What changed in this filing

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Item 1. Business

2024-09-19 compared with 2023-09-14 · 107 added, 47 removed, 93 unchanged (62% of the section changed)

Rezolute, Inc.

(“Rezolute”, the “Company”, “we” or “us”) is a clinical-stage biopharmaceutical business developing therapies for metabolic diseases related to chronic glucose imbalance.

(“Rezolute”, the “Company”, “we” or “us”) is a late-stage rare disease company focused on significantly improving outcomes for individuals with hypoglycemia caused by hyperinsulinism (“HI”).

Summary of Clinical Assets

Our lead clinical asset, RZ358, is a potential treatment for congenital hyperinsulinism (“HI”), an ultra-rare pediatric genetic disorder characterized by excessive production of insulin by the pancreas .

If untreated, the elevated insulin levels in patients suffering with congenital HI can induce extreme hypoglycemia (low blood sugar) events, increasing the risk of neurological and developmental complications, including persistent feeding problems, learning disabilities, recurrent seizures, brain damage or even death.

There are no FDA approved therapies for all forms of congenital HI and the current standard of care treatments are suboptimal.

Ersodetug (formerly RZ358)

Our lead clinical asset, ersodetug (formerly RZ358), is a potential treatment for hypoglycemia caused by multiple forms of hyperinsulinism.

Ersodetug is an intravenously administered human monoclonal antibody that binds to a unique site (allosteric) on the insulin receptor in insulin target tissues, such as in the liver, fat, and muscle.

The antibody down modulates insulin’s binding, signaling, and action thereby counteracting the effects of elevated insulin in the body, and helping to restore glucose to a more normalized range.

Ersodetug shows dose dependent pharmacokinetics with a half-life greater than 2 weeks, which has the potential for twice or even once monthly dosing.

Therefore, we believe that ersodetug is ideally suited as a potential therapy for conditions characterized by excessive insulin levels, and it is being developed to treat hyperinsulinism and low blood sugar.

As ersodetug acts downstream from the beta cells, it has the potential to be universally effective at treating hypoglycemia related to HI, whether genetic or caused by tumors.

Ersodetug for congenital HI

Congenital HI is the most common cause of recurrent and persistent hypoglycemia in children.

Individuals with congenital HI typically present with signs or symptoms of hypoglycemia shortly after birth.

Hypoglycemia can result in significant brain injury and death if not recognized and managed appropriately.

Additionally, recurrent, or cumulative, hypoglycemia can lead to progressive and irreversible damage over time, including serious and devastating brain injury, seizures, neuro-developmental problems, feeding difficulties, and significant impact on patient and family quality of life.

In cases that are unresponsive to medical management, surgical removal of the pancreas may be required.

In those with diffuse disease where the whole pancreas is affected, a near-total pancreatectomy can be undertaken, although ongoing medical treatment of hypoglycemia is generally required for several years after surgery, before eventual insulin-dependent diabetes ensues.

There are no U.S.

Food and Drug Administration (“FDA”) approved therapies for all forms of congenital HI and the current standard of care treatments are suboptimal.

The current treatments used by physicians include glucagon, diazoxide, somatostatin analogues and pancreatectomy.

RZ358 is an intravenously administered human monoclonal antibody that binds to a unique site (allosteric) on the insulin receptor in insulin target tissues, such as in the liver, fat, and muscle.

The antibody down modulates insulin’s binding, signaling, and action to maintain glucose levels in a normal range thereby counteracting the effects of elevated insulin in the body.

RZ358 shows dose dependent pharmacokinetics with a half- life greater than two weeks which has the potential for twice or even once monthly dosing.

Therefore, we believe that RZ358 is ideally suited as a potential therapy for conditions characterized by excessive insulin levels, and it is being developed to treat hyperinsulinism and low blood sugar.

As RZ358 acts downstream from the beta cells, it has the potential to be universally effective at treating congenital HI caused by any of the underlying genetic defects.

In the fourth quarter of 2023, we plan to initiate a pivotal Phase 3 clinical study of RZ358 for the treatment of hypoglycemia in participants with congenital HI (the “sunRIZE” study) outside of the U.S.

The sunRIZE study is a randomized, double-blind, placebo-controlled, parallel arm evaluation of RZ358 in participants with congenital HI who are not adequately responding to standard of care medical therapies.

Topline results from the study are anticipated to be available in the first half of 2025.

The Phase 3 study follows the Company’s multinational Phase 2b study (“RIZE”) conducted in participants 2 years of age and older who were failing medical therapies.

The RIZE study demonstrated that RZ358 was generally safe and well-tolerated, as well as highly effective in improving hypoglycemia.

We have concluded our pre-Phase 3 regulatory and scientific advice meetings with Regulatory Authorities outside of the U.S.

and have reached agreement on the design of the Phase 3 study that will include participants 3 months of age and older.

In the U.S., we had similar interactions with the U.S.

Food and Drug Administration (“FDA”) culminating in a meeting held with the agency on May 24, 2023 (as confirmed by meeting minutes received from FDA on June 22, 2023), and FDA has maintained an existing age restriction of 12 years of age and older on RZ358 clinical studies, and imposed dose level restrictions based on historical rat toxicology findings.

We believe that the FDA restrictions make it infeasible to include the U.S.

in the Phase 3 study at this time, since that the pediatric population with congenital HI has the greatest therapeutic need.

We are pursuing some additional nonclinical studies that may potentially address FDA’s concerns, in parallel with the initiation and advancement of the Phase 3 study outside of the U.S.

Please see Management’s Discussion and Analysis of Financial Condition and Results of Operation’s on this Form 10-K for more information on our plans.

The sunRIZE study will evaluate the safety and efficacy of RZ358 in participants with congenital HI who are unable to achieve control of low blood sugars (<70 mg/dL) with available medical therapies (“hypoglycemia”).

The study will determine the ability of RZ358 to correct hypoglycemia as assessed by (i) hypoglycemia events using self-monitored blood glucose (“SMBG”) and (ii) time in hypoglycemia using continuous glucose monitoring (“CGM”) over 24 weeks of treatment.

The study will also measure the levels of RZ358 and its effects on other important blood and clinical markers of hypoglycemia, as well as quality of life measures.

We estimate that in the U.S.

alone the addressable market for congenital HI is more than 1,500 individuals.

Ersodetug has received Orphan Drug Designation in the U.S.

and European Union for the treatment of congenital HI, as well as Rare Pediatric Disease Designation in the U.S., a prerequisite for a request for a Rare Pediatric Disease Priority Review Voucher upon Biologics License Application (“BLA”) submission.

Based on the multinational Phase 2b clinical trial (“RIZE”) outcomes and the evidence of benefit in this serious condition with substantial unmet medical need, ersodetug was subsequently granted a priority medicines (“PRIME”) designation by the European Medicines Agency (“EMA”) and an Innovation Passport designation by the UK Innovative Licensing and Access Pathway (“ILAP”) Steering Group for the treatment of congenital HI.

Phase 3 sunRIZE

We are actively enrolling a pivotal Phase 3 clinical study (the “sunRIZE” study) of ersodetug for the treatment of hypoglycemia in participants with congenital HI, an ultra-rare pediatric genetic disorder characterized by excessive production of insulin by the pancreas.

The sunRIZE study is a randomized, double-blind, placebo-controlled, parallel arm evaluation of ersodetug in participants 3 months of age and older with congenital HI who are not adequately responding to standard of care medical therapies.

Specifically, the study is evaluating the safety and efficacy of ersodetug in participants who are unable to achieve control of low blood sugars (“hypoglycemia” [<70 mg/dL]).

The study will determine the ability of ersodetug to correct hypoglycemia as assessed by (i) hypoglycemia events using self-monitored blood glucose (“SMBG”) and (ii) time in hypoglycemia using continuous glucose monitoring (“CGM”) over 24 weeks of treatment.

To date, we have been screening and enrolling participants outside the U.S.

because the FDA had imposed an age restriction of 12 years of age and older on ersodetug clinical studies as well as dose level restrictions based on historical rat toxicology findings.

On September 4, 2024, FDA lifted those restrictions and now the Company is conducting study start-up activities at sites in the U.S.

in anticipation of enrolling U.S.

participants in the sunRIZE study in the first part of 2025.

Topline results from the study are anticipated to be available in the second half of calendar 2025.

The study will also measure the levels of ersodetug and its effects on other important blood and clinical markers of hypoglycemia, as well as quality of life measures.

The primary and key secondary efficacy endpoints are the following:

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Approximately 56 participants between 3 months and 45 years of age are intended to be enrolled.

Participants between 1 and 45 years of age (approximately 48 participants) will be enrolled in a randomized, double-blind, placebo-controlled fashion to receive RZ358 or placebo at dose levels of 5 or 10 mg/kg while on standard of care.

Infant participants between 3 months and 1 year of age (approximately 8 participants) will be enrolled in open label fashion to receive RZ358 at a starting dose level of 5 mg/kg, which may be increased to 10 mg/kg at the discretion of the investigator.

Participants will receive RZ358 as an intravenous infusion every 2 weeks over an initial 4-week loading period (3 doses), followed by monthly doses over an additional 16-week maintenance period (4 doses), for a total of 7 doses over the total 24-week treatment period.

Participants between 1 and 45 years of age (approximately 48 participants) will be enrolled in a randomized, double-blind, placebo-controlled fashion to receive ersodetug or placebo at dose levels of 5 or 10 mg/kg while on standard of care.

Infant participants between 3 months and 1 year of age (approximately 8 participants) will initially be enrolled in open-label fashion to receive ersodetug at a starting dose level of 5 mg/kg, which may be increased to 10 mg/kg at the discretion of the investigator.

Thereafter, pending agreement by an independent Data Monitoring Committee, infant patients may be permitted to be enrolled into the randomized, controlled study.

Participants will receive ersodetug as an intravenous infusion every 2 weeks over an initial 4-week loading period (3 doses), followed by monthly doses over an additional 16-week maintenance period (4 doses), for a total of 7 doses over the total 24-week treatment period.

Following the study period, participants may proceed into an open-label extension program where investigators shall be permitted to:

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placebo (n = 16)

● Infant Participants:

● Initial Infant Participants:

starting at 5 mg/kg (n = 8)

Our second clinical asset, RZ402, is an oral plasma kallikrein inhibitor (“PKI”) being developed as a potential therapy for the chronic treatment of diabetic macular edema (“DME”).

Ersodetug for tumor HI

Tumor HI may be caused by two distinct types of tumors:

neuroendocrine islet cell tumors (“ICTs”) and non-islet cell tumors (“NICTs”), both of which lead to hypoglycemia due to excessive activation of the insulin receptor.

Insulinomas are the most common type of functional ICT and mediate hypoglycemia through excessive insulin production.

NICTs are generally associated with relatively large, solid tumors such as hepatocellular carcinoma, fibrosarcoma and mesothelioma, and can cause hypoglycemia by producing and secreting insulin-like paraneoplastic substances such as IGF-2 or related variants that bind to and activate the insulin receptor.

This form of hypoglycemia can occur in more than 15 different tumor types.

Current therapies for insulinomas and NICTs can be grouped into two main categories:

(a) tumor-directed de-bulking therapies (e.g.

surgery, chemotherapy, radiotherapy), which may indirectly and/or eventually lead to decreased levels of

circulating insulin and/or insulin-like substances, and therefore control HI and related hypoglycemia;

and/or (b) medical therapies that directly treat HI and the associated hypoglycemia.

Tumor-directed therapies do not directly treat hypoglycemia caused by insulinomas or NICTs.

In many cases, tumor-directed therapies are administered concurrently with medical therapies for hypoglycemia and in other cases successful treatment of hypoglycemia often enables the initiation and/or continuation of tumor-directed therapies, as indicated.

During the period from diagnosis to surgical treatment, or if surgery is contraindicated or refused, medical treatments are often necessary to directly manage the HI and hypoglycemia induced by the tumor.

Additionally, chronic medical management of refractory hypoglycemia is often necessary for patients who cannot be cured by surgery, such as those with extensive disease of the pancreas, multi-focal insulinomas, inoperable or unresectable benign or malignant insulinomas, metastatic insulinomas, non-pancreatic insulinomas, or NICT hypoglycemia resulting from a variety of other tumors.

A significant unmet need exists for treatment options with improved efficacy and tolerability as normalization of glucose levels is crucial to prevent serious signs and symptoms of hypoglycemia, improve patient quality of life and overall function, and even to ensure patients are fit to receive cancer treatment and to reduce mortality.

Unfortunately, some patients are unresponsive to the current standard of care medical therapies for tumor HI and experience debilitating hypoglycemia that is otherwise untreatable.

Currently available medical therapies are directed at reducing or eliminating insulin production and/or secretion from tumors, which may be challenging when the tumor is differentiated or dysregulated, and therefore not responding to usual control mechanisms for suppressing insulin production.

In some cases, commonly utilized somatostatin analog therapies may even worsen hypoglycemia due to suppression of glucagon.

Therefore, currently available medical therapies directed at suppressing insulin production may have limited effectiveness in tumor HI.

While we believe the total addressable market may be larger, the immediately addressable market for the combined indications causing tumor HI is estimated to be approximately 1,500 patients in the U.S.

alone, including approximately 500 with islet cell tumor hypoglycemia (“ICTH”) and approximately 1,000 with non-islet cell tumor hypoglycemia (“NICTH”).

On August 5, 2024, we announced FDA clearance of our Investigational New Drug (“IND”) application for a Phase 3 registrational study of ersodetug for the treatment of hypoglycemia due to tumor HI.

This is the second rare disease program with ersodetug in Phase 3 development.

We are initiating start-up activities for the study, which will be primarily conducted in the U.S., and patient enrollment is planned to commence in the first half of calendar 2025.

The Phase 3 registrational study is a double-blind, randomized, placebo-controlled trial of 24 participants who have inadequately controlled hypoglycemia because of tumor HI.

Eligible participants will be randomized in 1:1 fashion (12 per treatment arm) to receive ersodetug 9 mg/kg per week or matched placebo, as an add-on to standard of care.

Up to 24 additional participants may be enrolled into an open-label arm, in participants whose hypoglycemia is being managed by IV glucose in a hospital setting.

Following a 6-week pivotal treatment period, all participants may receive ersodetug in open-label extension.

The primary endpoint is the change in Level 2 (moderate) and Level 3 (severe) hypoglycemia events by self-monitored blood glucose.

Additional endpoints include overall hypoglycemia events, time in hypoglycemia by continuous glucose monitor, patient reported quality of life, hospitalizations, and change in glucose requirements (for open-label hospitalized participants).

Expanded Access Program

Ersodetug has been shown to counteract excessive insulin action downstream, at the insulin-receptor on target organs.

The unique mechanism of action of ersodetug makes the therapy a potential universal treatment for any form of hyperinsulinism.

We maintain an EAP for a variety of HI indications for the purpose of making ersodetug available on a compassionate use basis when available therapeutic options have failed, and an individual’s hypoglycemia is unmanageable.

In the fourth quarter of 2022, we received and approved an EAP request from Dr.

Mary Elizabeth Patti, Director of the Hypoglycemia Clinic at the Harvard Medical School and Beth Israel Medical Center-affiliated Joslin Diabetes Center, for a patient with intractable hypoglycemia caused by a metastatic insulinoma.

Patti received a single patient IND approval from the FDA's Office of Cardiology, Hematology, Endocrinology and Nephrology - Division of Diabetes, Lipid Disorders, and

Obesity (“Division”) to treat the patient with ersodetug.

Patti reported that the patient safely achieved correction of hypoglycemia with ersodetug, enabling the patient to wean off continuous intravenous dextrose and several other medications for hypoglycemia, leave the hospital after a prolonged stay, and resume receiving concurrent treatment for his cancer with tumor-directed therapies.

The patient remained on ersodetug for more than a year until he eventually passed away due to progression of his underlying malignant/metastatic insulinoma.

We have received and approved several additional requests to date for use of ersodetug in patients with tumor HI caused by metastatic insulinomas and other insulin secreting metastatic cancer (cervical).

In the U.S., these requests have all been approved by the Division.

These patients have been refractory to usual standard of care therapies for chronic management of hypoglycemia and required continuous high volume/concentration intravenous dextrose or nutritional infusion and were hospitalized and in life-threatening or hospice-bound condition because of uncontrollable hypoglycemia.

Further treatment with tumor-directed therapies (e.g., embolization, radiotherapy, chemotherapy) was often deferred as a result of the debilitating hypoglycemia.

Generally, dosing for tumor HI patients has been either 6 mg/kg or 9 mg/kg every 1-2 weeks.

In all cases to date, ersodetug has led to substantial improvement in hypoglycemia and has been well tolerated.

Within a relatively short period of time after administration of ersodetug, continuous intravenous dextrose was discontinued or substantially reduced and hospitalized patients were able to be discharged and receive maintenance ersodetug doses on an outpatient basis, with durable benefit.

In most cases, other background medical therapies for hypoglycemia were able to be weaned or stopped, and patients were able to resume tumor-directed therapies for treatment of their underlying cancer.

Patients with metastatic tumor HI often have underlying hepatic injury (abnormal enzymes) at baseline due to hepatic metastases or previous tumor-directed treatments (e.g., partial liver resection or embolization).

The patients with hepatic injury that have been treated under the EAP have not exhibited any indication of hepatic toxicity with the use of ersodetug.

Our second clinical asset, RZ402, is an oral plasma kallikrein inhibitor (“PKI”) and potential therapy for the chronic treatment of diabetic macular edema (“DME”).

DME is a vascular complication of diabetes and a leading cause of blindness in the U.S.

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This fluid leakage creates distorted vision, and if left untreated, blindness.

Currently available treatments for DME include anti-vascular growth factor (anti-VEGF) injections into the eye or laser surgery.

RZ402 is designed to be a once daily oral therapy for the treatment of DME and unlike the anti-VEGF therapies, RZ402 targets the Kallikrein-Kinin System to address inflammation and vascular leakage.

We believe that systemic exposure through oral delivery is critical to target the retinal microvasculature at the back of the eye.

Further, as an oral therapy, RZ402 has the potential to substantially change the therapeutic paradigm for patients suffering with DME by providing a convenient, self-administered treatment option to encourage earlier initiation of therapy, adherence to prescribed treatment guidelines, and improved overall outcomes.

In December 2022, we initiated a Phase 2 multi-center, randomized, double-masked, placebo-controlled, parallel-arm study to evaluate the safety, efficacy, and pharmacokinetics of RZ402 administered as a monotherapy over a 12-week treatment period in participants with DME who are naïve to, or have received limited anti-VEGF injections.

The study population is comprised of DME patients with mild to moderate non-proliferative diabetic retinopathy.

Eligible participants are being randomized equally, to one of three RZ402 active treatment arms at doses of 50, 200, and 400 mg, or a placebo control arm, to receive study drug once daily for 12 weeks, before completing a four-week follow-up.

The study is expected to enroll up to approximately 100 patients overall, across approximately 25 investigational sites in the United States.

The principal endpoints of the trial include (i) changes in central subfield thickness of the macula, as measured by Spectral Domain Ocular Coherence Tomography, (ii) changes in visual acuity as measured by the early treatment diabetic retinopathy scale, (iii) the repeat dose pharmacokinetics of RZ402 in patients with DME, and (iv) the safety and tolerability of RZ402.

We expect to announce topline results from the study in the first quarter of calendar year 2024.

In May 2024, we completed a Phase 2 multi-center, randomized, double-masked, placebo-controlled, parallel arm study to evaluate the safety, efficacy, and pharmacokinetics of RZ402 administered as a monotherapy over a 12-week treatment period in participants with DME who are naïve to, or have received limited anti-VEGF injections.

The study population was comprised of DME patients with mild to moderate non-proliferative diabetic retinopathy.

Eligible participants were randomized equally, to one of three RZ402 active treatment arms at doses of 50, 200, and 400 mg, or a placebo control arm, to receive study drug once daily for 12 weeks, before completing a 4-week follow-up.

The study enrolled 94 patients in the U.S.

The study met both primary endpoints, demonstrating a significant reduction in central subfield thickness (“CST") in the study eye at all RZ402 dose levels compared to placebo (up to approximately 50 micron improvement), as well as good safety and tolerability.

The program is available for partnering and we are actively engaged in conversations with potential partners to take RZ402 into further development.

Intellectual Property

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Limited exceptions apply to the protection conferred by the SPC.

As further described in the “XOMA License Agreement” section below, we hold a worldwide, exclusive license from XOMA to patents covering the RZ358 molecule, including 37 issued patents worldwide and in the U.S.

As further described in the “XOMA License Agreement” section below, we hold a worldwide, exclusive license from XOMA to patents covering the ersodetug molecule, including 37 issued patents worldwide and in the U.S.

(3 U.S.) and pending patent applications with claims directed to compositions of matter and methods of use in therapy.

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We face competition from pharmaceutical and biotechnology companies, academic institutions, governmental agencies, and private research organizations in recruiting and retaining highly qualified scientific personnel and consultants and in the development and acquisition of technologies.

There are other companies developing therapies for HI that are potential competitors to RZ358, including, Eiger Biopharmaceuticals, Hanmi Pharmaceuticals, and Zealand Pharma.

There are other companies developing therapies for HI that are potential competitors to ersodetug, including, Amylyx Pharmaceuticals, Hanmi Pharmaceuticals, and Zealand Pharma.

There are also companies developing therapies for DME that are potential competitors to our PKI including Curacle, KalVista, Ocuphire Pharma, Oxurion and Verseon.

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the experimental use of animals;

and the use and disposal of hazardous or potentially hazardous substances, including radioactive compounds and infectious disease agents, used in connection with our research, development and manufacturing.

and the use and disposal of

hazardous or potentially hazardous substances, including radioactive compounds and infectious disease agents, used in connection with our research, development and manufacturing.

Research and Development

We incurred approximately $55.7 million and $43.8 million in research and development expenses for the fiscal years ended June 30, 2024 and 2023, respectively.

For further discussion of activities related to our RZ358 and RZ402 product candidates, please refer to the discussion above.

For further discussion of activities related to ersodetug and RZ402 product candidates, please refer to the discussion above.

For further discussion of our research and development expenses, please refer to the discussion under the caption Results of Operations under Item 7 of this Annual Report.

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As part of our measures to attract and retain personnel, we provide a number of benefits to our full-time employees, including health insurance, life insurance, retirement plans, paid holiday and vacation time.

In addition, we grant stock options to certain key employees as added incentive to remain in our employment.

In addition, we grant stock options to certain key employees as an added incentive to remain in our employment.

We believe that we maintain good relations with our employees.

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Corporate Information

We were incorporated in Delaware in 2010 and we re-incorporated in Nevada in June 2021.

We were incorporated in Delaware in 2010, and we reincorporated in Nevada in June 2021.

We maintain an executive office located at 275 Shoreline Drive, Suite 500, Redwood City, CA 94065 and our phone number is (650) 206-4507.

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We file annual, quarterly, current reports, proxy statements and other information with the Securities and Exchange Commission (“SEC”).

The SEC maintains a website that contains our public filings and other information regarding the Company, at www.sec.gov.

The SEC maintains a website that contains our public

filings and other information regarding the Company, at www.sec.gov.

The information contained in, or that can be accessed through, our website is not part of, and is not incorporated into this document.

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