Next-generation allosteric modulators: A glance at the biotech pipeline in 2026

Next-generation allosteric modulators: A glance at the biotech pipeline in 2026 By Willow Shah-Neville 12 minutesmins March 31, 2026 12 minutesmins Share WhatsApp Twitter Linkedin Email Photo credits: Silvan Arnet Newsletter Signup - Under Article / In Page"*" indicates required fieldsCompanyThis field is for validation purposes and should be left unchanged.Subscribe to our newsletter to get the latest biotech news!By clicking this I agree to receive Labiotech's newsletter and understand that my personal data will be processed according to the Privacy Policy.*Company name*Job title*Business email* Unlike traditional drugs that bind directly to a protein’s active site, allosteric modulators act at separate regulatory sites, allowing them to fine-tune biological activity and act more like a “dimmer switch” rather than simply an “on/off switch”. This added precision has made them an increasingly popular strategy in the biotech industry, with a growing number of companies advancing allosteric candidates in both preclinical and clinical development. These therapies are potentially very versatile and are being explored across a wide range of diseases, including neurological disorders, cancer, and immune-mediated conditions. In this article, we explore what allosteric modulators are, their benefits and drawbacks, and which companies have made headlines recently in their quest to bring their allosteric modulator therapies to the market. Table of contentsThe lowdown: What exactly are allosteric modulators? Allosteric modulators are compounds that bind to a site on a protein that is distinct from the active (officially known as the orthosteric) site, inducing a conformational change that alters the protein’s activity. But rather than directly activating or blocking a receptor, they influence how it responds to its natural ligand. This can result in more nuanced control of biological pathways, as the effect of the drug depends on the presence and concentration of the endogenous signaling molecule. Structurally, this mechanism often also allows for greater selectivity, because allosteric sites tend to be less conserved across protein families than active sites. Allosteric modulators do not all fall under the same bracket; instead, they are typically classified as positive allosteric modulators or negative allosteric modulators. Positive allosteric modulators work by enhancing the effect of a natural ligand, either by increasing binding affinity or amplifying downstream signaling, while negative allosteric modulators do the opposite, diminishing the ligand’s effect by reducing receptor responsiveness. There are also so-called “silent” or “neutral” allosteric modulators, which bind to the allosteric site without directly affecting activity – but they can influence how other modulators interact with the protein. The concept of allostery dates back to the 1960s, when it was first described in the context of enzyme regulation by Jacques Monod, Jeffries Wyman, and Jean-Pierre Changeux. Since then, several allosteric drugs have reached the market. Technically speaking, benzodiazepines like Librium and Valium, introduced in the early 1960s, were the first clinically approved allosteric modulators based on their biochemical mechanism. However, it was Cinacalcet, approved by the U.S. Food and Drug Administration (FDA) in 2004, that is officially described as being the first allosteric drug – or, more specifically, the first allosteric modulator of a G protein-coupled receptor (GPCR) – to reach the market, as it was the first drug developed intentionally using allosteric modulation as its design principle. Despite their promise, allosteric modulators do come with a unique set of challenges. Their effects can be highly context-dependent, varying with endogenous ligand levels and tissue-specific expression patterns, which, in turn, can complicate dose-response relationships and clinical predictability. Meanwhile, in some cases, allosteric binding sites are less well-defined or more transient than active sites, making them harder to identify and target reliably. Additionally, small changes in molecular structure can lead to disproportionate changes in activity. Suggested Articles Small but mighty: The role of small-molecule drugs in disease treatment Brain Awareness Week: could ongoing R&D spur neuroscience breakthroughs? 11 neuroscience biotech companies you should know about Nine promising small molecule drug discovery companies to look out for in 2025 GPCR therapies: Eight promising biotechs hacking the cell signaling pathway Another difficulty lies in translating preclinical findings into clinical success. Because allosteric modulators often rely on subtle modulation rather than outright activation or inhibition, their therapeutic effects may be less pronounced or harder to measure using traditional endpoints. This has contributed to higher attrition rates in some programs, particularly in complex indications like central nervous system (CNS) disorders. Furthermore, achieving the right balance between efficacy and safety can be tricky, as excessive modulation may still lead to off-target effects or pathway dysregulation. But biotechs are now working on next-generation allosteric modulators to overcome these limitations through improved selectivity, tunability, and predictability, with recent advances in structure-based drug design and artificial intelligence (AI)-driven modeling helping researchers better understand dynamic protein conformations and identify more druggable allosteric sites. Allosteric modulators advancing through the clinic Over the past year, there have been several announcements from biotechs related to the development of allosteric modulators. Below, we look at some of these companies, whose candidates are currently being tested in clinical trials. Rapport Therapeutics’ RAP-219 produces positive topline results in a phase 2a trial Dedicated to discovering and developing small molecule precision medicines for patients with neurological and psychiatric disorders, Rapport Therapeutics’ lead candidate, RAP-219, is a TARPγ8-specific AMPA receptor (AMPAR) negative allosteric modulator being investigated for the treatment of focal onset seizures. While AMPARs are distributed widely in the CNS, the receptor associated protein TARPγ8 is only expressed in discrete brain regions, including the hippocampus and neocortex, where focal seizures often originate. Therefore, by dampening activity only in these areas, RAP-219 is designed to dial down seizures without triggering any of the sedating/motor function side effects that are often associated with broader-acting drugs. In September 2025, Rapport announced positive topline results from its phase 2a trial of RAP-219 in patients with drug-resistant focal onset seizures. The drug candidate met its primary endpoint, demonstrating a statistically significant reduction in long episodes – an objective electrographic biomarker for clinical seizure reduction – compared with baseline over an eight-week treatment period. Patients also saw a 77.8% reduction in clinical seizures, with 24% remaining seizure-free over the eight-week period. Two global registrational trials of RAP-219 are now planned in the same indication, with the phase 3 program expected to be initiated in the second quarter of 2026. Rapport also recently entered into a strategic collaboration with Chinese biotech company Tenacia Biotechnology, granting it exclusive rights to develop and commercialize RAP-219 in Greater China. Tenacia’s regional expertise here will expand the global reach of the candidate and will accelerate development efforts for RAP-219 by adding phase 3 clinical trial sites in China. As part of the agreement, Rapport received $20 million upfront and is eligible to receive up to $308 million in potential milestone payments. Atavistik Bio raises $160 million in series B funding to advance the clinical development of ATV-1601 Atavistik Bio is focused on the development of the next generation of selective allosteric therapies, and its lead candidate, ATV-1601, is an oral allosteric AKT1-selective inhibitor for the treatment of Hereditary Hemorrhagic Telangiectasia (HHT), a severe inherited bleeding disorder that affects more than 1.6 million people globally, with no approved therapies currently available. The condition often leads to frequent bleeding episodes and vascular shunts, resulting in chronic anemia, multiorgan damage, and life-threatening complications. AKT1 hyperactivation is a hallmark of HHT and has been shown to drive the vascular pathology of the disease; it is the primary AKT isoform and driver of abnormal endothelial growth implicated in HHT. According to the company, selectively inhibiting AKT1 offers a novel and potentially disease-modifying therapeutic approach for the condition. Although there has been substantial investment in pan-AKT inhibitors, their use is limited by AKT2-driven toxicities, most notably hyperglycemia, which impact tolerability and restrict their use for chronic dosing. In August last year, Atavistik dosed the first patient in a phase 1 oncology study of ATV-1601. From this study, the company found that its candidate demonstrated a favorable safety profile, and it is now focusing its development efforts on advancing it for the treatment of HHT instead, anticipating that it will initiate a clinical trial in the condition in the first half of 2026. To help fund the clinical advancement of ATV-1601, Atavistik has recently raised a total of $160 million in series B financing, having initially bagged $120 million in December 2025, before closing another $40 million extension in March. Gain Therapeutics’ GT-02287 produces positive early phase 1b data in Parkinson’s disease Specifically focused on the discovery and development of next-generation allosteric therapies, Gain Therapeutics’ lead drug candidate, GT-02287, is currently being evaluated for the treatment of Parkinson’s disease with or without a GBA1 mutation in a phase 1b trial. GT-02287 is an orally administered, brain-penetrant allosteric enzyme modulator that restores the function of the lysosomal enzyme glucocerebrosidase (GCase), which becomes misfolded and impaired due to mutations in the GBA1 gene, the most common genetic abnormality associated with Parkinson’s disease, or other age-related stress factors. According to the company, in preclinical models of Parkinson’s disease, the candidate restored GCase enzymatic function and reduced endoplasmic reticulum (ER) stress, lysosomal and mitochondrial pathology, aggregated α-synuclein, neuroinflammation, and neuronal death, as well as plasma neurofilament light chain (NfL) levels, a biomarker of neurodegeneration. In rodent models of both GBA1-PD and idiopathic Parkinson’s disease, the allosteric therapy was shown to rescue deficits in motor function and gait and prevent the development of deficits in complex behaviors such as nesting. In October 2025, Gain Therapeutics presented promising initial data from its phase 1b study of GT-02287 in Parkinson’s disease patients, showing that it was generally well tolerated, with no treatment-emergent serious adverse events observed. Additionally, several participants experienced an improvement in their Unified Parkinson’s Disease Rating Scale (UPDRS) – an assessment tool used by clinicians to measure both motor and non-motor symptoms of Parkinson’s disease – Part II and III scores after 90 days of dosing with GT-02287. The mean improvement in Parts II and III by day 90, which was not observed by day 30, suggests that GT-02287 has a disease-slowing effect. This data, along with more recently presented biomarker data from the phase 1b study, certainly supports the continued development of Gain Therapeutics’ allosteric candidate. Neurosterix begins phase 1 study of lead candidate NTX-253 for schizophrenia Neurosterix, a spinout of Addex Therapeutics – a foundational contributor to the field of allosteric therapies – launched back in 2024 with $63 million in series A funding to advance allosteric modulators for the treatment of neurological disorders. The company has leveraged decades of investment made by Addex in building a leading allosteric modulator discovery technology platform, which has a track record of identifying highly selective, brain-penetrant small molecule drugs. Fast forward to this year, and Neurosterix announced in January that it had begun a phase 1 study of its lead candidate, NTX-253, a potent, selective, orally available positive allosteric modulator of the M4 muscarinic receptor, which is a validated target for treating schizophrenia and related disorders through the indirect modulation of dopamine signaling. The therapy works by fine-tuning muscarinic signaling with the potential to reduce psychosis symptoms while avoiding the movement disorders and metabolic complications associated with traditional dopamine antagonists. Preclinical studies of the asset have demonstrated a robust antipsychotic-like activity and a favorable safety profile, which supported its advancement into clinical trials for the treatment of schizophrenia. Axsome Therapeutics acquires receptor positive allosteric modulator for the treatment of epilepsy Neuroscience biotech Axsome Theapeutics, which has a variety of candidates in its pipeline, announced in November 2025 that it had obtained exclusive global rights to a novel oral GABAA receptor α2,3 subtype-selective positive allosteric modulator. This came about through Axsome’s acquisition of a 100% equity interest in Baergic Bio – a subsidiary of Avenue Therapeutics – which had originally licensed the candidate from AstraZeneca. Previously known as BAER-101 or AZD7325, the asset is now called AXS-17 under Axsome’s control and is intended for the treatment of epilepsy. It has already completed phase 1 trials, and, in clinical studies in over 700 patients to date, has demonstrated a favorable safety and tolerability profile. It has also shown anti-convulsant effects in preclinical seizure models. In February, Axsome said in a press release that it had initiated tech transfer activities and phase 2 trial-enabling activities for the allosteric modulator. What does the future hold for allosteric modulators? These recent milestones signal that allosteric modulation is now moving from a niche concept to a promising strategy in drug development. As more biotech companies invest in this approach, it is becoming clear that the ability to fine-tune – rather than simply switch on or off – biological pathways offers a meaningful advantage that is especially important in complex diseases, where precision can make the difference between a treatment that works and one that causes unwanted side effects. The growing pipeline of allosteric therapies also reflects a broader shift in how drugs are designed. Instead of targeting the most obvious binding site, researchers are increasingly exploring the full landscape of protein structure and function. This has opened the door to treating conditions that were once considered too difficult or too risky to target with traditional approaches, including disorders of the brain, immune system, and certain cancers. At the same time, challenges do remain. Allosteric drugs can behave in subtle and sometimes unpredictable ways, and translating promising early data into clear clinical success is not always straightforward. However, advances in technology are helping to reduce this uncertainty and guide more effective drug design that could eventually result in more allosteric modulators successfully progressing through clinical trials. With this in mind, the next wave of these therapies is likely to be more selective, more reliable, and better tailored to individual disease biology. And, as they continue to mature and more companies focus on their development, they have the potential to expand treatment options for a wide variety of diseases. This article is reserved for subscribers Subscribe for free to continue reading.Enter your details to log in or subscribe. Email Company name Job title Continue Readingor Continue with Microsoft Continue with LinkedIn By continuing, I agree to receive Labiotech's newsletter and understand that my personal data will be processed according to the Privacy Policy. Explore other topics: GPCRNeurological disordersSmall molecules ADVERTISEMENT