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Item 1. Business

2025-09-17 compared with 2024-09-19 · 58 added, 101 removed, 99 unchanged (62% of the section changed)

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Summary of Clinical Assets

Ersodetug (formerly RZ358)

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

Our lead clinical asset, ersodetug, 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

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

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

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

Ersodetug for Congenital Hyperinsulinism

sunRIZE Phase 3 Study

We completed enrollment in May 2025 of 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 study was to enroll approximately 56 participants in more than a dozen countries around the world, inclusive of U.S.

patients, and enrollment target was exceeded.

Topline results from the study are anticipated to be available in December 2025, but the specific date of the availability of such results may vary.

The sunRIZE study is a global, 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 and experience hypoglycemia (blood sugars below 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.

On July 14, 2025, we presented “Preliminary Patient Demographics and Baseline Characteristics From a Phase 3 Study (sunRIZE) of Ersodetug for Hypoglycemia Due to Congenital Hyperinsulinism:

Trial in Progress” at the Annual Meeting of the Endocrine Society (“ENDO”).

Comparable to what we witnessed in the Phase 2 RIZE study, the average age of study participants is younger (3.4 years) with 35% of the participants under the age of 2.

95% of participants were taking one or more standard of care treatments (40% on Diazoxide), and had an average of 15 hypoglycemia events per week with 19% daily time spent in hypoglycemia.

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

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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.

In cases where individuals have diffuse disease, a near-total pancreatectomy may 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 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.

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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.

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.

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]).

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:

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 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:

(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)

● Initial Infant Participants:

starting at 5 mg/kg (n = 8)

Ersodetug for tumor HI

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

Based on the multinational Phase 2b clinical trial 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”), an Innovation Passport designation by the UK Innovative Licensing and Access Pathway (“ILAP”) Steering Group for the treatment of congenital HI, and the Breakthrough Therapy Designation by the FDA in the United States.

Additionally, ersodetug has received PRIME and ILAP designations in the European Union and United Kingdom, respectively.

Ersodetug for Tumor Hyperinsulinism

Based on clinical trial data across the overall HI program and a recognition of the mechanistic applicability to tumor HI, further validated by real-world experience in tumor HI patients who have been successfully treated with ersodetug throughout the U.S.

in the Company's Expanded Access Program, ersodetug was granted Breakthrough Therapy Designation by the FDA in May 2025.

upLIFT Phase 3 Study

In mid-2025 we initiated the Phase 3 registrational study (“upLIFT”) of ersodetug for the treatment of hypoglycemia due to tumor HI.

Topline results from the study are anticipated to be available in the second half of calendar 2026, but the specific date of the availability of such results may vary.

At a meeting held with FDA on August 19, 2025, the agency agreed to modifications to the design of the study including removing the need to conduct a double-blind randomized placebo-controlled trial.

The truncated study will include as few as 16 participants and will be limited to the single-arm open-label portion of the upLIFT study.

The upLIFT study is a Phase 3 registrational, single-arm, open-label, pivotal trial in participants with tumors who have uncontrolled hypoglycemia caused by tumor HI.

Eligible participants requiring continuous intravenous (“IV”) glucose will receive ersodetug 9 mg/kg per week for 8 weeks, as an add-on to standard of care.

Following this 8-week pivotal treatment period, all participants may receive ersodetug in long-term extension.

The primary endpoint is the number of participants achieving at least a 50 percent reduction from baseline in IV glucose requirements (glucose infusion rate;

Additional endpoints include the time to discontinuation of GIR, time to discharge from the hospital, extent of hypoglycemia events and hypoglycemia time in the outpatient setting by self-monitored blood glucose and continuous glucose monitor, respectively, and patient reported quality of life.

Utilizing Breakthrough Therapy Designation, we plan to engage further with FDA to discuss the necessary data package to support a BLA filing and potential approval for the tumor HI indication, as an expansion of the congenital HI indication.

Tumor HI may be caused by two distinct types of solid 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.

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(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.

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 such as glucocorticoids that are used to attempt to treat the 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.

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.

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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.

Expanded Access Program (“EAP”)

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.

In clinical and real-world experience, 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 HI.

To date, we have received over 25 unsolicited inbound physician inquiries regarding the use of ersodetug in patients with tumor HI caused by metastatic insulinomas or non-islet cell tumors, which has thus far resulted in the request, approval, and initiation of ersodetug in 13 ICTH and NICTH patients.

In the U.S., these requests have all been individually approved by the FDA's Office of Cardiology, Hematology, Endocrinology and Nephrology - Division of Diabetes, Lipid Disorders, and Obesity (“Division”).

The tumor HI patients that have received ersodetug have been refractory to the standard of care therapies for chronic management of hypoglycemia.

These patients have generally required continuous intravenous dextrose or nutritional infusion in order to prevent severe hypoglycemia and were typically hospitalized and in life-threatening or hospice-bound condition at the time of request.

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

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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.

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, 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.

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.

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

No participants have discontinued the therapy due to lack of response or safety, and the duration of treatment has ranged from several months to more than one year in several instances, in this subset of tumor HI patients with significantly advanced and metastatic tumor burden.

Five patients with congenital HI are currently receiving ersodetug as part of our EAP, which has served to support patients on a compassionate use basis prior to availability of the Phase 3 sunRIZE clinical trial.

These participants were refractory to usual therapies and include one infant where off-label or surgical (pancreatectomy) therapies were being considered.

The duration of treatment in these participants ranges from one to approximately 3 years, with ongoing benefit.

Intellectual Property

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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 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.

Government Regulation

Regulation by governmental authorities in the U.S.

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

and other countries and potential changes in regulatory philosophy and focus 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.

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We incurred approximately $61.5 million and $55.7 million in research and development expenses for the fiscal years ended June 30, 2025 and 2024, respectively.

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

For further discussion of activities related to our clinical programs, 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.

Human Capital Management

As of June 30, 2024, we had 59 full time employees, of which 42 employees were engaged in research and development, manufacturing, clinical operations, regulatory and quality activities and 17 employees were engaged in administrative functions.

As of June 30, 2025, we had 71 full-time employees, of which 52 employees were engaged in research and development and 19 employees were engaged in general and administrative functions.

Of the 71 employees, all were located in the United States.

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None of our employees are covered by a collective bargaining agreement, and we have experienced no work stoppages nor are we aware of any employment circumstances that are likely to disrupt work at any of our facilities.

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 an added incentive to remain in our employment.

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 benefits, paid holiday and vacation time.

In addition, we grant stock options, restricted stock units, and other equity compensation 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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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