[Edaily Reporter KIM SAE-MI ] AprilBio Co.,Ltd.(397030)Since “APB-A1” (Lu AG22515), which was licensed to Lundbeck, failed to demonstrate the expected clinical efficacy in thyroid-associated ophthalmopathy (TED), the company is now seeking a new indication. Given that there are precedents where candidate compounds that experienced clinical failures or rights reversion in the past have been revived as new drugs by changing their indications, analysts suggest that APB-A1 still has a chance.

According to the biotech industry on the 20th, Danish pharmaceutical company Lundbeck recently announced in its first-half earnings report that it had confirmed biological activity in the CD40-CD40L pathway through the Phase 1b TED clinical trial of APB-A1, including a reduction in thyroid-stimulating hormone (TSH) receptor autoantibodies. However, the company assessed that this activity did not lead to the expected clinical improvement in the disease. Lundbeck reported that the safety and tolerability results support further development and decided to explore other indications where the CD40-CD40L pathway is more directly involved.

Failed New Drugs Can Be “Revived” by Changing Indications

It is difficult to conclude that a candidate compound’s mechanism of action has failed simply because it did not achieve the expected efficacy for a specific indication. This is because there have been cases, both domestically and internationally, where candidates have successfully made a comeback by changing their indications or development strategies following clinical failure or the return of rights.

In Korea, “Epinopegduotide” by HanmiPharm(128940)is a prime example. HanmiPharm licensed this compound to Janssen in 2015 as a treatment for diabetes and obesity but had the rights returned in 2019. Subsequently, the company shifted the development focus to metabolic-associated steatohepatitis (MASH) and successfully licensed the compound again to Merck (MSD) in the U.S. in 2020 for an upfront payment of $10 million (approximately 13.9 billion won) and development, approval, and commercialization milestones totaling up to $860 million (approximately 1.1993 trillion won).

Eli Lilly also terminated its collaboration on “teplizumab,” an anti-CD3 antibody developed by the U.S. biotech company MacroGenics, after the drug failed to meet its primary endpoint in a Phase 3 clinical trial for Type 1 diabetes. Subsequently, the development strategy was shifted from treating patients who had already developed Type 1 diabetes to delaying the onset of Type 1 diabetes in high-risk patients at Stage 3. Provention Bio subsequently continued development and received FDA approval, and Sanofi acquired Provention Bio in 2023 for approximately $2.9 billion (about 4 trillion won). Last June, the drug received additional approval for an indication to delay the decline in endogenous insulin production in children recently diagnosed with stage 3 type 1 diabetes.

Another example is Orinia Pharmaceuticals’ “voclosporin,” which was originally developed as a treatment for non-infectious uveitis but failed to meet its primary endpoint in Phase 3 clinical trials, leading to the return of the ophthalmic rights from its partner, Lux BioSciences. The company subsequently shifted the indication to lupus nephritis and received FDA approval in 2021. In 2020, just before approval, the company also signed a development and commercialization agreement with Otsuka for regions including Europe and Japan, under terms that included a $50 million (approximately 69.7 billion won) upfront payment and regulatory and reimbursement milestones totaling up to $50 million.

TED Failure ≠ Mechanism Failure… Hope Remains for APB-A1

Although the TED clinical trial failed, there are cases where positive results were achieved in clinical trials for other autoimmune diseases. In particular, the fact that competing drugs targeting CD40L, such as APB-A1, have demonstrated efficacy in other autoimmune diseases is cited as evidence that it is difficult to conclude, based solely on the TED results, that the APB-A1 target itself has failed. A clinical development expert also noted, “Even for the same drug, clinical success or failure can vary depending on the indication.”

HANALL BIOPHARMA CO.,LTD(009420)The FcRn inhibitor “batoclimab,” developed by [Company Name], failed to meet the primary endpoint in both of its Phase 3 TED trials this year. In contrast, it successfully met the primary endpoint in a previous Phase 3 trial for myasthenia gravis (MG). Since TED and MG were developed in parallel, this is not a case of changing the indication following a failure in the TED trial; however, it demonstrates that clinical success or failure can vary depending on the disease, even for the same drug. Immunovant has currently halted the development of batoclimab and is focusing on its follow-up FcRn inhibitor, “IMVT-1402.”

Positive clinical data are also accumulating in the CD40L class, such as APB-A1. UCB and Biogen’s “dapirolimab pegol” met its primary endpoint in a Phase 3 clinical trial for systemic lupus erythematosus (SLE). Sanofi’s “prexalimumab” also met its primary endpoint in a Phase 2 clinical trial for relapsing multiple sclerosis (MS), reducing new brain lesions by 89% compared to placebo at high doses. This serves as a form of “target validation,” demonstrating that the CD40L blockade strategy can be clinically effective in other autoimmune diseases.

What Does APB-A1 Need to Prove to Make a Comeback?

However, these precedents do not guarantee the success of APB-A1’s subsequent development. Experts point out that Lundbeck must do more than simply choose a different indication instead of TED; it must re-establish evidence that APB-A1 can deliver actual clinical benefits in the new indication.

Clinical development experts identified nonclinical evidence for the new indication as the first factor to be verified in APB-A1’s subsequent development.

One clinical development expert stated, “It is advisable to evaluate the risks, likelihood of success, and feasibility of development and execution for all disease groups treatable by the target from the early stages of development, and to define an entry indication along with two or three backup indications,” adding, “At the very least, nonclinical data supporting efficacy in the subsequent indication is necessary to establish a basis for proceeding with further development.”

Another clinical development expert also noted, “The pace of development can vary depending on how much data has already been secured for subsequent indications,” adding, “If the indication changes, additional preclinical data may be required depending on the mechanism of action.”

Some also pointed out that simply confirming drug efficacy in preclinical studies is insufficient. They argued that it is necessary to assess whether the drug is competitive compared to the existing standard of care for the disease and to quantitatively determine the dosage and administration regimen capable of delivering actual efficacy in the new indication, based on the safety and pharmacokinetic (PK) data obtained from the TED clinical trial.

A clinical development expert emphasized, “What is more important than the drug itself being effective is determining at what dosage and administration regimen it demonstrates efficacy,” adding, “The fact that an early efficacy signal has emerged in a competing drug is merely evidence that ‘it’s worth a try,’ but it does not guarantee success.”

Ultimately, whether APB-A1 can turn this situation around hinges not only on which indication Lundbeck chooses but also on why it chose that particular indication. This means that, based on existing preclinical data and human data obtained from the TED trial, Lundbeck must reprioritize the diseases for which CD40L blockade is most likely to lead directly to clinical improvement. The follow-up indications Lundbeck is set to announce, along with the supporting preclinical evidence, dosage and administration protocols, and clinical development strategy, are expected to serve as key benchmarks for assessing APB-A1’s potential for a comeback.