Takeda casts doubt on the remaining approach to amyloidosis

After last year’s flop of Prothena’s NEOD001, Takeda’s Ninlaro fails to treat the underlying cause of the non-genetic form of this disease.

Given how similar the underlying basis of light-chain amyloidosis is to that of multiple myeloma, yesterday’s failure of Takeda’s Ninlaro in the former disease – the drug is approved in the latter – should come as a surprise.

The setback could also call into question the study of other multiple myeloma drugs, like Darzalex, Revlimid, Velcade and Emplicity, in amyloidosis. This should be a concern, given last year’s failure of Prothena’s NEOD001 and the lack of progress among other projects that, like NEOD001, had aimed to hit amyloid deposits instead of the underlying cells involved.

Taken together, the failures of these distinct approaches have left the light-chain amyloidosis pipeline looking extremely thin. In fact, only repurposed marketed drugs remain in active studies, and just one of these, that of Johnson & Johnson/Genmab’s Darzalex, is being sponsored by an originator company.

Lack of logic?

To understand the logic behind attempted treatments it is necessary to appreciate the underlying cause of the disease.

Light chain (also known as AL) amyloidosis is a condition resulting from a malfunctioning of plasma cells, meaning B cells that are producing antibodies. The affected cells produce antibodies with misfolded light chains, which are deposited as amyloid in tissues, something that can lead to organ dysfunction.

Coincidentally, multiple myeloma is caused by abnormal and uncontrolled growth of a plasma cell clone. Thus – the logic might go – if you can treat multiple myeloma using a drug that knocks out plasma cells then the same drug should also be able to treat a patient with AL amyloidosis.

However, Takeda’s Ninlaro study, Tourmaline-AL1, casts doubt on this hypothesis. Yesterday the group said Ninlaro had failed to improve overall haematological response versus physician’s choice, the first of the trial’s two co-primary efficacy measures; the 248-patient study, one of the largest in AL amyloidosis, has been terminated.

Ninlaro, a proteasome inhibitor like Velcade, has been sold for multiple myeloma since 2015. Tourmaline-AL1 was the drug’s only phase III study in AL amyloidosis, so its development in this disease might now be over.

Not so Darzalex, whose 370-subject pivotal study in combination with Velcade is scheduled to read out early next year. Shortly afterwards an investigator-initiated AL amyloidosis study of Bristol-Myers Squibb’s Empliciti will yield data.

And that, pretty much, is that. A third marketed multiple myeloma product, Celgene’s Pomalyst, completed an early study in AA amyloidosis last November, with no data having been disclosed. Sylvant, a drug sold by Eusa Pharma for Castleman disease, is in a small academic study in subjects with either multiple myeloma or AL amyloidosis.

The AL amyoidosis pipeline thins out
Project Description Sponsor Trial ID Data?
Existing drugs marketed for other use(s)
Darzalex (Velcade combo) Multiple myeloma drug J&J NCT03201965 Feb 2020
Empliciti (Revlimid combo) Multiple myeloma drug IST NCT03252600 Sep 2020
Sylvant Castleman disease drug IST NCT03315026 Oct 2020
Ninlaro Multiple myeloma drug Takeda NCT01659658 Failed
Pomalyst Multiple myeloma drug IST NCT01570387 Ended 2018; status unknown
Kyprolis Multiple myeloma drug IST NCT02545907 Ended 2016; status unknown
Venclexta Haem-onc drug IST NCT03000660 On clinical hold
Zydelig CLL drug IST NCT02590588 Terminated
Novel drugs specifically for AL amyloidosis
CAEL-101 Fibril-reactive MAb IST NCT02245867 Ended 2017; status unknown
NEOD001 Anti-beta-amyloid MAb Prothena NCT02312206 Failed
GSK2315698 + GSK2398852 SAP depleter + anti-SAP MAb  Glaxosmithkline NCT03044353 Terminated
Note: IST = investigator-sponsored trial.

Meanwhile, after last year’s resounding failure of Prothena’s NEOD001, all other novel approaches to treating the disease appear to have been abandoned (Prothena’s Pronto failure raises pipeline doubts, April 23, 2018).

These include Glaxosmithkline’s GSK2315698 and GSK2398852, whose phase II trial was terminated in March after a “change in benefit/risk profile”. Fortress Biotech’s fibril-reactive monoclonal antibody CAEL-101 completed phase I testing in mid-2017, demonstrating reasonable safety, but has made no progress since.

Also suspended or terminated are studies of marketed drugs including Zydelig, Venclexta and Kyprolis. If the worries about repurposing such existing drugs for AL amyloidosis centred on commercial considerations then the clinical flops of Ninlaro, NEOD001 and GSK2315698/GSK2398852 suggest that the scientific rationale might be flawed too.

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