What changed in this filing

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Item 1. Business

2022-03-24 compared with 2021-03-31 · 169 added, 148 removed, 303 unchanged (51% of the section changed)

Eledon Pharmaceuticals, Inc.

(“Eledon” or the “Company”) is a clinical stage biopharmaceutical company focused on developing life-changing, targeted medicines for persons living with an autoimmune disease, requiring an organ or cell-based transplant, or living with amyotrophic lateral sclerosis (“ALS”) .

Our lead product candidate, AT-1501, is a humanized monoclonal antibody (mAb), designed to target CD40 Ligand (“CD40L”), also called CD154), a molecule expressed on the surface of human immune system T cells.

The central role of CD40/CD40L signaling in generating pro-inflammatory responses makes it an attractive candidate for therapeutic intervention in autoimmune disease, induction and maintenance of transplant tolerance, and neuroinflammation.

Blocking the activation of the CD40L pathway prevents acute and long-term allograft transplant rejection in multiple animal species and ameliorates disease progression and pathology in preclinical models of autoimmunity and ALS.

(“Eledon” or the “Company”) is a clinical stage biopharmaceutical company focused on developing life-changing, targeted medicines for persons requiring an organ or cell-based transplant, living with autoimmune disease, or living with amyotrophic lateral sclerosis (“ALS”) .

The Company’s lead compound in development is AT-1501, an IgG1, anti-CD40L antibody with high affinity for CD40 Ligand (“CD40L”, also called “CD154”), a well-validated biological target that we believe has broad therapeutic potential.

AT-1501 is engineered to potentially both improve safety and provide pharmacokinetic, pharmacodynamic, and dosing advantages compared to other anti-CD40 approaches.

The CD40L/CD40 pathway is recognized for its prominent role in immune regulation.

CD40L is primarily expressed on activated CD4+ T cells, platelets and endothelial cells while the CD40 receptor is constitutively expressed on antigen presenting cells such as macrophages and dendritic cells, as well as B cells.

By blocking CD40L and not the CD40 receptor, AT-1501 inhibits both the CD40 and CD11 costimulatory signaling pathways, providing the potential for improved efficacy compared to anti-CD40 receptor approaches.

Blocking CD40L also increases polarization of CD4+ lymphocytes to Tregs, a specialized subpopulation of T cells that act to suppress an immune response, thus creating a more tolerogenic environment, which may play a therapeutic role for autoimmune diseases and in the transplant setting.

AT-1501 is designed to negate the risk of thrombolytic events seen in the first generation of anti-CD40L antibodies by introducing structural modifications that have been shown in preclinical models to eliminate binding to the Fcγ receptors associated with platelet activation without altering the binding of AT-1501 to CD40L.

In non-human primate studies, dosing of AT-1501 up to 200 mg/kg per week for 26 weeks, demonstrated no adverse events regarding coagulation, platelet activation or thromboembolism.

In September 2020, we acquired Anelixis Therapeutics, Inc.

(“Anelixis”), the company that owned or controlled the intellectual property related to AT-1501.

AT-1501 is a humanized IgG1 anti-CD40L antibody lacking Fc effector function.

It is designed to inhibit signaling via CD40L, a costimulatory type II membrane receptor expressed on activated T cells and CD40, a receptor expressed on Antigen Presenting Cells (“APC”s).

Interactions between B cells expressing CD40, and activated CD4+ “helper” T cells expressing CD40L, play a critical role in promoting germinal center formation, clonal expansion, antibody production, and the secretion of pro-inflammatory cytokines that amplify immune response.

The role of CD40 in B cells has been extensively characterized and shown to have an important role in the generation of primary and secondary humoral immune responses to T cell dependent antigens.

Anti-CD40L antibodies also inhibit both CD40 as well as CD11 costimulatory receptors on antigen presenting cells, thus inhibiting the pro-inflammatory polarization of CD4+ and CD8+ lymphocytes.

Finally, blocking CD40L also polarizes CD4+ lymphocytes to FoxP3 positive Tregs, a specialized subpopulation of T cells that act to suppress immune response and create a more tolerogenic environment.

Importantly, blocking the CD40-CD40L pathway has not been shown to cause systemic lymphopenia.

Our business strategy is to optimize the clinical and commercial value of AT-1501 and become a global biopharmaceutical company with a focused autoimmune franchise.

In non-human primate studies, dosing of AT-1501 up to 200 mg/kg per week for 26 weeks, demonstrated no adverse events regarding coagulation, platelet activation or thromboembolism.

We have completed a single ascending dose Phase 1 study of AT-1501 in healthy volunteers and people with ALS.

In this study, the doses of AT-1501 studied were well tolerated in healthy subjects and adults with ALS, and demonstrated a safety profile comparable to placebo.

In this study, the doses of AT-1501 studied were well tolerated in healthy subjects and adults with ALS.

AT-1501 demonstrated low anti-drug antibody responses that were not dose related, linear dose proportionality across the dose ranges, and a half-life of up to 26 days.

We plan to develop AT-1501 in up to four indications:

prevention of kidney allograft rejection, prevention of islet cell allograft rejection, autoimmune nephritis, and ALS.

ALS, prevention of kidney allograft rejection, prevention of islet cell allograft rejection, and IgA Nephropathy (“IgAN”).

We selected our indications based on preclinical and clinical data that was generated with either our molecule or historical anti-CD40L molecules.

In October 2020, we initiated a Phase 2a clinical trial of AT-1501 in ALS.

In November 2020, we received clearance from Health Canada to proceed with the initiation of a Phase 2 clinical trial of AT-1501 in islet cell transplantation for the treatment of type 1 diabetes.

Prior to our acquisition of Anelixis, we had been focused on developing medicines for patients with disorders of the ear, nose, and throat (“ENT”).

In November 2020, we received clearance from Health Canada to proceed with the initiation of a Phase 2a clinical trial of AT-1501 for people with type 1 diabetes undergoing islet cell transplantation.

In July 2021, we received clearance from Health Canada to proceed with initiation of a Phase 1b clinical trial of AT-1501 in patients undergoing kidney transplantation.

In November 2021, we received investigational new drug (“IND”) clearance from the FDA for a Phase 2a clinical trial of AT-1501 for people with type 1 diabetes undergoing islet cell transplantation in the United States.

In December 2021, we received approval for a Phase 1b clinical trial of AT-1501 in kidney transplantation in the United Kingdom and received regulatory approvals for a Phase 2a clinical trial of AT-1501 in IgAN in Australia and New Zealand.

In January 2022, the United States Adopted Names (“USAN”) Council adopted “tegoprubart” as the unique non-proprietary name for AT-1501.

Going forward, Eledon will generally use tegoprubart in reference to AT-1501.

Prior to our acquisition of Anelixis, we focused on developing medicines for patients with disorders of the ear, nose, and throat (“ENT”).

In June 2020, we announced that our lead program did not achieve statistical significance for the primary efficacy endpoints in the treatment of acute otitis media.

As a result of this failure to achieve the primary study endpoint, we suspended the clinical development of our legacy ENT assets while we assessed potential development strategies.

Following the June 2020 announcement, we significantly curtailed development expenses as we sought to identify strategic alternatives that would maximize stockholder value.

Following the June 2020 announcement, we significantly curtailed development expenses as we sought to identify strategic alternatives

that would maximize stockholder value.

As a result of these activities, we acquired Anelixis and raised additional capital in September 2020, as described above.

Subsequent to our acquisition of Anelixis, we undertook a strategic review of the legacy ENT assets.

We concluded this review and determined that the best path forward was to terminate license agreements associated with these ENT assets and return the rights to the original license holders, which we did in July 2021.

There was no financial impact to returning these assets.

Amyotrophic Lateral Sclerosis

ALS is a progressive, paralytic disorder characterized by degeneration of motor neurons in the brain and spinal cord.

In the U.S., the incidence is estimated at approximately 5,000 cases per year with a prevalence of approximately 30,000 cases overall.

Despite 2 approved drugs, in most cases, death from respiratory failure occurs approximately 3 to 5 years after diagnosis, with 50% of patients living at least 3 years from diagnosis and only 20% of patients living at least 5 years from diagnosis.

While the exact pathogenic mechanism of ALS is still not fully understood, there is strong evidence indicating that neuroinflammation plays an important role in the disease’s pathogenesis.

Neuroinflammation in ALS is characterized by the infiltration of lymphocytes and macrophages into the central nervous system, and the activation of microglia and reactive astrocytes.

Reactive astrocytes and microglia as well as infiltrating lymphocytes, dendritic cells, monocytes, macrophages, and immune complexes have been identified in cerebrospinal fluid and neural tissues in both animal models of ALS and at autopsy in ALS patients.

Tegoprubart is designed to block CD40L binding to CD40, thereby potentially inhibiting neuroinflammatory pathways leading to disease progression in ALS.

In vitro proof-of-concept studies have shown that tegoprubart binds to CD40L in human cells and blocks CD40L binding on APCs and activated T cells.

The potential for therapeutic benefit of CD40L blockage in treating ALS has been demonstrated in a SOD1 mouse model of ALS, where a murine anti-CD40L antibody, MR1, prolonged survival and delayed the onset of neurological disease progression.

These clinical manifestations are believed to be due to reduced immune cell infiltration of macrophages into skeletal muscle and their destroying denervated nerves.

The plasticity of the nervous system to repair itself in the absence of this immune cell attack is believed to result in improved neuromuscular junction occupancy and improved muscle function.

Blocking CD40L signaling also prevents pro-inflammatory polarization of lymphocytes, reduced neuroinflammation and improved motor neuron survival in rodent ALS models (Figure 1).

Blocking CD40L Improves Survival and Pathophysiology Associated with ALS

Anti-CD40L (“MR1”) treatment decreases CD68+ macrophages, improves neuromuscular junction occupancy and improves motor neuron survival.

(A) Quantification of reduction of CD68+ macrophages by anti-CD40L treatment at day 100.

(White bar, control IgG);

gray bar (anti-CD40L–treatment);

black bar (untreated age-matched non-transgenic mice) (B) Quantification of neuromuscular occupancy in SOD1 mice prior to overt symptoms (day 70) versus

after symptom onset (day 85) treated with an IgG control antibody (veh icle ) or anti-CD40L antibody.

(C) Quantitative comparison of lumbar spinal cord motor neuron counts per mm2 in IgG vehicle control (White bar) versus anti-CD40L treated mice (grey bar) at day 100 (Lincecum, 2010).

In October 2020, we initiated a Phase 2a, open-label, multi-center study to evaluate the safety and tolerability of multiple doses of tegoprubart in adult subjects with ALS.

Fifty-four subjects with ALS have been enrolled into the study in the United States and Canada at 13 ALS treatment sites.

Ascending doses of tegoprubart are being administered as IV infusions to four sequentially enrolling cohorts.

The first two cohorts consisted of nine participants, and the last two cohorts of 18 participants each.

All enrolled subjects are to receive six bi-weekly infusions of tegoprubart over a 12-week study period.

Blood samples for target engagement, and exploratory biomarkers for inflammation and neurodegeneration are being taken and analyzed.

Participant-focused clinical outcomes will also be assessed.

We completed enrollment in all four cohorts in December 2021.

Kidney transplantation:

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Kidney transplantation is the most common type of solid organ transplantation in the United States with an estimated 227,000 Americans living with a transplanted kidney.

In 2019, an estimated 23,000 kidneys were transplanted, of which 10-15% were re-transplants in persons that had already received at least one other kidney.

Yet, over 90,000 people in the U.S.

In 2019, an estimated 23,000 kidneys were transplanted, of which up to 15% were re-transplants in persons that had already received at least one other kidney.

Over 90,000 people in the U.S.

are waiting for a kidney transplant and in 2014, nearly 5,000 Americans died waiting for a kidney with another nearly 4,000 becoming too sick to receive a transplant.

Calcineurin inhibitor (“CNI”s) are a critical component of many immunosuppressive regimens to prevent acute and long-term kidney transplant rejection.

However, chronic exposure to certain CNIs including tacrolimus is associated with nephrotoxicity, cardiotoxicity, an increase in opportunistic infections, increased malignancies, and an increase in type 1 diabetes due to pancreatic Beta cell toxicity.

These liabilities may result in a requirement for reduced exposures to CNIs over long periods of time and a resulting decrease in the ability to prevent long-term rejection.

AT-1501 seeks to address challenges associated with current immunosuppressive transplantation regimens using CNI-based therapies.

However, chronic exposure to certain CNIs including tacrolimus is associated with nephrotoxicity, cardiotoxicity, new onset diabetes due to pancreatic Beta cell toxicity and an increase in both opportunistic infections and malignancies.

Over time, these CNI side effects may significantly damage transplanted kidneys or result in a requirement for reduced exposures to CNIs and a resulting potential decrease in the ability to prevent long-term rejection.

Tegoprubart seeks to address challenges associated with current immunosuppressive transplantation regimens using CNI-based therapies.

The ability to prevent acute and chronic transplant rejection without the need for CNIs has the potential to transform the clinical management of preventing graft rejection by mitigating the adverse events associated with CNIs and improving long-term graft survival, thus potentially decreasing the need for repeat kidney transplants.

Several historical studies have described the effects of anti-CD40L antibodies in nonhuman primate models of kidney transplant and shown that even short courses of anti CD40L therapy can prevent both acute rejection and long-term rejection in nonhuman primates with durable efficacy (Figure 2).

Historical Anti-CD40L Antibody 5c8 Prevents Acute and Long Term Kidney Transplant Rejection in Nonhuman Primates.

(A) Kaplan Meier Graph:

ABI793, an anti-CD40L antibody or an IgG isotype control antibody was given intravenously to seven monkeys on postoperative days (PODs) 0, 1, 4, 11, 18, 28, 56, and 84 at a dose of 20 mg/kg (Kanmaz, 2004).

(B) The combination of anti-CD154 dAb with basiliximab, mycophenolate mofetil, and steroids significantly improved rejection-free allograft survival (Kim, 2017).

Islet cell transplantation (“ICT”):

In aggregated data from the published studies referenced in Figure 2 below , non-human primates undergoing allograft renal transplantation receiving anti-CD40L monotherapy (e.g., 5c8, AI794, IDEC-131) had longer average survival than both those receiving anti-CD40 monotherapy (e.g., 4D11, cH5D12, Chi220, ASKP1240) and untreated controls (Figure 2).

Inhibition of CD40L improved survival vs.

CD40 inhibition in non-human primate kidney transplantation monotherapy studies

Kaplan-Meir estimates of the probability of rejection free survival by treatment group from eleven published studies of allograft kidney transplant in non-human primates.

Median survival of untreated animals is 6 days (red line), monotherapy anti CD40 treated animals 131 days (gray line), and monotherapy anti CD40L treated animals 352 days (blue line), log rank test P= 0.0001.

( Kirk, 1999;

Preston, 2005;

Montgomery, 2002;

Kanmaz, 2004;

Aoyagi, 2009;

Haanstra, 2003;

Pearson, 2002;

Cordoba 2015).

Analysis not based on head-to-head comparison.

Differences between any individual programs may vary.

In July 2021, the Company initiated a preclinical renal transplant study evaluating AT-1501 monotherapy in at least four non-human primates.

In July 2021, the company received a No Objection Letter (NOL) from Health Canada for a Phase 1b clinical trial of tegoprubart, in 6 to 12 subjects, replacing tacrolimus as an immunosuppressive regimen component in patients undergoing kidney transplantation.

In December 2021, we received approval for a Phase 1b clinical trial of tegoprubart, replacing tacrolimus as an immunosuppressive regimen component in patients undergoing kidney transplantation in the United Kingdom.

Islet cell transplantation:

prevention of allograft rejection

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Impaired awareness of hypoglycemia for people with type 1 diabetes is associated with severe hypoglycemic events which can lead to significant symptoms and even death.

Pancreatic islet cell transplantation is gaining attention as a therapeutic option for type 1 diabetes because it can restore physiological insulin secretion, minimize the risk of hypoglycemic unawareness, and reduce the risk of death due to severe hypoglycemia.

The advances made in this field over the past decade have improved patient outcomes, and the procedure has been evolving from an experimental treatment to a clinical treatment option.

In November 2020, we received clearance from Health Canada to proceed with the initiation of a Phase 2 clinical trial of AT-1501 in islet cell transplantation for the treatment of type 1 diabetes.

A number of issues are believed to continue to hamper the overall success of ICT and to need to be addressed in order for there to be widespread clinical acceptance.

Pancreatic islet cell transplantation may be a therapeutic option for type 1 diabetes because it can restore physiological insulin secretion, minimize the risk of hypoglycemic unawareness, and reduce the risk of death due to severe hypoglycemia.

The advances made in this field over the past decade have improved patient outcomes.

A number of issues are believed to continue to hamper the overall success of islet cell transplantation and need to be addressed in order for there to be widespread clinical acceptance.

These include the acute loss of transplanted islets with current immunosuppressive treatments, particularly those with CNI-based therapies, due to islet cell toxicity and alloreactive immunologic responses to transplanted islets.

Over time, the progressive loss of islet cells and decline in islet cell function often leads to the need for multiple donors in order for BTID patients to have optimal response to blood glucose levels and possibly achieve insulin independence.

AT-1501 seeks to address the challenges associated with current ICT immunosuppressive regimens using CNI-based therapies, by replacing the CNIs with AT-1501.

CD40L blockade may abolish many effector mechanisms of inflammation, prevent and intervene in the progression of autoimmunity, and instill transplant tolerance.

Over time, the progressive loss of islet cells and decline in islet cell function

often leads to the need for multiple transplant procedures in order for BT 1 D patients to have optimal response to blood glucose levels and possibly achieve insulin independence.

We believe that treatment with t egoprubart will address the challenges associated with current islet cell transplantation immunosuppressive regimens using CNI-based therapies, by replacing the CNIs with tegoprubart .

CD40L blockade may abolish many effector mechanisms of inflammation, prevent , and intervene in the progression of autoimmunity, and instill transplant tolerance without causing harm to islet cells .

Historical studies in nonhuman primate models of islet cell transplantation have demonstrated that treatment with anti-CD40L antibodies induces long term islet cell function and graft survival, even as a monotherapy.

AT-1501 has shown pre-clinical, proof-of-concept efficacy in a non-human primate model of type 1 diabetes, where animals undergoing ICT maintained glucose control and sustained levels of C-peptide with chronic AT-1501 treatment for up to a year.

Compared to combination immunosuppressive therapy including CNIs, AT-1501 monotherapy was more effective in preventing long term islet cell rejection, associated with better graft function, and showed an improved safety profile (Figure 3).

Fasting, Postprandial Blood Glucose and C-Peptide Levels Over Time .

Daily fasting glucose levels (black circles);

post prandial glucose levels (green line) and exogenous insulin (blue line) versus time (days).

Bottom Graphs :

C peptide levels fasting blue bars) and post prandial (red bars) versus time (days).

Left Panel Standard of Care (SOC ):

Thymoglobulin at 5 mg/kg on post-operative day (POD) -2, -1, 0, 1, 2, Enbrel at 0.8 mg/kg on POD 0 and at 0.4 mg/kg on POD 3, 7, 10.

Sirolimus, starting on POD -2 at 0.02 mg/kg;

target trough levels 8-12 ng/ml and Tacrolimus, starting on POD 1 at 0.025 mg/kg target trough levels 4-6 ng/ml.

Right Panels AT-1501 Monotherapy :

AT-1501 at 23-26 mg/kg in the first 3 months post-transplant on POD -1, 0, 3, 10, 18, 23, 28 and then every 14 days until end of study.

Autoimmune Nephritis

Autoimmune Nephritis refers to a group of autoimmune disorders associated with inflammation and eventual destruction of the kidney.

These disorders include Lupus Nephritis (“LN”), focal segmental glomerulosclerosis (“FSGS”) and IgA Nephropathy (“IgAN”).

Systemic lupus erythematosus, (“SLE”), is one of the largest autoimmune populations globally and up to an estimated 40 percent of people with SLE develop LN, which may lead to kidney dysfunction, dialysis and end stage renal disease.

LN is an orphan disease with an estimated prevalence of between 65,000 and 120,000 persons in the United States.

FSGS is also an orphan disease with an estimated prevalence of 40,000 people in the US and variable progression to end stage renal failure.

FSGS results from renal podocyte injury associated with immune complex formation in the glomeruli.

IgAN, also called Berger’s disease, is a type of glomerulonephritis that occurs when galactose-deficient IgA immune complexes build up in the kidneys, causing inflammation that ultimately damages kidney tissues.

With an estimated prevalence of approximately 140,000 persons in the United States, IgAN is one of the most common, orphan, kidney diseases.

There are currently no European Medicines Agency (“EMA”) or U.S.

Food and Drug Administration (“FDA”) approved treatments for IgAN or FSGS, and only two approved for LN, although immunosuppressants such as systemic steroids and CNIs are prescribed off-label.

In historical preclinical animal models of lupus nephritis, anti-CD40L antibodies ameliorated disease progression, improved kidney function, reduced immune cell infiltrate into the kidney, and improved survival.

Systemic biomarkers of SLE such as anti-dsDNA antibodies have also been reduced with anti-CD40L treatment in animal models.

Similar data has been described in preclinical models of FSGS.

FSGS models using historical anti-CD40L treatments have shown ameliorated kidney function as measured by a reduction in proteinuria and were associated with a decrease in immune cell infiltrate into the glomeruli (Figure 3).

Tegoprubart has shown pre-clinical, proof-of-concept efficacy in a non-human primate model of type 1 diabetes, where animals undergoing islet cell transplantation maintained glucose control and sustained levels of C-peptide with chronic tegoprubart treatment for up to a year.

Compared to combination immunosuppressive therapy including CNIs, tegoprubart monotherapy was more effective in preventing long term islet cell rejection, associated with better graft function, and showed an improved safety profile (Figure 3 and Figure 4).

Prolonged Graft Survival vs.

CNI Containing Regimen (“CIS”) in a non-human primate islet cell transplant model

Non-human primates treated with tegoprubart (blue bars) had longer rejection free survival and longer overall graft survival vs CNI containing regimen (gray bars).

(Kenyon, 2021).

Tegoprubart treatment was associated with improved health and superior metabolic control compared to CNI containing treatment

Animals treated with tegoprubart had a statistically significant improvement in bodyweight post islet cell transplant compared to CNI treated animals.

The improvement in bodyweight is associated with improved appetite in the tegoprubart treated animals (data not shown).

Animals treated with tegoprubart had improved metabolic control compared to animals treated with CNIs as shown by improved fasting and meal stimulated blood glucose levels as well as a statistically significant improvement in fasting and stimulated C peptide levels, a surrogate of improved islet cell function.

(Kenyon, 2021)

In November 2020, we received clearance from Health Canada to proceed with the initiation of a Phase 2a clinical trial of tegoprubart for people with type 1 diabetes undergoing islet cell transplantation.

In November 2021, we received IND clearance from the FDA to proceed with the initiation of a Phase 2a clinical trial of tegoprubart for people with type 1 diabetes undergoing islet cell transplantation in the United States.

IgA Nephropathy

IgAN is the leading cause of glomerulonephritis, a state of inflammation producing damage to the filtering part of the kidney.

Disease manifestation and clinical presentation involves renal dysfunction characterized by proteinuria with a slow relentless course.

Approximately 30%-40% of patients ultimately reach end stage renal disease (ESRD).

The standard of care for ESRD is dialysis or kidney transplant, which represents a significant economic burden as well as a major impact on a patient’s quality of life.

With an estimated prevalence of approximately 150,000 persons in the United States, IgAN is one of the most common kidney diseases.

There are currently no European Medicines Agency (“EMA”) approved treatments for IgAN, although in the United States budesonide was approved for use in IgAN by the FDA in December 2021.

The pathophysiology of IgAN has been well characterized, and based on its mechanism of action, tegoprubart has the potential to impact the disease process both upstream, at the source of the immune complexes, and downstream in the kidney itself, where it may reduce inflammation in the glomeruli.

By disrupting multiple steps in the IgAN’s pathophysiology, tegoprubart has the potential to affect the clinical course of the disease and improve outcomes for patients.

The inhibition of

CD40L has been shown to be effective in models of multiple glomerulonephritides, as measured by a reduction in proteinuria and were associated with a decrease in immune cell infiltrate into the glomeruli (Figure 5 ).

Blocking CD40L Improves Survival and Pathophysiology Associated with Autoimmune Nephritis

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(A) The survival curves of anti-CD40L treated and HIg controls differ significantly ( p < 0.001 by Wilcoxon test).

Control mice receiving HIgG control die rapidly with the onset of severe nephritis, and all but one are dead by age 12 mo while all anti-CD40L treated mice are alive when the study is terminated at age 15.5 months (Kalled.1998).

Control mice receiving HIgG control die rapidly with the onset of severe nephritis, and all but one are dead by age 12 months while all anti-CD40L treated mice are alive when the study is terminated at age 15.5 months (Kalled, 1998).

(B) Urine was monitored weekly for proteinuria.

11 unchanged sentences

Adriamycin alone group (Kairatis, 2003).

Amyotrophic Lateral Sclerosis

ALS is a progressive, paralytic disorder characterized by degeneration of motor neurons in the brain and spinal cord.

In the U.S., the incidence is estimated at approximately 5,000 cases per year with a prevalence of approximately 30,000 cases overall.

Despite 2 approved drugs, in most cases, death from respiratory failure occurs approximately 2 to 5 years after diagnosis, with 50% of patients living ≥ 3 years from diagnosis and only 20% of patients living ≥ 5 years from diagnosis.

Neuroinflammation in ALS is characterized by the infiltration of lymphocytes and macrophages into the central nervous system, and the activation of microglia and reactive astrocytes.

Reactive astrocytes and microglia as well as infiltrating lymphocytes, dendritic cells, monocytes, macrophages and immune complexes have been identified in cerebrospinal fluid and neural tissues in both animal models of ALS and at autopsy in ALS patients.

While the exact pathogenic mechanism of ALS is still not fully understood, there is strong evidence indicating that this neuroinflammation plays an important role in the disease’s pathogenesis.

AT-1501 is designed to block CD40L binding to CD40, thereby potentially inhibiting neuroinflammatory pathways leading to disease progression in ALS.

In vitro proof-of-concept studies have shown that AT-1501 binds to CD40L in human cells and blocks CD40L binding on APCs and activated T cells.

These clinical manifestations are believed to be due to reduced immune cell infiltration of macrophages into skeletal muscle and their destroying denervated nerves.

The plasticity of the nervous system to repair itself in the absence of this immune cell attack is believed to result in improved neuromuscular junction occupancy and improved muscle function.

Blocking CD40L signaling also prevents pro-inflammatory polarization of lymphocytes, reduced neuroinflammation and improved motor neuron survival in rodent ALS models (Figure 5).

Blocking CD40L Improves Survival and Pathophysiology Associated with ALS

Anti-CD40L (MR1) treatment decreases CD68+ macrophages, improves neuromuscular junction occupancy and improves motor neuron survival.

(A) Quantification of reduction of CD68+ macrophages by anti-CD40L treatment at day 100.

(White bar, control IgG) ;

gray bar (anti-CD40L–treatment);

black bar (untreated age-matched non-transgenic mice) (B) Quantification of neuromuscular occupancy in SOD1 mice prior to overt symptoms (day 70) versus after symptom onset (day 85) treated with an IgG control antibody (veh) or anti-CD40L antibody.

(C) Quantitative comparison of lumbar spinal cord motor neuron counts per mm2 in IgG vehicle control (White bar) versus anti-CD40L treated mice (grey bar) at day 100 (Lincecum, 2010).

In October 2020, we initiated a Phase 2a, open-label, multi-center study to evaluate the safety and tolerability of multiple doses of AT-1501 in adult subjects with ALS.

Approximately 54 subjects with ALS are planned to be enrolled into the study in the United States and Canada at up to 13 ALS treatment sites.

Ascending doses of AT-1501 will be administered as IV infusions to four sequentially enrolling cohorts.

The first two cohorts will consist of nine participants, and the last two cohorts of 18 participants, who will each receive six bi-weekly infusions of AT-1501 over a 12-week study period.

Blood samples for target engagement, and exploratory biomarkers for inflammation and neurodegeneration will be taken and analyzed.

Participant-focused clinical outcomes will also be assessed.

In December 2021, we received regulatory clearances to initiate a phase 2a study in IgAN in Australia and New Zealand, and plan to expand to other countries.

The global study will include up to 42 subjects in a high dose and a low dose cohort, with endpoints starting at 24 weeks including change in urinary protein.

The competitive conditions faced by the Company are described in greater detail in Part I, Item 1A.

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Intellectual Property

Eledon’s success depends in part on its ability to obtain and maintain proprietary protection for its product candidates, novel discoveries, product technologies and other know-how, to operate without infringing on the proprietary rights of others and to prevent others from infringing Eledon’s proprietary rights.

Eledon seeks to protect its product candidates by, among other methods, filing U.S.

and foreign patent applications related to its proprietary technology, inventions and improvements that are important to the development and implementation of its business.

Eledon also relies on trademarks, trade secrets, know-how, continuing technological innovation and potential in-licensing opportunities to develop and maintain Eledon’s proprietary protection for Eledon’s product candidates.

Eledon’s intellectual property portfolio includes issued patents and patent applications directed toward isolated antibodies and methods of treatment using the isolated antibodies that block the interaction of CD40L and CD40 to treat CD-40L related diseases or disorders.

Eledon has exclusive rights to three patent families.

Two of the three families are directed to AT-1501 and related antibodies.

Eledon’s success depends in part on our ability to obtain and maintain proprietary protection for our product candidates, novel discoveries, product technologies and other know-how, to operate without infringing on the proprietary rights of others and to prevent others from infringing our proprietary rights.

We seek to protect our product candidates by, among other methods, filing U.S.

and foreign patent applications related to our proprietary technology, inventions and improvements that are important to the development and implementation of our business.

We also rely on trademarks, trade secrets, know-how, continuing technological innovation and potential in-licensing opportunities to develop and maintain proprietary protection for our product candidates.

Our intellectual property portfolio includes issued patents and patent applications directed toward isolated antibodies and methods of treatment using the isolated antibodies that block the interaction of CD40L and CD40 to treat CD-40L related diseases or disorders.

We have exclusive rights to three patent families.

Two of the three families are directed to tegoprubart and related antibodies.

The first family is directed to methods for treating amyotrophic lateral sclerosis with antibodies and includes two United States patent s and 14 foreign patents (Japan, Hong Kong, Belgium, China, Germany, Denmark, Spain, Finland, France, Great Britain, Ireland, Italy, the Netherlands, and Sweden).

The second family is directed to AT-1501 (JB5 in the patents/applications in this family).

AT-1501 is the current clinical candidate, with 14 pending applications, and issued/allowed patents including two issued United States patents, one allowed United States patent application, and a Russian patent.

The third family is directed to AT-1501 with 15 pending applications, including one United States patent application.

The second family is directed to tegoprubart (JB5 in the patents/applications in this family).

Tegoprubart is the current clinical candidate, with 14 pending applications, and issued/allowed patents including two issued United States patents, one allowed United States patent application, and a Russian patent.

The third family is directed to tegoprubart with 15 pending applications, including one United States patent application.

In the first family, the patents will expire in December 2029, absent any term adjustments or extensions.

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In the third family, any issued patent will expire in May 2038, absent any term adjustments or extensions.

Eledon’s intellectual property portfolio also includes issued patents and patent applications directed towards products derived from Eledon’s surfactant platform and foam platform with claims to drug substance, pharmaceutical preparations as well as to methods of treatment.

For OP0201, Eledon owns or has exclusive rights to one U.S.

patent application, one international application, and seven foreign patent applications.

If allowed, the last to expire patent application will expire in December 2039, absent any adjustments or extensions.

For OP0101 and OP0102, Eledon owns or has exclusive rights to two families of patents, one with three United States and seven foreign patents (Canada, France, Germany, Israel, Italy, Spain, and the United Kingdom), and a second with two United States and five foreign patents (France, Germany, Italy, Spain and the United Kingdom).

In the first family the last to expire issued patent in the United States will expire in September 2027, including patent term adjustment.

In the second family the last to expire issued patent in the United States will expire in December 2033.

Subsequent to our acquisition of Anelixis, we undertook a strategic review of the legacy ENT assets.

There was no financial impact to returning these assets.

Patents extend for varying periods according to the date of patent filing or grant and the legal term of patents in various countries where patent protection is obtained.

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In addition, Eledon also requires confidentiality or service agreements from third parties that receive confidential information or materials.

Commitments and Contingencies under the caption “Grants and Licenses” for further information about the Company’s intellectual property.

Commitments and Contingencies of the consolidated financial statements included elsewhere herein under the caption “Grants and Licenses” for further information about the Company’s intellectual property.

Manufacturing

We do not own or operate manufacturing facilities for the production of tegoprubart or any future product candidates, nor do we have plans to develop our own manufacturing operations in the foreseeable future.

We currently rely on third parties for raw materials and the manufacturing of drug substance and drug product for nonclinical and clinical activities.

As of the date of this Annual Report, we have not experienced any difficulty in obtaining raw materials required with respect to the manufacturing of tegoprubart.

We believe we have enough drug substance and drug product on hand and manufacturing capacity with our third-party manufacturing providers to meet forecasted clinical trial demand.

We also rely on third parties to label, store and distribute drug product for our nonclinical and clinical trials.

Government Regulation

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submission to the FDA of an IND which must become effective before human clinical trials may begin and must be updated annually;

approval by an independent institutional review board (“IRB”) or ethics committee representing each clinical site before each clinical trial may be initiated;

approval by an independent institutional review board (“ I RB ” ) or ethics committee representing each clinical site before each clinical trial may be initiated;

performance of adequate and well-controlled human clinical trials to establish the safety and efficacy of the product candidate for each proposed indication;

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a determination by the FDA within 60 days of its receipt of a BLA or NDA to file the application for review;

satisfactory completion of a FDA pre-approval inspection of the manufacturing facilities where the proposed product is produced to assess compliance with current Good Manufacturing Practices (“cGMP”) regulations;

satisfactory completion of an FDA pre-approval inspection of the manufacturing facilities where the proposed product is produced to assess compliance with current Good Manufacturing Practices (“cGMP”) regulations;

potential FDA audit of the clinical trial sites that generated the data in support of the BLA or NDA;

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The drug is administered to a limited patient population to evaluate dosage tolerance and optimal dosage, identify possible adverse side effects and safety risks, and preliminarily evaluate efficacy.

The drug is administered to an expanded patient population, generally at geographically dispersed clinical trial sites to generate enough data to evaluate dosage, clinical effectiveness and safety, to establish the overall benefit-risk relationship of the investigational new drug product, and to provide an adequate basis for physician labeling.

benefit-risk relationship of the investigational new drug product, and to provide an adequate basis for physician labeling.

In some cases, the FDA may condition approval of a BLA or NDA for a product candidate on the sponsor’s agreement to conduct additional clinical trials after approval.

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Submission of a BLA or NDA to the FDA

Assuming successful completion of all required testing (e.g.

completion of pivotal clinical trials) in accordance with all applicable regulatory requirements, detailed investigational new drug product information is submitted to the FDA in the form of a BLA or NDA requesting approval to market the product for one or more indications.

Assuming successful completion of all required testing (e.g., completion of pivotal clinical trials) in accordance with all applicable regulatory requirements, detailed investigational new drug product information is submitted to the FDA in the form of a BLA or NDA requesting approval to market the product for one or more indications.

Under federal law, the submission of most BLAs and NDAs is subject to an application user fee and these fees are typically increased on an annual basis.

Applications for orphan drug products are exempted from the BLA and NDA user fees and may be exempted from product and establishment user fees, unless the application includes an indication for other than a rare disease or condition.

No application user fees were paid for AT-1501 or OP0201 in calendar 2020.

No application user fees were paid for tegoprubart in calendar 2021.

A BLA or NDA for a new molecular entity must include all relevant data available from pertinent preclinical studies and clinical trials, including negative or ambiguous results as well as positive findings, together with detailed information relating to the product’s chemistry, manufacturing, controls, and proposed labeling, among other things.

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

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

specifications.

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

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Also, new government requirements, including those resulting from new legislation, may be established, or the FDA’s policies may change, which could delay or prevent regulatory approval of our products under development.

Pediatric Trials and Exclusivity

Under the Pediatric Research Equity Act of 2003 (“PREA”) as amended, BLAs and NDAs must contain data to assess the safety and effectiveness of an investigational new drug product for the claimed indications in all relevant pediatric populations and to support dosing and administration for each pediatric subpopulation for which the drug is safe and effective.

A sponsor who is planning to submit a marketing application for a drug product that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration must submit an initial Pediatric Study Plan (“PSP”) within sixty days of an end-of-phase 2 meeting or as may be agreed between the sponsor and the FDA.

The initial PSP must include an outline of the pediatric study or studies that the sponsor plans to conduct, including study objectives and design, age groups, relevant endpoints and statistical approach, or a justification for not including such detailed information, and any request for a deferral of pediatric assessments or a full or partial waiver of the requirement to provide data from pediatric studies along with supporting information.

The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults or full or partial waivers if certain criteria are met.

The FDA and the sponsor must reach agreement on the PSP.

A sponsor can submit amendments to an agreed-upon initial PSP at any time if changes to the pediatric plan need to be considered based on data collected from preclinical studies, early phase clinical trials, and/or other clinical development programs.

The requirements for pediatric data do not apply to any drug for an indication for which orphan designation has been granted.

In the future we may seek pediatric approval for tegoprubart applications in connection with renal and islet cell transplantations, which may require the submission of a PSP.

Pediatric exclusivity is another type of non-patent 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, including the five-year and three-year non-patent and orphan exclusivity.

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

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

rather, if the clinical trial is deemed to fairly respond to the FDA’s request, the additional protection is granted.

If reports of FDA-requested pediatric trials are submitted to and accepted by the FDA within the statutory time limits, whatever statutory or regulatory periods of exclusivity or patent protection covering the product are extended by six months.

This is not a patent term extension, but it effectively extends the regulatory period during which the FDA cannot accept or approve another application relying on the BLA or NDA sponsor’s data.

Post-Approval Requirements

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Orphan drug designation entitles a party to financial incentives such as opportunities for grant funding towards clinical trial costs, tax advantages, and user-fee waivers.

In addition, if a product is the first to receive FDA approval for the indication for which it has orphan designation, the product is entitled to orphan drug exclusivity, which means the FDA may not approve any other application to market the same drug 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.

The Company received an orphan drug designation for AT-150 1 for the treatment of ALS.

Pediatric Trials and Exclusivity

The FDA and the sponsor must reach agreement on the PSP.

The requirements for pediatric data do not apply to any drug for an indication for which orphan designation has been granted.

In the future we may seek pediatric approval for AT-1501 applications in connection with renal and islet cell transplantations, which may require the submission of a PSP.

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

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

rather, if the clinical trial is deemed to fairly respond to the FDA’s request, the additional protection is granted.

This is not a patent term extension, but it effectively extends the regulatory period during which the FDA cannot accept or approve another application relying on the BLA or NDA sponsor’s data.

The Company received an orphan drug designation for tegoprubart for the treatment of ALS.

Patent Term Restoration

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At the same time, the FDA must also determine that the generic drug is “bioequivalent” to the innovator drug.

Under the statute, a generic drug is bioequivalent to an RLD if “the rate and extent of absorption of the generic drug do not show a significant difference from the rate and extent of abs orption of the listed drug.

Upon approval of an ANDA, the FDA indicates that the generic product is “therapeutically equivalent” to the RLD and it assigns a therapeutic equivalence rating to the approved generic drug in its publication “Approved Drug Products with Therapeutic Equivalence Evaluations,” also referred to as the “Orange Book.” Physicians and pharmacists consider an “AB” therapeutic equivalence rating to mean that a generic drug is fully substitutable for the RLD.

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The FDCA also provides for a period of three years of exclusivity if the NDA includes reports of one or more new clinical investigations, other than bioavailability or bioequivalence studies, that were conducted by or for the applicant and are essential to the approval of the application.

This three-year exclusivity period often protects changes to a previously approved drug product, such as a new dosage form, route of administration, combination or indication.

This three-year exclusivity period

often protects changes to a previously approved drug product, such as a new dosage form, route of administration, combination or indication.

Hatch-Waxman Patent Certification and the 30-Month Stay

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The cost of establishing a regulatory compliance system for numerous varying jurisdictions can be very significant.

Although many of the issues discussed above with respect to the United States apply similarly in the context of the European Union (“EU”) and in other jurisdictions, the approval process varies between countries and jurisdictions and can involve additional product

testing and additional administrative review periods.

The time required to obtain approval in other countries and jurisdictions might differ from and be longer than that required to obtain FDA approval.

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The timing of PIP submission cannot be after initiation of pivotal trials or confirmatory (phase 3) trials.

I n the future we may seek pediatric approval for AT - 1501 applications in connection with renal and islet cell transplantations, which may require the submission of a PIP.

In the future we may seek pediatric approval for tegoprubart applications in connection with renal and islet cell transplantations, which may require the submission of a PIP.

Exclusivity of New Chemical Entities and New Fixed Dose Combinations

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Third-party payors are increasingly challenging the price and examining the medical necessity and cost-effectiveness of medical products and services, in addition to their safety and efficacy.

In order to obtain coverage and reimbursement for any

product that might be approved for sale, we may need to conduct expensive pharmacoeconomic studies in order to demonstrate the medical necessity and cost-effectiveness of our products, in addition to the costs required to obtain regulatory approvals.

In order to obtain coverage and reimbursement for any product that might be approved for sale, we may need to conduct expensive pharmacoeconomic studies in order to demonstrate the medical necessity and cost-effectiveness of our products, in addition to the costs required to obtain regulatory approvals.

Our product candidates may not be considered medically necessary or cost-effective.

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In January 2017, Congress voted to adopt a budget resolution for fiscal year 2017, that while not a law, is widely viewed as the first step toward the passage of legislation that would repeal certain aspects of the Affordable Care Act.

Further, on January 20, 2017, President Trump signed an Executive Order directing federal agencies with authorities and responsibilities under the Affordable Care Act to waive, defer, grant exemptions from, or delay the implementation of any provision of the Affordable Care Act that would impose a fiscal burden on states or a cost, fee, tax, penalty or regulatory burden on individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices.

would impose a fiscal burden on states or a cost, fee, tax, penalty or regulatory burden on individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices.

Congress also could consider subsequent legislation to replace elements of the Affordable Care Act that are repealed.

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The Affordable Care Act broadened the reach of the fraud and abuse laws by, among other things, amending the intent requirement of the federal Anti-Kickback Statute and the applicable criminal healthcare fraud statutes contained within 42 U.S.C.

Pursuant to the statutory amendment, a person or entity no longer needs to have actual knowledge of this statute or specific intent to violate it in order to have committed a violation.

Pursuant to the statutory amendment, a person or entity no longer needs to have actual knowledge of this

statute or specific intent to violate it in order to have committed a violation.

In addition, the Affordable Care Act provides that the government may assert that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the civil False Claims Act or the civil monetary penalties statute.

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If our operations are found to be in violation of any of the laws described above or any other governmental regulations that apply to us, we may be subject to penalties, including civil and criminal penalties, exclusion from participation in government healthcare programs, such as Medicare and Medicaid and imprisonment, damages, fines and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.

As of March 26, 2021, Eledon had ten full-time employees.

As of March 21, 2022, Eledon had twelve employees, all of whom are full time.

None of our employees are represented by labor unions or covered by collective bargaining agreements.

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Our executive offices are located at 19900 MacArthur Boulevard, Suite 550, Irvine, California 92612.

The Company also has research and development facilities in the Boston, Massachusetts area.

Our telephone number is (949) 238-8090 and our website is eledon.com.

The Company also has a research and development office in Burlington, Massachusetts.

Our telephone number is (949) 238-8090 and our website is www.eledon.com.

We do not incorporate the information on or accessible through our website into this Annual Report, and you should not consider any information on, or that can be accessed through, our website as part of this Annual Report on Form 10-K.

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In particular, please read our definitive proxy statement, which will be filed with the SEC in connection with our 2022 annual meeting of stockholders, our quarterly reports on Form 10-Q and any current reports on Form 8-K that we may file from time to time.

You may obtain copies of

these reports after the date of this annual report directly from us or from the SEC at its website at www.sec.gov.

You may obtain copies of these reports after the date of this annual report directly from us or from the SEC at its website at www.sec.gov.

We make our periodic and current reports available on our internet website, free of charge, as soon as reasonably practicable after such material is electronically filed with, or furnished to, the SEC.

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

What changed 10-K

Item 1. Business