Collaborative Leukemia Trial Orbits Moonshot Initiative

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Includes: ABSCF, AGIO, ALXN, BMY, CELG, CYCC, GILD, JAZZ, NVS
by: EP Vantage

The once-neglected blood cancer acute myeloid leukemia has seen a flurry of activity of late – which might explain why four companies with mid-stage projects are taking the unusual step of getting involved in a collaborative study.

The Beat AML trial, led by the US Leukemia & Lymphoma Society, will evaluate Celgene’s (NASDAQ:CELG) enasidenib, Boehringer Ingelheim’s BI 836858, Gilead’s (NASDAQ:GILD) entospletinib and Alexion’s (NASDAQ:ALXN) samalizumab as first-line therapies in patients aged over 60. AML studies commonly enroll relapsed or refractory patients so, if successful, the new trial could give the assets involved an edge over projects that are closer to the market (see tables below).

The over-60s are a population unable to tolerate intensive chemotherapy, the current first-line standard of care. The study will also analyze patients’ genomic data before deciding what treatment they will receive.

This is important for Agios (NASDAQ:AGIO)/Celgene’s IDH2 inhibitor enasidenib, for one – it is being trialled in patients with IDH2 mutations, which are present in 10-15% of the adult AML population.

Enasidenib, previously known as AG-221, looks the closest to the market of the four projects in Beat AML. Celgene has said it plans to submit it to the FDA by the end of the year on the back of data from a phase I/II trial in relapsed/refractory disease (Just like buses, three come at once in leukemia regulatory queue, September 08, 2016).

Enasidenib is already in a phase III trial in relapsed or refractory AML. Beat AML could add first-line disease to its repertoire.

New agents nearing

But the IDH2 inhibitor might be beaten to approval by Jazz Pharmaceuticals’ (NASDAQ:JAZZ) Vyxeos, a liposomal preparation of cytarabine and daunorubicin, and Novartis’ (NYSE:NVS) FMS-like tyrosine kinase 3 inhibitor midostaurin. The latter is targeting newly diagnosed patients, but is limited to the genetic subtype of FLT3-mutated AML.

Jazz is seeking approval for Vyxeos, which it gained through the acquisition of Celator, in older patients with secondary AML. The group started a rolling NDA in October.

These frontrunners look unlikely to be troubled by Boehringer’s volasertib, which stumbled in its pivotal trial in June. The company said work would continue, but it is notable that it is also participating in the Beat AML with BI 836858, which being an anti-CD33 MAb has a different mechanism of action.

A dark horse in the AML race could be Cyclacel’s (NASDAQ:CYCC) sapacitabine, which is due to report data from the phase III Seamless study, in elderly patients with newly diagnosed AML, soon. However, expectations are low after the trial failed its interim futility analysis in December 2014 (Event – Cyclacel’s date with decitabine, August 22, 2016).

In any case, the fact that genetic screening is being carried out in Beat AML could give the products involved a well-defined subgroup to target.

In this, the leukemia trial is taking a page from the NCI-Match study in lung cancer, although the investigators will clearly need to be more cautious about obtaining higher-quality biopsies (Vantage point – NCI initiative could see drugs for mutations, not tumour types, June 11, 2015).

An additional model is provided in a second collaborative trial – Lung MAP, which has added new agents as research has progressed. The Leukemia & Lymphoma Society says other pharma companies have expressed an interest in joining Beat AML, and it could add more treatment arms, with a total of up to 10 mooted.

Competitive edge

Alexion looks like it is making a last throw of the dice with samalizumab, which reported phase I/II results in 2010, but it was last listed in the group’s pipeline in 2011. Unlike the already submitted AG-221, this project is fortunate to have little competition in the CD-200 targeting class, where only Bristol-Myers (NYSE:BMY) has an early-stage asset.

Beat-AML projects and their competitors

Pharmacology class

Project

Company

Status

Anti-CD200 MAb

ALXN6000 (samalizumab)*

Alexion/Dyax

Phase II**

TTI-200.7

Bristol-Myers Squibb/Trillium Therapeutics

Preclinical

Anti-CD33 MAb

BI 836858*

Boehringer Ingelheim

Phase II

Anti-CD33 MAb-PBD conjugate

vadastuximab talirine

Seattle Genetics

Phase III

Anti-CD33/CD3 bispecific BiTE MAb

AMG 330

Amgen

Phase I

Anti-CD33 CAR-T cell therapy

Acute Myeloid Leukemia Research Project

Ziopharm Oncology/Intrexon/MD Anderson

Preclinical

Bispecific CD33/CD3 TandAbs antibody

AMV-564

Affimed/Amphivena Therapeutics

Preclinical

IDH-2 inhibitor

AG-221/CC-90007 (enasidenib)*

Celgene/Agios Pharmaceuticals

Phase III

IDH-1 inhibitor

AG-120

Agios Pharmaceuticals

Phase II

BAY1436032

Bayer

Phase I

IDH1 Mutant Selective Inhibitor Program

Daiichi Sankyo

Preclinical

IDH305

Novartis

Phase I

IDH-1 & 2 inhibitor

AG-881

Celgene/Agios Pharmaceuticals

Phase I

Syk inhibitor

entospletinib*

Gilead Sciences

Phase II

AB8779

AB Science

Preclinical

*Beat AML projects.

**Alexion has not listed ALXN6000 as an active project since 2011 and it had been assumed abandoned.

Click to enlarge
Click to enlarge

Likewise, Gilead’s only blood cancer competitor looks like AB Science (OTCPK:ABSCF) – the Syk inhibition class is largely being used for autoimmune, inflammatory and respiratory diseases. AB Science’s AB8779 has undergone preclinical study in non-Hodgkin lymphoma and chronic lymphocytic leukemia.

Boehringer’s CD33-targeting antibody, on the other hand, has healthy competition in all the hot areas of oncology research, including adoptive T-cell therapies, antibody-drug conjugates and bispecific antibodies.

Any projects graduating from Beat AML should of course emerge with a built-in competitive advantage in a biomarker-defined subgroup, and will have generated these data in a trial that someone else helped pay for. It is not hard to see why companies would want to participate, although past studies of this type show that screening will need to be high quality for the effort to be judged a success.

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