First-ever RIPTAC enters clinic: all you need to know about this new cancer approach

You may already be familiar with protein degraders, drugs designed to eliminate disease-causing proteins, which have shown promising activity as cancer therapies. But have you heard of Regulated Induced Proximity Targeted Chimeras (RIPTACs), a new protein technology that targets tumor cells? Halda Therapeutics has now brought the first-ever RIPTAC into clinical trials, aiming to advance the next generation of induced proximity therapies.

In this article, we’ll explore what RIPTACs are, how they differ from existing protein degraders, and why Halda Therapeutics’ clinical milestone matters.

How do RIPTACs work?

RIPTACs are bifunctional small molecules designed to selectively target tumor cells by bringing together two distinct proteins: one that is highly expressed in tumor cells and another that is essential for cellular survival. Each RIPTAC consists of two ligands connected by a linker – one ligand binds specifically to a tumor-associated protein, while the other binds to a protein critical for cell viability. By physically linking these two proteins, RIPTACs can precisely disrupt essential cellular functions, leading to the targeted elimination of tumor cells.

This setup may remind you of antibody-drug conjugates (ADCs), which are composed of a monoclonal antibody, a cytotoxic drug – typically a chemotherapy – and a linker. But unlike ADCs, which deliver the drug specifically to the tumor as the monoclonal antibody binds to a specific target protein on the surface of cancer cells, RIPTACs create a neo-protein-protein interaction surface in a stable complex. 

Christian Schade, chief executive officer (CEO) of American biotech Halda Therapeutics, explained that by doing so, it leads to tumor-specific cell death. 

“The RIPTAC is highly selective and highly potent, akin to an ADC, but in a small molecule, oral format,” said Schade.

HLD-0915: Halda Therapeutics’ revolutionary approach to targeting cancer

Invented by Halda Therapeutics, HLD-0915 is the investigational drug that has just set foot into the clinic. It is a RIPTAC that binds to the androgen receptor (AR) – highly expressed in prostate cancer cells – and to an undisclosed protein that is essential for cell function, explained Schade. The drug is designed to drive specific interactions between these two proteins to achieve optimal activity and pharmacology through what Halda calls the “hold and kill” mechanism. 

This has been illustrated in preclinical studies where HLD-0915 exhibited tumor shrinkage and the decline of circulating prostate-specific antigen (PSA) – a protein produced by the prostate gland and a tool in prostate cancer screening – in models including ones of drug resistance, “while delivering a favorable therapeutic index.”

“We are excited to share data demonstrating the mechanism of action of RIPTAC molecules, as well as how the protein proximity paradigm can be extended into direct cancer cell killing,” said Kanak Raina, lead author of the preclinical study and head of Biology at Halda, in a press release. “Insights gained from the detailed interrogation of this chemical biology model have provided Halda with a robust foundation that has resulted in our pipeline of RIPTAC therapeutics for major cancers.”

Can RIPTACs tackle unmet needs of patients with prostate cancer?

This is a step forward in prostate cancer research. The typical oral drugs for people with prostate cancer target the AR signaling pathway, like RIPTACs. However, tumor cells adapt to these agents through a myriad of mechanisms, and resistance occurs through AR-dependent signaling – caused by splice variants such as AR-V7, a key driver of resistance to these therapies – and even independent cell signaling, Schade pointed out. This poses a significant challenge in prostate cancer care since treatments may eventually lose effectiveness. As this unmet need stands out, RIPTACs are designed to get around the issue of drug resistance.

“Unlike other oral modalities, RIPTACs only need the presence of AR in the tumor cell but do not rely on AR being the disease driver. As a result, HLD-0915 is expected to have broad activity in this large patient population,” said Schade.

Moreover, Halda’s RIPTAC HLD-0915 is an oral therapy. This minimizes the difficulties of having to get frequent intravenous injections at the hospital.

“Patients can take home a bottle of pills as opposed to having to go into the clinic to get intensive weekly infusions. Other intravenous agents that may be options have tremendous complexities of manufacturing and patient access, none of which are an issue with HLD-0915,” expressed Schade.

Therapies such as radiopharmaceuticals, ADCs, and T-cell engagers deploy a molecule to engage a cancer cell and ultimately, selectively cause its death. While they are ”designed to offer similar benefits,” “only RIPTACs offer the convenience and simplicity of an oral drug agent,” expressed Schade.

To add to that, these other therapies rely on engaging cancer cells “extracellularly.” According to a research paper published in the journal Cell Chemical Biology, they are unable to take advantage of most cancer-selective proteins, making it a less targeted approach.

“HLD-0915 is a significant step towards an oral, small molecule therapy that overcomes the multitude of resistance mechanisms that arise in response to other drugs,” said Schade. “Prostate cancer is treated first and foremost in the community setting, and a broadly effective oral drug fits with this treatment setting, in contrast to injectable medicines that require complex care and medical monitoring.”

How similar are RIPTACs to PROTACs?

Before RIPTACs appeared on the scene, protein degraders called proteolysis-targeting chimeras, familiarly known as PROTACs, have been studied for more than two decades. They are a type of small molecule that promotes the degradation of specific proteins by recruiting the cellular ubiquitin-proteasome system (UPS) to target proteins for destruction. While a PROTAC is yet to be approved by the U.S. Food and Drug Administration (FDA), there are a few in the clinic, like Arvinas’ vepdegestrant and C4 Therapeutics’ CFT1946. 

Motivated by the success of molecular glues and PROTACs, RIPTACs could pave the way beyond traditional protein degraders, according to a report in the National Library of Medicine. But just because they’re both bifunctional molecules, they don’t work the same way.

“RIPTACs operate via an entirely different mechanism of action compared to degraders,” said Schade. “Degraders can be effective if full-length AR is driving the tumor growth but become less effective when independent resistance mechanisms arise, especially upon progression on approved agents.”

While RIPTACs leverage tumor-specific AR expression to act selectively on cancer cells, they do not target its activity. 

“As a result, they are effective even in AR-independent settings. Similarly, because clinical degraders do not target AR splice variants, like AR-V7, they are ineffective in tumors driven by this mechanism. However, because AR-V7 expression in tumor cells occurs alongside full-length AR, RIPTACs can still kill the tumor cell by leveraging this full-length AR expression to form a trimer complex with the essential protein.”

Bifunctional therapies: a young but diverse therapeutic field

Although RIPTACs are a creation of Halda Therapeutics, the National Library of Medicine pointed out that other bifunctional therapies based on a similar mechanism have been discovered. These include deubiquitinase-targeting chimeras (DUBTACs), phosphorylation-inducing chimeras (PHICs), phosphatase-recruiting chimeras (PhoRCs), dephosphorylation-targeting chimeras (DEPTACs), phosphorylation-targeting chimeras (PhosTACs), acetylation tagging systems (AceTAGs), and transcriptional/epigenetic chemical inducers of proximity (TCIPs), all of which are in very early stages of preclinical research.

DUBTACs, like RIPTACs, are heterobifunctional molecules consisting of a protein-targeting ligand, but they are instead linked to a DUB recruiter via a linker. DUBs are deubiquitinating enzymes, which are proteases that remove ubiquitin tags from proteins, and so, DUBTACs aim to stabilize the levels of actively ubiquitinated proteins that are degraded by the proteasome. When treated in cells, a DUBTAC will induce the proximity of a DUB with a target protein to remove polyubiquitin chains to prevent the protein from undergoing proteasome-mediated degradation in order to stabilize protein levels, according to another report published in the National Library of Medicine. U.S.-based Vicinitas Therapeutics has licensed a platform from UC Berkeley and pharma giant Novartis to potentially lead DUBTAC therapeutics. 

Aside from DUBTACs, PHICs are formed by linking small-molecule binders of the kinase and the target protein, whereas PhosTACs and DEPTACs, both of which are inspired by PROTACs, modulate protein phosphorylation by recruiting phosphatases to target proteins to aid in dephosphorylation – the process of removing a phosphate group from a protein. Meanwhile, AceTAGs induce the acetylation – adding an acetyl group – of target proteins.

With the first-ever RIPTAC now in the clinic, Halda also has a couple of other preclinical RIPTACs in development. Not much has been disclosed about the ones in the discovery stage, but its investigational New Drug (IND)-enabling candidate is currently being evaluated to treat hormone receptor positive (HR+) metastatic breast cancer.

As with HLD-0915, only time will tell whether or not it will survive the clinic. But with growing research on heterobifunctional molecules in cancer, the class of drugs could expand treatment options for a treatment-resistant and ever-evolving disease like cancer.