Ash 2018 – Immunogen makes its case for a Jazz gig

The first day of the haematology conference sees first-in-human data from two antibody-drug conjugates belonging to Immunogen, a company eager to draw a line under a troubled past and hoping to attract further attention from Jazz Pharmaceuticals.

Jazz became one of the beneficiaries of a recent spate of acute myelogenous leukaemia approvals, specifically through its 2016 takeover of Celator and its lead drug, Vyxeos. The group next needs to decide whether to supplement its AML pipeline by exercising options over two assets in development by Immunogen.

At the first day of the Ash conference in San Diego today Immunogen made its case, presenting phase I results with both assets, IMGN779 and IMGN632. The data showed some encouraging signs of responses, but attention focused on safety, especially given Immunogen’s troubled past with earlier projects.

IMGN779 and IMGN632 are antibody-drug conjugates respectively targeting the CD33 and CD123 antigens. But their main feature is the use of a novel class of indolinobenzodiazeprine pseudodimer cytotoxic payloads called IGNs.

Such payloads induce single rather than double-strand breaks in DNA, Dr Jorge Cortes of MD Anderson Cancer Center, presenting the IMGN779 data, told Ash. The aim is to improve the therapeutic index and limit the possibility of myelosuppression versus earlier-generation ADCs; Immunogen’s early ADC technologies suffered on account of design flaws that led to toxicity concerns.

First-in-human data

At Ash it was IMGN632 that generated most interest, even though its first-in-human study only began enrolment early this year.

MD Anderson’s Dr Naval Daver said IMGN632 was preclinically more powerful than Seattle Genetics’ SGN-CD123A, another CD123-targeting conjugate, and employed an IGN payload 10 to 20 times more potent than that used in IMGN779.

The phase I study of IMGN632 recruited 30 AML subjects plus three with a related but much rarer condition, blastic plasmacytoid dendritic cell neoplasm. So far six complete responses have been seen in the former, while in the latter there was one partial remission and an unconfirmed CR.

The most intriguing aspect was that five of these eight remissions occurred at the relatively low IMGN632 doses of 0.045mg/kg and 0.09mg/kg; the dose-escalation trial took patients through three further dose levels, up to 0.45mg/kg.

This is important because of IMGN632’s safety profile: dose-limiting toxicities, including febrile neutropenia and veno-occlusive crisis, were seen at the higher dose levels, and there was one death classified as “possibly related” to IMGN632. But no dose-limiting toxicities occurred at the efficacious lower doses, making a strong case for taking these forward into phase II.

CD33 positive

IMGN779, meanwhile, began its own AML trial, specifically in subjects whose cancers express the CD33 antigen, in 2016. This is the same setting in which Pfizer’s rival anti-CD33 drug Mylotarg was approved last year.

The study has now recruited 57 subjects, and Ash saw efficacy data from 29 of these. This showed evidence of what Dr Cortes called “anti-leukaemia activity” in 12 patients, but according to strict CR criteria the rate was 7%, which was termed “limited ... at the doses examined to date”.

There were three IMGN779-related toxicities, comprising two infusion-related reactions and one case of febrile neutropenia.

Jazz paid Immunogen $75m up front in August 2017 to secure opt-in rights to the two ADC assets; the previous year it had bought Celator, marking its move into oncology. Jazz stands to pay Immunogen a further $100m to support development of IMGN779 and IMGN632, and exercising the opt-in would trigger milestone payments and tiered royalties.

The two assets have so far attracted limited investor attention, and EvaluatePharma reveals no sellside consensus revenue estimates, presumably because most analyst models do not feature any contribution from them in Immunogen’s valuation. Further progress – not to mention a Jazz opt-in – would change this.

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