IRLAB Therapeutics — Quarterly update recapping active pipeline plans

IRLAB continues to progress the development of its pipeline, spanning preclinical to Phase III readiness (Exhibit 1). As previously noted this quarter, IRLAB secured full ownership and rights to the mesdopetam project for the treatment of levodopa-induced dyskinesia (PD-LIDs), which had been previously out-licensed to Ipsen. The transfer of data and materials related to mesdopetam from Ipsen to IRLAB is ongoing and due to be complete by the end-October. As presented at the CMD, IRLAB is collaborating with two US-based advisory groups, Clintrex (a clinical research company) and ProPharma Group (a research consulting organisation), for guidance in preparing a brief package to request an EoP2 meeting with the FDA, possibly in H124. Management indicated that the project is Phase III ready and we await further updates regarding the trial design and commencement date.

IRLAB’s second asset, pirepemat, has been progressing in the ongoing Phase IIb study assessing the drug for the treatment of impaired balance and falls (PD-Falls). In July 2023, it received an encouraging interim review from the independent data and safety monitoring board (DSMB) of the study based on the initial 25 patients completing treatment. The DSMB unanimously recommended that the trial should continue according to the approved protocol without any modifications. This ongoing Phase IIb study is recruiting patients at the planned sites, but management has communicated that recruitment had been slightly slower than anticipated in recent months. Recruitment is now expected to be complete in Q124, pushed back slightly from end-2023, but IRLAB states that top-line results are on track for H124, consistent with prior guided timelines. We believe that top-line results for the Phase IIb study could represent the next major clinical catalyst for the company.

IRLAB plans for its three preclinical assets to be Phase I ready in 2024: IRL757 (for the treatment of apathy) by end-2023, IRL942 (to improve cognitive function) by H124 and IRL1117 (as a once daily treatment for Parkinson’s disease (PD), either as a monotherapy with the potential to replace levodopa or as an add-on therapy) by end-2024. We note that the McQuade Center for Strategic Research and Development and IRLAB are currently evaluating a collaboration for the early development of IRL757 and IRL942.

The clinical development of mesdopetam for the treatment of PD-LIDs remains a key strategic focus for IRLAB, as it prepares for an EoP2 meeting with the FDA ahead of a Phase III clinical trial. While the Phase IIb trial did not meet the primary objective of change in daily hours of good ON time compared to placebo in January 2023, it did meet the key secondary efficacy endpoint on the Unified Dyskinesia Rating Scale (UDysRS), a clinically recognised scale for measuring dyskinesias versus placebo.

A detailed analysis of the Phase IIb trial data was published in August 2023. This included the four arms of the study (ie 2.5mg, 5mg, 7.5mg and placebo twice daily (bid) for 12 weeks) with an analysis of two sets of the patient population: full analysis set or intent-to-treat (FAS) and protocol-compliant (PS). In the FAS, the effect of mesdopetam on good ON time based on Hauser diary entries was not statistically significant. However, in the PS, patients taking the highest tested dose of mesdopetam (7.5mg bid) saw a significant and clinically meaningful increase in good ON-time (1.75 hours vs placebo, p=0.05). Furthermore, in the FAS, the effect of mesdopetam based on UDysRS (sum of parts 1, 3 and 4) measured a notable reduction in dyskinesia (6.2 points vs placebo, p=0.026) at 7.5mg, but this was numerically larger in the PS (9.2 points vs placebo, p=0.011). Also, a clear dose-dependent and sustained reduction was seen in OFF time (Exhibits 1 and 2).

This update on the Phase IIb trial data confirmed the safety and tolerability of mesdopetam and demonstrated that the drug has dose-dependent anti-dyskinetic and anti-Parkinsonian effects. It also provided a guided dose of 7.5mg bid for Phase III.

As an additional analysis of the data, the study met an important parameter in assessing the effectiveness of the drug (Exhibit 3). The improved OFF time and reduction in bad ON time (with dyskinesia) both indicate that there was neither untoward Parkinsonian nor untoward effect on normal motor function. We note that the Phase IIb results for mesdopetam are in line with the endpoint data for amantadine extended release (ER), Exhibit 3. Amantadine ER (sold under the brand name Gocovri) is an FDA-approved drug used to treat dyskinesia in Parkinson's patients receiving levodopa, as well as the extrapyramidal side effects of medications. In 2017, the ER formulation was approved for use in the treatment of PD-LIDs. However, we note that it has safety limitations due to instances of hallucinations, peripheral edema, falls, suicidality and depression, potentially giving mesdopetam a competitive edge, in our view.

We note that, along with Phase IIb study, IRLAB conducted multiple Phase I studies in collaboration with Ipsen, including a drug-drug interaction study (assessing the effect of other drugs on the pharmacokinetic profile of mesdopetam), a human mass study (using radioactive material to study the distribution of the drug in the body, as well as excretion from the body) and a pharmacokinetic study in different genetic populations (Asia versus US populations). Each of these studies has supported the safety and tolerability of mesdopetam and, with the clear dose-dependent anti-dyskinetic and anti-Parkinsonian effects observed in the Phase IIb trial, management is confident in moving forward with the clinical development of the drug.

In August 2023, IRLAB secured full ownership rights to the mesdopetam project from Ipsen. Following a detailed analysis of the study data in August 2023 and with a growing body of evidence to support the drug’s potential, management plans to proceed to Phase III. As the next step, it is preparing a submission package for the EoP2 meeting (type B) with the FDA. To do this, IRLAB recently collaborated with two US-based advisory groups, Clintrex and ProPharma Group. We note that these type B meetings are usually conducted at critical points like pre-IND (Investigational New Drug), EoP2 or pre-NDA (New Drug Application) and are in-person meetings compared to written communications for other stages. Hence, it provides an important opportunity for IRLAB to discuss the data obtained to date on mesdopetam and to obtain feedback on the planned Phase III study, including details on entry criteria, outcome measures, study duration and analytic approaches. After this, IRLAB may intend to request an SPA with the FDA, to reduce the possibility of future conflicts/challenges on regulatory clearance. If it is successful in negotiating an agreeable SPA, it will result in an agreement with the regulatory authorities regarding specific requirements for the study protocol design and plan for analysis, as well as clearly identifying the results that must be achieved to complete Phase III successfully.

We believe IRLAB is likely to conduct a pivotal trial to demonstrate the clinical benefits of mesdopetam with a short treatment duration of 12–13 weeks, alongside long-term safety data at the maximum dosage for at least one year. The focus of such a trial will be on demonstrating an improvement in dyskinesia, while also aiming to provide a decrease in OFF time (with indefinite treatment duration). Management has indicated that this should require enrolment of less than 100 participants per arm. Here, the UDysRS scale data have the potential to be submitted for confirmatory evidence, as the FDA has already confirmed the clinical relevance of this scale. We note that this will be a shorter trial than other typical central nervous system studies, such as those for Alzheimer’s disease, which typically require a minimum of 18 months as the focus of the treatment is on reducing the rate of cognitive decline. For example, AbbVie is currently going through the FDA regulatory process for Vyalev (or ABBV-951, a formulation of carbidopa-levodopa administered by a subcutaneous pump device) for the treatment of motor fluctuations in patients with advanced PD. The company reported positive data (NDA submission) from the M15-736 study which involved a treatment duration of 12 weeks, alongside the M15-741 study assessing the long-term safety of ABBV-951 over one year. We note that AbbVie received a Complete Response Letter from the FDA in March 2023, requesting more information on the pump device but, importantly, no questions were raised on efficacy or safety data; AbbVie plans to resubmit the NDA as soon as possible. As another example, the FDA has approved Supernus Pharmaceuticals’ Xadago (or safinamide) as an add-on treatment for PD patients who are currently taking levodopa/carbidopa and experiencing OFF episodes, based on a short treatment duration of 24 weeks.

PD is a complex and progressive neurodegenerative disease, characterised by a triad of cardinal motor symptoms (rigidity, bradykinesia and tremor), although non-motor symptoms (psychosis, dementia and cognitive impairment) can be as debilitating and remain undertreated. We note that despite intensive research efforts in the last few decades, the current mainstay of drug treatment is limited to oral therapies such as levodopa in first-line treatment for PD. However, the drug is associated with a myriad of side effects, with long-term use leading to dyskinesia. While existing medications such as levodopa do alleviate the motor symptoms of PD, they have no impact on non-motor symptoms and are believed not to halt disease progression. Hence, major areas of unmet need include PD-LIDs and treatment options for the broad range of non-motor symptoms. Currently there are no approved disease-modifying drugs for this progressive disease that slow or alter its progression.

It is estimated that PD afflicts approximately one million people in the US alone and more than 10 million people worldwide. This figure is expected to double by 2040 due to an ageing population. Furthermore, IQVIA estimates the global value of the PD market in 2029 to be $5.2bn (a 4% CAGR from 2019). We therefore believe that IRLAB’s active clinical pipeline targets a sizeable market opportunity, with the potential to address a growing unmet medical need (Exhibit 4).

IRLAB is targeting this unmet need with its range of preclinical- and clinical-stage assets, which aim to address complications and symptoms across all stages of the disease (Exhibit 5). The two lead clinical-stage assets include mesdopetam, an oral D3 antagonist for the treatment of PD-LIDs, and pirepemat, a prefrontal cortex enhancer for the treatment of PD-Falls. IRLAB’s preclinical portfolio includes IRL757 for the treatment of apathy, for which there are currently no approved therapies, IRL942 as a treatment to improve cognitive function, designed to activate frontal cortical neurotransmission, and IRL1117 as a PD treatment that can be taken once daily, either as a monotherapy with the potential to replace levodopa, or as an add-on therapy. Management expects these assets to be Phase I ready by end-2023, H124 and end-2024, respectively.

During Q323, IRLAB recorded an operating loss of SEK40.7m, higher than SEK23.9m in Q322. This was mainly associated with lower revenue of SEK0.4m (service revenue) during the quarter (vs SEK16.5m in Q322) due to the absence of licensing income in Q323. As a reminder, IRLAB received a total upfront payment of SEK239.6m as part of its licensing agreement with Ipsen in July 2021, of which SEK61.2m was recognised as FY22 revenue. Overall operating expenses were up by a nominal 1.7% to SEK41.1m in Q323, with R&D expenses comprising 85% of total expenses (up 4.0% y-o-y). However, ytd R&D expenses were lower at 80% of total operating expenses, compared to 85% in the prior period due to the conclusion of the mesdopetam Phase IIb study. Based on the operating expenses run rate in Q323, we have made slight adjustments to our FY23 operating expense estimate, which now stands at SEK193.5m vs SEK175.4m previously. Our revised operating loss forecast for FY23 stands at SEK186.3m (vs SEK168.3m previously). We have also slightly increased our operating expenses for FY24 from SEK184.0m to SEK202.5m, assuming the Phase III trial gets the go-ahead from the FDA and the Phase I trials of IRL757 and IRL942 are initiated as expected.

Operating cash outflows for Q323 were recorded at SEK36.7m and the company ended the quarter with a net cash position of SEK118.8m, which we estimate should fund operations through H124. Hence, we project the need to raise additional funds to continue the company’s business operations. IRLAB has also mentioned that it is actively exploring funding opportunities through partnerships, licensing agreements, share issues or other capital markets transactions. We continue to estimate that it will need to raise SEK750m before becoming self-sustainable in FY28 with the projected launches of mesdopetam and pirepemat. We account for this funding as illustrative debt in our model and have distributed the raise (SEK250m per year) across three consecutive years (FY24–26). Alternatively, if this funding is realised through an equity issue (assuming at the current trading price of SEK7.16/share), IRLAB would need to issue 109.0m shares, resulting in our per-share valuation decreasing to SEK32.7 from SEK87.0 currently (the number of shares outstanding would increase from 51.9m to 160.9m).

Our valuation for IRLAB slightly improves to SEK4.51bn or SEK87.0 per share (vs SEK4.47bn or SEK86.1 per share previously). The change in valuation incorporates the impact of above-mentioned changes in estimates, along with rolling forward our model and the net cash balance at end-Q323. A breakdown of our rNPV valuation is shown in Exhibit 6 below.