Macrogenics takes another shot at a novel immune checkpoint

Having failed with orlotamab, and with enoblituzumab’s potential narrowing, Macrogenics generates interest around MGC018.

Company events

For some investors Macrogenics is all about the approved drug Margenza, but an earlier asset is increasingly getting the sellside excited. That asset is MGC018, and it faces an important catalyst this year: an update to clinical data whose initial release a year ago had caused some analysts to add it to financial forecasts.

MGC018 is an antibody-drug conjugate against B7-H3, and interestingly it is Macrogenics’ third shot at this immune checkpoint; the group’s B7-H3-targeting bispecific and naked MAb appear to have been deemphasised. The MGC018 data will undoubtedly be early, but Leerink analysts, for one, reckon they amount to a major catalyst in terms of possible stock impact.

Project MGC018
Company Macrogenics
Market cap $1.9bn
Product NPV $85m
% of market cap 4%
Event type Phase 1 data updates
Indication mCRPC, and possibly NSCLC & TNBC
Date Mid-2021 (possibly Asco and later)
Trial ID NCT03729596

The clinical trial in question is a phase I test in solid tumours, but activity in metastatic castration-resistant prostate cancer is the most immediate focus. The first data, at Asco 2020, were most promising in efficacy terms in mCRPC, where five of seven patients yielded ≥50% PSA reductions.

There were no remissions, but only one mCRPC subject was evaluable by Recist criteria, and showed tumour reduction approaching a partial response. Of the other 14 evaluable subjects, a notable tumour reduction was seen also in a sixth-line NSCLC patient.

The big question, however, concerned therapeutic window: 60% of patients experienced grade 3 treatment-related adverse events, and there was one death, from pneumonitis. These will undoubtedly remain in focus in upcoming clinical updates, which might come at this year’s Asco and afterwards.

Side effects are a worry because Macrogenics’ anti-B7-H3 bispecific, orlotamab, was put on clinical hold over liver toxicity in 2018, and no longer appears in the group’s R&D pipeline.

Meanwhile, Macrogenics’ other B7-H3 asset, enoblituzumab, an Fc-engineered MAb, has shown responses in several tumours, and its key indication is now front-line head and neck cancer.

But Macrogenics has tinkered with study design. An initial phase 2/3 study, in combination with Macrogenics’ Incyte-partnered anti-PD-1 MAb, retifanlimab, was withdrawn before starting, and a new phase 2 in the head and neck indication pairs enoblituzumab either with retifanlimab or with tebotelimab, an anti-PD-1/Lag-3 bispecific.

Clearly enoblituzumab is not dead, but it seems that Macrogenics is increasingly pinning its B7-H3 hopes on MGC018. The phase 1 MGC018 trial will also test a retifanlimab combo, but for now the focus is on monotherapy.

One reason analysts are cautiously optimistic about MGC018 is that this uses an antibody that is inert without the toxic payload, and which is distinct from that used in enoblituzumab and orlotamab.

Expectations

As far as efficacy expectations for MGC018 go, the focus will be on any Recist remissions in the mCRPC cohort, as well as their durability. Macrogenics also cites NSCLC and triple-negative breast cancer as possible indications, and any activity here in the phase 1 trial would be a big bonus.

It is also noteworthy that the anti-B7-H3 space features only four other clinical-stage competitors. Daiichi Sankyo’s DS-7300a is seen as promising, using an ADC technology similar to Enhertu and generating remissions. The most advanced asset, Y-Mabs’ omburtamab, a radiolabelled conjugate, was submitted for neuroblastoma but received a US refusal-to-file latter last October and is now mired in a regulatory delay.

Finally, scientists will note the relevance of B7-H3 as a target, it being a member of the B7 superfamily that also includes B7-H1 – a protein better known as PD-L1. Macrogenics has clearly made it a mission to exploit this mechanism, and clinical success could enable it to get a head-start on the competition.

Selected B7-H3-targeting projects
Project Company Modality Status
Omburtamab Y-Mabs Therapeutics Anti-B7-H3 MAb-iodine I-124 & I-131 conjugate Filed (RFT Oct 2020; resumbission due Q2/Q3 2021)
Enoblituzumab Macrogenics Anti-B7-H3 MAb Ph2 after ph2/3 trial was withdrawn
MGC018 Macrogenics Anti-B7-H3 MAb-cytotoxic drug conjugate Ph1/2 updates due 2021
DS-7300a Daiichi Sankyo Anti-B7-H3 MAb-topoisomerase I inhibitor conjugate Ph1/2
ABBV-155 Abbvie Anti-B7-H3 MAb-cytotoxic drug conjugate First ph1 data due 2021
SHR-A1811 Jiangsu Hengrui Medicine Anti-B7-H3 MAb-cytotoxic drug conjugate Ph1/2 starts Apr 2021
MVC-280 Takeda (ex Maverick) Anti-B7-H3 & CD3 bispecific MAb Preclinical; note Mar 2021 takeover
B7-H3-SADA Y-Mabs Therapeutics Anti-B7-H3 MAb Preclinical
GTB-5550 GT Biopharma Anti-B7-H3 & CD3 bispecific MAb Preclinical
CD276 ADC Biomed Valley Discoveries Anti-B7-H3 MAb-cytotoxic drug conjugate Preclinical
TCB005 TC Biopharm Anti-B7-H3 Car-T therapy Preclinical
Orlotamab (MGD009) Macrogenics Anti-B7-H3 & CD3 bispecific MAb Abandoned after ph1 safety scare
DS-5573a Daiichi Sankyo Anti-cell surface antigen (B7-H3) MAb Discontinued after ph1 termination
Source: company statements.

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