Death cap poison: the latest weapon in the fight against cancer

The death cap mushroom is feared throughout much of the world because of the deadly toxin it contains, amanitin. But could the poison reputedly used by Agrippina to murder her husband, the Roman emperor Claudius, be used to destroy cancer, asks Richard Staines.

Known to modern science as an inhibitor of RNA polymerase II, alpha-Amanitin is a poison that when ingested by eating mushrooms such as the death cap (Amanita phalloides), destroys liver cells.

In many cases symptoms emerge within a day, signalling that damage has already occurred. Severe effects on the liver and kidney may also then manifest, with death occurring in around 15% of cases.

But one company, Germany-based Heidelberg Pharma AG , wants to exploit the destructive power of alpha-Amanitin to attack cancer cells, by attaching it to an antibody that binds to tumours, while leaving healthy tissues unaffected.

It’s one of a group of biotechs developing antibody-drug conjugates (ADCs), a class of drugs that has become a “hot topic” in recent years after first hitting the market around the turn of the century.

ADCs consist of an antibody, linked to a “payload” that typically kills a cancer cell, without damage to healthy tissues.

Heidelberg Pharma expects that its compound, which is the first and only amanitin-based ADC in clinical development and currently demonstrating promising initial first in human results in relapsed and refractory multiple myeloma in a Phase 1/2a study, could provide an alternative mechanism of action that can overcome cancers that are resistant to standard therapy.

Delving deeper into the properties of alpha-Amanitin, the compound is unique in cancer research in that it targets the transcription process at the heart of all cells, where information stored in DNA is converted into messenger RNA (mRNA) that codes for the proteins that are essential for a cell’s functioning and survival.

It’s the only known inhibitor of RNA polymerase II, and is also very stable and hydrophilic, so it is easily dissolved in water.

Prof. Dr Andreas Pahl , CEO of Heidelberg Pharma AG , said during its R&D webinar following novel data presented at AACR: “This was the core idea – to exploit and harness this compound for cancer therapy and to use ADC technology to make that compound amenable to cancer therapy.”

The compound is so unique that it is also capable of attacking dormant cancer “stem” cells that are not dividing, a distinctive property among the “payloads” that are used in ADCs. In the long term, these cells allow tumours to regrow after treatment with standard therapy.

According to Heidelberg Pharma’s Prof. Pahl, the company has not found a tumour cell so far that is resistant to amanitin. In multiple myeloma, where lead candidate HDP-101 is being tested in a phase 1/2a study, patients likely to respond can be stratified, leading to a potential accelerated approval with the FDA if upcoming results are supportive.

After the antibody part of HDP-101 has bonded with the BCMA receptor on the surface of tumour cells, the amanitin warhead is taken up by the tumour cells, meaning there are low levels of the free toxin outside of the cells when used as part of an ADC.

From non-clinical studies in monkeys, the main drawback highlighted by Heidelberg Pharma is liver toxicity that is caused when the ADC infiltrates the liver and is taken up by liver cells, causing them to die. According to the company this is not caused by free amanitin in the body, which would be a much more concerning issue.

Of the evaluable results from 18 patients in the Phase 1 portion of the trial, 6 patients had progressive disease, 7 had stable disease and 3 partial responses as best responses, including a patient with previous exposure to BCMA and GPRC5D drugs – for the latter think J&J’s recently approved Talvey (talquetamab).

The R&D webinar also highlighted the most important questions that Heidelberg Pharma will have to answer in order to get approval.

Aside from conclusive efficacy, Heidelberg Pharma must show that the drug is safe and that the side effects are manageable. None of the ocular side effects that led to GSK’s BCMA-targeting ADC, Blenrep (belantamab mafodotin), being removed from the market in the U.S. and Europe have been observed so far with HDP-101.

When Blenrep failed to produce confirmatory results phase III, the U.S. FDA and European Medicines Agency retracted its marketing authorisation in relapsed and refractory multiple myeloma, ruling that its benefits did not outweigh the side effects. GSK has since announced plans to reintroduce Blenrep as a combination therapy with chemotherapy in relapsed and refractory multiple myeloma following supportive phase 3 results.

According to John Kaufman , associate professor of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta, the most common adverse event with HDP-101 was thrombocytopenia, present in 6 patients at the highest dose.

But what was not observed were ocular or renal toxicities, infusion reactions, myelosuppression or severe liver damage.

“Ocular toxicity has really hampered other BCMA-targeted antibody-drug conjugates in this space.”

While there were transient increases in biochemical signals of liver damage, Kaufman noted that there was no evidence of liver dysfunction.

Addressing the issue of liver toxicity, Kaufman told a Q&A session with investors and media: “The patient who had the transient increases in ALT and AST [liver toxicity indicators] was my patient and very clearly this was transient and there were confounding variables during administration of the medication. There really is no evidence having looked at all the data of liver toxicity.”

He added that a dose optimisation strategy has been recommended and already included in cohort 6 to overcome issues of the dose-limiting thrombocytopenia.

Overall, his assessment is that HDP-101 is “ripe for further development” in multiple myeloma patients and especially those with the 17p deletion, who represent an unmet need, noting its lack of ocular side-effects. The 17p deletion refers to the partial loss of genetic material located on the short arm of chromosome 17, and mainly appears in very aggressive cancers with a poor prognosis. Tumour cells with 17p deletion are particularly sensitive to amanitin.

While amanitin brought Claudius’ life to a tragic end, Heidelberg Pharma suggests that it may prolong life for those with cancer.

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