous system ("CNS")-penetrant, soluble guanylate cyclase ("sGC") stimulator that is currently in clinical development for Alzheimer's disease with vascular pathology ("ADv"), Cognitive Impairment Associated with Schizophrenia ("CIAS"), and Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes ("MELAS").

sGC stimulators are small molecules that act synergistically with nitric oxide ("NO") as positive allosteric modulators of sGC to boost production of cyclic guanosine monophosphate ("cGMP").

cGMP is a key second messenger that, when produced by sGC, regulates diverse and critical biological functions in the CNS including neuronal function, neuroinflammation, cellular bioenergetics, and vascular function.

or “we”) is a biopharmaceutical company on a mission to develop treatments for serious diseases.

Cyclerion's portfolio includes novel soluble guanylate cyclase ("sGC") stimulators that modulate a key node in a fundamental signaling network in both the central nervous system ("CNS") and the periphery.

The nitric oxide ("NO") soluble guanylate cyclase ("sGC") cyclic guanosine monophosphate ("cGMP") signaling pathway is a fundamental mechanism that precisely controls key aspects of physiology throughout the body.

The NO-sGC-cGMP pathway regulates diverse and critical biological functions including mitochondrial function, neuronal function, inflammation, and hemodynamics.

Although this pathway has been successfully targeted with several drugs in the periphery, this mechanism has yet to be fully leveraged therapeutically, particularly in the CNS, where impaired NO-sGC-cGMP signaling is believed to play an important role in the pathogenesis of many neurodegenerative and neuropsychiatric diseases.

Zagociguat (previously CY6463) is a clinical-stage CNS-penetrant sGC stimulator that has shown rapid improvement in cerebral blood flow, functional brain connectivity, brain response to visual stimulus, cognitive performance, and biomarkers associated mitochondrial function and inflammation in clinical studies.

CY 3018 is a CNS-targeted sGC stimulator that preferentially localizes to the brain and has a pharmacology profile that suggests its potential for the treatment of neuropsychiatric diseases and disorders.

Praliciguat is a systemic sGC stimulator that is licensed to Akebia Therapeutics, Inc.

("Akebia") and being advanced in rare kidney disease.

Olinciguat is a clinical-stage vascular sGC stimulator that the Company intends to out-license for cardiovascular diseases.

Cyclerion is actively evaluating the best combination of capital, capabilities, and transactions available to it to advance the development of zagociguat and its other clinical development candidates and to maximize shareholder value.

The following table presents the status of our portfolio of sGC stimulators:

Cyclerion became an independent public company on April 1, 2019 after Ironwood Pharmaceuticals, Inc., or Ironwood, completed a tax-free spin-off of its sGC business, which we refer to herein as the "Separation".

We are led by an accomplished team, with a track record of discovering, developing and commercializing meaningful therapies for patients while creating value for stockholders and with a long history of experience in the NO-sGC-cGMP pathway and expertise in CNS.

CY6463 is the core of our CNS portfolio with ongoing clinical programs in ADv, CIAS, and MELAS.

In addition, our next-generation CNS asset, CY3018, is intended to expand the potential of sGC simulation for the treatment of disorders of the CNS.

Outside of our CNS portfolio, we have clinical, preclinical and discovery phase compounds which are outside of our strategic focus and are available for out-licensing.

We have successfully out-licensed praliciguat to Akebia Therapeutics, Inc.

("Akebia") for subsequent development in kidney disease.

The following table presents the status of CNS pipeline and development-phase non-CNS programs in our portfolio:

The status of our programs in the table above represents the ongoing phase of development and does not correspond to the completion of a particular phase.

led by an accomplished team, with a track record of discovering, developing, and commercializing meaningful therapies for patients while creating value for stockholders and with expertise and deep experience in the NO-sGC-cGMP pathway.

Drug development involves a high degree of risk and investment, and the status, timing and scope of our development programs are subject to change.

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Research and Development programs

CY6463 is an orally administered CNS-penetrant sGC stimulator that is being developed as a symptomatic and potentially disease-modifying therapy for serious CNS diseases.

NO-sGC-cGMP is a fundamental signaling network that is widely used in the nervous system.

CY6463 enhances the brain’s natural ability to produce cGMP, an important second messenger in the CNS, by stimulating sGC, a key node in the NO-sGC-cGMP pathway.

This pathway is critical to basic CNS functions, and deficient NO-sGC-cGMP signaling is believed to play an important role in the pathogenesis of neurodegenerative diseases.

Agents that stimulate sGC to produce cGMP may compensate for deficient NO signaling.

On January 13, 2020, we announced positive results from our Phase 1 first-in-human study that provided the foundation for continued development of CY6463.

The results from this study indicate that CY6463 was well tolerated.

Pharmacokinetic (PK) data, obtained from both blood and cerebral spinal fluid (CSF), support once-daily dosing with or without food and demonstrated CY6463 penetration of the blood-brain-barrier with CSF concentrations expected to be pharmacologically active.

On October 14, 2020, we announced positive topline results from our CY6463 Phase 1 translational pharmacology study in healthy elderly participants.

Treatment with CY6463 for 15 days in this 24-subject study confirmed and extended results seen in the earlier first-in-human Phase 1 study:

Zagociguat is an orally administered CNS-penetrant sGC stimulator.

NO-sGC-cGMP is a fundamental signaling network, including in the brain where it is critical to basic CNS functions.

Deficient NO-sGC-cGMP signaling is believed to play an important role in the pathogenesis of many peripheral and CNS disorders.

As an sGC stimulator, zagociguat amplifies endogenous NO signaling by acting as a positive allosteric modulator to sensitize the sGC enzyme to NO and increase the production of cGMP.

By compensating for deficient NO-sGC-cGMP signaling, zagociguat may have broad therapeutic potential as a treatment for people with serious diseases.

On January 13, 2020, we announced positive results from our Phase 1 first-in-human study that provided the first clinical data supporting the development of zagociguat.

The results from this study indicate that zagociguat was well tolerated.

Pharmacokinetic data, obtained from both blood and cerebral spinal fluid, support once-daily dosing with or without food and demonstrated zagociguat penetration of the blood-brain-barrier with concentrations in the CSF expected to be pharmacologically active.

On October 14, 2020, we announced positive topline results from our zagociguat Phase 1 translational pharmacology study in healthy elderly participants.

Treatment with zagociguat for 15 days in this 24-subject study confirmed and extended results seen in the earlier first-in-human Phase 1 study:

once-daily oral treatment demonstrated blood-brain-barrier penetration with expected CNS exposure and target engagement.

Results also showed significant improvements in neurophysiological and objective performance measures as well as in inflammatory biomarkers associated with aging and neurodegenerative diseases.

CY6463 was safe and generally well tolerated in the study.

Significant effects on cerebral blood flow and markers of bioenergetics were not observed in this study of healthy elderly participants.

We believe that these results, together with nonclinical data, support continued development of CY6463 as a potential new medicine for serious CNS diseases.

We have initiated exploratory clinical trials with CY6463 in ADv, CIAS and MELAS.

The ADv study will be supported in part by a grant from the Alzheimer’s Association’s Part the Cloud-Gates Partnership Grant Program ("PTC Grant"), which provides Cyclerion with $2 million of funding over two years.

Our next generation CNS asset, CY3018, is a differentiated CNS-penetrant sGC stimulator with greater CSF-to-plasma exposure relative to CY6463.

CY3018 is intended to expand the potential of sGC stimulation for the treatment of disorders of the CNS.

Non-CNS assets

We have other assets that are outside of our current strategic focus.

These non-core assets are not being internally developed at this time.

Results also showed significant improvements in neurophysiological and objective performance measures as well as decreases in inflammatory biomarkers associated with aging and neurodegenerative diseases.

Zagociguat was safe and generally well tolerated in the study.

These results, together with nonclinical data, supported the continued development of zagociguat as a potential new medicine for serious diseases involving the CNS.

On June 10, 2022, we announced positive topline clinical data for zagociguat in our signal-seeking clinical study for the potential treatment of Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes ("MELAS").

In this open-label, single-arm study of the oral, once-daily sGC stimulator in eight adults aged 18 or older with MELAS, improvements were seen across a range of endpoints reflecting multiple domains of disease activity, including mitochondrial disease-associated biomarkers such as lactate and GDF-15, a broad panel of inflammatory biomarkers, cerebral blood flow, and functional connectivity between neural networks.

These positive effects after 29 days of dosing were supported by correlations among several endpoints with each other and with zagociguat plasma concentrations.

Zagociguat was well tolerated with no serious or severe adverse events and no events leading to discontinuation.

Pharmacokinetics were consistent with the Phase 1 studies in healthy volunteers.

The positive data from this study support the potential of zagociguat to provide therapeutic benefit to people living with mitochondrial diseases, including MELAS.

On July 28, 2022, we announced positive topline data from our signal-seeking clinical study of zagociguat for the potential treatment of Cognitive Impairment Associated with Schizophrenia ("CIAS").

Data from the 14-day, double-blind, randomized, placebo-controlled, multiple-ascending-dose study in 48 adults aged 18-50 with stable schizophrenia on a stable, single, atypical antipsychotic regimen demonstrated that once-daily zagociguat was safe and well tolerated, with no reports of serious adverse events, severe adverse events, or treatment discontinuation due to adverse events.

We further announced that study data demonstrated a strong effect on cognitive performance after two weeks of 15mg once-daily dosing and that positive movement on inflammatory biomarkers was also observed.

These signals on exploratory endpoints are consistent with pro-cognitive and anti-inflammatory effects of zagociguat observed in preclinical studies and prior clinical trials and support the further development of oral, once-daily zagociguat.

In October 2022, the WHO International Nonproprietary Names committee and the United States Adopted Name council selected zagociguat as a nonproprietary name for CY6463.

On October 6, 2022, we announced that we had recently capped enrollment in our signal-seeking clinical study of zagociguat for the potential treatment of Alzheimer's disease with vascular pathology ("ADv").

Data from the ADv study are expected in the first half of 2023.

The ADv study is supported in part by a $2 million grant from the Alzheimer’s Association’s Part the Cloud-Gates Partnership Grant Program (the "PTC Grant").

On March 22, 2023, we announced that given the significant capital and capabilities necessary to ensure that the MELAS Phase 2b study is executed efficiently and with the highest quality, and the currently unfavorable capital market conditions, we are actively evaluating the best combination of capital, capabilities, and transactions available to us to advance the development of zagociguat and our other clinical development candidates and to maximize shareholder value.

CY3018 is a CNS-targeted sGC stimulator in preclinical development that preferentially localizes to the brain and has a pharmacology profile that suggests its potential for the treatment of neuropsychiatric diseases and disorders.

Praliciguat is an orally administered, once-daily systemic sGC stimulator.

On June 3, 2021, we entered into a License Agreement with Akebia Therapeutics, Inc.

("Akebia") relating to the exclusive worldwide license to Akebia of our rights to the development, manufacture, medical affairs and commercialization of pharmaceutical products containing praliciguat and other related products and forms thereof enumerated in such agreement.

On June 3, 2021, we entered into a license agreement with Akebia relating to the exclusive worldwide license to Akebia of our rights to the development, manufacture, medical affairs, and commercialization of pharmaceutical products containing praliciguat and other related products and forms thereof enumerated in such agreement.

Cyclerion is eligible to receive up to $585 million in total potential future development, regulatory, and commercialization milestone payments.

Cyclerion is also eligible to receive tiered, sales-based royalties ranging from single-digit to high-teen percentages.

Olinciguat is an orally administered, once-daily, vascular sGC stimulator that was evaluated in a Phase 2 study of participants with sickle cell disease.

We released topline results from this study in October 2020.

This asset is available for licensing to a third-party partner.

Our mission is to develop treatments that treat cognitive impairment.

Key elements of our strategy include:

delivering results from our ongoing exploratory, clinical studies in ADv, CIAS and MELAS that enable go/no-go decisions and inform the subsequent development strategy for CY6463;

identifying additional indications for clinical development where the scientific rationale is strong and the unmet need is high, creating a compelling opportunity;

advancing our differentiated next-generation, CNS-penetrant, sGC stimulator program;

maintaining our out-license of non-CNS praliciguat with Akebia;

considering an out-license of olinciguat, in order to advance global development;

actively seeking partnerships and additional assets when we believe doing so will offer the greatest risk-adjusted value for our shareholders and accelerate global patient access to our drugs;

leveraging our experienced team of individuals who have a passion for innovative drug development by applying leading edge analytics and data collection techniques to best segment patient populations and measure pharmacodynamic changes in patients with cognitive impairment;

growing external CNS network of advisors and collaborators to augment our core team

We intend to out-license olinciguat to an entity with strong cardiovascular and/or cardiopulmonary capabilities.

Our mission is to develop treatments for serious diseases.

The first step is identifying indications for clinical development where the scientific rationale is strong and the unmet need is high, creating a compelling opportunity.

We have several product opportunities including zagociguat for mitochondrial diseases, CY3018 for neuropsychiatric diseases, and olinciguat for cardiovascular/cardiopulmonary diseases.

Our focus right now is to find the best combination of capital, capabilities, and transactions that will enable the advancement of these assets for patients in a way that maximizes shareholder value.

Intellectual Property

We vigorously protect the intellectual property and proprietary technology that we believe is important to our business, including by pursuing and maintaining U.S.

and foreign patents that cover our products and compositions, their methods of use and the processes for their preparation, as well as any other relevant inventions and improvements that are commercially important to the development of our business.

and foreign patents that cover our product candidates and compositions, their methods of use and the processes for their preparation, as well as any other relevant inventions and improvements that are commercially important to the development of our business.

We also rely on trade secrets to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection.

Our commercial success depends in part on our ability to obtain and maintain patent and other proprietary protection for commercially important technology, inventions, improvements and know-how related to our business, defend and enforce our patents, preserve the confidentiality of our trade secrets and operate without infringing the valid and enforceable patents and proprietary rights of third parties.

We have twenty-one issued U.S.

patents, thirty pending U.S.

patents applications (of which eight are in the provisional stage), three pending Patent Cooperation Treaty, or PCT, application, and numerous foreign patents and pending patent applications.

We have twenty-six issued U.S.

patents, twenty-eight pending U.S.

patents applications (of which six are in the provisional stage), four pending Patent Cooperation Treaty, or PCT, application, and numerous foreign patents

and pending patent applications.

The PCT applications are filed under an international patent law treaty that provides a unified procedure for filing a single initial patent application to seek patent protection for an invention simultaneously in each of the 153 contracting states, followed by the process of entering national phase, which requires a separate application in each of the member states in which national patent protection is sought.

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The intellectual property portfolios for our most advanced product candidates are summarized below.

CY6463 Patent Portfolio

Our patent portfolio includes two U.S.

issued patents, four pending US applications, two PCT applications, and numerous foreign patents and pending patent applications.

The two issued U.S.

patents, US 10,858,363 and US 10,472,363 are directed to CY6463 and related compounds, and their pharmaceutical compositions thereof and will expire in 2037.

Zagociguat Patent Portfolio

Our patent portfolio includes four U.S.

issued patents, eight pending US applications, (including three provisional cases), one PCT application, and numerous foreign patents and pending patent applications.

Two of the issued U.S.

patents, US 10,858,363 and US 10,472,363 are directed to zagociguat and related compounds, and their pharmaceutical compositions thereof and will expire in 2037.

The terms of these U.S.

patents may be eligible for patent term extension as described below.

One of the pending US patent applications is directed to compounds related to CY6463 and, if issued, will expire in 2037 or later.

Another one of the pending U.S.

patent applications is directed to methods of treating mitochondrial diseases with sGC stimulators, including CY6463 and, if issued, will expire in 2039 or later.

Two additional pending U.S.

patent applications are directed to solid forms and processes for the large-scale synthesis of CY6463 and, if issued, will expire in 2039 or later.

One PCT pending application is directed to the treatment of cognition using CY6463 and if issued will expire in 2041.

Another PCT pending application is directed to compounds related to CY6463 and if issued will expire in 2041.

Furthermore, we have one European issued patent expiring in 2037, which was validated in multiple countries, and two issued patents in other foreign jurisdictions, also expiring in 2037.

All of these are directed to CY6463 and related compounds.

patent, US 11,466,015 is directed to polymorphs of zagociguat and will expire in 2039.

The fourth U.S.

patent, US 11,466,014, is directed to methods of manufacturing zagociguat, and will expire in 2039.

Two of the pending U.S.

patent applications are directed to solid forms and processes for the large-scale synthesis of zagociguat and, if issued, will expire in 2039.

Two other pending U.S.

patent application are directed to compounds related to zagociguat, and, if issued, will expire in 2037 and 2041, respectively.

An additional pending U.S.

patent application is directed to methods of treating mitochondrial diseases with sGC stimulators including zagociguat, and, if issued, will expire in 2039.

Three provisional patent applications are directed to additional methods of treatment using zagociguat.

One PCT pending application is directed to the treatment of cognition using zagociguat and if issued will expire in 2041.

Furthermore, we have one European issued patent expiring in 2037, which was validated in multiple countries, one granted patent in Japan, and eleven issued patents in other foreign jurisdictions, ten expiring in 2037, and two expiring in 2039.

All of these are directed to zagociguat and related compounds, polymorphs or manufacturing processes.

Some of these patents may be eligible for patent term extension depending on the jurisdiction.

CY3018 Patent Portfolio

Our CY3018 patent portfolio includes one pending U.S.

provisional application, two PCT applications and several applications in foreign jurisdictions.

The two PCT applications and foreign applications are directed to CY3018 and related compounds and their methods of use and if granted will expire in 2042.

Some of the resulting patents, if issued, may be eligible for patent term extension or the foreign jurisdiction equivalent, depending on the jurisdiction.

Praliciguat Patent Portfolio

Our praliciguat patent portfolio includes six U.S.

issued patents, ten pending U.S.

patent applications, one PCT application, and numerous patents and pending patent applications in foreign jurisdiction.

Our praliciguat patent portfolio includes ten U.S.

issued patents, eight pending U.S.

patent applications, and numerous patents and pending patent applications in foreign jurisdiction.

One of the U.S.

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patent, US 10,183,021 will expire in 2034 and is directed to the treatment of resistant hypertension with praliciguat or combinations of praliciguat and known anti-hypertensives.

The fifth U.S.

patent, US 209,639,308 will expire in 2034 and is directed to the treatment of diabetic nephropathy with praliciguat or combinations of praliciguat with other agents.

patent, US 209,639,308 will expire in 2034

and is directed to the treatment of diabetic nephropathy with praliciguat or combinations of praliciguat with other agents.

The sixth U.S.

patent, US 10,927,136 covers phosphorus prodrugs of praliciguat and will expire in 2037.

The seventh U.S.

Patent, US 11,389,449, is directed to the treatment of metabolic syndrome with praliciguat and will expire in 2038.

The eighth U.S.

Patent, US 11,357,777, is directed to the treatment of NASH with praliciguat and other compounds and will expire in 2037.

The ninth and tenth U.S.

Patents, US 11,319,308 and 11,274,096, are directed to the syntheses of intermediates useful in the manufacture of praliciguat.

Two pending U.S.

patent applications that, if issued, will expire in 2031 and 2034, respectively, or later, provide generic coverage for praliciguat.

We have a pending PCT and two U.S.

applications directed to methods of treating diabetic nephropathy and other diseases with praliciguat, that if issued, will expire in 2037 or later.

We have a pending U.S.

application directed to a praliciguat formulation, that, if issued, will expire in 2036 or later.

The remaining five pending U.S.

applications are directed to prodrugs of praliciguat, deuterated forms of praliciguat and processes and synthetic intermediates for preparing praliciguat that, if issued, will expire in 2037 or later.

Furthermore, we have three granted European patents, one expiring in 2031, another one in 2032 and the third one in 2034, each of them validated in multiple countries;

three granted Japanese patents, one expiring in 2031, another in 2034, and another in 2037;

four granted Chinese patents, two expiring in 2031, one in 2032, and the third expiring in 2034;

and twenty-one issued patents in other foreign jurisdictions, one expiring in 2032, twelve of them expiring in 2031, seven expiring in 2034, and one expiring in 2037.

patent applications that, if issued, will expire in 2031 and 2034, respectively, provide generic coverage for praliciguat.

Two additional U.S.

patent applications that, if issued, will expire in 2037, and 2039, respectively, provide coverage for methods of large scale preparation of praliciguat.

We also have a pending U.S.

application directed to a praliciguat formulation, that, if issued, will expire in 2036.

Another of the U.S.

pending applications is directed to methods of treating diabetic nephropathy with praliciguat, that if issued, will expire in 2040 or later.

The remaining two pending U.S.

applications are directed to prodrugs of praliciguat, and deuterated forms of praliciguat and, if issued, will expire in 2037 and 2040, respectively.

Furthermore, we have four granted European patents, one expiring in 2031, another one in 2032, a third one in 2034, and a fourth one in 2037, each of them validated in multiple countries;

five granted Japanese patents, one expiring in 2031, another in 2034, one in 2036 and two others in 2037;

six granted Chinese patents, two expiring in 2031, one in 2032, two in 2034, and one expiring in 2037;

and thirty-nine issued patents in other foreign jurisdictions, two expiring in 2032, twelve of them expiring in 2031, nine expiring in 2034, three expiring in 2036, and thirteen in 2037.

Some of these patents may be eligible for patent term extension depending on the jurisdiction.

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Olinciguat Patent Portfolio

Our olinciguat patent portfolio includes six U.S.

issued patents, eight pending U.S.

patent applications (including three provisional applications) and numerous patents and pending applications in foreign jurisdictions.

Our olinciguat patent portfolio includes nine U.S.

issued patents, five pending U.S.

patent applications, one PCT patent application and numerous patents and pending applications in foreign jurisdictions.

One of the U.S.

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patent, US 10,517,874, which will expire in 2034 is directed to the treatment of SCD using olinciguat alone or in combinations with other therapeutic agents.

The fifth U.S.

issued patent, US 10,889,577, will expire in 2037 and is directed to polymorphs of olinciguat.

The sixth issued patent, US 11,207,323, will expire in 2034 and provides coverage for stereoisomers of olinciguat.

A pending U.S.

patent application, if issued, will expire in 2031 or later, and provides generic coverage for olinciguat.

issued patents, US 11,319,308 and 11,274,096, are directed to the syntheses of intermediates useful in the manufacture of olinciguat and will expire in 2037 and 2039, respectively.

The ninth U.S.

Patent, US 11,357,777, is directed to the treatment of NASH with olinciguat and other compounds and will expire in 2037.

Two pending U.S.

patent applications, if issued, will expired in 2037 and provide additional coverage for polymorphs of olinciguat.

Another pending U.S.

patent application, if issued, will expire in 2031, and provides generic coverage for olinciguat.

The remaining pending U.S.

patent applications are directed to other methods of use of olinciguat, deuterated forms of olinciguat, polymorphs of olinciguat and processes and synthetic intermediates for preparing olinciguat and, if issued, will expire in 2037 or later.

Furthermore, we have three granted European patents, one expiring in 2031, another in 2032, and a third one in 2034, the first two validated in multiple countries;

and the third one pending validation in numerous countries;

three granted Japanese patents, one expiring in 2031 and two others in 2034;

four granted Chinese patents, two expiring in 2031, another one in 2032, and a fourth one in 2034;

and twenty issued patents in other foreign jurisdictions, twelve of them expiring in 2031, one expiring in 2032 and six expiring in 2034 and one expiring in 2037.

patent applications are directed to deuterated forms of olinciguat and processes and synthetic intermediates for preparing olinciguat and, if issued, will expire in 2040 and 2037, respectively.

The PCT patent application is directed to the treatment of heart failure with preserved ejection fraction (HFpEF) in post-menopausal women with olinciguat and other sGC stimulators.

If issued, the corresponding patents will expire in 2042.

Furthermore, we have four granted European patents, one expiring in 2031, another in 2032, a third one in 2034, and a fourth one in 2037, each of them validated in multiple countries;

seven granted Japanese patents, one expiring in 2031, three others in 2034, and three expiring in 2037;

five granted Chinese patents, two expiring in

2031, another one in 2032, and two more in 2034;

and forty issued patents in other foreign jurisdictions, twelve of them expiring in 2031, two expiring in 2032, ten expiring in 2034, and sixteen expiring in 2037.

We also have numerous pending patent applications in foreign jurisdictions.

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Additional Intellectual Property

In addition to the patents and patent applications related to CY6463, praliciguat and olinciguat, we currently have seven issued U.S.

six patents granted in foreign jurisdictions, including European patents that have each been validated in several countries;

In addition to the patents and patent applications related to zagociguat, CY3018, praliciguat, and olinciguat, we currently have seven issued U.S.

eight patents granted in foreign jurisdictions, including European patents that have each been validated in several countries;

and a number of pending U.S.

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The extended patent term cannot exceed the shorter of five years beyond the non-extended expiration of the patent or 14 years from the date of the FDA approval of the drug.

Some foreign jurisdictions,

including Europe and Japan, have similar patent term extension provisions, which allow for extension of the term of a patent that covers a drug approved by the applicable foreign regulatory agency.

Some foreign jurisdictions, including Europe and Japan, have similar patent term extension provisions, which allow for extension of the term of a patent that covers a drug approved by the applicable foreign regulatory agency.

Trade Secrets and Proprietary Information

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In addition, our trade secrets may otherwise become known or be independently discovered by competitors.

To the extent that our commercial partners, collaborators, employees and consultants use intellectual property owned by others in their work for us, disputes may arise as to the rights in related or resulting know-how and inventions.

To the extent that our commercial partners, collaborators, employees and consultants use intellectual

property owned by others in their work for us, disputes may arise as to the rights in related or resulting know-how and inventions.

Government Regulation

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The conduct of nonclinical studies that determine the product safety information for administration to humans must comply with federal regulations and requirements, including GLP regulations.

The sponsor must submit the results of the nonclinical studies, together with manufacturing information, analytical data, any available clinical data or literature and a proposed clinical study protocol, to the FDA as part of an IND, which must become effective before clinical trials in a given indication may be commenced.

a given indication may be commenced.

The IND will become effective automatically 30 days after receipt by the FDA, unless the FDA raises concerns or questions about the content of the IND or the conduct of the proposed trial(s) as outlined in the IND prior to that time.

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On the basis of the FDA's evaluation of the NDA and accompanying information, including the results of the inspection of the manufacturing facilities, FDA will issue either an approval letter or a Complete Response Letter.

An approval letter authorizes commercial marketing of the drug and is accompanied by specific prescribing

information for specific conditions of use.

An approval letter authorizes commercial marketing of the drug and is accompanied by specific prescribing information for specific conditions of use.

A Complete Response Letter indicates that the review cycle of the application is complete and the application will not be approved in its present form.

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Competitors, however, may receive approval of different active moieties for the same indication or obtain approval for the same active moiety for a different indication.

If one of our products designated as an orphan drug receives marketing approval for an indication broader than that which is designated, it may not be entitled to orphan drug exclusivity.

If one of our product candidates designated as an orphan drug receives marketing approval for an indication broader than that which is designated, it may not be entitled to orphan drug exclusivity.

Expedited Review and Approval

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Pediatric Exclusivity

Pediatric exclusivity is another type of non-patent marketing exclusivity in the United States and, if granted, provides for the attachment of an additional six months of marketing protection to the term of any existing regulatory exclusivity for both drugs and biologics, and also unexpired Orange Book listed patents in the case of drugs.

regulatory exclusivity for both drugs and biologics, and also unexpired Orange Book listed patents in the case of drugs.

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

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The MAA for the product must include the results of pediatric clinical trials conducted in accordance with the PIP, unless a waiver applies or a deferral has been granted, in which case the pediatric clinical trials must be completed at a later date.

Where the MAA includes the results of all pediatric studies conducted in accordance with the PIP and the results are reflected in the approved summary of product characteristics, the holder of a patent or supplementary protection certificate is entitled to receive a six-month extension of the protection under a supplementary protection certificate or, in the case of orphan medicinal products, the product is eligible for a two-year extension of the orphan

market exclusivity.

This pediatric reward is subject to specific conditions and is not automatically available when data in compliance with the PIP are developed and submitted.

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Competition can be viewed as through at least two lenses:

1) companies that are developing products with a different mechanism of action but to address the same therapeutic need and 2) companies that are developing products that act through the same mechanism of action (i.e., sGC modulators).

1) companies that are developing products with a different mechanism of action to address the same therapeutic need and 2) companies that are developing products that act through the same mechanism of action (i.e., sGC modulators).

Competition within target therapeutic areas .

There are currently no approved treatments for MELAS or Mitochondrial Disease in the United States.

We are aware of the following companies engaged in clinical development of products for the treatment of MELAS or Mitochondrial Disease, which include patients with MELAS:

PTC Therapeutics has a registrational Phase 2/3 study ongoing of vatiquinone, an antioxidant/NQO1 modulator, assessing the treatment of Mitochondrial Disease in participants with refractory epilepsy.

Khondrion B.V has a Phase 2b study ongoing with sonlicromanol, a redox modulator, assessing the attention domain of cognitive function in MELAS-spectrum disorders.

Abliva AB has a Phase 1a/b study ongoing of KL1333, an NAD+ modulator, in Primary Mitochondrial Disease.

Abliva AB has announced plans to initiate a pivotal clinical Phase II/III study of KL1333 in MELAS-Maternally inherited diabetes and deafness (MIDD) and Kearns-Sayre syndrome (KSS)-Chronic progressive external ophthalmoplegia (CPEO) spectrum disorders during 2021.

Reneo Pharma LTD ran a Phase 1 study of REN001, a PPARδ

agonist, in patients with Primary Mitochondrial Myopathy and has a planned Phase 2/3 study of REN001 in Primary Mitochondrial Myopathy.

Astellas Pharma Inc has a planned Phase2/3 study of ASP0367, a PPARδ

modulator, in patients with Primary Mitochondrial Myopathy.

There are currently no approved products in the United States to treat ADv.

There are six products approved in the United States to treat AD symptoms.

Aricept® (donepezil) is a cholinesterase inhibitor indicated for the treatment of dementia of the Alzheimer’s type, including in patients with mild, moderate and severe AD.

Razadyne® (galantamine) and Exelon® (rivastigmine) are cholinesterase inhibitors indicated for treatment of mild to moderate dementia of the Alzheimer’s type.

Namenda® (memantine) is an N-methyl-D-aspartate (NMDA) receptor antagonist indicated for the treatment of moderate to severe dementia of the Alzheimer’s type.

Namzaric® is a combination of donepezil and memantine indicated for the treatment of moderate to severe dementia of the Alzheimer’s type in patients stabilized on 10 mg of donepezil hydrochloride once daily.

Biogen received FDA approval for aducanumab, an anti-amyloid beta (Aβ) mAb, for the treatment of AD.

We are not aware of any companies engaged in clinical development of products for the treatment of ADv.

There are many companies developing treatments for AD, which could be our competitors.

These include the following companies engaged in the late-stage clinical development of products for the treatment of AD:

There are multiple Aβ

targeting agents in Phase 3 studies for the treatment of AD, including Eli Lilly’s solanezumab (anti-Aβ

mAb), Eisai/Biogen’s BAN2401 (anti-Aβ

mAb) , Roche’s gantenerumab (anti-Aβ

mAb), Alzheon’s ALZ-801 (Aβ

aggregation inhibitor) and AZTherapies’ALZT-OP1 (Aβ

aggregation inhibitor).

Compounds in Phase 3 studies with other mechanisms of action include TauRx’s TRx0237/LMTX (Tau aggregation inhibitor), Shanghai Greenvalley Pharmaceutical Co., Ltd.’s GV-971 (oligomannate), AB Science’s masitinib (c-Kit, Lyn, Fyn and CSF1R kinase inhibitor), Cassava Science’s simufilam (restores filamin A conformation) and Novo Nordisk’s semaglutide (glucagon-like-peptide 1 receptor agonist).

Compounds in Phase 2/3 studies include AgeneBio’s AGB-101 (SV2A inhibitor), Grifols IVIG (Immunoglobulin), Cortexyme’s atuzaginstat (bacterial protease inhibitor), Anavex’s ANAVEX 2-73 (Sigma-1, M2/M3 RA), and vTv Therapeutics’

azeliragon/TTP-488 (RAGE antagonist).

There are many other companies engaged in earlier stage clinical development for products targeting AD.

There are currently no approved products in the United States to treat CIAS.

There are many companies developing treatments for CIAS.

These include the following companies engaged in the late-stage clinical development of products for the treatment of CIAS.

Boehringer Ingelheim has three ongoing registrational Phase 3 studies of the glycine transporter type-1 inhibitor, BI 425809, assessing safety and efficacy for the treatment of CIAS.

Biogen has an ongoing Phase 2 study of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor positive allosteric modulator, BIIB104, assessing safety and efficacy in participants with CIAS.

Neurocrine Biosciences has an ongoing Phase 2 study of the d-amino acid oxidase inhibitor, luvadaxistat, in participants with CIAS.

atai Life Sciences has announced plans for a Phase 2 study of the cholinergic, glutamatergic and gamma-aminobutyric acid- B receptor modulator, RL-007, for the treatment of CIAS.

We believe Biogen, Sage, Otsuka, Neumora, Tonix, Neurocrine, Pfizer, atai Life Sciences, Alto Neuroscience, Cerevel, Karuna, PTC Therapeutics, Khondrion B.V, Abliva AB, Reneo, Travere Therapeutics, Dimerix Limited, Vertex Pharmaceuticals, Chinook Therapeutics, Boehringer Ingelheim, Acelyrin, River 3 Renal Corp, Astellas, Pfizer, Eli Lilly, Novartis, AstraZeneca, Bayer and Merck are our most direct competitors with respect to zagociguat, CY3018, praliciguat, and olinciguat.

Competition within the sGC mechanism .

There is one major competitor that is actively developing sGC modulators.

We are not aware of any efforts to develop sGC modulators for treatment of CNS or mitochondrial diseases Bayer and Merck have an active collaboration on sGC stimulators, focused primarily on cardiovascular, pulmonary, and renal indications.

Bayer and Merck have an active collaboration on sGC stimulators, focused primarily on cardiovascular, pulmonary, and renal indications.

They have two approved sGC stimulators, ADEMPAS® (riociguat), indicated for PAH and CTEPH, and VERQUVO® (vericiguat) for heart failure with reduced ejection fraction (HFrEF).

We are not aware of any efforts to develop sGC modulators for treatment of CNS diseases.

Manufacturing

We do not own or operate, and currently have no plans to establish, any manufacturing facilities.

We depend on third-party contract manufacturing organizations, or CMOs, for all our requirements of raw materials, drug substance and drug product for our ongoing clinical trials of CY6463 and our nonclinical research.

We intend to continue to rely on CMOs for the supply of CY6463 for all stages of clinical development and commercialization, as well as for the supply of any other product candidates that we may identify.

We intend to continue to rely on CMOs for the supply of zagociguat and CY3018 for all stages of clinical development and commercialization, as well as for the supply of any other product candidates that we may identify.

We require all our CMOs to conduct manufacturing activities in compliance with current GMP requirements.

We believe that CY6463 drug substance and drug product may be manufactured from readily available raw materials and the processes are amenable to large-scale production and do not require unusual equipment or handling.

We believe adequate supply of CY6463 drug substance and drug product is readily available from our current CMOs to satisfy our immediate clinical and nonclinical demands.

We obtain our supplies from these CMOs on a purchase order basis and do not have arrangements in place for long-term supply or redundant supply of CY6463;

We believe that zagociguat and CY3018 drug substance and drug product may be manufactured from readily available raw materials and the processes are amenable to large-scale production and do not require unusual equipment or handling.

We believe adequate supply of zagociguat and CY3018 drug substance and drug product is readily available from our current CMOs to satisfy our immediate clinical and nonclinical demands.

We obtain our supplies from these CMOs on a purchase order basis and do not have arrangements in place for long-term supply or redundant supply of zagociguat and CY3018;

however, we are working with our CMOs to implement improvements to our drug substance and drug product manufacturing processes to further ensure product capacity adequate to meet further development demands.

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Human Capital Resources

We have built an exceptional and diverse team of individuals who have a passion for developing important new medicines that will have a profound impact on the lives of patients with serious CNS diseases.

We have an exceptional and diverse team of individuals who have a passion for developing important new medicines that will have a profound impact on the lives of patients with serious CNS diseases.

As a small, innovative company, our success depends on attracting, retaining and motivating highly skilled and experienced scientific, medical and other personnel.

Our ability to recruit and retain such employees depends on a number of factors, including our distinct corporate culture, our collaborative work environment and offering opportunities for our employees to grow and develop in their careers.

We provide robust compensation and benefits programs which include competitive salaries, potential annual discretionary bonuses, stock awards, a 401(k) plan with employer match, healthcare and insurance benefits, health savings and flexible spending accounts, unlimited vacation time, among others.

Our ability to recruit and retain such employees depends on a number of factors, including our distinct corporate culture, and our collaborative work environment.

Our employees are further guided by our code of conduct and our cultural values of seeking to serve patients, acting with integrity, empowering people and innovating for solutions.

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We provide our employees and their families with access to a variety of innovative, flexible and convenient health and wellness programs.

In response to the COVID-19 pandemic, we implemented significant changes that were determined to be in the best interest of our employees and the communities in which we live and work, while continuing to ensure the safety of patients in our trials.

In response to the COVID-19 pandemic, we implemented significant changes that were determined to be in the best interest of our

employees and the communities in which we live and work, while continuing to ensure the safety of patients in our trials.

Employee Profile

As of December 31, 2021, we had thirty-two (32) employees, of which fifteen (15) employees hold M.D.

Approximately three (3) employees are in discovery research, thirteen (13) are in our drug development organization, six (6) are in our strategy and corporate development organizations and ten (10) are in general and administrative functions.

None of our employees is subject to a collective bargaining agreement or represented by a trade or labor union.

As of December 31, 2022, we had sixteen (16) employees, of which eight (8) employees hold Ph.D.

Of the sixteen (16) employees, eight (8) are in our development organization, two (2) are in our strategy and corporate development organizations and six (6) are in general and administrative functions.

None of our employees are subject to a collective bargaining agreement or represented by a trade or labor union.

We consider our employee relations to be good.

During the years ended December 31, 2020 and 2019, we initiated certain reductions in our workforce.

During the year ended December 31, 2022, we initiated certain reductions in our workforce.

Refer to Note 12, Workforce Reduction, to our consolidated financial statements appearing elsewhere in this Annual Report on Form 10-K for further details.

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Our telephone number is (857) 327-8778.

Our common stock is listed on the Nasdaq Global Market under the symbol “CYCN.”

Our common stock is listed on the Nasdaq Capital Market under the symbol “CYCN.”

Available Information

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Our website and information included in or linked to our website are not part of this Annual Report.

Our annual reports on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K and amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended, are available free of charge through our website as soon as reasonably practicable after they are

electronically filed with or furnished to the Securities and Exchange Commission, or the SEC.

The SEC maintains an internet site that contains reports, proxy and information statements and other information.

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Risk Factors Summary

Risks Related to Our Financial Position and Capital Needs

We are a clinical-stage biopharmaceutical company with a limited operating history and no products approved for commercial sale.

We are a biopharmaceutical company with a limited operating history and no products approved for commercial sale.

We have incurred significant losses and have never generated revenue from product sales;

we anticipate that we will continue to incur significant losses for the foreseeable future and may never be profitable.

We will need to raise additional funding to advance our product candidates, which may not be available on acceptable terms, or at all, and may dilute existing shareholders or restrict our operations.

Risks Related to our Business and Industry

There is substantial doubt regarding our ability to continue as a going concern.

We will need to raise additional funding, which may not be available on acceptable terms, if at all to continue as a going

concern and advance our product candidates.

Failure to obtain capital when needed may force us to delay, limit or terminate our product development efforts or other operations.

Raising additional capital may dilute our existing shareholders, restrict our operations or cause us to relinquish valuable rights.

Our approach to the discovery and development of our product candidates may never lead to marketable products.

We may encounter substantial delays in our clinical studies, or we may fail to demonstrate safety and efficacy to the satisfaction of applicable regulatory authorities in the development of our compounds.

The COVID-19 pandemic may continue to disrupt our business, including our clinical development activities.

We may encounter substantial delays in our activities, or we may fail to demonstrate safety and efficacy to the satisfaction of applicable regulatory authorities in the development of our compounds.

The COVID-19 pandemic may continue to disrupt our business, including our development activities.

We could encounter difficulties in enrolling participants in our clinical studies, which could delay or prevent progress of our product candidates.

The FDA regulatory approval process is lengthy, time-consuming and inherently unpredictable.

We may be unable to obtain regulatory approval for our product candidates and unable to generate product revenue.

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We may have to change our nonclinical or clinical study protocols due to regulatory reasons or unanticipated events, which could result in increased costs to us and could delay our development timeline.

Risks Related to Our Reliance on Third Parties

We may not succeed in our pursuit of capital, capabilities, and transactions for the development and commercialization of our assets.

Akebia may not be successful in developing any therapies through the praliciguat out-license with the Company.

We may enter into a collaboration or license arrangement in the future that ultimately is not successful.

We rely, and expect that we will continue to rely, on third parties to conduct nonclinical or clinical studies and to manufacture drug supplies for our product candidates.

We may enter into collaboration or license arrangements in the future that ultimately are not successful.

We rely, and expect that we will continue to rely, on third parties to conduct nonclinical and clinical studies and to manufacture drug supplies for our product candidates.

If these third parties do not execute successfully, our business could be substantially harmed.

We share confidential information with third-party vendors, including trade secrets and know-how, which increases the possibility that our confidential information will be misappropriated or disclosed.

Risks Related to Our Intellectual Property Rights

We may be unable to adequately protect our proprietary technologies or obtain and maintain issued patents that are sufficient to protect our product candidates.

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We may be subject to damages resulting from claims that we or our employees, consultants or advisors have wrongfully used or disclosed alleged trade secrets of their current or former employers.

Risks Related to the Future Commercialization of Our Product Candidates

If the market opportunities for our product candidates are smaller than we estimate, our revenue and ability to achieve profitability may be harmed.

Even if we obtain regulatory approval for our product candidates, they may not achieve broad market acceptance by patients, physicians and healthcare payors, which would limit our revenue.

We may fail to comply with healthcare and other regulations and could face substantial penalties.

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The impact of healthcare reform and other governmental and private payor initiatives may harm our business.

Risks Related to Our Business Operations

Our prospects for success depend on our ability to retain our management team and to attract, retain and motivate qualified personnel.

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Foreign Corrupt Practices Act, or the FCPA, and other worldwide anti-bribery laws.

Risks Related to the Separation

Our rights under the intellectual property license agreement with Ironwood could be challenged.

We may be required to make payments to indemnify Ironwood for certain liabilities in connection with the Separation.

Risks Related to Ownership of Our Common Stock

We have limited trading history and a relatively low-volume trading market for our shares and our market price of our common stock may fluctuate widely.

Our common stock market price is particularly volatile, and we expect it to be more volatile than that of a seasoned issuer.

We may not attract securities or industry analysts to initiate or maintain coverage of our stock;

analysts may publish negative reports or change their recommendations regarding our stock adversely and our stock price and trading volume could decline.

Our failure to regain compliance with Nasdaq's continued listing requirements, could result in the delisting of our common stock.

We have limited trading history and a relatively low-volume trading market for our shares and our common stock market price may fluctuate widely.

We have adopted anti-takeover provisions in our articles of organization and bylaws and are subject to provisions of Massachusetts law that may frustrate any attempt to remove or replace our current board of directors or to effect a change of control or other business combination involving our company.

Risks Related to Our Financial Position and Capital Needs

As we are a clinical-stage biopharmaceutical company with a limited operating history and no products approved for commercial sale, valuing our business and predicting our prospects is challenging.

We are a clinical-stage biopharmaceutical company that was incorporated in 2018.

As we are a biopharmaceutical company with a limited operating history and no products approved for commercial sale, valuing our business and predicting our prospects are challenging.

We are a biopharmaceutical company that was incorporated in 2018.

Our business was conducted within Ironwood prior to that time, and we had no history as an independent company prior to the completion of the Separation.

We are developing a pipeline of sGC stimulators, but we have no products approved for commercial sale, and we have never generated revenue from product sales.

Our operating activities to date have been limited primarily to organizing and staffing our company, business planning, raising capital, developing our technology, identifying potential product candidates, pursuing partnership opportunities and conducting early-stage clinical trials for our product candidates, including CY6463.

To date, we have not obtained marketing approval for any of our product candidates, engaged, on our own or through a third party, in commercial scale manufacturing, or conducted sales and marketing activities necessary for the successful commercialization of our product candidates.

Our operating activities to date have been limited primarily to organizing and staffing our company, business planning, raising capital, developing our technology, identifying potential product candidates, pursuing partnership opportunities, and conducting early-stage clinical trials for our product candidates.

To date, we have not obtained marketing approval for any of our product candidates;

engaged, on our own or through a third party, in commercial scale manufacturing or conducted sales and marketing activities necessary for the successful commercialization of our product candidates.

Our short operating history offers limited insight into our prospects for success or even viability.

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Our net losses for the years ended December 31, 2022 and 2021 were $44.1 million and $51.6 million, respectively.

incur significant losses for several years, as we continue our research activities and conduct development of, and seek regulatory approvals for, our product candidates.

We expect to incur significant losses for several years, as we continue our research activities and conduct development of, and seek regulatory approvals for, our product candidates.

Our ability to generate revenue from our product candidates and achieve profitability depends on our ability, alone or with strategic partners, to complete the development of, and obtain the necessary regulatory and essential pricing and reimbursement approvals to commercialize, our product candidates.

We do not know when, if ever, we will generate revenues from sales of our products.

We do not know when, if ever, we will generate revenues from sales of our product candidates.

Our expenses could increase beyond expectations if we are required by the FDA, the European Medicines Agency (EMA), or other regulatory agencies, domestic or foreign, to perform clinical and other studies in addition to those that we currently anticipate.

Even if one or more of the product candidates that we develop is approved for commercial sale, we may never generate revenue in amounts sufficient to achieve and maintain profitability.

We will need to raise additional funding to advance our product candidates, which may not be available on acceptable terms, or at all.

There is substantial doubt about our ability to continue as a going concern.

We will need to raise additional funding, which may not be available on acceptable terms, if at all to continue as a going concern and advance our product candidates.

Failure to obtain capital when needed may force us to delay, limit or terminate our product development efforts or other operations.

Raising additional capital may dilute our existing shareholders, restrict our operations or cause us to relinquish valuable rights.

There is substantial doubt regarding our ability to continue as a going concern.

As of December 31, 2022, we had unrestricted cash and cash equivalents of approximately $13.4 million.

Our management believes that such cash and cash equivalents will be sufficient to fund our current priorities, including the ADv, CIAS, and MELAS studies.

However, we will require significant additional funding to advance our product candidates, alone or with strategic partners, through clinical studies and to seek marketing approval, as well as to continue advancing our research and development efforts with our other product candidates.

We may also need to raise additional funds sooner than currently anticipated if we choose to pursue additional indications or geographies for our product candidates, identify additional product candidates to advance through clinical development or otherwise expand more rapidly than we presently anticipate.

In addition, if we obtain marketing approval for any of our product candidates, we expect to incur significant expenses related to product sales, medical affairs, marketing, manufacturing and distribution.

We are seeking funds through collaborations, strategic alliances, or licensing arrangements with third parties, and such agreements may impact rights to our product candidates or technologies, future revenue streams, research programs or products candidates or to grant licenses on terms that may not be favorable to us.

Our management believes that such cash and cash equivalents will not be sufficient to fund our operating expenses and capital requirements for one year after the date the financial statements are issued, whether or not we curtail efforts with respect to certain of our product candidates.

We will require significant additional funding to advance any of our product candidates beyond the short-term and to sustain our operations.

We are seeking funds through collaborations, strategic alliances, or licensing arrangements with third parties, and such agreements may impact rights to our product candidates or technologies, future revenue streams, research programs or product candidates or to grant licenses on terms that may not be favorable to us.

Such arrangements will limit our participation in the success of any of our product candidates that receive regulatory approval.

We may also seek to raise such capital through public or private equity, royalty financing or debt financing.

Raising funds in the then-current economic environment may be challenging, and such financing may not be available in sufficient amounts or on acceptable terms, if at all.

Raising funds in the current economic environment may be challenging, and such financing may not be available in sufficient amounts or on acceptable terms, if at all.

The terms of any financing may harm existing shareholders.

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Incurring debt would result in increased fixed payment obligations, and we may agree to restrictive covenants, such as limitations on our ability to incur additional debt or limitations on our ability to acquire, sell or license intellectual property rights that could impede our ability to conduct our business.

If we are unable to raise capital when needed or on reasonable terms, we may curtail, delay or discontinue our research or development programs, scale back or cease any commercialization efforts or wind down our business.

In addition, such additional fundraising efforts may divert our management from their day-to-day activities, which may impede our ability to develop and commercialize our product candidates.

Risks Related to our Business and Industry

Our approach to the discovery and development of product candidates for the treatment of serious CNS diseases may never lead to marketable products.

We are focusing our research and development efforts on addressing serious CNS disorders.

The development of CNS therapies presents unique challenges, including an imperfect understanding of the biology, the presence of the blood-brain barrier that can restrict the flow of drugs to the brain, a frequent lack of translatability of nonclinical study results in subsequent clinical trials and dose selection, and the product candidate having an effect that may be too small to be detected using the outcome measures selected in clinical trials or if the outcomes measured do not reach statistical significance.

There are few effective therapeutic options available for patients with MELAS and ADv and other CNS disorders.

We are focusing our research and development efforts on addressing serious CNS diseases.

nonclinical study results in subsequent clinical trials and dose selection, and the product candidate having an effect that may be too small to be detected using the outcome measures selected in clinical trials or if the outcomes measured do not reach statistical significance.

Our future success is highly dependent on the successful development of our technology and our product candidates for treating CNS.

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If we do not successfully develop and commercialize product candidates, we will not become profitable and the value of our common stock may decline.

We are currently pursuing clinical development activities for CY 6463, and next generation compound, CY3018.

Research and development of biopharmaceutical products is inherently risky.

Our business depends heavily on the successful development, clinical testing, regulatory approvals and commercialization of our lead product candidates.

On October 14, 2020, we announced topline results from our Phase 1 translational pharmacology study of CY6463, the first sGC stimulator in clinical development for CNS disorders, which supported the ongoing development of CY6463 in serious CNS diseases.

The Company also announced its focus on discovering, developing and commercializing innovative medicines for people with serious diseases of the CNS.

Although we have several product candidates, CY6463 and CY3018 are the only product candidates we are now developing internally.

CY6463, CY3018.

and any of our other current or potential product candidates, will require regulatory approvals based on substantial additional development and testing prior to commercialization.

We may encounter substantial delays in our activities, including our clinical studies, or we may fail to demonstrate safety and efficacy to the satisfaction of applicable regulatory authorities in the development of zagociguat and CY3018 to treat patients with serious diseases.

Our business depends heavily on the successful development, clinical testing, regulatory approvals and commercialization of our product candidates.

Any of our current or potential product candidates, will require regulatory approvals based on substantial additional development and testing prior to commercialization.

Before obtaining regulatory approvals for the commercial sale of any of our product candidates, we must demonstrate through lengthy, complex and expensive nonclinical and clinical studies that our product candidates are both safe and effective for use in each target indication.

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most product candidates that begin clinical studies are never approved for commercialization by regulatory authorities.

Favorable results in earlier stage trials, such as the topline results from CY6463’s Phase 1 translational pharmacology study may not be replicated in later stage trials.

If we fail to produce positive results in our clinical trials of CY6463, the development timeline, regulatory approval and commercialization prospects of CY6463 and, correspondingly, our business and financial prospects, would be materially adversely affected.

The COVID-19 pandemic continues to disrupt our business, including our clinical development activities.

Many nations, including the United States, continue to implement stay-at-home orders, travel restrictions, and other limiting measures to contain the coronavirus (COVID-19) pandemic that, along with other related mitigation measures, has limited and may continue to limit our ability to access patients and physicians at certain local clinical centers that are participating in our development activities.

To a limited extent, the pandemic delayed and disrupted our recently completed studies.

Favorable results in earlier stage trials may not be replicated in later stage trials.

If we fail to produce positive results in our clinical trials, the development timeline, regulatory approval and commercialization prospects of our assets and, correspondingly, our business and financial prospects, would be materially adversely affected.

The COVID-19 pandemic continues to disrupt our business, including our development activities.

Many nations, including the United States, continue to implement mitigation measures, that have limited and may continue to limit our ability to access patients and physicians at certain local clinical centers that are participating in our development activities.

We may continue to face limitations and difficulties enrolling patients in our planned and future clinical trials if the patient populations that are eligible for our clinical trials continue to be affected by the coronavirus and/or the COVID-19 vaccines.

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Delays and disruptions from the pandemic, or future outbreaks of infectious disease, may increase our capital needs while potentially interfering with our access to capital.

If we encounter difficulties in enrolling participants in our clinical studies, we could be delayed or prevented from proceeding with clinical trials of our product candidates.

Identifying and qualifying participants to participate in clinical studies of our product candidates is critical to our success.

The timing of our clinical studies depends in part on the speed at which we can recruit participants to participate in testing our product candidates.

Estimates of the prevalence of our target indications vary considerably.

Determining the incidence of these conditions, including in specific geographies or demographic groups, is challenging.

The lower the actual prevalence of these conditions, the more challenges we will encounter enrolling participants in our clinical studies, which could delay development of our product candidates.

In the event of difficulties in enrolling participants in any clinical studies conducted on our product candidates, those clinical trials could be delayed or prevented from proceeding.

Identifying and qualifying participants to participate in any clinical studies of our product candidates would be critical to the success of those clinical trials.

The timing of any clinical studies will depend in part on the speed at which participants can be recruited to participate in testing our product candidates.

Estimates of the prevalence of target indications may vary considerably.

Determining the incidence of these conditions, including in specific geographies or demographic groups, would be challenging.

The lower the actual prevalence of these conditions, the more challenges would be encountered enrolling participants in those clinical studies, which could delay development of those product candidates.

Clinical trial enrollment may also encounter difficulties for a variety of other reasons.

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The number of participants required to power the statistical analysis of the study's endpoints may be very large leading to an extended enrollment period.

Issues such as the proximity of participants to a study site, the complexity of the study design, our ability to recruit investigators with appropriate skill and experience, competing clinical studies for similar therapies or targeting similar participants, perceptions of the benefit-risk profile of the product candidate relative to other available therapies or product candidates, and ability to obtain and maintain institutional review board, or IRB, or ethics committee, or EC, approvals and participant consents all could have a substantial impact on the timing of clinical trial enrollment.

If we are unable to enroll sufficient participants in clinical studies in a timely way, obtaining study results will be delayed, which may harm our business, prospects, financial condition and results of operations.

Issues such as the proximity of participants to a study site, the complexity of the study design, the ability to recruit investigators with appropriate skill and experience, competing clinical studies for similar therapies or targeting similar participants, perceptions of the benefit-risk profile of the product candidate relative to other available therapies or product candidates, and ability to obtain and maintain institutional review board, or IRB, or ethics committee, or EC, approvals and participant consents all could have a substantial impact on the timing of clinical trial enrollment.

If sufficient participants cannot be enrolled in clinical studies in a timely way, obtaining study results would be delayed, which may harm our business, prospects, financial condition and results of operations.

The regulatory approval processes of the FDA and comparable foreign regulatory authorities are lengthy, time-consuming and inherently unpredictable.

If we are ultimately unable to obtain regulatory approval for our product candidates, we will be unable to generate product revenue and our business will be substantially harmed.

We cannot commercialize a product until the appropriate regulatory authorities have reviewed and approved the product candidate.

If we or our licensees, as applicable, are ultimately unable to obtain regulatory approval for our product candidates, we will be unable to generate product revenue and our business will be substantially harmed.

A product candidate cannot be commercialized until the appropriate regulatory authorities have reviewed and approved the product candidate.

The time required to obtain approval by the FDA and comparable foreign regulatory authorities is unpredictable, typically takes many years following the commencement of clinical studies and depends upon numerous factors, including the type and complexity of the product candidates involved.

Regulatory authorities have substantial discretion in the approval process and may refuse to accept an application for review or may decide that our data are insufficient for approval and require additional nonclinical, clinical, or other information (e.g., product quality data or manufacturing controls).

We have not requested or obtained regulatory approval for any product candidate, and it is possible that none of our existing product candidates or any product candidates we may seek to develop in the future will ever obtain regulatory approval.

Our ongoing clinical studies may not be completed on schedule, and our planned clinical studies may not begin on schedule, if at all.

Regulatory authorities have substantial discretion in the approval process and may refuse to accept an application for review or may decide that data are insufficient for approval and require additional nonclinical, clinical, or other information (e.g., product quality data or manufacturing controls).

No regulatory approval for any of our product candidates has been requested or obtained, and it is possible that none of our existing product candidates or any product candidates we or our licensees may seek to develop in the future will ever obtain regulatory approval.

Any ongoing clinical studies may not be completed on schedule, and any planned clinical studies may not begin on schedule, if at all.

The completion or commencement of clinical studies can be delayed or prevented for a number of reasons, including, among others:

the FDA or other regulatory bodies may not authorize us or our investigators to commence planned clinical studies, or require that we suspend ongoing clinical studies through imposition of clinical holds;

negative results from our ongoing studies or other industry studies involving product candidates modulating the same or similar mechanism of action;

the FDA or other regulatory bodies may not authorize us or our investigators to commence planned clinical studies, or require that ongoing clinical studies be suspended through imposition of clinical holds;

negative results from ongoing studies or other industry studies involving product candidates modulating the same or similar mechanism of action;

delays in reaching or failing to reach agreement on acceptable terms with prospective contract research organizations, or CROs, and clinical study sites, the terms of which can be subject to considerable negotiation and may vary significantly among different CROs and study sites;

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difficulties obtaining EC or IRB approval(s) to conduct a clinical study at a prospective site or sites;

challenges in recruiting and enrolling participants in clinical studies, the proximity of participants to study sites, eligibility criteria for the clinical study, the nature of the clinical study protocol, the availability of approved effective treatments for the relevant disease and competition from other clinical study programs for similar indications;

availability of approved effective treatments for the relevant disease and competition from other clinical study programs for similar indications;

severe or unexpected drug-related side effects experienced by participants in a clinical study;

the presence of unanticipated metabolites in participants in a clinical study may require considerable nonclinical and clinical assessment;

we may decide, or regulatory authorities may require us, to conduct additional clinical studies or abandon product development programs;

we or our licensees may decide, or regulatory authorities may require the conduct of additional clinical studies or abandonment of product development programs;

delays in validating, or inability to validate, any endpoints utilized in a clinical study;

the FDA or other regulatory bodies may disagree with our clinical study design and our interpretation of data from clinical studies, or may change the requirements for approval even after it has reviewed and commented on the design for our clinical studies;

the FDA or other regulatory bodies may disagree with a clinical study's design and the interpretation of data from clinical studies, or may change the requirements for approval even after it has reviewed and commented on the design for clinical studies;

reports from nonclinical or clinical testing of other competing candidates that raise safety or efficacy concerns;

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Clinical studies may also be delayed or terminated as a result of ambiguous or negative interim results.

In addition, a clinical study may be suspended or terminated by us, the FDA or other comparable authorities, the IRBs or ECs overseeing a clinical study, a data and safety monitoring board overseeing the clinical study, or other regulatory authorities due to a number of factors, including, among others:

failure to conduct the clinical study in accordance with regulatory requirements or our clinical protocols;

inspection of the clinical study operations or study sites by the FDA or other regulatory authorities that reveals deficiencies or violations that require us to undertake corrective action, including in response to the imposition of a clinical hold;

unforeseen safety issues, including any that could be identified in our ongoing studies, adverse side effects or lack of effectiveness;

In addition, a clinical study may be suspended or terminated by us, our licensees, the FDA or other comparable authorities, the IRBs or ECs overseeing a clinical study, a data and safety monitoring board overseeing the clinical study, or other regulatory authorities due to a number of factors, including, among others:

failure to conduct the clinical study in accordance with regulatory requirements or clinical protocols;

inspection of the clinical study operations or study sites by the FDA or other regulatory authorities that reveals deficiencies or violations that require undertaking corrective action, including in response to the imposition of a clinical hold;

unforeseen safety issues, including any that could be identified in ongoing studies, adverse side effects or lack of effectiveness;

changes in government regulations or administrative actions;

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lack of adequate funding to continue clinical studies.

Our product candidates may cause side effects that are presented in the product labeling approved by regulatory authorities.

Our product candidates may cause side effects or adverse events that are presented in the product labeling approved by regulatory authorities.

Some may result in label restrictions.

The most commonly reported adverse events in the repeat-dose clinical studies for CY6463 were headache and GI-related symptoms, most commonly dyspepsia.

As with ADEMPAS® (riociguat), the only FDA-approved sGC stimulator to date, CY6463 may cause serious birth defects if taken while pregnant, and our clinical studies require stringent contraceptive safeguards to prevent pregnancy.

These side effects and any other undesirable side effects observed with our product candidates could cause us or regulatory authorities to interrupt, delay or halt clinical studies and could result in restrictive label language or delay or denial of regulatory approval.

Changes in regulatory requirements, FDA guidance or unanticipated events during our nonclinical studies and clinical studies of our product candidates may occur, which may result in changes to nonclinical or clinical study protocols or additional nonclinical or clinical study requirements, which could result in increased costs to us and could delay our development timeline.

Changes in regulatory requirements, FDA guidance or unanticipated events during our nonclinical studies and clinical studies may force us to amend nonclinical studies and clinical study protocols or the FDA may impose additional nonclinical studies and clinical study requirements.

Amendments or changes to our clinical study protocols would require resubmission to the FDA and IRBs for review and approval, which may increase the cost or delay the timing or successful completion of clinical studies.

Similarly, amendments to our nonclinical studies may increase the cost or delay the timing or successful completion of those nonclinical studies.

If we experience delays completing, or if we terminate, any of our nonclinical or clinical studies, or if we are required to conduct additional nonclinical or clinical studies, the commercial prospects for our product candidates may be harmed and our ability to generate product revenue will be delayed.

Obtaining and maintaining regulatory approval of our product candidates in one jurisdiction does not mean that we will be successful in obtaining regulatory approval of our product candidates in other jurisdictions.

In order to market any product outside of the United States, we must establish and comply with the numerous and varying safety, efficacy and other regulatory requirements of other countries.

Obtaining and maintaining regulatory approval of our product candidates in one jurisdiction does not guarantee that we will be able to obtain or maintain regulatory approval in any other jurisdiction, but a failure or delay in obtaining regulatory approval in one jurisdiction may have a negative effect on the regulatory approval process in others.

As with ADEMPAS® (riociguat), and VERQUVO® (vericiguat), the only FDA-approved sGC stimulators to date, our product candidates may cause serious birth defects or miscarriage if taken while pregnant, and clinical studies for these product candidates require stringent contraceptive safeguards to prevent pregnancy.

Additionally, undesirable side effects that may be observed with our product candidates could cause us, our licensees, or regulatory authorities to interrupt, delay or halt clinical studies and could result in restrictive label language or delay or denial of regulatory approval.

Changes in regulatory requirements, FDA guidance or unanticipated events during nonclinical studies and clinical studies may force amendment to nonclinical studies and clinical study protocols or the FDA may impose additional nonclinical studies and clinical study requirements.

Amendments or changes to clinical study protocols

would require resubmission to the FDA and IRBs for review and approval, which may increase the cost or delay the timing or successful completion of clinical studies.

Similarly, amendments to nonclinical studies may increase the cost or delay the timing or successful completion of those nonclinical studies.

In the event of delays in completing, or the termination of, any of nonclinical or clinical studies, or if it is required that additional nonclinical or clinical studies be conducted, the commercial prospects for product candidates may be harmed and our ability to generate product revenue will be delayed.

Obtaining and maintaining regulatory approval of our product candidates in one jurisdiction does not mean that there will be success in obtaining regulatory approval of our product candidates in other jurisdictions.

In order to market any product outside of the United States, compliance with the numerous and varying safety, efficacy and other regulatory requirements of other countries is required.

Obtaining and maintaining regulatory approval of our product candidates in one jurisdiction does not guarantee that obtaining or maintaining regulatory approval in any other jurisdiction will be possible, but a failure or delay in obtaining regulatory approval in one jurisdiction may have a negative effect on the regulatory approval process in others.

For example, even if the FDA or other comparable foreign regulatory authority grants marketing approval of a product candidate, comparable regulatory authorities in foreign jurisdictions must also approve the manufacturing, marketing and promotion of the product candidate in those countries.

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In many jurisdictions outside the United States, a product candidate must be approved for reimbursement before it can be approved for sale in that jurisdiction.

In some cases, the price that we intend to charge for our product candidates is also subject to approval.

Obtaining foreign regulatory approvals and compliance with foreign regulatory requirements could result in significant delays, difficulties and costs for us and could delay or prevent the introduction of our products in certain countries.

Failure to obtain marketing approval in other countries or any delay or other setback in obtaining such approval would impair our ability to market our product candidates in such countries.

Any such impairment would reduce the size of our potential market, which could have a material adverse impact on our business, prospects, financial condition and results of operations.

In some cases, the price intended to be charged for a product candidate is also subject to approval.

Obtaining foreign regulatory approvals and compliance with foreign regulatory requirements could result in significant delays, difficulties and costs and could delay or prevent the introduction of our product candidates in certain countries.

Failure to obtain marketing approval in other countries or any delay or other setback in obtaining such approval would impair the ability to market product candidates in such countries.

Any such impairment would reduce the size of the potential market, which could have a material adverse impact on our business, prospects, financial condition and results of operations.

Data/market exclusivity may be more limited than we expect based upon the competitive landscape and other factors outside of our control that may occur during development or after approval

There are many types of data/market exclusivity mechanisms that we may seek to secure for our product candidates.

There are many types of data/market exclusivity mechanisms that we or our licensees may seek to secure for our product candidates.

Many of these have risk of loss of exclusivity if the competitive landscape changes or regulations are revised.

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Risks Related to Our Reliance on Third Parties

Akebia may not be successful in developing any therapies through the praliciguat out-license and we may not realize any eligible revenue from the out-license.

We may not succeed in our pursuit of capital, capabilities, and transactions for the development and commercialization of zagociguat and our other clinical stage assets, which would affect our financial condition.

We are seeking capital, capabilities, and transactions to advance the development of zagociguat and our other clinical stage assets.

There can be no assurance that this process will result in any effective negotiations toward, reaching terms of, executing agreements relating to, or completing any transaction or that any such

transaction will be successful.

Failure to complete any of the foregoing efforts would materially adversely affect our business, prospects, financial condition and results of operations.

Akebia may not be successful in developing any therapies through the praliciguat out-license and we may not realize any future revenue from the out-license.

On June 3, 2021, we entered into a license agreement with Akebia relating to the exclusive worldwide license to Akebia of our rights to the development, manufacture, medical affairs and commercialization of pharmaceutical products containing the pharmaceutical compound praliciguat and other related products and forms thereof enumerated in such agreement.

Under the agreement, Akebia will be responsible for all future research, development, regulatory, and commercialization activities for certain products.

Cyclerion is eligible to receive up to $15 million in the first 18 months of the term.

Under the agreement, Akebia is responsible for all research, development, regulatory, and commercialization activities for certain products.

Cyclerion is eligible to receive up to $12 million upon the initiation of a phase 2 clinical trial.

Further milestone cash payments by Akebia are scheduled in the Agreement based on the initiation of phase 3 clinical trials in the U.S.

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Any collaboration or license arrangements that we enter into in the future may not be successful, which could impede our ability to develop and commercialize our product candidates.

We intend to seek collaboration or license arrangements for the commercialization, and/or potentially for the development, of certain of our product candidates depending on the merits of retaining commercialization rights for ourselves as compared to entering into collaboration or license arrangements.

We will face significant challenges in seeking appropriate partners.

We may seek additional collaboration or license arrangements for the commercialization, and/or potentially for the development, of certain of our product candidates depending on the merits of retaining commercialization rights for ourselves as compared to entering into collaboration or license arrangements.

We face significant challenges in seeking appropriate partners.

Moreover, collaboration and license arrangements are complex and time-consuming to negotiate, document, implement and maintain.

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a partner with marketing, manufacturing and distribution rights to one or more products may not commit sufficient resources to or otherwise not perform satisfactorily in carrying out these activities;

that could jeopardize or invalidate our intellectual property or proprietary information or expose us to potential liability;

partners may not properly maintain or defend our intellectual property rights or may use our intellectual property or proprietary information in a way that gives rise to actual or threatened litigation that could jeopardize or invalidate our intellectual property or proprietary information or expose us to potential liability;

collaboration and license arrangements may be terminated, and, if terminated, this may result in a need for additional capital to pursue further development or commercialization of the applicable current or future product candidates;

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We rely, and expect that we will continue to rely, on third parties to conduct any nonclinical or clinical studies for our product candidates.

If these third parties do not successfully carry out their contractual duties or meet expected deadlines, we may not be able to obtain regulatory approval for or commercialize our product candidates and our business could be substantially harmed.

If these third parties do not successfully carry out their contractual duties or meet expected deadlines, necessary regulatory approvals for or commercialization of our product candidates may not be obtainable and our business could be substantially harmed.

We do not have the infrastructure or internal resources and capabilities to independently conduct nonclinical or clinical studies.

We rely on contract laboratories, medical institutions, clinical investigators, and other third parties, such as CROs, to conduct nonclinical studies on our discovery compounds and product candidates and clinical studies on product candidates.

We rely on contract laboratories, medical institutions, clinical investigators, licensees and other third parties, such as CROs, to conduct nonclinical studies on our discovery compounds and product candidates and clinical studies on product candidates.

We rely heavily on such parties for execution of nonclinical and clinical studies and can control only certain aspects of their activities.

As a result, we have less direct control over the conduct, timing and completion of our nonclinical and clinical studies and the management of data developed through these studies than would be the case if we were relying entirely upon our own staff.

As a result, we have limited direct control over the conduct, timing and completion of our nonclinical and clinical studies and the management of data developed through these studies.

Communicating with outside parties can also be challenging, potentially leading to mistakes as well as difficulties in coordinating activities.

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These factors may materially impede the willingness or ability of third parties to complete quality nonclinical and clinical studies and may subject us to unexpected cost increases that are beyond our control.

Nevertheless, we are responsible for ensuring that each of our nonclinical and clinical studies is conducted in accordance with any applicable protocol, legal, regulatory and scientific requirements and standards, and our reliance on CROs and other third parties does not relieve us of our regulatory responsibilities.

Nevertheless, we may be responsible for ensuring that each of our nonclinical and clinical studies is conducted in accordance with any applicable protocol, legal, regulatory and scientific requirements and standards, and our reliance on CROs and other third parties does not necessarily relieve us of our regulatory responsibilities.

We, our CROs and other third parties are required to comply with regulations and guidelines, such as good laboratory practices (GLPs), good clinical practices (GCPs), and current Good Manufacturing Practices.

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The FDA enforces compliance to regulations through periodic inspections of clinical study sponsors, principal investigators, and third parties.

If the FDA determines there was a failure to comply with the regulations the clinical data generated in our clinical studies may be deemed unreliable and the FDA or comparable foreign regulatory authorities may require us to perform additional clinical studies before approving our marketing applications.

If the FDA determines there was a failure to comply with the regulations the clinical data generated in any clinical studies may be deemed unreliable and the FDA or comparable foreign regulatory authorities may require the performance of additional clinical studies before approving any marketing applications.

We cannot assure you that, upon inspection, the FDA will determine that any of our nonclinical studies, clinical studies or product manufacturing complies with these regulations.

Our failure or the failure of our CROs to comply with these regulations may require us to repeat clinical studies, which would delay the regulatory approval process and could also subject us to enforcement action up to and including civil and criminal penalties.

Although we design or approve the designs of our product candidate clinical studies, CROs conduct all of the clinical studies.

As a result, many important aspects of the execution of our drug development programs are outside of our direct control.

In addition, the CROs may not perform all of their obligations under arrangements with us or in compliance with regulatory requirements, but we remain responsible and are subject to enforcement action that may include civil penalties and criminal prosecution for any violations of FDA laws and regulations during the conduct of our clinical studies.

If the CROs do not perform clinical studies in a satisfactory manner, breach their

obligations to us or fail to comply with regulatory requirements, the development and commercialization of our product candidates may be delayed or our development program materially and irreversibly harmed.

We may fail to control the amount and timing of resources these CROs devote to our program or our clinical products.

If we are unable to rely on clinical data collected by our CROs, we could be required to repeat, extend the duration of, or increase the size of our clinical studies and this could significantly delay commercialization and require significantly greater expenditures.

If any of our relationships with these third-party CROs terminate, we may not be able to enter into arrangements with alternative CROs.

If CROs do not successfully carry out their contractual duties or obligations or meet expected deadlines, if they need to be replaced, or if the quality or accuracy of the clinical data they obtain is compromised due to the failure to adhere to our clinical protocols, regulatory requirements or for other reasons, any clinical studies such CROs are associated with may be extended, delayed or terminated, and we may not be able to obtain regulatory approval for or successfully commercialize our product candidates.

As a result, we believe that our financial results and the commercial prospects for our product candidates in the approved indication would be harmed, our costs could increase and our ability to generate revenue could be delayed.

We rely completely on third-party suppliers to manufacture our nonclinical and clinical drug supplies for our product candidates, and we intend to rely on third parties to produce commercial supplies of any product candidates that are approved.

Our failure or the failure of our CROs or other third parties to comply with these regulations may require the repeat of those clinical studies, which would delay the regulatory approval process and could also result in enforcement action up to and including civil and criminal penalties.

Although we or our licensees may design or approve the designs of our product candidate clinical studies, CROs and other third parties conduct those clinical studies.

As a result, many important aspects of the execution of the development programs for our product candidates may be outside of our direct control.

In addition, the CROs, or other third parties, may not perform all of their obligations under arrangements with us or our licensees or in compliance with regulatory requirements, but we may remain responsible and are subject to enforcement action that may include civil penalties and criminal prosecution for any violations of FDA laws and regulations during the conduct of clinical studies.

If the CROs, or our licensees, do not perform clinical studies in a satisfactory manner, breach their obligations to us or fail to comply with regulatory requirements, the development and commercialization of our product candidates may be delayed or our development program materially and irreversibly harmed.

We may not be able to control the amount and timing of resources these CROs or our licensees devote to our clinical products.

If any relationships with these third-party CROs terminate, arrangements with alternative CROs, may not be achievable.

If CROs do not successfully carry out their contractual duties or obligations or meet expected deadlines, if they need to be replaced, or if the quality or accuracy of the clinical data they obtain is compromised due to the failure to adhere to required clinical protocols, regulatory requirements or for other reasons, any clinical studies such CROs are associated with may be extended, delayed or terminated, and required regulatory approval for or successfully commercialization of our product candidates may not be obtainable.

As a result, we believe that our

financial results and the commercial prospects for our product candidates in the approved indication would be harmed, our costs could increase and our ability to generate revenue could be delayed, or lost.

Except as out-licensed, we must rely completely on third-party suppliers to manufacture any nonclinical and clinical drug supplies for our product candidates, and we intend to rely on third parties to produce commercial supplies of any product candidates that are approved.

We do not currently have, nor do we plan to acquire, the infrastructure or capability to internally manufacture the drug supply of our product candidates, or any future product candidates, for use in the conduct of our nonclinical and clinical studies.

We lack the internal resources and the capability to manufacture any product candidates on any scale.

We depend on third-party contract manufacturing organizations, or CMOs, for all our requirements of raw materials, drug substance and drug product for our future and/or ongoing nonclinical studies and clinical trials of CY6463.

We do not have long-term supply agreements in place with our CMOs and each batch of our product candidates is individually contracted under a services agreement on a purchase order basis.

We expect to continue to rely on CMOs for the supply of CY6463 for later-stage development and commercialization, as well as for the supply of any other discovery compounds or product candidates that we may identify, and we may not be able to enter into long-term supply agreements with such CMOs on favorable terms.

We expect to continue to rely on CMOs for the supply of later-stage development and commercialization, as well as for the supply of any other discovery compounds or product candidates that we may identify, and we may not be able to enter into long-term supply agreements with such CMOs on favorable terms.

As a further result, we are subject to price fluctuations for our clinical drug supplies.

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These agreements typically limit the rights of the third parties to use or disclose our confidential information, such as trade secrets and know-how.

Despite these contractual provisions, the need to share our confidential information with third parties increases the risk that confidential information such as trade secrets and know-how becomes

known by our competitors, is inadvertently incorporated into the technology of others, or is disclosed or used in violation of these agreements.

Despite these contractual provisions, the need to share our confidential information with third parties increases the risk that confidential information such as trade secrets and know-how becomes known by our competitors, is inadvertently incorporated into the technology of others, or is disclosed or used in violation of these agreements.

Given that our proprietary position is based, in part, on our confidential information including know-how and trade secrets, a competitor's discovery of our confidential information or other unauthorized use or disclosure could impair our competitive position and may have a material adverse effect on our business, prospects, financial condition and results of operations.

Risks Related to Our Intellectual Property Rights

If we are unable to adequately protect our proprietary technologies, or obtain and maintain issued patents that are sufficient to protect our product candidates, others could compete against us more directly, which would have a material adverse impact on our business, prospects, financial condition and results of operations.

Our success will depend significantly on our ability to obtain and maintain patent and other proprietary protection in the United States and other countries for commercially important technology, inventions and know-how related to our business, defend and enforce our patents, should they issue, preserve the confidentiality of our trade secrets and operate without infringing the valid and enforceable patents and proprietary rights of third parties.

We strive to protect and enhance the proprietary technologies that we believe are important to our business, including seeking patents intended to cover our products and compositions, their methods of use and any other inventions that are important to the development of our business.

We have twenty-one issued U.S.

patents, thirty pending U.S.

patents applications (of which eight are in the provisional stage), three pending Patent Cooperation Treaty, or PCT, application, and numerous foreign patents and pending patent applications.

Our issued US patents covering 6463 expire in 2037, subject to patent term extension.

Our issued U.S.

and foreign patents covering olinciguat expire between 2031 and 2037 and our issued U.S.

and foreign patents covering praliciguat and related compounds expire between 2031 and 2037, in each case subject to patent term extensions.

Multiple pending U.S.

and foreign patents applications covering different aspects of CY6463, praliciguat, and olinciguat will expire between 2031 and 2041, subject to patent term extensions.

If we or our licensees are unable to adequately protect proprietary technologies, or obtain and maintain issued patents that are sufficient to protect our product candidates, others could compete against us more directly, which would have a material adverse impact on our business, prospects, financial condition and results of operations.

Our success will depend significantly on our and our licensees ability to obtain and maintain patent and other proprietary protection in the United States and other countries for commercially important technology,

inventions and know-how related to our business, defend and enforce patents, should they issue, preserve the confidentiality of trade secrets and operate without infringing the valid and enforceable patents and proprietary rights of third parties.

We strive to protect and enhance the proprietary technologies that we believe are important to our business, including seeking patents intended to cover our product candidates and compositions, their methods of use and any other inventions that are important to the development of our business.

We have twenty-six issued U.S.

patents, twenty-eight pending U.S.

patents applications (of which six are in the provisional stage), four pending Patent Cooperation Treaty, or PCT, applications, and numerous foreign patents and pending patent applications.

See “Business —

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The patent positions of biotechnology and pharmaceutical companies, including ours, involve complex legal and factual questions, which in recent years have been the subject of much litigation, and, therefore, the issuance, scope, validity, enforceability and commercial value of any patent claims that we may obtain cannot be predicted with certainty.

Our pending patent applications may not be granted as issued patents in any particular jurisdiction and, even if they do, these patents may not include claims with a sufficient scope to protect our product candidates or otherwise provide any competitive advantage.

Even if our patent applications are issued, competitors and other third parties may infringe, misappropriate or otherwise violate our patents and other intellectual property rights.

We may not be able to prevent infringement, misappropriation or other violations of our intellectual property rights, particularly in countries where the laws may not protect those rights as fully as in the United States.

To counter infringement or unauthorized use, we may be required to file infringement claims, which can be expensive and time-consuming and divert the attention of our management and key personnel from our business operations

Moreover, our patents, if issued, may be challenged, deemed unenforceable, invalidated or circumvented in the United States and abroad.

Patent applications may not be granted as issued patents in any particular jurisdiction and, even if they do, these patents may not include claims with a sufficient scope to protect our product candidates or otherwise provide any competitive advantage.

Even if patent applications are issued, competitors and other third parties may infringe, misappropriate or otherwise violate patents and other intellectual property rights.

We may not be able to prevent infringement, misappropriation or other violations of intellectual property rights, particularly in countries where the laws may not protect those rights as fully as in the United States.

To counter infringement or unauthorized use, filing infringement claims may be required, which can be expensive and time-consuming and divert the attention of management and key personnel from business operations.

Moreover, patents, if issued, may be challenged, deemed unenforceable, invalidated or circumvented in the United States and abroad.

patents and patent applications may also be subject to interference, derivation, ex-parte reexamination, post-grant review, or inter-partes review proceedings, supplemental examination and challenges in district court.

Interference proceedings provoked by third parties or brought by us may be necessary to determine the priority of inventions with respect to our patents or patent applications.

An unfavorable outcome could require us to cease using the related technology or to attempt to license rights to it from the prevailing party.

Our business could be harmed if the prevailing party does not offer us a license on commercially reasonable terms.

Our involvement in litigation or interference proceedings may fail and, even if successful, may result in substantial costs, and distract our management and other employees.

Furthermore, an adverse decision in an interference or derivation

proceeding can result in a third party receiving the patent right sought by us, which in turn could affect our ability to develop, market or otherwise commercialize our product candidates.

Interference proceedings provoked by third parties or brought by us or our licensees may be necessary to determine the priority of inventions with respect to patents or patent applications.

An unfavorable outcome could require ceasing the use of the related technology or to attempt to license rights to it from the prevailing party.

Our business could be harmed if the prevailing party does not offer a license on commercially reasonable terms.

Involvement in litigation or interference proceedings may fail and, even if successful, may result in substantial costs, and distract management and other employees.

Furthermore, an adverse decision in an interference or derivation proceeding can result in a third party receiving the sought-out patent right, which in turn could affect the ability to develop, market or otherwise commercialize our product candidates.

Patents may also be subjected to opposition, post-grant review or comparable proceedings lodged in various foreign, both national and regional, patent offices or courts.

Such proceedings could result in revocation or amendment of our patents in such a way that they no longer cover our product candidates or competitive products.

Such proceedings could result in revocation or amendment of patents in such a way that they no longer cover our product candidates or competitive products.

In addition, such proceedings may be costly.

Thus, any patents, should they issue, that we may own or exclusively license may not provide any protection against competitors.

Furthermore, though a patent, if it were to issue, is presumed valid and enforceable, its issuance is not conclusive as to its validity or its enforceability and it may not provide us with adequate protection to exclude competitors from making similar products.

Thus, any patents, should they issue, may not provide any protection against competitors.

Furthermore, though a patent, if it were to issue, is presumed valid and enforceable, its issuance is not conclusive as to its validity or its enforceability and it may not provide adequate protection to exclude competitors from making similar products.

Even if a patent issues and is held to be valid and enforceable, competitors may be able to design around or circumvent our patents, such as by using pre-existing or newly developed technology or products in a non-infringing manner.

If these developments were to occur, they could have a material adverse effect on our business, prospects, financial condition and results of operations.

Any litigation to enforce or defend our patent rights, even if we were to prevail, would be costly and time-consuming and would divert the attention of our management and key personnel from our business operations.

Any litigation to enforce or defend patent rights, even if successful, would be costly and time-consuming and would divert the attention of management and key personnel from business operations.

We may not prevail in any lawsuits that we initiate, and the damages or other remedies awarded if we were to prevail may not be commercially meaningful.

In addition, proceedings to enforce or defend our patents, if and when issued, put our patents at risk of being invalidated, held unenforceable or not infringed, or interpreted narrowly.

Such proceedings could also provoke third parties to assert counterclaims against us, including that some or all of the claims in one or more of our patents are invalid, not infringed or unenforceable.

In addition, proceedings to enforce or defend any patents, if and when issued, put those patents at risk of being invalidated, held unenforceable or not infringed, or interpreted narrowly.

Such proceedings could also provoke third parties to assert counterclaims, including that some or all of the claims in one or more patents are invalid, not infringed or unenforceable.

Grounds for a validity challenge include alleged failures to meet any of several statutory requirements, including lack of novelty, obviousness or non-enablement.

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Patent and Trademark Office, or the USPTO, or made a misleading statement, during prosecution of the patent application.

In an infringement proceeding, a court may disagree with our allegations and refuse to stop the other party from using the technology at issue on the grounds that our patents do not cover the technology in question, or may decide that a patent of ours is invalid or unenforceable.

An adverse result in any litigation, defense or post-grant proceedings could result in one or more of our patents being invalidated or interpreted narrowly.

Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of our confidential information could be compromised by disclosure during this type of litigation.

In an infringement proceeding, a court may disagree with allegations and refuse to stop the other party from using the technology at issue on the grounds that patents do not cover the technology in question or may decide that a patent is invalid or unenforceable.

An adverse result in any litigation, defense or post-grant proceedings could result in one or more patents being invalidated or interpreted narrowly.

Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some confidential information could be compromised by disclosure during this type of litigation.

There could also be public announcements of the results of hearings, motions or other interim proceedings or developments.

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The outcome following legal assertions of invalidity and unenforceability is unpredictable.

With respect to validity, for example, we cannot be certain that there is no invalidating prior art, of which we and the patent examiner were unaware during prosecution.

If a defendant were to prevail on a legal assertion of invalidity and/or unenforceability, we would lose at least part, and perhaps all, of the patent protection on our product candidates.

If any of our patents, if and when issued, covering our product candidates are invalidated or found not infringed or unenforceable, our business, prospects, financial condition and results of operations could be materially harmed.

With respect to validity, for example, there cannot be certainty that there is no invalidating prior art, of which we, our licensees and the patent examiner were unaware during prosecution.

If a defendant were to prevail on a legal assertion of invalidity and/or unenforceability, at least part, and perhaps all, of the patent protection on our product candidates could be lost.

If any patents, if and when issued, covering our product candidates are invalidated or found not infringed or unenforceable, our business, prospects, financial condition and results of operations could be materially harmed.

We may infringe the intellectual property rights of others, which may prevent or delay our product development efforts and stop us from commercializing or increase the costs of commercializing our product candidates, if approved.

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Other parties may allege that our product candidates or the use of our technologies infringes or otherwise violates patent claims or other intellectual property rights held by them or that we are employing their proprietary technology without authorization.

third-party patents or patent applications with claims to compositions, materials, formulations, methods of manufacture or methods for treatment related to our product candidates.

There may be third-party patents or patent applications with claims to compositions, materials, formulations, methods of manufacture or methods for treatment related to our product candidates.

Because patent applications can take many years to issue, third parties may have currently pending patent applications which may later result in issued patents that our product candidates may infringe, or which such third parties claim are infringed by our technologies.

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In addition, we may not have sufficient resources to bring these actions to a successful conclusion.

If we are unable to avoid infringing the patent rights of others, we may be required to seek a license, defend an infringement action or challenge the validity of the patents in court, or redesign our products.

In addition, if any such claim were successfully asserted against us and we could not obtain such a license, we may be forced to stop or delay developing, manufacturing, selling or otherwise commercializing our product candidates.

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Even if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management and other employees.

Obtaining and maintaining our patent protection depends on compliance with various procedural, document submission, fee payment and other requirements imposed by governmental patent agencies and our patent protection could be reduced or eliminated for non-compliance with these requirements.

The USPTO and various foreign governmental patent agencies require compliance with a number of procedural, documentary, fee payment and other similar provisions over the lifetime of our owned patents and applications.

Obtaining and maintaining patent protection depends on compliance with various procedural, document submission, fee payment and other requirements imposed by governmental patent agencies and patent protection could be reduced or eliminated for non-compliance with these requirements.

In some cases, an inadvertent lapse can be cured by payment of a late fee or by other means in accordance with the applicable rules.

However, there are situations in which noncompliance can result in abandonment or lapse of the patent or patent application, resulting in partial or complete loss of patent rights in the relevant jurisdiction.

In such an event, competitors or other third parties might be able to enter the market earlier

than would otherwise have been the case and this circumstance could have a material adverse effect on our business, prospects, financial condition and results of operations.

We may not seek to protect our intellectual property rights in all jurisdictions throughout the world and we may not be able to adequately enforce our intellectual property rights even in the jurisdictions where we seek protection.

In such an event, competitors or other third parties might be able to enter the market earlier than would otherwise have been the case and this circumstance could have a material adverse effect on our business, prospects, financial condition and results of operations.

We and our licensees may not seek to protect our intellectual property rights in all jurisdictions throughout the world and we may not be able to adequately enforce our intellectual property rights even in the jurisdictions where we seek protection.

The statutory deadlines for pursuing patent protection in individual foreign jurisdictions are based on the priority date of each of our patent applications and we may not timely file foreign patent applications.

Thus, for each of the patent families that we believe provide coverage for our product candidates, we will need to decide whether and where to pursue protection outside the United States.

Filing and prosecuting patent applications and defending patents on product candidates in all countries and jurisdictions throughout the world would be prohibitively expensive, and so we are unlikely to pursue and maintain patents in all countries worldwide.

As such, competitors may use our technologies in jurisdictions where we do not pursue and obtain patent protection to develop their own products.

Thus, for each of the patent families that are believed to provide coverage for our product candidates, we, and our licensees, will need to decide whether and where to pursue protection outside the United States.

Filing and prosecuting patent applications and defending patents on product candidates in all countries and jurisdictions throughout the world would be prohibitively expensive, and so it is unlikely to pursue and maintain patents in all countries worldwide.

As such, competitors may use technologies in jurisdictions where patent protection is not pursued and obtained to develop their own products.

The laws of some foreign countries may not protect intellectual property rights to the same extent as the laws of the United States.

Consequently, we may not be able to prevent third parties from practicing our inventions in all countries outside the United States even if we have a patent in that jurisdiction.

Further, a competitor may export otherwise infringing products to territories where we have patent protection, but enforcement is not as strong as that in the United States.

These products may compete with our products and our patents or other intellectual property rights may not be effective or sufficient to prevent them from competing.

Even if we pursue and obtain issued patents in particular jurisdictions, our patent claims or other intellectual property rights may not be effective or sufficient to prevent third parties from so competing.

Consequently, it may not be possible to prevent third parties from practicing our inventions in all countries outside the United States even if there is a patent in that jurisdiction.

Further, a competitor may export otherwise infringing products to territories where patent protection exists, but enforcement is not as strong as that in the United States.

These products may compete with our product candidates and patents or other intellectual property rights may not be effective or sufficient to prevent them from competing.

Even pursuing and obtaining issued patents in particular jurisdictions, patent claims or other intellectual property rights may not be effective or sufficient to prevent third parties from so competing.

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

The legal systems of some countries, particularly developing countries, do not favor the enforcement of patents and other intellectual property protection, especially those relating to biotechnology or pharmaceuticals.

This could make it difficult for us to stop the infringement of our patents, if obtained, or the misappropriation of or marketing of competing products in violation of our other intellectual property rights.

This could make it difficult to stop the infringement of patents, if obtained, or the misappropriation of or marketing of competing products in violation of other intellectual property rights.

For example, many foreign countries have compulsory licensing laws under which a patent owner must grant licenses to third parties.

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Patent protection must ultimately be sought on a country-by-country basis, which is an expensive and time-consuming process with uncertain outcomes.

Accordingly, we may choose not to seek patent protection in certain countries, and we will not have the benefit of patent protection in such countries.

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

We may not prevail in any lawsuits that we initiate and the damages or other remedies awarded, if any, may not be commercially meaningful.

Accordingly, our efforts to enforce our intellectual property rights around the world may be inadequate to obtain a significant commercial advantage from the intellectual property that we develop or license.

If we do not obtain additional protection under the Drug Price Competition and Patent Term Restoration Act of 1984, or the Hatch-Waxman Act, and similar foreign legislation by extending the patent terms and obtaining data exclusivity for our product candidates, our business, prospects, financial condition and results of operations may be materially harmed.

Accordingly, patent protection might not be sought in certain countries, and there will not be a benefit of patent protection in such countries.

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

We, or our licensees, may not prevail in any lawsuits that we initiate, and the damages or other remedies awarded, if any, may not be commercially meaningful.

Accordingly, efforts to enforce intellectual property rights around the world may be inadequate to obtain a significant commercial advantage from the intellectual property that developed or licensed.

If we, or our licensees, do not obtain additional protection under the Drug Price Competition and Patent Term Restoration Act of 1984, or the Hatch-Waxman Act, and similar foreign legislation by extending the patent terms and obtaining data exclusivity for our product candidates, our business, prospects, financial condition and results of operations may be materially harmed.

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

patents we own may be eligible for a limited patent term extension under the Hatch-Waxman Act, which permits a patent term extension as compensation for patent term lost during the FDA regulatory review process.

patents owned may be eligible for a limited patent term extension under the Hatch-Waxman Act, which permits a patent term extension as compensation for patent term lost during the FDA regulatory review process.

A maximum of five years can be restored to the eligible patent.

In all cases, the total patent life for the product with the patent extension cannot exceed 14 years from the product's approval date, or in other words, 14 years of potential marketing time.

However, we may not be granted an extension 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.

However, an extension might not be granted 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.

Moreover, the applicable time period or the scope of patent protection afforded could be less than we request.

If we are unable to obtain a patent term extension or the term of any such extension is less than we request, the duration of patent protection we obtain for our product candidates may not provide us with any meaningful commercial or competitive advantage, our competitors may obtain approval of competing products earlier than they would otherwise be able to do so, and our ability to generate revenues could be harmed.

If unable to obtain a patent term extension or the term of any such extension is less than we request, the duration of patent protection obtained for our product candidates may not provide any meaningful commercial or competitive advantage, competitors may obtain approval of competing products earlier than they would otherwise be able to do so, and our ability to generate revenues could be harmed.

Changes in U.S.

patent law could diminish the value of patents in general, thereby impairing our ability to protect our products.

patent law could diminish the value of patents in general, thereby impairing our ability to protect our product candidates.

As is the case with other biotechnology companies, our success is heavily dependent on intellectual property, particularly patents.

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The America Invents Act includes a number of significant changes to U.S.

These provisions affect the way patent applications will be prosecuted and may also affect patent litigation.

These provisions affect the way patent applications will be prosecuted and

may also affect patent litigation.

It is not yet clear what, if any, impact the America Invents Act will have on the operation of our business.

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The incidence and prevalence for all the conditions we aim to address with our programs vary considerably.

Our projections of both the number of people who have these diseases, as well as the subset of people with these

diseases who have the potential to benefit from treatment with our product candidates, are based on beliefs and estimates.

Projections of both the number of people who have these diseases, as well as the subset of people with these diseases who have the potential to benefit from treatment with our product candidates, are based on beliefs and estimates.

These estimates have been derived from a variety of sources, including the scientific literature, surveys of clinics, patient foundations or market research, and may prove to be incorrect.

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The total addressable market across all of our product candidates will ultimately depend upon, among other things, the diagnosis criteria included in the final label for each of our product candidates, if approved for sale for these indications, acceptance by the medical community and patient access, drug pricing and reimbursement.

The number of patients in the United States and other major markets and elsewhere may turn out to be lower than expected, patients may not be otherwise amenable to treatment with our products or new patients may become increasingly difficult to identify or gain access to, all of which would harm our results of operations and our business.

Further, even if we obtain significant market share for our product candidates, because the potential target populations are very small, we may never achieve profitability despite obtaining such significant market share.

The number of patients in the United States and other major markets and elsewhere may turn out to be lower than expected, patients may not be otherwise amenable to treatment with our product candidates or new patients may become increasingly difficult to identify or gain access to, all of which would harm our results of operations and our business.

Further, even if significant market share for our product candidates is obtained, because the potential target populations are very small, we may never achieve profitability despite obtaining such significant market share.

If we are unable to establish sales and marketing capabilities or enter into agreements with third parties to sell and market any product candidates, if approved, we may not be successful in commercializing those product candidates if and when they are approved.

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This may be costly, and our investment would be lost if we cannot retain or reposition our commercialization personnel.

If we enter into arrangements with third parties to perform sales, marketing, commercial support and distribution services, our product revenue or the profitability of product revenue may be lower than if we were to market and sell any products we may develop ourselves.

If we enter into arrangements with third parties to perform sales, marketing, commercial support and distribution services, any product candidate revenue or the profitability of that revenue may be lower than if we were to market and sell any products we may develop ourselves.

In addition, we may fail to enter into arrangements with third parties to commercialize our product candidates or may be unable to do so on terms that are favorable to us.

We may have little control over such third parties, and any of them may fail to devote the necessary resources and attention to sell and market our products effectively.

We may have little control over such third parties, and any of them may fail to devote the necessary resources and attention to sell and market our product candidates effectively.

If we do not establish commercialization capabilities successfully, either on our own or in collaboration with third parties, or if we are unable to do so on commercially reasonable terms, we will not be successful in commercializing our product candidates if approved and our business, prospects, financial condition and results of operations will be materially harmed.

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limitations or warnings contained in the labeling approved for our product candidates by the FDA or other applicable regulatory authorities;

any restrictions on the use of our products together with other medications or restrictions on the use of our products in certain types of patients;

any restrictions on the use of our product candidates together with other medications or restrictions on the use of our products in certain types of patients;

the prevalence and severity of any adverse effects associated with our product candidates;

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the effectiveness of our sales and marketing strategies;

publicity concerning our products or competing products and treatments.

publicity concerning our product candidates or competing products and treatments.

If our product candidates are approved but do not achieve an adequate level of acceptance by patients, physicians and payors, we may not generate sufficient revenue from our product candidates to become or remain profitable.

Before granting reimbursement approval, healthcare payors may require us to demonstrate that our product candidates, in addition to treating these target indications, also provide incremental health benefits to patients.

Our efforts to educate the medical community and third-party payors about the benefits of our product candidates may require significant resources and may never be successful.

Reimbursement may be limited or unavailable in certain market segments for our product candidates, which could make it difficult for us to sell our products profitably.

Efforts to educate the medical community and third-party payors about the benefits of our product candidates may require significant resources and may never be successful.

Reimbursement may be limited or unavailable in certain market segments for our product candidates, which could make it difficult for us to sell our product candidates profitably.

Price controls may be imposed in certain markets, which may harm our future profitability.

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and neither experimental nor investigational.

Obtaining coverage and reimbursement approval for a product from a government or other third-party payor is a time consuming and costly process that could require us to provide supporting scientific, clinical and cost-effectiveness data for the use of our products to the payor.

Obtaining coverage and reimbursement approval for a product from a government or other third-party payor is a time consuming and costly process that could require the provision of supporting scientific, clinical and cost-effectiveness data for the use of our product candidates to the payor.

We or our partners may not be able to provide data sufficient to gain acceptance with respect to coverage and reimbursement.

We cannot be sure that coverage or adequate reimbursement will be available for any of our product candidates.

Also, we cannot be sure that reimbursement amounts will not reduce the demand for, or the price of, our products.

If reimbursement is not available or is available only to limited levels, we may not be able to commercialize certain of our products.

Also, we cannot be sure that reimbursement amounts will not reduce the demand for, or the price of, our product candidates.

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

In addition, in the United States, third-party payors are increasingly attempting to contain health care costs by limiting both coverage and the level of reimbursement of new drugs.

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Political, economic and regulatory developments may further complicate pricing negotiations, and pricing negotiations may continue after reimbursement has been obtained.

Reference pricing used by various European

Union member states and parallel distribution, or arbitrage between low-priced and high-priced member states, can further reduce prices.

Reference pricing used by various European Union member states and parallel distribution, or arbitrage between low-priced and high-priced member states, can further reduce prices.

In some countries, we or our partners may be required to conduct a clinical trial or other studies that compare the cost-effectiveness of our product candidates to other available therapies in order to obtain or maintain reimbursement or pricing approval.

Publication of discounts by third-party payors or authorities may lead to further pressure on the prices or reimbursement levels within the country of publication and other countries.

If reimbursement of our products is unavailable or limited in scope or amount, or if pricing is set at unsatisfactory levels, our business could be harmed.

If reimbursement of our product candidates is unavailable or limited in scope or amount, or if pricing is set at unsatisfactory levels, our business could be harmed.

If we fail to comply with healthcare and other regulations, we could face substantial penalties and our business, prospects, financial condition and results of operations could be harmed.

The product candidates that we are evaluating in clinical studies are subject to certain federal and state healthcare laws and regulations that may affect our business.

Any product candidates that we may evaluate in clinical studies are subject to certain federal and state healthcare laws and regulations that may affect our business.

These laws and regulations include:

federal healthcare program anti-kickback laws, which prohibit, among other things, persons from offering, soliciting, receiving or providing remuneration, directly or indirectly, as an inducement or reward for their past, current or potential future prescribing, purchase, use, recommending for use, referral, formulary placement, or dispensing of our products;

the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which prohibits executing a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters and which also imposes certain requirements relating to the privacy, security and transmission of individually identifiable health information;

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Moreover, achieving and sustaining compliance with applicable federal and state privacy, security, fraud and reporting laws may prove costly.

We face significant competition in an environment of rapid technological and scientific change, and our competitors may achieve regulatory approval before us or develop therapies that are safer, more advanced or more effective than ours, which may harm our ability to successfully market or commercialize any product candidates we may develop and ultimately harm our financial condition.

Our future success depends on our ability to demonstrate and maintain a competitive advantage with respect to the design, development and commercialization of our product candidates.

Our objective is to design, develop and commercialize new products with superior efficacy, safety, tolerability and convenience.

In many cases, our product candidates that we commercialize will compete with existing, market-leading products.

The development and commercialization of new drug products is highly competitive.

We may face competition with respect to any product candidates that we seek to develop or commercialize in the future from major pharmaceutical companies, specialty pharmaceutical companies and biotechnology companies worldwide.

We face significant competition in an environment of rapid technological and scientific change, and our competitors may achieve regulatory approval before us or develop therapies that are safer, more advanced or more effective than ours, which may harm our ability, or a licensee's ability, to successfully market or commercialize any product candidates we may develop and ultimately harm our financial condition.

Our future success depends on our ability, or a licensee's ability, to demonstrate and maintain a competitive advantage with respect to the design, development and commercialization of our product candidates.

In many cases, our product candidates that may be commercialized will compete with existing, market-leading products.

development and commercialization of new drug products is highly competitive.

We may face competition with respect to any product candidates that are developed or commercialized in the future from major pharmaceutical companies, specialty pharmaceutical companies and biotechnology companies worldwide.

Potential competitors also include academic institutions, government agencies and other public and private research organizations that conduct research, seek patent protection and establish collaborative arrangements for research, development, manufacturing, and commercialization.

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Such sGC products may compete directly with our own product candidates in our non-CNS target indications.

Because Bayer/Merck already have experience conducting successful clinical trials and obtaining regulatory approvals for an sGC product, they may be able to conduct clinical trials and obtain regulatory approvals for additional product candidates and target indications more quickly or efficiently than we can.

Furthermore, we are aware of a number of other approved products and late-stage product candidates for the treatment of our target indications.

There are currently no approved treatments for MELAS or Mitochondrial Disease in the United States.

We believe the following companies are engaged in clinical development of products for the treatment of MELAS or Mitochondrial Disease, which include patients with MELAS: