Largely talking, each different early stage biopharma I cowl begins out with a candidate focusing on some type of leukemia/lymphoma. Right here’s yet another so as to add to that checklist – Enliven Therapeutics, Inc. (NASDAQ:ELVN) – a part 1 stage lately launched firm with a ~$600mn valuation.
Though I stated “lately launched,” Enliven is definitely the results of a merger between privately-held Enliven and publicly traded Imara Therapeutics. The merger closed in February this yr, and the brand new entity started life, progressing two oncology candidates from Enliven. This reverse merger benefitted IMRA shareholders, which was in any other case a lifeless inventory. IMRA, with its “dying breath,” additionally managed to promote considered one of its property for a substantial sum.
In the meantime, Enliven, too, did its bit to strengthen the newly-formed firm. In addition to finishing a profitable merger, it raised $165mn in a non-public placement led by Fairmount (co-lead), Venrock Healthcare Capital Companions (co-lead), Constancy Administration & Analysis Firm, RA Capital Administration, Frazier Life Sciences and Commodore Capital. All its current institutional traders additionally participated within the personal placement. The money stability permits it to fund its pipeline by way of a number of near-term catalysts. These are:
Ph1a knowledge anticipated in 2024 for extremely selective energetic website BCR-ABL inhibitor together with T315I for Power Myeloid Leukemia
Ph1a knowledge anticipated in 2024 for CNS penetrant, selective and irreversible HER2/pan-HER2 mutant inhibitor for HER2-driven cancers
Each property, the corporate says, are “ supported by preclinical proof of an improved therapeutic index.” They’re each in part 1 trials. Right here’s the pipeline:
Lead candidate ELVN-001 is focusing on CML as an preliminary indication. There are lots of permitted medication within the area, together with generics, they usually drive over $6bn in annual gross sales. Nevertheless, the corporate says that barring asciminib, all different permitted TKIs have “poor kinase selectivity, leading to tolerability points that affect efficacy.” Numerous sufferers change therapies due to this, and due to lack of molecular response. A few of these medication additionally include comorbidities, drug-drug interplay associated restrictions, and troublesome dosing routine, which limit adoption. Growing variety of sufferers within the 3L setting additionally creates an unmet want.
this from one other angle, six small-molecule inhibitors have been permitted by the FDA to deal with a selected sort of leukemia known as BCR-ABL1-driven Power Myeloid Leukemia (CML). These inhibitors, often called TKIs or tyrosine kinase inhibitors, embrace Imatinib, Nilotinib, Dasatinib, Ponatinib, and Bosutinib. They work by focusing on a selected a part of a protein known as ABL1 tyrosine kinase.
Though these TKIs are useful in treating CML, they’ve a specificity downside. They’ll unintentionally have an effect on different proteins within the physique, inflicting undesirable negative effects. Consequently, they won’t work as successfully as they may to deal with CML.
One other problem with these TKIs is that they’ll cease working extra time. It’s because the most cancers cells can change in a method that makes the TKIs much less efficient. One particular change known as the T315I mutation. It makes the TKIs much less in a position to do their job.
Nevertheless, a brand new TKI known as Asciminib has been permitted in 2021. This one works in a different way. It interacts with a particular a part of the ABL1 protein, which makes it extra particular and causes fewer negative effects.
However there is a catch with Asciminib. To work in opposition to a selected change within the ABL1 protein (the T315I mutation), sufferers must take a better dose – 5 instances greater – in comparison with what’s usually permitted. This greater dose could make it more durable for some sufferers to tolerate the therapy.
Additionally, the issue of most cancers cells changing into proof against therapy remains to be there with Asciminib. Some modifications within the ABL1 protein can nonetheless make the therapy much less efficient. It is a problem, particularly when these modifications occur in the identical particular a part of the protein that Asciminib targets.
ELVN-001 additionally targets ABL1, however it’s far more particular. Not like different TKIs, it doesn’t trigger issues like low blood cell counts, swelling, and coronary heart points. In preclinical assessments, ELVN-001 labored nicely in opposition to BCR-ABL1-driven CML. Certainly, preclinical knowledge for ELVN-001 was higher than these permitted friends, and it labored nicely even in TKI-resistant tumors.
ELVN-001 was additionally protected, with good PK/PD knowledge – it was absorbed, unfold across the physique, and faraway from the physique simply and shortly. Animal research confirmed sturdy therapeutic results in tumor cells.
The second asset, ELVN-002, is a CNS penetrant, selective, and irreversible pan-mutant HER2 TKI. Which means it may well get by way of the blood mind barrier, is particular to HER2 and its mutations, and its results are long-lasting. Selectivity is vital to distinguish between HER2 and EGFR, that are structurally comparable. Thus, permitted medication which are twin EGFR/HER2 inhibitors – which is most of them – are dose-limited by EGFR-driven toxicity. Tucatinib is the one permitted HER2-selective TKI, however its downside is that it’s not pan-mutant like ELVN-002, and doesn’t have efficiency in opposition to key mutants like HER2 YVMA, the commonest Exon 20 insertion mutation (E20IM) in NSCLC, and L755, the commonest HER2 breast most cancers mutation. Furthermore, these TKIs are usually not sufficiently mind penetrating, and don’t adequately tackle mind metastases.
Distinction that with what the corporate claims for ELVN-002:
Designed to irreversibly inhibit HER2 and a number of key HER2 mutations, together with HER2 YVMA and L755
Selectively inhibit HER2 whereas sparing EGFR to stop EGFR-related toxicities, with the potential for improved efficacy in NSCLC and different cancers
Demonstrated superior pre-clinical exercise in HER2- amplified subcutaneous and intracranial fashions, and an improved security margin in NHPs in comparison with tucatinib.
Thus far so good, however like I at all times warn my readers, preclinical knowledge has practically nothing to supply traders. Their import is for scientific investigators who must take them by way of human trials and show their claims; so in case you are shopping for a preclinical stage firm, you didn’t get that concept from me. Though, to be sincere, some preclinical knowledge are extra promising than others, and this one is someplace in between. Its logic is promising, however its claims want extra vigorous proving.
ELVN has a market cap of $631mn and a money stability of $277mn. R&D bills had been $15.2 million for the second quarter of 2023, whereas G&A bills had been $5.0 million. At that charge, the corporate has a money runway of 12 quarters, however, in fact, bills will improve over time.
The inventory is nearly fully held by PE/VC corporations, establishments and hedge fund managers. keyholders are 5AM Ventures, Orbimed and FMR LLC. IMRA was closely transacted by insiders, however ELVN is but to start that a lot.
Enliven Therapeutics is a preclinical firm with no human knowledge, and I don’t counsel investing in such firms. These are usually not for normal traders.
The corporate is newly-launched, subsequently, their present money place could not adequately replicate their future bills.
Enliven Therapeutics, Inc. does present a robust logic for its packages, and there’s supporting preclinical knowledge. I’ll revisit this firm in all probability subsequent yr, once they have human knowledge to point out.