Ash therapy focus – the other amyloidosis gets its day in the sun

While investors’ attention has been focused on the race to launch a treatment for the inherited form of amyloidosis, quiet progress is being made in non-genetic disease as novel agents and established blood-cancer products are vying to improve on front-line chemotherapies.

The Ash meeting convening this week will be an opportunity for Johnson & Johnson to present new data on Darzalex in amyloidosis, while Fortress Biotech will talk up early results for its novel antibody CAEL-101. Meanwhile, several drugs used to treat multiple myeloma are in mid and late-stage development in amyloidosis, with Ninlaro and Pomalyst due to report next year (see table below).

Bone marrow disease

As a disorder of the bone marrow, light-chain amyloidosis – also known as AL amyloidosis – is treated similarly to many haematological cancers. This disease differs from the inherited form of disease, known as TTR amyloidosis, in which a mutated gene causes the liver to produce a dysfunctional form of the protein transthyretin, leading to amyloid accumulation – for now, this can only be cured through a liver transplant.

Light-chain amyloidosis patients have been a bit more fortunate in that some effectiveness has been seen with treatment regimens for multiple myeloma. The reason is that both diseases are the result of problems with plasma cells (B cells that are producing antibody), the latter resulting from an uncontrolled production of this cell type.

Melphalan-based chemotherapy and stem cell transplantation have been used to eliminate and replace plasma cells that produce the faulty amyloid protein in AL amyloidosis. For patients not eligible for transplant, specialists have evolved from alkylator-based chemotherapies to add in more novel agents like Velcade or Revlimid – these, however, remain off-label uses. The fact that these chemotherapy regimens have proven effective means that newer agents must be added to them, rather than being used as monotherapies.

Something old, something new: the AL amyloidosis pipeline
Status Project Company Pharma class Trial
Phase III Darzalex Johnson & Johnson/Genmab Anti-CD38 MAb NCT03201965
Ninlaro Takeda Proteasome inhibitor NCT01659658
NEOD001 Prothena Anti-beta-amyloid MAb NCT02312206
Phase II Empliciti Bristol-Myers Squibb Anti-signalling lymphocyte activation molecule 7 MAb NCT03252600
Phase I GSK2315698 + GSK2398852 GlaxoSmithKline Serum amyloid P component depleter + Anti-serum amyloid P component MAb NCT03044353
CAEL-101 Fortress Biotech Anti-chimeric fibril-reactive MAb NCT02245867

Enter Ninlaro and Darzalex – like Velcade and Revlimid, already approved in multiple myeloma and now looking to expand into adjacent diseases. Takeda and Johnson & Johnson are sponsoring phase III trials in amyloidosis, suggesting that they intend to seek formal regulatory approval.

Last week, J&J paid Darzalex’s originator Genmab a $20m milestone related to progress of the phase III Andromeda trial, which uses a Velcade-based chemo cocktail as a backbone. Meanwhile, at Ash, data from two phase II Darzalex trials will be the subject of oral presentations.

Ninlaro’s phase III trial is in combination with dexamethasone-based chemotherapy to detect haematological response, as well as vital organ deterioration and mortality at two years as primary endpoints; secondary endpoints are overall survival and progression free survival. The 248-patient study has been underway since 2012, and readout could come next year.

Bristol-Myers Squibb’s multiple myeloma entrant, Empliciti, is in an investigator-led phase II trial in combination with Revlimid-based chemotherapy as a maintenance therapy.

Focus on amyloidosis

While the pipeline is stocked with haemotological cancer agents being repurposed for amyloidosis, four agents stand out in their focus on the rare disease: Prothena’s NEOD001, Fortress Bio’s CAEL-101, and GlaxoSmithKline’s GSK2315698 and GSK2398852. Fortress’s project, a fibril-reactive monoclonal antibody also codenamed 11-1F4, targets amyloid deposits on internal organs and will be the subject of an Ash oral presentation featuring data from its phase I dosing studies.

Meanwhile, NEOD001 is an amyloid beta antibody now in a phase III trial in 236 newly diagnosed patients due to read out next year, in which it is being tested in addition to a proteasome inhibitor-based chemotherapy to see if it can reduce all-cause or cardiovascular mortality when compared to chemo alone.

A second NEOD001 study due to read out next year is a phase II open-label extension in second-line patients who may also receive chemotherapy. This will measure cardiovascular, renal and neurological biomarkers as well as patient function through 38 months.

In light-chain amyloidosis, NEOD001, or birtamimab, is the project to which the sellside has made forecasts. EvaluatePharma’s consensus puts 2022 sales at $626m.

Glaxosmithkline is shooting for a combined AL and TTR amyloidosis therapy with its pairing of GSK2315698 and GSK2398852. Together these two agents are thought to help clear amyloid deposits from organs, and an ongoing phase II trial will test whether this activity can reduce cardiovascular complications in TTR amyloidosis along with post-chemo and newly diagnosed AL patients.

Unlike in TTR, where supportive care and liver transplant is the only option, Glaxo and all other candidates will need to improve on established treatments to achieve regulatory approval. Given that many of these treatments have done so in multiple myeloma, it seems likely that one or more will break through in amyloidosis.

To contact the writer of this story email Jonathan Gardner in Virginia at or follow @ByJonGardner on Twitter

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