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Item 1. Business

2023-03-02 compared with 2022-03-10 · 140 added, 159 removed, 588 unchanged (34% of the section changed)

We are a clinical-stage biopharmaceutical company.

Our ImmTOR® platform encapsulates rapamycin, also known as sirolimus, an FDA approved immunomodulator, in biodegradable nanoparticles ImmTOR is designed to induce antigen-specific immune tolerance.

By combining ImmTOR with antigens of interest, our precision immune tolerance platform has the potential to restore self-tolerance to auto-antigens in autoimmune diseases, amplify the efficacy of biologics (including gene therapies) and mitigate the formation of anti-drug antibodies, or ADAs, against biologic drugs.

ADAs can start developing in the body with the first dose of a biologic therapy and can render subsequent doses ineffective or unsafe, potentially depriving patients of life-saving therapeutic options and limiting the likelihood of success for many otherwise promising novel biologic drugs and technologies.

We continually seek to enhance ImmTOR.

In recent preclinical studies we have conducted, we have observed that ImmTOR may have synergistic activity with interleukin-2, or IL-2, molecules that have been engineered to be selective for regulatory T cells, or Tregs.

Treg-selective IL-2 mutant molecules, or IL-2 muteins, have been shown to transiently expand all pre-existing Tregs in preclinical studies conducted by others.

We have observed in preclinical studies that the combination of ImmTOR, a Treg-selective IL-2 mutein and an antigen elicited an approximately three-fold increase in antigen-specific Tregs beyond ImmTOR alone with evidence of enhanced durability of immune tolerance and the potential for ImmTOR dose sparing.

We are a clinical-stage biotechnology company leveraging our ImmTOR® platform to develop tolerogenic therapies designed to selectively mitigate unwanted immune responses.

With a proven ability to induce tolerance to highly immunogenic proteins, ImmTOR has the potential to amplify the efficacy of biologic therapies, including redosing of life-saving gene therapies, as well as restore the body's natural self-tolerance in autoimmune diseases.

We have several proprietary and partnered programs in our pipeline focused on enzyme therapies, gene therapies, and autoimmune diseases.

In preclinical studies, we have observed that ImmTOR may have synergistic activity with interleukin-2, or IL-2, molecules that have been engineered to be selective for regulatory T cells, or Tregs.

Treg-selective IL-2 molecules have been shown to transiently expand all pre-existing Tregs in preclinical and clinical studies conducted by others.

We have observed in preclinical studies that the combination of ImmTOR, a Treg-selective IL-2 molecule and an antigen exhibited substantial synergistic activity in inducing and expanding antigen-specific Tregs beyond ImmTOR alone with evidence of enhanced durability of immune tolerance and the potential for ImmTOR dose sparing.

This combination of ImmTOR with a Treg selective IL-2 molecule represents an evolution of the ImmTOR platform, which we call ImmTOR-IL ™ .

We believe this combination has the potential to be a best-in-class therapy in diseases where expansion of total Tregs may prove beneficial.

We believe ImmTOR and ImmTOR-IL have the potential to enhance both the efficacy and safety of biologic therapies (including gene therapies), improve product candidates under development, and enable novel therapeutic modalities in autoimmune disease.

We believe this combination has the potential to be a "first-in-class" antigen specific IL-2 therapy for autoimmune disease.

We believe ImmTOR and ImmTOR-IL have the potential to enable novel therapeutic modalities in autoimmune disease as well as enhance both the efficacy and safety of biologic therapies (including gene therapies) and improve product candidates under development.

In clinical trials, ImmTOR has been observed to inhibit the formation of neutralizing antibodies to adeno-associated virus (AAV) capsids, potentially enabling re-dosing of gene therapies.

Additionally, based on preclinical data in AAV gene therapies, we believe that ImmTOR has the potential to improve efficacy and safety by increasing transgene expression, reducing hepatic inflammation and inhibiting undesired immune responses to both the AAV capsid and the transgene product that can occur with the first dose of gene therapy.

In biologic therapies, clinical activity of ImmTOR in humans has been observed with pegadricase, a highly immunogenic pegylated uricase enzyme being developed for the treatment of patients with chronic refractory gout to conventional therapy.

The combination of ImmTOR and pegadricase is currently being evaluated in a Phase 3 clinical trial that we are conducting on behalf of our partner Swedish Orphan Biovitrum AB, or Sobi.

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Low doses of IL-2 have been shown by others to selectively activate Tregs resulting in expansion of pre-existing Tregs.

Clinical trials of low dose IL-2 have generated evidence of efficacy in autoimmune diseases, such as systemic lupus erythematosus.

Clinical trials of low dose IL-2 have generated evidence of efficacy in autoimmune diseases.

Other investigators have shown that IL-2 can be engineered to selectively bind to the high affinity IL-2 receptor and expand pre-existing Tregs.

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We believe these results suggest that the addition of a Treg-selective IL-2 to ImmTOR has the potential to increase the durability of tolerance allow for dose-sparing of ImmTOR and thus, potentially enabling chronic dosing of ImmTOR-IL in the treatment of autoimmune disease.

The following graphs illustrate the combination of ImmTOR and IL-2 mutein mitigated the formation of anti-AAV antibodies.

The following graphs illustrate that the combination of ImmTOR and IL-2 mutein mitigated the formation of anti-AAV antibodies in response to a high vector dose of 5E13 vg/kg.

These results suggest that ImmTOR-IL has the potential to enable repeat dosing of AAV vectors at 5E13 vg/kg which could be used as a strategy to avoid the toxicities that have been observed at doses of 1E14 vg/kg or higher in some clinical trials.

Product Candidates

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This is an example of an immunogenic enzyme that we are combining with ImmTOR with the intention of improving the enzyme’s efficacy and safety.

We believe that ImmTOR has the potential to enable and expand the use of enzymes derived from microbial sources, such as bacterial immunoglobulin A, or IgA, protease for the treatment of IgA nephropathy and bacterial IgG protease, or Xork, for the treatment of IgG-mediated autoimmune disease flares.

We selected a next generation IgA protease candidate from a commensal bacteria with a lower level of baseline ADAs from IGAN Biosciences for the treatment of IgA nephropathy.

By combining ImmTOR with this next generation IgA protease candidate, we believe our novel approach has the potential to mitigate the formation of new ADAs and address the underlying pathophysiology of the disease.

Additionally, we believe advances in protein engineering may lead to innovative therapeutic enzymes with improved pharmaceutical properties or entirely novel specificity and/or activity, but which may be recognized as foreign by the immune system.

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The formation of neutralizing antibodies against AAV after initial treatment with AAV mediated gene therapies effectively prevents the possibility of re-dosing in patients who may benefit from additional doses due to either the failure to achieve therapeutic benefit or loss of transgene expression over time.

Additionally, a significant number of patients who would benefit from treatment by gene therapies are ineligible due to pre-existing immunity to the AAV vectors from a natural infection.

This pre-existing immunity could potentially be addressed through an IgG protease pre-treatment to open a dosing window for AAV gene therapies.

We believe that the combination of ImmTOR and Xork could simultaneously address the two key issues facing the AAV gene therapy modality and make them more accessible while also making them safer and more durable.

We have observed that ImmTOR, when used in combination with AAV gene therapy vectors, inhibited the immune response to the viral vector and enabled successful re-dosing in both mice and non-human primates.

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In a study conducted in non-human primates, or NHP, we observed that co-administration of AAV vector and ImmTOR resulted in higher and more durable transgene expression after the first dose of gene therapy as well as robust inhibition of anti-AAV8 immunoglobulin G, or IgG and neutralizing antibodies.

We believe the observation that co-administration of AAV vector and ImmTOR can lead to higher transgene expression illustrates the potential for dosing lower levels of AAV gene therapies when combined with ImmTOR.

We believe the observation that co-administration of AAV vector and ImmTOR can lead to higher transgene expression illustrates the potential for

dosing lower levels of AAV gene therapies when combined with ImmTOR.

Integrating ImmTOR into a gene therapy protocol has the potential to provide a first dose benefit by enhancing liver-directed transgene expression and durability, as well as the potential to enable re-dosing to restore or augment transgene expression.

We have observed in preclinical studies that ImmTOR may also have hepatoprotective effects in mouse models of inflammation.

As hepatotoxicity is associated with higher vector doses, one potential strategy that we are pursuing is to use ImmTOR to enable multiple lower doses of AAV vectors to mitigate toxicity risks associated with high vector

We are concurrently working with our partner Ginkgo to develop a proprietary AAV capsid with improved transduction for liver-directed gene therapy.

The below illustration depicts the potential benefits of ImmTOR in systemic AAV gene therapy.

We recently completed a human proof-of-concept trial (SEL-399) in healthy volunteers who were treated with an empty AAV8 capsid (EMC-101), which is an AAV capsid containing no transgene, alone or in combination with ImmTOR.

We conducted a human proof-of-concept trial (SEL-399) in healthy volunteers who were treated with an empty AAV8 capsid (EMC-101), which is an AAV capsid containing no transgene, alone or in combination with ImmTOR.

This clinical trial was conducted in Belgium in partnership with Asklepios BioPharmaceutical, Inc., or AskBio (a Bayer AG subsidiary).

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We plan to develop Xork with the intention of enabling access to AAV gene therapy for those patients who are currently excluded due to pre-existing anti-AAV antibodies.

In January 2023, we announced an exclusive licensing and development agreement for Xork to be developed for use with AT845, Astellas Gene Therapies' investigational AAV-based treatment for Late-Onset Pompe disease in adults.

We are responsible for the early development activities and manufacturing of Xork and will maintain the rights for the development of additional indications beyond Pompe disease.

Through our analysis of genetic diseases, we have identified applications and patient segments that we believe would benefit from our ImmTOR platform.

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Low doses of IL-2 have been shown by others to selectively activate Tregs resulting in expansion of pre-existing Tregs.

Clinical trials of

low dose IL-2 have shown evidence of efficacy in small clinical trials of autoimmune diseases, such as systemic lupus erythematosus.

Other investigators have shown that IL-2 can be engineered to selectively bind the high affinity IL-2 receptor and expand pre-existing Tregs.

In our preclinical studies, we observed that ImmTOR combined with a Treg-selective IL-2 mutant protein, or IL-2 mutein, exhibited substantial synergistic activity in increasing the percentage and durability of total Treg expansion in the spleen.

In our preclinical studies, we observed that ImmTOR combined with a Treg-selective IL-2 molecule exhibited substantial synergistic activity in increasing the percentage and durability of total Treg expansion in the spleen.

We believe that this combination has the potential to be a best-in-class therapy in diseases where expansion of total Treg may prove beneficial.

Furthermore, in our preclinical studies, when we combined ImmTOR-IL with an antigen, we measured an approximately three-fold increase in antigen-specific T regulatory cells vs ImmTOR alone.

Our first program in autoimmune diseases is in primary biliary cholangitis, or PBC.

PBC has a significant unmet medical need and a well-defined target antigen.

This antigen specificity differentiates ImmTOR-IL from other IL-2 molecule approaches which do not show an antigen specific T-cell expansion.

Thus, we believe that not only is ImmTOR-IL a potentially "best-in-class" IL-2 where generalized T cell expansion can be beneficial, but also a “first-in-class” antigen specific IL-2 therapy.

Furthermore, in our preclinical studies, when we combined ImmTOR-IL with an antigen, we measured an approximately three-fold increase in antigen-specific T regulatory cells versus ImmTOR alone.

Our Product Candidates

Below is a summary of our ongoing discovery, research, and development programs:

Program Phase of Development Anticipated Next Steps Commercial Rights

Biologic Therapies

(Chronic Refractory Gout) Phase 3 clinical trials

(DISSOLVE I / DISSOLVE II) Top-line data Q4 2022

IgA nephropathy Preclinical IND enabling studies, 2022 Selecta

Gene Therapies

Methylmalonic acidemia (MMA) IND filed / Phase 1 IND approval and study commencement, 2022 Selecta

Ornithine Transcarbamylase (OTC) Deficiency IND-enabling Currently paused Selecta

IgG protease (Xork) Preclinical IND enabling studies, 2022 Selecta

Pompe disease Preclinical Plans to be announced

by our collaborator AskBio

Duchenne muscular dystrophy (DMD) Preclinical Plans to be announced

by our collaborator Sarepta

Limb-girdle muscular dystrophy (LGMD) Preclinical Plans to be announced

by our collaborator Sarepta

Two indications for lysosomal storage disorders Preclinical Plans to be announced

by our collaborator Takeda

Tolerogenic Therapies for Autoimmune Disease

Proprietary IL-2

receptor agonist Preclinical Selecta

Primary biliary cholangitis (PBC) Preclinical Selecta

Biologic Therapies – Chronic Refractory Gout

SEL-212 consists of ImmTOR co-administered with pegadricase.

Our pegadricase consists of a yeast-derived uricase modified with PEG.

Uricase is an enzyme endogenous to all mammals, except for humans and certain primates, which converts uric acid to the more soluble metabolite, allantoin.

There is a natural limit to the amount of uric acid that can be excreted by the kidneys, which decreases with age and can be reduced by some medications.

By converting uric acid to allantoin, uricase provides an additional way for the body to reduce uric acid.

Pegadricase is designed for the treatment of patients with chronic gout, refractory to standard uric acid lowering treatment, by breaking down the excess serum uric acid, or sUA, to the more soluble allantoin.

However, the immune response to

pegadricase limits administration to a single dose which is effective for less than one month.

The addition of ImmTOR to pegadricase (SEL-212) allows multiple monthly doses to be administered, thus reducing uric acid for a prolonged time.

Our pegadricase consists of a yeast-derived uricase modified with polyethylene glycol moieties.

Uricase is an enzyme endogenous to all mammals, except for humans and certain primates, which converts serum urate to the more soluble metabolite, allantoin.

There is a natural limit to the amount of serum urate that can be excreted by the kidneys, which decreases with age and can be reduced by some medications.

By converting serum urate to allantoin, uricase provides an additional way for the body to reduce serum urate.

Pegadricase is designed for the treatment of patients with chronic gout, refractory to standard serum urate lowering treatment, by breaking down the excess serum urate, or SU, to the more soluble allantoin.

However, the immune response to pegadricase limits administration to a single dose which is effective for less than one month.

The addition of ImmTOR to pegadricase (SEL-212) allows multiple monthly doses to be administered, thus reducing serum urate for a prolonged time.

In preclinical studies and in our Phase 1b and Phase 2 clinical trials, we observed that ImmTOR, when co-administered with pegadricase, SEL-212 substantially reduced the formation of associated ADAs.

We believe that SEL-212 serves as proof of concept for the ImmTOR platform in ameliorating the unwanted immune response to an immunogenic biologic.

SEL-212 is in two pivotal Phase 3 studies versus placebo, which we refer to as DISSOLVE I and DISSOLVE II, with top-line data expected in the fourth quarter of 2022.

SEL-212 is in two pivotal Phase 3 studies versus placebo, which we refer to as DISSOLVE I and DISSOLVE II, with top-line data expected first quarter of 2023.

SEL-212 has been licensed (except as to Greater China) to Sobi, pursuant to our license and development agreement dated June 11, 2020, with Sobi, or the Sobi License.

Enrollment into the DISSOLVE II trial is ongoing and the study is being conducted in the United States and four countries across eastern Europe.

Enrollment into the DISSOLVE II trial is complete and the study is being conducted in the United States and four countries across eastern Europe.

As a result of the ongoing and rapidly evolving geopolitical situation in Ukraine and Russia, we have proactively undertaken mitigation steps to prioritize the safety of our patients and investigators, as well as address any potential disruptions.

While we have temporarily closed screening and randomization at sites in both Russia and Ukraine, we have added 11 sites in the United States to further enrollment in DISSOLVE II.

Out of these additional enrollment sites, nine have been activated and two are pending initiation, with activation expected imminently.

Subject to ongoing geopolitical developments, we believe we remain on track to report data in the fourth quarter of 2022, and we will continue to work closely with our partner Sobi, clinical trial providers and regulatory authorities to evaluate any potential delays or adjustments to the timeline of the trial as a result of the circumstances.

We have reserved existing clinical trial supplies in these countries for those already enrolled in the DISSOLVE II trial.

In agreement with our study partner, Sobi, we increased enrollment in DISSOLVE II to 153 subjects for potential loss of subjects enrolled in Russia and Ukraine due to operational or other issues arising from instability in the region.

As of the filing of this Annual Report, we expect to report DISSOLVE I and DISSOLVE II topline results in the first quarter of 2023.

The market for gout therapy

Gout is a painful and potentially disabling form of arthritis associated with elevation of sUA levels caused by an overproduction of uric acid and/or an inability of the kidneys to excrete adequate amounts of uric acid from the body.

High concentrations of sUA lead to formation of uric acid crystals in joints and tissues, causing pain, inflammation and joint damage, and increase the risk for other conditions, including cardiovascular, cardiometabolic, joint and kidney disease.

Patients who are unable to reduce their sUA levels below 6.0 mg/dL with oral drugs are defined as having refractory gout.

Chronic refractory gout constitutes a subset of gout patients exhibiting chronic high sUA levels and painful and damaging uric acid deposits.

Gout is a painful and potentially disabling form of arthritis associated with elevation of SU levels caused by an overproduction of serum urate and/or an inability of the kidneys to excrete adequate amounts of serum urate from the body.

High concentrations of SU lead to formation of serum urate crystals in joints and tissues, causing pain, inflammation and joint damage, and increase the risk for other conditions, including cardiovascular, cardiometabolic, joint and kidney disease.

Patients who are unable to reduce their SU levels below 6.0 mg/dL with oral drugs are defined as having refractory gout.

Chronic refractory gout constitutes a subset of gout patients exhibiting chronic high SU levels and painful and damaging serum urate deposits.

We estimate that there are approximately 160,000 chronic refractory gout patients in the U.S.

We believe SEL-212 may potentially address several key unmet needs in the treatment of chronic refractory gout:

the durable control of sUA levels, the elimination of painful and damaging uric acid deposits, reduction in incidence and severity of flares, based on our preclinical studies, clinical trials, and market research.

the durable control of SU levels, the elimination of painful and damaging serum urate deposits, reduction in incidence and severity of flares, based on our preclinical studies, clinical trials, and market research.

SEL-212 is designed to address these unmet medical needs while improving the dosing regimen to a once-monthly treatment.

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• Clinical proof-of-concept:

• Demonstrate sustained reduction of SUA with repeat dosing

• Demonstrate sustained reduction of SU with repeat dosing

• Select dose to take into Phase 3

In the Phase 1a trial, we observed that a single dose of pegadricase rapidly reduced SUA levels below 6.0 mg/dL for each dose level, although SUA levels returned close to baseline by day 30.

In the Phase 1a trial, we observed that a single dose of pegadricase rapidly reduced SU levels below 6.0 mg/dL for each dose level, although SU levels returned close to baseline by day 30.

Consistent with our preclinical studies in animals, pegadricase induced uricase-specific ADAs in all patients with varying levels in this Phase 1a trial.

The following table depicts the observations from the single ascending dose trial of pegadricase in patients with hyperuricemia.

In this trial, patients with SUA > 6 mg/dL at screening were assigned to one of five cohorts receiving a single IV infusion of pegadricase (0.1, 0.2, 0.4, 0.8 or 1.2 mg/kg).

In this trial, patients with SU > 6 mg/dL at screening were assigned to one of five cohorts receiving a single IV infusion of pegadricase (0.1, 0.2, 0.4, 0.8 or 1.2 mg/kg).

Each cohort consisted of five patients, except for cohort 5 (1.2 mg/kg) which enrolled two patients.

In the Phase 1b clinical trial, we observed the potential for increasing doses of ImmTOR to mitigate the formation of pegadricase ADAs and sustain the anti-uricase enzyme activity through 30 days.

The cohort of subjects who received a single 0.4 mg/kg dose of pegadricase alone showed development of uricase ADAs, a short pegadricase half-life, and poor control of SUA at 30 days.

Three cohorts who received 0.4 mg/kg of pegadricase plus ascending doses of ImmTOR (0.1, 0.15 and 0.3 mg/kg) showed a dose related reduction in uricase ADAs, an increase in pegadricase half-life, and substantial reduction in SUA.

This graphs below depict the observed correlation of SUA with anti-uricase IgG and serum pegadricase activity.

In these graphs, anti-uricase IgG titers, serum pegadricase activity, and SUA are plotted against time for individual patients in cohorts A, G, H, and I.

The cohort of subjects who received a single 0.4 mg/kg dose of pegadricase alone showed development of uricase ADAs, a short pegadricase half-life, and poor control of SU at 30 days.

This graphs below depict the observed correlation of SU with anti-uricase IgG and serum pegadricase activity.

In these graphs, anti-uricase IgG titers, serum pegadricase activity, and SU are plotted against time for individual patients in cohorts A, G, H, and I.

Each line represents an individual patient.

The Phase 2 trial included patients with symptomatic gout and elevated SUA levels in an open-label, multiple ascending-dose clinical trial of SEL-212 to demonstrate sustained reduction of SUA and identify the best dose for Phase 3.

Five monthly doses of SEL-212 reduced SUA to less than 6.0 mg/dL in 21 of 32 patients, or 66%.

In distinct contrast, pegadricase alone reduced SUA to less than 6.0 mg/dL in only three of 19 patients one month after a single injection (data from pegadricase alone cohorts from the SEL-037/101, SEL-212/101, and SEL-212/201 trials).

We believe these results support our view that the addition of ImmTOR to pegadricase is able dramatically enhance the efficacy of pegadricase in the long-term reduction of SUA in gout patients.

The chart below depicts SUA after five monthly doses of SEL-212.

The Phase 2 trial included patients with symptomatic gout and elevated SU levels in an open-label, multiple ascending-dose clinical trial of SEL-212 to demonstrate sustained reduction of SU and identify the best dose for Phase 3.

Five monthly doses of SEL-212 reduced SU to less than 6.0 mg/dL in 21 of 32 evaluable patients, or 66%.

In distinct contrast, pegadricase alone reduced SU to less than 6.0 mg/dL in only three of 19 patients one month after a single injection (data from pegadricase alone cohorts from the SEL-037/101, SEL-212/101, and SEL-212/201 trials).

We believe these results support our view that the addition of ImmTOR to pegadricase is able dramatically enhance the efficacy of pegadricase in the long-term reduction of SU in gout patients.

The chart below depicts SU after five monthly doses of SEL-212.

We have observed that SEL‑212 and its components, ImmTOR and pegadricase, were generally well-tolerated in the Phase 1a, 1b, and 2 clinical trials.

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We observed a numerically higher response rate to pegloticase on the primary endpoint during months three and six combined but did not meet the primary endpoint of statistical superiority.

SEL-212 did generate a statistically significant higher response rate of SEL-212 during the third month of treatment, as well as a statistically significant greater overall reduction in mean SUA levels in SEL-212 versus pegloticase in months three and six combined.

SEL-212 did generate a statistically significant higher response rate to pegloticase during the third month of treatment, as well as a statistically significant greater overall reduction in mean SU levels in SEL-212 versus pegloticase in months three and six combined.

We observed a numerically higher response rate of SEL-212 during the sixth month of treatment.

In patients with tophi at baseline, we observed substantially higher responder rates for SEL-212 compared to pegloticase on the primary endpoint, and a statistically significant reduction in mean SUA levels when compared to pegloticase.

Approximately 41% of patients in the Phase 2 COMPARE trial had visible tophi at baseline, which is lower than we expected for the general refractory gout population.

However, in these most severe patients with tophi, SEL-212 was superior to

pegloticase with a 58% responder rate for SEL-212 versus a 39 % responder rate for pegloticase.

However, in these most severe patients with tophi, SEL-212 was superior to pegloticase with a 58% responder rate for SEL-212 versus a 39 % responder rate for pegloticase.

Response rates observed in patients with tophi at baseline are depicted below.

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We refer to these trials as DISSOLVE I and DISSOLVE II.

Each trial is expected to enroll up to 120 patients, with up to 40 patients receiving 0.1 mg/kg of ImmTOR and 0.2 mg/kg of pegadricase, up to 40 patients receiving 0.15 mg/kg of ImmTOR and 0.2 mg/kg of pegadricase, and up to 40 patients receiving placebo.

An additional 15 patients were added to the study sample size to account for potential treatment discontinuations that may occur due to the ongoing COVID-19 pandemic as a result of the emergence of COVID-19 variants which were not accounted for in the sample size calculations.

Each trial was expected to enroll up to 120 patients, with up to 40 patients receiving 0.1 mg/kg of ImmTOR and 0.2 mg/kg of pegadricase, up to 40 patients receiving 0.15 mg/kg of ImmTOR and 0.2 mg/kg of pegadricase, and up to 40 patients receiving placebo.

An additional 15 patients were added to the study sample size to account for potential treatment discontinuations due to the ongoing COVID-19 pandemic as a result of the emergence of COVID-19 variants which were not accounted for in the sample size calculations.

We commenced enrollment of DISSOLVE I in September 2020 and DISSOLVE II in December 2020.

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DISSOLVE I has a six-month primary endpoint followed by a six-month safety extension.

In June 2022, we announced the completion of enrollment of the DISSOLVE II trial.

DISSOLVE II will have a six-month primary endpoint with no extension.

The primary endpoint of the DISSOLVE program is the maintenance of sUA levels below 6 mg/dL at six months.

We currently expect that topline data from the Phase 3 DISSOLVE clinical program is expected in the fourth quarter of 2022.

Enrollment into the DISSOLVE II trial is ongoing and the study is being conducted in the United States and four countries across eastern Europe.

While we have temporarily closed screening and randomization at sites in both Russia and Ukraine, we have added 11 sites in the United States to further enrollment in DISSOLVE II.

Out of these additional enrollment sites, nine have been activated and two are pending initiation, with activation expected imminently.

Subject to ongoing geopolitical developments, we currently believe we remain on track to report data in the fourth quarter of 2022, and we will continue to work closely with our partner Sobi, clinical trial providers and regulatory authorities to evaluate any potential delays or adjustments to the timeline of the trial as a result of the circumstances.

The primary endpoint of the DISSOLVE program is

the maintenance of SU levels below 6 mg/dL at six months.

As of the filing of this Annual Report, we expect to report DISSOLVE I and DISSOLVE II topline results in first quarter of 2023.

Biologic Therapies – IgA Nephropathy

The second indication in our biologic therapies program is IgA nephropathy, an autoimmune kidney disease that occurs when immune complexes of a subclass of antibodies called immunoglobulin A1, or IgA1, accumulates in the kidneys.

The second development program in biologic therapies is in IgA nephropathy, an autoimmune kidney disease that occurs when immune complexes of a subclass of antibodies called immunoglobulin A1, or IgA1, accumulates in the kidneys.

Previous studies in animal models conducted at independent laboratories demonstrated that bacterial IgA protease has the potential to remove injurious IgA immune complexes from kidneys and reduce inflammation, fibrosis, and hematuria.

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The barrier to IgA protease commercialization has been the bacterial origin of the protease, which makes it highly immunogenic.

Based on the learnings of SEL-212, we believe the combination of ImmTOR with an IgA protease could potentially enable repeated dosing to treat IgA nephropathy.

In clinical trials, we have observed ImmTOR mitigating the formation of ADAs to immunogenic enzymes.

We intend to combine an IgA protease with our ImmTOR platform to develop a novel combination product candidate for the treatment of IgA nephropathy and IgA-mediated diseases.

In December 2022, we announced the selection of a next generation IgA protease candidate from IGAN Biosciences for its IgA nephropathy program.

In October 2020, we entered into an Option and License Agreement, or the IGAN Agreement, with IGAN Biosciences, Inc., or IGAN.

Pursuant to the IGAN Agreement, IGAN granted us an exclusive license to research, evaluate, and conduct pre-clinical development activities on IGAN’s proprietary IgA proteases.

We have an option term of 24 months, during which we can elect to obtain an exclusive license to further develop and commercialize the product candidate to treat all IgA-mediated diseases, including IgA nephropathy, Linear IgA bullous dermatitis, IgA pemphigus, and Henoch-Schonlein purpura (also known as IgA vasculitis).

In October of 2021 we entered into a Collaboration and License Agreement, or the First Ginkgo Agreement, with Ginkgo.

We had an initial option term of 24 months, during which we could elect to obtain an exclusive license to further develop and commercialize the product candidate to treat all IgA-mediated diseases, including IgA nephropathy, Linear IgA bullous dermatitis, IgA pemphigus, and Henoch-Schonlein purpura (also known as IgA vasculitis).

In May 2022, we entered into Amendment No.

1 to the IGAN Agreement, or the First IGAN Amendment, with IGAN.

The First IGAN Amendment provided an extension to the option term of 24 months from the date of the First IGAN Amendment.

In December 2022, we exercised our option to opt-in to an exclusive license agreement and selected a next generation IgA protease candidate from a commensal bacteria with a lower level of baseline ADAs from IGAN for the treatment of IgA nephropathy.

In October 2021, we entered into a Collaboration and License Agreement, or the First Ginkgo Agreement, with Ginkgo.

Pursuant to the First Ginkgo Agreement, Ginkgo will leverage their high throughput enzyme discovery, design and screening capabilities to identify and further optimize a proprietary, next generation IgA protease.

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The feasibility study and license agreement with AskBio, or AskBio Collaboration Agreement, otherwise remains in effect.

Manufacturing of a new lot has been completed and is currently undergoing final release testing.

We filed an IND to conduct a Phase 1/2 clinical trial of SEL-302 in pediatric patients with methylmalonic acidemia in the third quarter of 2021.

On November 23, 2021, this trial was placed on clinical hold by the FDA, with questions specifically relating to chemistry, manufacturing and controls, or CMC, of the AAV vector.

On February 9, 2022, we submitted a written response to the FDA to answer its questions.

On March 9, 2022, we received a letter from the FDA indicating the clinical hold was removed and the trial may proceed.

Gene Therapies – OTC Deficiency

Our second proprietary gene therapy product candidate, SEL-313, is being developed to treat ornithine transcarbamylase, or OTC deficiency, and is currently in preclinical development.

OTC deficiency is a rare genetic disorder that causes ammonia to accumulate in the blood due to mutations in the OTC gene, which is critical for proper function of the urea cycle.

The most severe form of the disorder presents within the first few days of life.

Severe symptoms include inability to control body temperature and breathing rate, seizures, coma, developmental delays and intellectual disability.

Less severe forms of the disorder are characterized by delirium, erratic behavior, aversion to high protein foods, vomiting and seizures.

The development of this program is currently paused.

Gene Therapies – Xork

We filed an IND to conduct a Phase 1/2 clinical trial of our SEL-302 product candidate in pediatric patients with methylmalonic acidemia in the third quarter of 2021.

ImmTOR manufacturing, controlled by us, continues to proceed in accordance with our expectations and we have not observed any impact to any of our ImmTOR programs.

In October and November 2020, we received rare pediatric disease designation and orphan drug designation, respectively, from the FDA for MMA-101, for the treatment of MMA due to methylmalonyl-CoA mutase, or MMUT gene mutations.

In December 2022, we initiated ReiMMAgine, the Phase 1/2 clinical trial of SEL-302.

The ReiMMAgine trial is now enrolling patients and aims to evaluate the safety, tolerability and efficacy of SEL-302.

Gene Therapies – IgG Protease (Xork)

We have exclusively licensed Xork, an IgG-specific protease from Genovis, an enzyme technology company.

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Currently, significant proportions of the potential patient populations for many gene therapy trials are ineligible for treatment by AAV mediated gene therapies due to pre-existing antibodies which limits transduction efficiency of the therapy and could trigger potentially dangerous immune responses.

IgG proteases are derived from bacteria.

Xork exhibits low cross-reactivity to antibodies in normal human serum and is differentiated from IgG proteases derived from Streptococcus pyogenes, a common human pathogen.

Because of this, the commercial potential of many gene therapies may be significantly limited due to the ineligibility of large segments of the target patient population.

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We plan to explore the application of Xork in combination with our wholly owned gene therapies, as well as explore partnering opportunities for the enzyme with other gene therapy companies.

We are responsible for the early development activities and manufacturing of Xork and will maintain the rights for the development of additional indications beyond Pompe disease.

Tolerogenic Therapies for Autoimmune Disease – ImmTOR & ImmTOR-IL

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We believe that ImmTOR, in combination with an autoantigen of interest, could create self-tolerance to auto-antigens and thus be a novel approach to the treatment of autoimmune diseases.

Additionally, in preclinical studies we have observed ImmTOR, in combination with IL-2 muteins, expanding T-regulatory cells beyond IL-2 alone and we intend to pursue a combination of ImmTOR and IL-2 (ImmTOR-IL) in diseases where general T cell expansion has shown a therapeutic benefit.

Additionally, in our preclinical data we have observed a three-fold increase in antigen specific regulatory T cells when ImmTOR and IL-2 is combined with an antigen of interest.

Additionally, in preclinical studies we have observed ImmTOR, in combination with IL-2 molecules, expanding T-regulatory cells beyond IL-2 alone and we intend to pursue a combination of ImmTOR and IL-2 (ImmTOR-IL) in diseases

where general T cell expansion has shown a therapeutic benefit.

Additionally, we have observed in preclinical studies that the combination of ImmTOR, a Treg-selective IL-2 molecule and an antigen, exhibited substantial synergistic activity in inducing and expanding antigen specific regulatory T cells when ImmTOR and IL-2 is combined with an antigen of interest.

We intend to pursue and develop treatments for autoimmune diseases with well-defined antigens using either ImmTOR or ImmTOR-IL.

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These Treg cells are a specialized subpopulation of T cells involved in suppressing certain immune responses and maintaining the body’s self-tolerance.

In preclinical studies investigating the effects of ImmTOR in combination with a Treg-selective IL-2 mutant protein, or IL-2 mutein, we have observed a substantial synergistic activity in increasing the percentage and durability of Treg expansion in the spleen.

In preclinical studies investigating the effects of ImmTOR in combination with a Treg-selective IL-2 molecule we have observed a substantial synergistic activity in increasing the percentage and durability of Treg expansion in the spleen.

Our lead autoimmune diseases indication is PBC, a T cell driven autoimmune disease that causes progressive destruction of the bile ducts.

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Ginkgo Bioworks Holdings, Inc.

On October 25, 2021, we entered into the First Ginkgo Agreement with Ginkgo.

In October 2021, we entered into the First Ginkgo Agreement with Ginkgo.

Under the First Ginkgo Agreement, Ginkgo will design next generation IgA proteases with potentially transformative therapeutic potential.

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Ginkgo is also entitled to potential further downstream value in the form of royalties on sales.

On October 21, 2021, we entered into a strategic licensing agreement with Genovis, or the Genovis Agreement.

Genovis AB (publ.)

In October 2021, we entered into a strategic licensing agreement with Genovis, or the Genovis Agreement.

Under the Genovis Agreement, we paid to Genovis an upfront payment in exchange for an exclusive license to Genovis’ Xork enzyme technology for all therapeutic uses in humans, excluding research, preclinical, diagnostic, and other potential non-therapeutic applications of the enzyme.

Genovis is eligible to earn development and sales-based milestones, as well as tiered royalties on worldwide sales in the low double digits.

Genovis is eligible to earn development and sales-based milestones and sublicensing fees, as well as tiered royalties on worldwide sales in the low double digits.

Cyrus Biotechnology, Inc.

On September 7, 2021, we entered into a Collaboration and License Agreement with Cyrus, or the Cyrus Agreement, pursuant to which Cyrus agreed to grant us an exclusive, worldwide license to certain intellectual property in order to form a protein engineering collaboration combining the ImmTOR platform with Cyrus’ engineered protein therapeutics.

In September 2021, we entered into a Collaboration and License Agreement with Cyrus, or the Cyrus Agreement, pursuant to which Cyrus agreed to grant us an exclusive, worldwide license to certain intellectual property in order to form a protein engineering collaboration combining the ImmTOR platform with Cyrus’ engineered protein therapeutics.

We expect that novel engineered protein therapeutic candidates from the partnership will be used to expand our proprietary pipeline and further bolster the ImmTOR platform.

In return for the licensed intellectual property, we made an upfront payment and will pay certain discovery, development, and sales-based milestones which could potentially total up to approximately $1.5 billion across multiple programs.

IGAN Biosciences

In October 2020, we entered into the IGAN Agreement.

In June 2022, we mutually agreed with Cyrus that the preclinical key in-vitro success milestone had been achieved.

IGAN Biosciences, Inc.

In October 2020, we entered into the IGAN Agreement with IGAN.

Pursuant to the IGAN Agreement, IGAN granted us an exclusive license to research, evaluate, and conduct preclinical development activities on IGAN’s proprietary IgA proteases.

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If we opt-in to an exclusive license agreement, we may terminate the IGAN Agreement upon 120 days’ written notice.

On May 25, 2022, we entered into Amendment No.

1 to the IGAN Agreement, or the First IGAN Amendment, with IGAN.

The First IGAN Amendment provided an extension to the option term of 24 months from the date of the First IGAN Amendment.

On December 14, 2022, we exercised our option to opt-in to an exclusive license agreement and selected a next generation IgA protease candidate from a commensal bacteria with a lower level of baseline ADAs from IGAN for the treatment of IgA nephropathy.

Astellas Therapeutics, Inc.

In January 2023, we entered into a License and Development Agreement with Astellas Therapeutics, Inc., or Astellas.

Under this agreement, Astellas obtained the sole and exclusive right to commercialize Xork for use in Pompe disease with an Astellas gene therapy investigational or authorized product, with a current focus on AT845.

We received a $10 million upfront payment and are eligible to receive $340.0 million for certain additional development and commercial milestones plus royalties on any potential commercial sales where Xork is used as a pre-treatment for AT845.

As a result of the sublicense of Xork to Astellas, we made a $4.0 million payment to Genovis in February 2023.

Takeda Pharmaceuticals USA, Inc.

On October 1, 2021, we entered into a strategic licensing agreement with Takeda, or the Takeda Agreement.

In October 2021, we entered into a strategic licensing agreement with Takeda, or the Takeda Agreement.

Under the Takeda Agreement, we granted Takeda an exclusive license to our ImmTOR technology initially for two specified disease indications within the field of lysosomal storage disorders.

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We are also eligible for tiered royalties on future commercial sales of any licensed products.

Swedish Orphan Biovitrum

Swedish Orphan Biovitrum AB (publ.)

In June 2020, we announced that we had entered into the Sobi License, pursuant to which we agreed to grant Sobi an exclusive, worldwide (except as to Greater China) license to develop, manufacture and commercialize SEL-212, which is currently in development for the treatment of chronic refractory gout.

In September 2020, pursuant to the Sobi License, Sobi paid us a one-time, upfront payment of $75 million.

Sobi has also agreed to make milestone payments totaling up to $630

million to us upon the achievement of various development and regulatory milestones and sales thresholds for annual net sales of SEL-212, and tiered royalty payments ranging from the low double digits on the lowest sales tier to the high teens on the highest sales tier.

Sobi has also agreed to make milestone payments totaling up to $630 million to us upon the achievement of various development and regulatory milestones and sales thresholds for annual net sales of SEL-212, and tiered royalty payments ranging from the low double digits on the lowest sales tier to the high teens on the highest sales tier.

In July 2022, we received $10.0 million for the completion of the enrollment of the DISSOLVE II trial.

Additionally, Sobi purchased an aggregate of 5,416,390 shares of our common stock at a purchase price of $4.6156 per share for aggregate gross proceeds of $25 million, which we refer to as the Sobi Private Placement.

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Under the Sobi License, we will have operational oversight of the Phase 3 DISSOLVE clinical program of SEL-212 (DISSOLVE I and DISSOLVE II) that commenced in September 2020, at Sobi’s expense.

Sarepta Therapeutics

We expect to report DISSOLVE I and DISSOLVE II topline results in first quarter of 2023.

Sarepta Therapeutics, Inc.

In June 2020, we entered into a research license and option agreement with Sarepta, or the Sarepta Agreement.

Pursuant to the agreement, we granted Sarepta a license to research and evaluate ImmTOR in combination with Sarepta’s AAV gene therapy or gene editing technology, using viral or non-viral delivery, or the Sarepta Product, to treat Duchenne Muscular Dystrophy and certain Limb-Girdle Muscular Dystrophy subtypes, or the Sarepta Indications.

Sarepta will have an option term of 24 months during which it can opt-in to obtain an exclusive license to further develop and commercialize the Sarepta Product to treat at least one Sarepta Indication, with a potential to extend the option term if Sarepta pays an additional fee to us.

Sarepta made an upfront payment to us upon signing of the agreement, and we are eligible to receive additional payments under the option term.

Sarepta will have an option term of 24 months during which it can opt-in to obtain an exclusive license to further develop and commercialize the Sarepta Product

to treat at least one Sarepta Indication, with a potential to extend the option term if Sarepta pays an additional fee to us.

Sarepta made an upfront payment of $2.0 million to us upon signing of the agreement, and we are eligible to receive additional payments under the option term.

If Sarepta opts-in to an exclusive license agreement, we could receive option exercise payments per indication and we would be entitled to significant development and commercial milestone payments and tiered royalties ranging from the mid-to-high single digits based on net sales.

In June 2021, we received a payment of $3.0 million for the achievement of certain pre-clinical milestones.

Feasibility Study and License Agreement

In August 2022, we received a payment of $2.0 for a nine-month extension to Sarepta’s options to both Duchenne muscular dystrophy and certain limb-girdle muscular dystrophies and a payment of $4.0 million for the achievement of certain pre-clinical milestones.

Asklepios Biopharmaceutical, Inc.

In August 2019, we entered into a feasibility study and license agreement with AskBio, or the AskBio Collaboration Agreement.

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The feasibility study and license agreement with AskBio, or AskBio Collaboration Agreement, otherwise remains in effect.

We filed an IND to conduct a Phase 1/2 clinical trial of our SEL-302 product candidate in pediatric patients with methylmalonic acidemia in the third quarter of 2021.

On November 23, 2021, this trial was placed on clinical hold by the FDA, with questions specifically relating to CMC of the AAV vector.

On February 9, 2022, we submitted a written response to the FDA to answer its questions.

On March 9, 2022, we received a letter from the FDA indicating the clinical hold was removed and the trial may proceed.

ImmTOR manufacturing, controlled by us, continues to proceed in accordance with our expectations and we have not observed any impact to any of our ImmTOR programs.

License Agreement for Pompe Disease

In December 2019, we entered into the AskBio License Agreement which provides AskBio with exclusive worldwide rights to our ImmTOR platform to research, develop and commercialize certain AAV-gene therapy products targeting the GAA gene, or derivatives thereof, to treat Pompe Disease.

Pursuant to the AskBio License Agreement, AskBio paid us upfront fees of an aggregate of $7.0 million.

Also pursuant to the AskBio License Agreement, AskBio agreed to make additional payments to us based on the achievement of certain development and commercial milestones of up to an aggregate of $237.0 million.

AskBio will also be obligated to make tiered royalty payments to us at percentages in the mid-to-high single digits based on achievement of certain sales milestones.

We will supply AskBio with our ImmTOR platform and AskBio will be responsible for all preclinical, clinical and commercial manufacture and supply of products licensed under the AskBio License Agreement (other than ImmTOR) and carry out all other activities related to the research, development, and commercialization of such products at its sole expense, including all regulatory activities related thereto.

The AskBio License Agreement contains other customary terms and conditions, including representations and warranties, covenants, termination, and indemnification obligations in favor of each party.

Massachusetts Institute of Technology

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We amended the MIT License in January 2010, August 2013, November 2016, December 2019 and June 2020.

Under the MIT License, we acquired an exclusive worldwide license, with the right to grant

sublicenses, to develop, make, sell, use and import certain licensed products that are therapeutic or prophylactic vaccines and use certain licensed processes in the exercise of rights to the licensed products, the manufacture, sale and practice of which are covered by patent rights owned or controlled by MIT, including patents jointly owned with Brigham and Women’s Hospital, or Brigham, the President and Fellows of Harvard College, the Immune Disease Institute and the Children’s Medical Center Corporation.

Under the MIT License, we acquired an exclusive worldwide license, with the right to grant sublicenses, to develop, make, sell, use and import certain licensed products that are therapeutic or prophylactic vaccines and use certain licensed processes in the exercise of rights to the licensed products, the manufacture, sale and practice of which are covered by patent rights owned or controlled by MIT, including patents jointly owned with Brigham and Women’s Hospital, or Brigham, the President and Fellows of Harvard College, the Immune Disease Institute and the Children’s Medical Center Corporation.

Our exclusivity is subject to certain retained rights of these institutions and other third parties.

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In June 2020, we entered into a Fifth Amendment to the MIT License, or the MIT Amendment, which was effective as of May 15, 2020.

Pursuant to the MIT Amendment, certain of our diligence obligations were extended to the second quarter of 2021, including a diligence obligation to commence a Phase 3 trial for a licensed product by a specific date in the second quarter of 2021.

Additionally, certain of our development and regulatory milestones and payments upon achievement of such milestones were adjusted.

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We manufacture ImmTOR using a scalable, self-assembly nanoemulsion process with well-defined, pharmaceutical unit operations.

This proprietary, highly specialized and precisely controlled manufacturing process enables us to reproducibly manufacture ImmTOR across many production scales, from milligram-scale at the laboratory bench to hundreds of grams to

multi-kilogram scale for commercial production.

We have also developed and executed the required detailed analytic characterization of our products.

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The licensed patents and patent applications cover various aspects of the technology being developed by us, including claims directed to compositions of matter and methods of use, and have been filed in various countries worldwide including in North America, Europe and Asia, with material expiration dates varying to, if claims are issued, 2042.

In addition to filing and prosecuting patent applications in the United States, we often file analogous patent applications in the European Union and in additional foreign countries where we believe such filing is likely to be beneficial, including but not limited to, Australia, Brazil, Canada, China, Europe, India, Israel, Japan, Mexico and/or South Korea.

Each patent’s term depends upon the laws of the countries in which they are obtained.

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

Our competitors also may obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for ours.

Our competitors also may obtain FDA or other regulatory approval for their products more rapidly than we may

obtain approval for ours.

In addition, our ability to compete may be affected in many cases by insurers or other third-party payors seeking to encourage the use of generic or biosimilar products.

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Large companies with active research to prevent the formation of ADAs and treat allergies or autoimmune diseases include Eli Lilly, Roche Holding AG, Sanofi S.A., Pfizer Inc., and Merck & Co., Inc.

Small, early-stage biopharmaceutical companies active in the research for new technologies to induce antigen-specific immune tolerance include Anokion SA, Apitope International NV, Cour Pharmaceutical Development Company, Inc., Cue Biopharma, Dendright International, Inc., Parvus Therapeutics, REGiMMUNE Corporation, Rubius Therapeutics, Inc., Tolerion, Inc., Topas Therapeutics GmbH, SQZ Biotechnologies and Txcell SA.

Biopharmaceutical companies active in the research for MMA include LogicBio, Poseida, and Moderna.

Biopharmaceutical companies active in the research for Ornithine transcarbamylase include Ultragenyx, Poseida, TranslateBio, Arcturus, and Kaleido.

Biopharmaceutical companies active in the research for IgA nephropathy include Omeros, Travere, EMD Serono, Novartis, Ionis, Visterra, Reata, and Alnylam.

Biopharmaceutical companies active in the PBC research include Intercept Pharmaceuticals, Genfit, GenKyoTex, GSK, Eli Lilly, and CymaBay.

Biopharmaceutical companies active in the IL-2 research include Roche Holding AG, Amgen, Bristol Myers Squibb, Eli Lilly, and Moderna.

Small, early-stage biopharmaceutical companies active in the research for new technologies to induce antigen-specific immune tolerance include Abata Therapeutics, Anokion SA, Cour Pharmaceutical Development Company, Inc., Cue Biopharma, Parvus Therapeutics, REGiMMUNE Corporation, Topas Therapeutics GmbH, Sangamo Therapeutics, and SQZ Biotechnologies.

Biopharmaceutical companies active in the research for MMA include BridgeBio Pharma, Inc., HemoShear Therapeutics, Inc., LogicBio, Poseida, and Moderna.

Biopharmaceutical companies active in the research for IgA nephropathy include Omeros, Travere, Novartis, Ionis, Visterra, Chinook Therapeutics, Calliditas Therapeutics AB, Vera Therapeutics, and Eledon Pharmaceuticals.

Biopharmaceutical companies active in autoimmune disease research include Calliditas Therapeutics AB, CymaBay, Genfit, and Intercept Pharmaceuticals.

Large biopharmaceutical companies active in the IL-2 research include Abbvie, Inc., Amgen, Bristol Myers Squibb, Eli Lilly, Sanofi S.A., and Merck & Co., Inc.

Government Regulation

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Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical study, dosing procedures, patient selection and exclusion criteria, and the parameters to be used to monitor patient safety.

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

Each protocol and

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

Clinical trials must be conducted and monitored in accordance with the FDA’s regulations comprising the GCP requirements, including the requirement that all research subjects provide informed consent.

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In addition, if a product receives the first FDA approval for the indication for which it has orphan designation, the product is entitled to orphan exclusivity, which means the FDA may not approve any other application to market the same product for the same indication for a period of seven years, except in limited circumstances, such as a showing of clinical superiority over the product with orphan exclusivity or where the manufacturer with orphan exclusivity is unable to assure sufficient quantities of the approve orphan product.

Competitors, however, may

receive approval of different products for the indication for which the orphan product has exclusivity or obtain approval for the same product but for a different indication for which the orphan product has exclusivity.

Competitors, however, may receive approval of different products for the indication for which the orphan product has exclusivity or obtain approval for the same product but for a different indication for which the orphan product has exclusivity.

Orphan product exclusivity also could block the approval of one of our products for seven years if a competitor obtains approval of the same biological product as defined by the FDA or if our product candidate is determined to be contained within the competitor’s product for the same indication or disease.

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Under the Centralized Procedure the maximum timeframe for the evaluation of a marketing authorization application is 210 days (excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP).

Accelerated evaluation might be granted by the CHMP in exceptional cases.

Accelerated evaluation might be granted by

the CHMP in exceptional cases.

Under the accelerated procedure the standard 210 days review period is reduced to 150 days.

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Products receiving orphan designation in the European Union can receive ten years of market exclusivity, during which time no marketing authorization application shall be accepted, and no marketing authorization shall be granted for a similar medicinal product for the same indication.

An orphan product can also obtain an additional two years of market exclusivity in the European Union for pediatric

An orphan product can also obtain an additional two years of market exclusivity in the European Union for pediatric studies.

No extension to any supplementary protection certificate can be granted on the basis of pediatric studies for orphan indications.

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Actions under the civil False Claims Act may be brought by the Department of Justice or as a qui tam action by a private individual in the name of the government.

Violations of the civil False Claims Act can result in very significant monetary penalties and treble damages, and may be accompanied by additional civil monetary penalties against

Violations of the civil False Claims Act can result in very significant monetary penalties and treble damages, and may be accompanied by additional civil monetary penalties against individuals.

Many states also have similar fraud and abuse statutes or regulations that apply to items and services reimbursed under Medicaid and other state programs, or, in several states, apply regardless of the payor.

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On January 2, 2013, the American Taxpayer Relief Act was signed into law, which, among other things, further reduced Medicare payments to several providers, including hospitals and imaging centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies.

Recently there has also been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several Congressional inquiries and proposed and enacted legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies.

Human Capital Resources

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Employees are also eligible to receive an annual cash bonus and to participate in a 401(k) retirement plan with an industry competitive company match.

In response to the COVID-19 pandemic, we initially implemented changes to our business practices in March 2020, taking precautions to protect the health and safety of our employees by instituting robust hygiene practices, installing temporary safety structures, increasing our cleaning protocols, implementing weekly COVID-19 testing, and limiting regular access to our facilities.

As the health environment continues to evolve, we remain committed to actively monitor and evolve our protocols to align with the Center for Disease Control’s best practices, including tracking vaccination and booster status and providing regular communication related to community resources.

Additionally, we introduced wellness initiatives as well as a flexible work environment policy and enhanced remote technology solutions, providing remote work opportunities for all employees both now, and well into the future.

Available Information

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• We may not have the funds necessary to fulfill our obligation to repurchase certain warrants.

• We are involved in two securities class action lawsuits.

• We have been in the past and may in the future be subject to securities class action lawsuits.

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business