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Item 1. Business

2023-09-14 compared with 2022-09-15 · 89 added, 64 removed, 51 unchanged (75% of the section changed)

Rezolute, Inc.

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

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

Summary of Clinical Assets

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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 modifies insulin’s binding and signaling to maintain glucose levels in a normal range which counteracts 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 semi-monthly dosing.

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.

A summary of the completed clinical studies for RZ358 is as follows.

A Phase 1 pharmacokinetic (“PK”) study of single intravenous doses of RZ358 at 0.1 to 9 mg/kg in healthy volunteers revealed dose-dependent pharmacokinetics with a half-life of 15 days, supporting the biweekly dosing approach.

In healthy volunteers, RZ358 prevented hypoglycemia induced by insulin administration, without producing hyperglycemia.

This effect showed a PK-pharmacodynamic (dose—response) correlation, with the hypoglycemia blunting effects of RZ358 lasting for two weeks.

The clinical proof-of-concept of RZ358 in congenital HI was evaluated in a Phase 2a study in a total of 14 patients with congenital HI.

The study investigated the PK, pharmacodynamics (“PD”), safety and preliminary efficacy of RZ358.

RZ358 was well-tolerated in adult and pediatric patients with congenital HI who received single intravenous doses in the Phase 2a study and the PK results from the Phase 2a studies were consistent with those in healthy volunteers.

There was a durable normalization of blood sugar in patients with hypoglycemia, with an approximate 50% improvement and near normalization of glucose control, which was sustained for more than two weeks after dosing.

RZ358 did not increase blood sugar levels in patients with normal blood sugar levels at baseline.

In calendar year 2022 we completed the RZ358-606 Phase 2b global clinical study for RZ358 (“RIZE”).

The RIZE study was conducted in a repeat-dose fashion to evaluate the safety, pharmacokinetics, dose-exposure response relationship and to assess the glycemic efficacy across a range of continuous glucose monitoring (“CGM”) and blood glucose monitoring-based principle glycemic endpoints to inform Phase 3.

In the study, eligible patients received RZ358 in open-label fashion in one of 4, sequentially conducted dosing cohorts of up to 8 participants per cohort.

RZ358 was administered as a 30 minute intravenous infusion every other week for eight weeks.

The first three cohorts were fixed dosing levels of RZ358 and the fourth cohort was designed to explore whether there were any advantages of a fixed titration approach.

The RIZE study enrolled 23 patients and was primarily in a young pediatric population, average ~6.5 years of age, and in a diverse group of patients across gender and genetic cause of congenital HIs.

A key entry criterion was for patients to

have continued hypoglycemia despite available therapies, to be eligible for enrollment.

We observed that patients enrolled on stable background therapies had clinically significant, and in many cases, substantial residual hypoglycemia as well as some hyperglycemia (> 180 mg/dL) at baseline.

Results from the RIZE study showed that target and expected RZ358 concentrations were achieved and dose-exposure dependent responses were also observed.

RZ358 was generally safe and well-tolerated and there were no adverse drug reactions, adverse events leading to study discontinuations, or dose-limiting toxicities.

Importantly, RZ358 demonstrated a ~50% improvement in hypoglycemia across all doses and cohorts and a ~75% improvement in hypoglycemia at the 6 mg/kg and 9 mg/kg cohorts.

Time in range by CGM improved 8% across all doses, 16% at the top dose, and more significantly (>25%) in patients without baseline hyperglycemia on SOC.

In calendar year 2022, we reported positive topline results from the RIZE study which were presented at the Pediatric Endocrine Society Meeting on May 1, 2022.

We believe that the positive results from the RIZE study will be Phase 3 enabling and accordingly we have initiated interactions with regulatory authorities in the US and Europe.

Our objective is to complete the regulatory dialogue prior to the end of the first quarter of calendar year 2023, which would facilitate initiation of a Phase 3 study in the first half of calendar year 2023.

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.

The primary and key secondary efficacy endpoints are the following:

Primary efficacy endpoint:

● Change in average weekly occurrence of hypoglycemia events as measured by SMBG after 24 weeks

Key secondary efficacy endpoint:

● Change in average daily percent time in hypoglycemia as measured by CGM after 24 weeks

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.

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

(i) adjust the dose between 5 and 10 mg/kg;

(ii) adjust the dosing frequency between 2 and 4 weeks;

and (iii) wean or stop other background hypoglycemia therapies.

In summary, the study will be comprised of the following treatment groups:

● Participants ≥1 year old:

5 mg/kg (n = 16)

● Participants ≥1 year old:

10 mg/kg (n = 16)

● Participants ≥1 year old:

placebo (n = 16)

● 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”).

DME is a vascular complication of diabetes and a leading cause of blindness in the US and elsewhere.

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

and elsewhere.

Chronic exposure to high blood sugar levels can lead to inflammation, cell damage, and the breakdown of blood vessel walls.

Specifically, in DME, blood vessels behind the back of the eye become porous and permeable leading to the unwanted infiltration of fluid into the macula.

Specifically, in DME, retinal blood vessels at the back of the eye become porous and permeable leading to the unwanted infiltration of fluid into the macula.

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

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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 microvasculature behind the back of the eye.

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.

Results from our single ascending dose (“SAD”) Phase 1a Study (“RZ402-101”) were reported in May 2021.

RZ402-101 was a first-in-human single-center, randomized, double-blind, placebo-controlled SAD study in healthy adult volunteers.

The study objectives were to characterize the safety profile and pharmacokinetics of RZ402 administered as single oral doses.

The study enrolled 30 individuals in three planned sequential dose- level cohorts of 25 mg, 100 mg, and 250 mg.

Within each ten-subject dose cohort, volunteers were randomized 8:2 to receive either RZ402 oral solution or matched placebo.

After receiving single doses, participants remained in the clinic for seven days for serial PK and safety assessments, before completing two outpatient follow-up visits at study days 14 and 30.

Dose advancement proceeded following blinded reviews of safety and PK data from the preceding cohort(s).

Single doses of RZ402 resulted in dose-dependent increases in systemic exposure.

Plasma concentrations of RZ402 significantly exceeded the 3.5 ng/mL target concentration that was pharmacologically active in animal models of DME for a 24-hour period after receipt of RZ402.

Across the dose and exposure range, there were no serious adverse events, adverse drug reactions, or discontinuations due to adverse events, and no imbalance of adverse events between the treatment and placebo control groups.

Similarly, regular laboratory, hemodynamic, cardiac, and ophthalmologic safety examinations were unremarkable.

Following the success of the SAD study, we undertook a follow-on multiple ascending dose (“MAD”) study (“RZ402-102”).

Results from the MAD Study were reported in February 2022.

RZ402-102 was a single center, randomized, double-blind, placebo-controlled, in healthy adult volunteers.

The objectives of the study were to characterize the repeat dose safety profile (including maximum tolerated dose) and PK of RZ402 administered as daily oral doses for two weeks.

study was conducted in 40 volunteers in sequential ascending dose cohorts with 10 individuals per cohort.

Within each cohort, participants were randomized in an 8:2 ratio to receive either RZ402 as an oral solution or a placebo.

Participants remained in the clinic throughout the two week dosing period for serial PK and safety assessments, before completing an outpatient follow-up visit at study day 28.

Blood biomarkers of target engagement (kallikrein activity) were explored as a systemic surrogate for DME, using a precedent from studies of kallikrein inhibitors in a systemic vascular leakage syndrome (hereditary angioedema).

Dose advancement proceeded in staggered fashion every three weeks as appropriate, following blinded reviews of data from the preceding cohort(s).

The MAD study showed dose-dependent increases in systemic exposures, with repeat-dosing to steady-state resulting in the highest concentrations of RZ402 explored to date, exceeding 200 ng/mL and 50 ng/mL at peak and 24-hour trough, respectively.

Following the precedent established in hereditary angioedema, steady-state plasma kallikrein activity in human plasma was measured on Day 14 as a biomarker of RZ402 target engagement.

Daily dosing with RZ402 inhibited plasma kallikrein in a dose and concentration-dependent manner (r=0.74;

Given that the in-vivo EC90 for RZ402 in animal models of DME is ~6 ng/mL, the results at both peak and 24-hour trough substantially exceeded target concentrations based on a combination of in-vitro and in-vivo profiling.

RZ402 was generally safe and well-tolerated, including at higher doses than previously tested in the SAD study.

There were no serious adverse events, adverse drug reactions or identified risks.

We are advancing developmental activities toward a Phase 2a proof-of-concept study, which we plan to initiate during the fourth quarter of calendar year 2022.

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.

Intellectual Property

Our success depends on an intellectual property portfolio that supports our future revenue streams and also erects barriers to our competitors.

We are maintaining and building our patent portfolio through filing new patent applications;

prosecuting existing applications;

and licensing patents and patent applications.

Furthermore we seek to protect our ownership of know-how, trade secrets and trademarks through an active program of legal mechanisms including registrations, assignments, confidentiality agreements, material transfer agreements, research collaborations and licenses.

While we have confidence in our agreements and security measures, either may be compromised, and we may not have adequate remedies.

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

patents, as well as most foreign patents, are generally effective for 20 years from the date the earliest application was filed.

patents that were issued on applications filed before June 8, 1995, may be effective until 17 years from the issue date, if that is later than the 20-year date.

In some cases, the patent term may be extended to recapture a portion of the term lost during regulatory review of the claimed therapeutic or, in the case of the U.S., because of U.S.

Patent and Trademark Office (USPTO) delays in prosecuting the application.

In the U.S., under the Drug Price Competition and Patent Term Restoration Act of 1984 (commonly known as the Hatch-Waxman Act), a patent that covers a drug approved by the FDA may be eligible for patent term extension (for up to five years, but not beyond a total of 14 years from the date of product approval) as compensation for patent term lost during the FDA regulatory review process.

The duration and extension of the term of foreign patents varies in accordance with local law.

In the EU, Supplementary Protection Certificates, or SPCs, are available to extend a patent term up to five years to compensate for patent protection lost during regulatory review.

Although all EU Member States must provide SPCs, SPCs must be applied for and granted on a country-by-country basis.

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.

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

These patents expire between 2030 to 2036.

We also are pursuing patent applications relating to formulations of the clinical product candidate.

In addition, for certain of our product candidates we also expect to have further exclusivity in the form of data and marketing exclusivity under pharmaceutical regulatory laws, including for example, potentially up to 12 years of exclusivity from the date of first BLA approval of our product candidates.

We also hold a worldwide, exclusive license from ActiveSite to patents covering the RZ402 molecule, certain prodrug forms of RZ402, and uses (as further described in the “ActiveSite License Agreement” section below), including 9 issued international patents and 7 issued U.S.

We have additional patents (2 U.S.) and pending patent applications (3 U.S.

and 29 international) with claims directed to formulations, solid forms of RZ402, methods of preparing RZ402, and methods of use in therapy.

These patents are expected to expire between 2040 and 2043.

We also expect to be granted further exclusivity in the form of data and marketing exclusivity under pharmaceutical regulatory laws in various jurisdictions.

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 Crinetics Pharmaceuticals, Eiger Biopharmaceuticals, Hanmi Pharmaceuticals, and Zealand Pharma.

There are other companies developing therapies for HI that are potential competitors to RZ358, including, Eiger Biopharmaceuticals, 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.

Government Regulation

Regulation by governmental authorities in the US and other countries is a significant factor in the development, manufacture and marketing of pharmaceutical products.

Regulation by governmental authorities in the U.S.

and other countries is a significant factor in the development, manufacture and marketing of pharmaceutical products.

All of our potential products will require regulatory approval by governmental agencies prior to commercialization.

In particular, pharmaceutical therapies are subject to rigorous preclinical testing and clinical trials and other pre-market approval requirements by FDA and regulatory authorities in foreign countries.

In particular, pharmaceutical therapies are subject to rigorous preclinical testing and clinical trials and other pre-market approval requirements by the FDA and Regulatory Authorities (as defined below) in foreign countries.

Various federal, state and foreign statutes and regulations also govern or influence the manufacturing, safety, labeling, storage, record keeping and marketing of such products.

We are also subject to various federal, state, and local laws, regulations and recommendations relating to safe working conditions;

In addition, we are subject to various federal, state, and local laws, regulations and recommendations relating to safe working conditions;

laboratory and manufacturing practices;

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Human Capital Management

As of June 30, 2022, we had 42 full time employees, of which 31 employees were engaged in research and development, manufacturing, clinical operations and quality activities and 11 employees in administrative functions.

As of June 30, 2023, we had 51 full time employees, of which 38 employees were engaged in research and development, manufacturing, clinical operations, regulatory and quality activities and 13 employees were engaged in administrative functions.

Of the 51 employees, all were located in the United States.

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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.

We believe that we maintain good relations with our employees.

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We believe that a rich culture of inclusion and diversity enables us to create, develop and fully leverage the strengths of our workforce.

In furtherance of our commitment to inclusion and diversity, on May 30, 2023 we adopted an equity and inclusion policy.

Human Resources, Hiring and Professional Development

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Our Board of Directors, management and staff are provided with training regarding our Code of Business Conduct and Ethics.

On May 30, 2023, we adopted an amended and restated Code of Business Conduct and Ethics.

The purpose of amending and restating the prior code was to improve its readability and clarify certain areas of importance, including with respect to compliance with laws, accounting and auditing matters, conflicts of interest, insider trading, confidentiality obligations and the reporting of violations of our Code of Business Conduct and Ethics.

Corporate Information

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

We maintain an executive office located at 201 Redwood Shores Parkway, Suite 315, Redwood City, CA 94065 and our phone number is (650) 206-4507.

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

Our website is located at www.rezolutebio.com .

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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