Rick Hawkins and John McKew Share Views on Interim P-II Data from the Two Trials Evaluating LUM-201 for Moderate Pediatric Growth Hormone Deficiency

Shots:

Rick and John spoke about the trial design and the results from the P-II OraGrowtH210 Trial and P-II OraGrowtH212 trial evaluating LUM-201 to treat pediatric growth hormone deficiency
They also elaborated on the timeline of the further clinical development of LUM-201
The interview gives an understanding of Lumos Pharma’s vision to develop new therapies for patients with rare diseases and the company's future plans

Smriti: Thanks, Rick, for taking out time to talk to us, firstly we would like to talk about PGHD (its epidemiology (US, EU5, and RoW), prognosis, and available treatment options.

Rick Hawkins: Great to be with you. Our company, Lumos Pharma, is developing a new investigational treatment option for pediatric growth hormone deficiency, or PGHD. PGHD is a rare disease where children do not make enough growth hormone (GH), which is a key hormone that supports linear growth and other metabolic functions. The reported incidence of PGHD around the world is variable, but in the US, we know that about 1 in 3,500 children are affected. PGHD can be caused by an underlying medical or genetic condition, but it can also be of unknown cause. When there is no clear cause, it is referred to as idiopathic PGHD (iPGHD), which represents approximately two-thirds of the overall PGHD population.

If left untreated, PGHD can result in short stature, delayed puberty, and in some cases growth failure. Children and adolescents affected by PGHD who do not receive timely diagnosis and treatment may not reach their potential adult height and be significantly shorter than their peers. Despite PGHD being a well-understood condition, there is currently only one treatment: injectable recombinant human growth hormone (rhGH). These injections are given either daily or weekly for many years while a child is actively growing and can result in as many as 2,500 injections in a patient’s lifetime.

Smriti: What is LUM-201 and how does it work?

Rick Hawkins: LUM-201, also known as ibutamoren, is an investigational, orally available growth hormone secretagogue – a substance that promotes GH secretion. It acts on specific receptors in the hypothalamus and the pituitary gland to stimulate GH release. Under LUM-201 stimulation, GH is released in a pulsatile fashion, as it is naturally, but the amplitude of these pulses is increased. LUM-201 stimulated GH release acts within the existing physiologic pathways for GH production and is subject to natural feedback mechanisms mediated by GH and IGF-1.

Smriti: Can we talk about the trial design of OraGrowtH210 and OraGrowtH212? And why LUM-201 is being assessed in 2 studies and what is the difference?

Rick Hawkins: Happy to explain. OraGrowtH210 is our multicenter randomized Phase 2 study comparing the efficacy of LUM-201 against the current standard of care, rhGH injections, in prepubertal children with moderate PGHD. We use a predictive enrichment marker (PEM) strategy to identify PGHD patients with moderate – or idiopathic – GH deficiency who are likely to benefit from LUM-201. The PEM strategy was based on pre-specified levels of two biomarkers, baseline IGF-1 level and GH level after a one-time stimulation. PEM-positive (PEM+) patients represent about 60% of all PGHD patients. Only PEM+ patients are enrolled in the OraGrowtH210 trial and receive either daily oral LUM-201 at one of 3 pre-specified doses (0.8 mg/kg/day, 1.6 mg/kg/day, or 3.2 mg/kg/day) or daily subcutaneous rhGH injections. We plan to enroll 80 patients. The primary endpoint is annualized height velocity on LUM-201 compared to rhGH after 6 months of treatment. This study will also enable us to confirm the utility of our PEM strategy, determine the optimal dose of LUM-201 for a Phase 3 study and monitor for any adverse events. Of note, children with PGHD caused by a defined medical or genetic condition are excluded from this study.

OraGrowtH212 is our single site, randomized, open-label study evaluating the pharmacokinetics (PK) and pharmacodynamics (PD) of LUM-201 in prepubertal PGHD patients who have never been treated with rhGH. Eligible patients are randomized to 2 arms to receive either 1.6 mg/kg/day or 3.2 mg/kg/day of LUM-201. Pulsatility and PK studies are to be completed after the first dose of LUM-201 and at 6 months post study initiation. The study is designed to enroll up to 24 patients, and the primary endpoints are as follows: evaluation of increased GH pulsatility by LUM-201, annualized height velocity, and PK characteristics of LUM-201. Similarly, children with PGHD attributed to an underlying medical or genetic condition are excluded from this study.

Smriti: Can Dr. John McKew tell us more about the results of these two studies in detail?

John McKew: These two studies, OraGrowtH210 and OraGrowtH212, are still ongoing but we recently conducted an interim analysis and observed encouraging results. Interim Phase 2 data from the OraGrowtH210 study in 41 moderate PGHD subjects showed LUM-201 produced an annualized height velocity (AHV) of 8.6 cm at 6 months at the 1.6 mg/kg/day dose, which is in line with the expected 8.3 cm in predictive enrichment marker positive (PEM+) patients. Notably, growth rates were consistent for patients taking this dose of LUM-201 from 6 to 12 months, suggesting the durability of LUM-201's effect. In this interim analysis, we observed a higher than anticipated AHV in the rhGH control arm, which is inconsistent with multiple historical trials in similarly characterized populations. This is likely due both to the presence of two growth outliers in this arm and to imbalances in several baseline characteristics between the rhGH cohort and the LUM-201 cohorts. We expect these imbalances to decrease as the study enrolls more patients. Of note, at this interim look, we did not observe treatment-related serious adverse events (SAEs) or meaningful safety signals, and there were no trial dropouts due to SAEs.

In our OraGrowtH212 study, we conducted an interim analysis of the AHV and safety data on 10 enrolled patients. The AHVs at 6 months for the two higher doses of LUM-201 (1.6 mg/kg and 3.2 mg/kg per day) were 7.14 cm/year and 8.60 cm/year, respectively, similar to growth seen in the OraGrowtH210 trial. In a small number of patients, we observed durable growth out to 12 months. Importantly, looking at these interim results, no SAEs were reported, and no meaningful safety signals were observed.

Smriti: What is the expected development timeline for LUM-201, expected completion of ongoing trials, upcoming milestones, and next step on clinical development?

John McKew: Lumos’ OraGrowtH210 trial reached ~80% enrollment in November 2022, and we anticipate primary outcome readout on all 80 subjects at six months in 2H 2023. In the OraGrowtH212 trial, we also expect to share primary outcome data on up to 24 subjects in 2H 2023.

As detailed in an earlier question, recent encouraging interim data showed growth response in PGHD patients, indicating that LUM-201 may serve as a potential oral alternative to injectable rhGH and disrupt the PGHD market. Combining AHV data from both OraGrowtH trials demonstrates comparable growth at the 1.6 and 3.2 mg/kg/day LUM-201 doses evaluated in the OraGrowtH210 and OraGrowtH212 trials and supports the selection of the 1.6 mg/kg/day dose for a pivotal Phase 3 trial, which we are currently planning and look forward to advancing.

Smriti: What is the Go-to-market strategy of Lumos for the launch of LUM-201 for the US & EU? On your own or expecting a partnership for marketing etc.?

Rick Hawkins: At this time, Lumos is focused on executing clinical milestones including the completion of the OraGrowtH210 and OraGrowtH212 studies. Though it is too soon to discuss specifics, the team is planning a go-to-market strategy that aims to position LUM-201 to be accessible to PGHD patients as quickly as possible.

Smriti: Is Lumos planning to assess LUM-201 in other GH / endocrine disorders also? If yes, which ones are those?

Rick Hawkins: Because of LUM-201's unique mechanism of action that works within the natural endocrine pathway, we believe there is potential for it to benefit patients in multiple GHD disorders treated by injectable growth hormone. Lumos Pharma’s current clinical trials are focused on moderate idiopathic PGHD. Other indications treated with injectable growth hormone include Prader-Willi Syndrome, Turner Syndrome, children born Small for Gestational Age (SGA), and Idiopathic Short Stature (ISS).

LUM-201 is also currently being investigated in a Phase 2 study in non-alcoholic fatty liver disease (NAFLD), a condition that has shown to be responsive to growth hormones in preliminary studies (ENDO 2022) and is estimated to be prevalent in approximately 25% of adults worldwide.

Source: Canva

About the Authors:

Rick Hawkins

Rick Hawkins is the CEO and Chairman of Lumos Pharma. Previously, Mr. Hawkins founded Pharmaco and as Chairman, President, and CEO, he managed the growth of that organization to over 700 employees. Mr. Hawkins currently serves as a Director for Plus Therapeutics (PSTV) and Savara Pharmaceuticals (SVRA).He was inducted into the Hall of Honor for the College of Natural Sciences at the University of Texas. He is a member of the National Ernst and Young Entrepreneur of the Year Hall of Fame. In 2015, he received Ohio University’s Konneker Medal, the highest award given to a faculty member or former student for entrepreneurial excellence. Mr. Hawkins has served on the Lumos Pharma Board since 2012 and Chairman since March 2020.

John McKew

John McKew is the President and CSO of Lumos Pharma. Dr. McKew has 27 years of experience developing novel therapeutics where he successfully advanced therapies through preclinical and clinical development. Beyond his work with Lumos Pharma, Dr. McKew is currently an Adjunct Professor at the Boston University School of Medicine and has previously served as the Chair-Elect, Chair, and Immediate Past Chair of the American Chemical Society’s Northeastern section. Dr. McKew graduated from the State University of New York at Stony Brook with B.S. degrees in Chemistry and Biochemistry, completed his Ph.D. in Organic Chemistry at the University of California, Davis, and held post-doctoral research positions at the University of Geneva and Firmenich, SA.