AACR 2023 – Moderna's immunotherapeutic splash

This year’s AACR meeting promises a surprising amount of clinical data relevant to biopharma investors.

Big pharma watchers and biotech investors alike will be looking forward to next month’s instalment of AACR. The meeting, normally a haven of early preclinical research, will in 2023 feature several prominent clinical results, the biggest of which might concern Moderna’s immunotherapeutic mRNA-4157, which attracted a $250m opt-in from Merck & Co last October.

On 17 April a session devoted to Kras/Raf signalling will show the clinical challengers that Amgen’s Lumakras and Mirati’s Krazati might soon face from Lilly, Roche and Innovent. And, not long after Astrazeneca formally signalled its intention to become a cell therapy player, AACR will shine a light on the UK company’s first efforts in Car-T therapy.

Last November Evaluate Vantage broke news of Astra’s work on AZD0754, a Car-T therapy against the novel antigen Steap2. AACR will feature a preclinical presentation on this, revealing it to be additionally “armoured” with a dominant-negative TGFβ receptor type II (dnTGFβRII) to block TGFβ signalling in T cells.

Such armouring is also used in Astra’s anti-GPC3 Car AZD5851, which the group revealed in a fourth-quarter pipeline update. AACR will also feature clinical data on Allogene’s anti-CD70 Car ALLO-316, after that company teased a 33% ORR among nine CD70-positive patients at its November R&D showcase.

Some cell therapies at AACR 2023
Project Mechanism Company Trial Comment Abstract
ALLO-316 Allogeneic anti-CD70 Car-T Allogene Traverse Relevant given relapses with Crispr's similarly acting Car CT011
C-CAR031 dnTGFβRII, anti-GPC3 Car-T Astrazeneca (?) Ph1 Authors affiliated to Astra, so possibly related to AZD5851 CT097 / 5
AZD0754 dnTGFbRII, anti-Steap2 Car-T Astrazeneca Preclinical First look at this asset LB085 / 1

The full abstracts covering late-breakers and the most interesting clinical data remain under wraps until April 14, so all investors have to go on for now are the presentation titles that AACR unveiled live last week.

Among these possibly the greatest excitement will centre on the Keynote-942 adjuvant melanoma trial of mRNA-4157 that prompted Moderna’s market cap to add $15bn. The asset, a personalised mRNA therapeutic created on demand based on the neoantigens present in each patient’s tumour, is the subject of a $250m deal with Merck & Co, and important statistical caveats surrounding the data might be discussed at AACR.

Late-stage datasets already toplined and being presented in full at AACR include the Imbrave-050 study of Roche’s Tecentriq, the Aegean trial of Astra’s Imfinzi, and Keytruda’s Keynote-966 study. Given the failure of Merck’s anti-Tigit vibostolimab in Keyvibe-002, data from Keymaker-U02 substudy 02C, which contains vibostolimab, might also be of interest.

AACR 2023: clinical-stage immuno-oncology
Project Mechanism Company Trial Comment Abstract
mRNA-4157 + Keytruda 34-neoantigen immunotherapeutic Moderna/ Merck & Co Keynote-942 Toplined Dec 2022 (one-sided p, HR CI upper bound >1.00) CT001
Keytruda + vibostolimab + Cavatak PD-1 + Tigit + oncolytic virus Merck & Co (ex Viralytics) Keymaker-U02 02C Vibostolimab failed in Keyvibe-002 CT002
Tecentriq Anti-PD-L1 MAb Roche Imbrave-050 Avastin combo; toplined Jan 2023 CT003
Imfinzi Anti-PD-L1 MAb Astrazeneca Aegean Toplined pCR, then EFS Mar 2023 CT005
Keytruda Anti-PD-1 MAb Merck & Co Keynote-966 OS toplined Jan 2023 CT008

While many of the above are interspersed among various clinical trial sessions, a 17 April minisymposium entitled “Targeting the Kras pathway in the clinic” will contain the most relevant presentations on Kras G12C-targeting small molecules.

Here, investors in Mirati will get a first clinical look at Lilly’s challenger, LY3537982. The session will also see the fruits of a Raf-focused 2018 deal between Beigene and Springworks, while after a worrying delay Kinnate will highlight the first clinical data for exarafenib, an asset said to target class 2 and 3, as well as class 1, Braf alterations.

AACR 2023: targeting Kras & Raf mutations
Project Mechanism Company Trial Comment Abstract
JDQ443 Kras G12C inhibitor Novartis Ph2 Kras G12C NSCLC with low PD-L1, or PD-L1 ≥1% + STK11 co-mutation CT048 / 6
LY3537982 Kras G12C inhibitor Lilly Ph1 First-in-human data CT028
GDC-6036 Kras G12C inhibitor Roche Ph1 Erbitux combo; asset already in ph2/3 NSCLC CT029
IBI351 (GFH925) Kras G12C inhibitor Innovent Ph1/2 Had data at Asco22 CT030
BGB-3245 Raf kinase inhibitor Springworks/ Beigene Ph1 First-in-human data CT031
Exarafenib (KIN-2787) Raf kinase inhibitor Kinnate Ph1 First-in-human data (readout delayed) CT032
Lifirafenib Raf dimer inhibitor Springworks/ Beigene Ph1/2 Mirdametinib (Mek inhibitor) combo CT033

As ever AACR will feature a multitude of novel pharmacologies, though overall there are perhaps fewer novel I-O mechanisms than before. There is plenty, for instance, on folate receptor α, which has re-emerged as a hot target, though most presentations are preclinical.

Another mechanism with a significant AACR presence is disruption of the association between transcriptional enhancer activator domain (TEAD) and its co-activator yes-associated protein (YAP). This is thought to suppress defective signalling through the so-called Hippo pathway, which some suggest is involved in cancer and other diseases.

Attention here could fall on Vivace Therapeutics’ YAP/TEAD inhibitor VT3989, which has an AACR oral presentation of first-in-human data. The findings will be relevant not only for Vivace, a little-known private biotech, but also for Ikena Oncology, whose TEAD inhibitor IK-930 entered phase 1 last year.

Other AACR 2023 abstracts of note
Project Mechanism Company Trial Comment Abstract
MEDI1191 IL-12 mRNA Moderna/ Astrazeneca Ph1 Imfinzi combo CT004
VT3989 YAP/TEAD inhibitor Vivace Therapeutics Ph1 First-in-human data CT006
AZD5335 Anti-FRα ADC Astrazeneca Preclinical First look at this asset LB025 / 17
LY3410738 IDH inhibitor Lilly (ex Loxo) Ph1 First-in-human data CT026
Petosemtamab (MCLA-158) Anti-EGFR x LGR5 bispecific MAb Merus Ph1 Impressed at 2021 EORTC-NCI-AACR (Triple) symposium CT012
RLY-2608 PI3Kα inhibitor Relay Rediscover First-in-human data CT017

The 2023 meeting of the AACR takes place in Orlando, Florida on 14-19 April.

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