Item 8.01. Other Events.
As set forth in Item 7.01 of this Current Report
on Form 8-K, the Company is providing an update on its clinical program for congenital hyperinsulinism (“congenital HI”).
Summary
In the fourth quarter of 2023, the Company plans
to initiate a pivotal Phase 3 clinical study of RZ358 for the treatment of hypoglycemia in participants with congenital HI (“sunRIZE”).
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. As of March 31, 2023, the Company had $129M in cash and cash equivalents with sufficient capital to sustain
operations through the third quarter 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.
The Company has concluded its pre-Phase 3 regulatory
and scientific advice meetings with health authorities outside of the US and has reached agreement on the design of the Phase 3 study
that will include participants 3 months of age and older. In the US, the Company has had similar interactions with the US Food and Drug
Administration (“FDA”) culminating in a meeting held with the agency on May 24, 2023 (as confirmed by meeting minutes received by the Company 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. The Company believes that the FDA restrictions make it infeasible to include the US in the Phase 3 study at this
time, particularly given that the pediatric population with congenital HI has the greatest therapeutic need. The Company is evaluating
potential nonclinical studies to address FDA’s concerns in parallel with the initiation and advancement of the Phase 3 study outside
of the US.
Regulatory Status
Toxicology studies in rats and monkeys were conducted
as part of the early RZ358 development program and in these studies, rats demonstrated a microvascular liver injury at potentially clinically
relevant doses and exposures (“rat findings”). However, there were no adverse liver findings in monkeys at dose levels
that were more than 10 times higher than doses that were toxic in rats, and more than 4 times higher than human doses evaluated in clinical
studies. Based on the absence of liver toxicity in monkeys and the lack of adverse liver findings in closely monitored human trials, the
Company believes that the toxicity is unique to rats and unlikely relevant to humans.
As is customary in pediatric drug development,
there is a progression of the inclusion of younger participants as a program advances through different stages and continues to demonstrate
a good safety profile and a prospect of benefit for children based on previous stages. After the completion of Phase 1 adult healthy
volunteer studies for RZ358, Phase 2a single-dose proof of concept studies (“Phase 2a”) were conducted in participants
with congenital HI who were 12 years of age and older in countries governed by regulatory authorities in the European Union and elsewhere
in Europe (collectively, “European Authorities”). In the US, FDA restricted enrollment in Phase 2a to participants
18 years of age and older and, based on the rat findings, imposed a human drug exposure limit equating to repeat doses of approximately
3 mg/kg per week (“exposure cap”).
Subsequently, in the RIZE study European Authorities
and other regulatory bodies continued the expected downward age progression, lowering the age for study participants down from 12 years
of age to 2 years of age and older. At the start of the RIZE study the clinical program in the US remained under the 18 years of age and
older restriction as well as the exposure cap. However, in the first half of 2020, while the RIZE study was underway, the Company reached
agreement with FDA to proceed with the RIZE study in the US at all dose levels (no exposure cap) and in younger participants (ages 12
and older). Following these developments, the study protocol was harmonized globally, other than a regional difference in the minimum
permitted age (12 years and older in the US versus 2 years and older in all other geographies).
After the completion of the RIZE study, in the
second half of 2022 and the first half of 2023, the Company conducted scientific advice meetings with European Authorities which resulted
in alignment with the Company’s proposed Phase 3 program including overall study design, dosing regimen, endpoints, sample size
and patient population. Notably, with all available nonclinical (including the rat findings) and clinical information under review, European
Authorities aligned with a further downward age progression whereby participants 3 months of age and older will be permitted to be enrolled
in the Phase 3 study.
Prior to engaging FDA on Phase 3 planning in the
US, the Company began interacting with the agency in the second half of 2022 to further liberalize the age restriction to achieve alignment
with the parameters established by the European Authorities in the RIZE study. Over the course of these post-RIZE regulatory interactions
with FDA, the agency revisited prior concerns regarding the rat findings and, despite the absence of new clinical or nonclinical data (other
than the RIZE data), the agency decided to maintain the age restriction of 12 years and above and re-imposed the previous exposure cap
which had been removed during the RIZE study (collectively, “New Restrictions”). In the second half of 2022 and
the first half of 2023, the Company interacted with FDA to resolve the New Restrictions, particularly in the context of the advancement
of the clinical program in the rest of the world. Nonetheless, FDA affirmed the New Restrictions at a meeting held with the Company on
May 24, 2023.
The
Company and FDA have discussed potential solutions that could enable removal of the New Restrictions and as a result, the Company is evaluating
nonclinical studies to address FDA’s concerns in parallel with the initiation and advancement of the sunRIZE study
outside of the US. Assuming that the Company can conduct the appropriate nonclinical studies and that the results adequately address FDA’s
concerns, the Company believes that the New Restrictions could be removed. If the Company is unable to satisfy FDA’s nonclinical
concerns, the Company’s development plans for congenital HI in the US could be negatively impacted.
Phase
3: “sunRIZE” study
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 |
The study will enroll approximately 56 participants between 3 months
and 45 years of age. 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) |
Update on the Commercial Opportunity for
Congenital HI
As the Company initiates the sunRIZE study in
the fourth quarter of 2023, it recognizes the importance of advancing commercial readiness. Congenital HI, like many ultra-rare conditions,
lacks robust epidemiology studies that accurately characterize the disease. Following RIZE, Rezolute has made a significant investment
to understand the patient journey from diagnosis to treatment and to characterize the impact of current standard of care practices on
patient outcomes. The Company has conducted primary research by engaging with patients, key opinion leaders, payers, and others to understand
the significant unmet need and economic burden to patients, their families, and the healthcare system. The Company has also engaged specialized
third parties to conduct claims-based market assessments to better characterize and quantify the number of individuals who live with congenital
HI in primary markets. This body of work has been further validated by third party epidemiological analysis as well as the Company’s
engagement with centers of excellence and international advocacy organizations. Collectively, the output from this research provides increased
certainty regarding certain fundamental characteristics of the disease:
| o | The estimated worldwide incidence of congenital HI is 1 in every 28,000 live births.1 |
|
o |
The average duration of therapy for an individual diagnosed with congenital HI is 25 years, particularly for those that are non-responsive to diazoxide.2 |
| o | Based on the live birth incidence and the average duration of therapy, the Company believes that the prevalence
of congenital HI exceeds 10,000 individuals in primary markets, including approximately 3,500 individuals in each of the US and Western
Europe. Importantly, the Company believes that more than half of these individuals lack adequate treatment options to control their hypoglycemia. |
(1) Congenital
Hyperinsulinism International (https://congenitalhi.org/congenital-hyperinsulinism/#overview)
(2) Clearview Healthcare Partners 2023 Commercial
Assessment