IKNA - Ikena: AACR2023 Validates Their Hippo Pathway Target But We Need Data

2023-05-18 03:56:32 ET

Summary

• Ikena is a pioneering developer of molecules targeting the Hippo pathway.
• This year's AACR showcased a number of programs, one of which showed this to be a druggable pathway.
• However, IKNA itself needs to show clinical data.

Ikena Oncology ( IKNA ) develops cancer therapies targeting the target nodes of cancer growth, spread, and therapeutic resistance in the Hippo and RAS oncosignaling networks. The pipeline is this:

Lead asset is a TEAD1 inhibitor IK-930 targeting the HIPPO pathway. It works through disruption of the link between transcriptional enhancer activator domain (TEAD') and its co-activator yes-associated protein (YAP), which is theorized to suppress defective Hippo signaling. They are running a phase 1 trial and they expect to publish monotherapy dose escalation data in all comers, mesothelioma, and EHE, in 2023. The second asset is MEK/RAF inhibitor IK-595 which is in IND-enabling studies. The third asset is IK-175, an AHR signaling molecule in partnership with BMS and showing clinical activity in bladder cancer, which showed a 40% disease control rate and 20% overall response rate in urothelial carcinoma patients.

IK-930 targets the TEAD transcription factor in the Hippo pathway. The Hippo pathway, genetically altered in approximately 10% of all human cancers, regulates cell fate, proliferation, and survival and is thus a key driver of cancer pathogenesis. In malignant Mesothelioma, over 40% patients have mutations in the pathway, while in epithelioid hemangioendothelioma (EHE), that figure is as high as 100%. IK-930 prevents expression of these mutated genes by binding to the TEAD transcription factors near the end of the Hippo pathway.

IK-930 is a TEAD1 selective inhibitor; it does not have a significant effect on TEAD2, 3 or 4. Selectivity is important because, according to research , "Hippo signaling may be dispensable for physiological homeostasis." Random inhibition of this signaling may be detrimental for various life processes, as has been seen in mouse models. In preclinical models, including in TEAD activated cell lines, IK-930 was seen to be a potent inhibitor of TEAD and the ensuing gene expression. Interestingly, selective TEAD1 inhibition has been shown to be comparable to panTEAD inhibitors in NF2 deficient Mesothelioma.

As we see in the above picture, in 30 days of treatment, tumor volume was equivalently reduced by a standard panTEADi, and IK-930. The same result was seen in LATS1/LATS2 Mutated Mesothelioma Model as well:

Here, the higher dose of IK-930 actually posted marginally better data than the other dosages.

IK-930 uses TEAD biology in an interesting way to block tumor activity. On the other hand, in a palmitoylation dependent manner, TEAD is an activator with YAP1 or TAZ. On the other hand, independent of palmitoylation, TEAD is a repressor with VGLL4. IK-930 works by using both these states to gain tumor repressive activity. Earlier efforts with the Hippo pathway produced unacceptable kidney toxicity. However, IK-930, the company claims, is designed to balance efficacy with kidney toxicity.

At this year's AACR, over ten programs targeting the Hippo pathway were discussed, and privately held Vivace published clinical data which validated the Hippo pathway, while also producing a poor tox profile. The molecule, VT3989, is a Tead palmitoylation inhibitor just like IK-930. The difference is that BT3989 is a panTREADi, and it caused proteinuria, as well as liver enzyme elevations and cardiomyopathy, in the trial. Ikena, while still without clinical data, had proteinuria in mind when it looked for higher TEAD selectivity, and in NHP trials, there was no proteinuria observed.

As Ikena says in its Corporate Presentation :

panTEAD inhibition has been seen to drive proteinuria and frank kidney toxicity (Kaneda et al, AACR 2019)

• In preclinical models it has been seen that YAP1 is required for podocyte (highly specialized kidney cell) viability (Schwartzman et al., 2016)

• IK-930's selectivity provide a far wider potential therapeutic window while demonstrating equivalent activity in multiple in vivo models

• 28-Day Monkey Study

IK-930

• No clinical signs or renal changes observed; all doses

• No toxicity to other systems

panTEADi

• Decreased activity, ataxia observed in both dose groups

• High dose halted on day 18 due to mortality and morbidity

The Vivace molecule produced partial responses in 6 out of 42 refractory mesothelioma patients, validating the TEAD/Hippo pathway as a druggable target. Among other such molecules, Novartis's photodynamic therapy Visudyne, according to some research , may also inhibit TEAD-Yap interaction, although not by design. Novartis now has a molecule called IAG933, which has a similar activity.

As for market opportunity in the monotherapy setting, there are 125,000 US cancer patients with known Hippo pathway mutations. In Malignant Mesothelioma, up to 40% patients present with NF2 loss of function mutations. In NSCLC, there are 6% YAP1 and 29% TAZ amplifications. In Meningioma, Head & Neck Cancers and Soft Tissue Sarcomas, similar Hippo Pathway involvement is observed.

Financials

IKNA has a market cap of $253mn and a cash balance of $157mn. Research and development expenses were $64.3 million for the year ended December 31, 2022 and general and administrative expenses were $22.2 million. At that rate, they have a cash runway of nearly two years.

The stock has a heavy smart money presence. Key holders are Atlas Ventures, Orbimed etc, with BMS also owning a 6% stake. Insider transactions are few, and equally spread between buys and sells.

Risks

Like the title of this article says, while data from another company has validated the pathway, IKNA needs to produce its own, positive, late stage data for investors to take it more seriously. They also need to improve their market presence - a phrase by which I mean a combination of market cap, cash, and stock price.

Bottomline

IKNA seems to be doing pioneering work in an obscure pathway which has significant potential. Their focus on neutralizing toxicity through selectivity is interesting, and preclinical validation does exist. As always, we will look at clinical data - available later this year, before taking a call.

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