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|
|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|
|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|
|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|
|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.