American Thyroid Association – Ret competitors move to thyroid cancer

The relatively niche cancer setting provides an important battleground for the targeted kinase inhibitor specialists Blueprint Medicines and Loxo Oncology.

After Blueprint and Loxo squared off at the World Lung conference in September the stage shifted to medullary thyroid cancer at the American Thyroid Association meeting over the weekend.

Thyroid cancer is relatively rare, but it is thought in many cases to be driven by the Ret mutation. In fact, as many as 60% of medullary thyroid cancer cases might have this as their basis, hence the relevance to both groups; Blueprint and Loxo’s respective projects BLU-667 and LOXO-292 are both Ret signalling inhibitors.

Investors wanting to play one stock off against the other will struggle based on currently available data, however. Numerically the datasets, from Blueprint’s Arrow and Loxo’s Libretto-001 trials, are similar, and each shows improving remission rates versus what had been presented at the AACR and Asco conferences respectively.

Libretto-001 now has 29 evaluable medullary thyroid cancer subjects, and among these the unconfirmed overall remission rate is 59%, up from the 45% of 20 patients said to have responded at Asco. The comparable number in Arrow, meanwhile, is a 49% unconfirmed response rate among 35 evaluable subjects reported on Saturday, up from 40% of 25 patients at AACR.

Safety

The big differentiator, Stifel analysts believe, could be safety, especially given that LOXO-292 was designed specifically to inhibit Ret signalling; like the selective Trk inhibitor larotrectinib, LOXO-292 was licensed by Loxo from Array Biopharma in 2013.

BLU-667, meanwhile, is thought to inhibit certain other kinases beyond Ret, perhaps the most relevant of which is Jak1. The risk is that this could result in off-target effects, though for now Leerink analysts maintain that both BLU-667 and LOXO-292 seem to have relatively clean safety profiles.

The studies of both projects include other cancer types. So far, grade 3 hypertension and grade 4 neutropenia have been respectively seen in 16% and 4% of the entire Blueprint dataset, which investors will no doubt be tracking closely. Stifel, which covers Loxo, suggested that BLU-667’s haematological toxicities might be related to activity at Jak1.

In Libretto-001 four of 82 patients in the overall safety dataset experienced grade 3 LOXO-292-related adverse events, comprising tumour lysis syndrome, liver enzyme elevation, diarrhoea and thrombocytopenia.

As for efficacy, the results showed BLU-667 and LOXO-292 alike having activity irrespective of patients’ prior exposure to other kinase inhibitors.

While thyroid cancer itself represents a relatively small market the presence of Ret mutations in such a high proportion of cases makes for an intriguing proposition for Blueprint and Loxo. In comparison, the much bigger indication of lung cancer also has some Ret involvement, though this amounts to only about 2% of NSCLC cases.

A Ret inhibitor faceoff
    2024e sales ($m)    
Company Project Total Thyroid cancer Study Trial ID
Loxo LOXO-292 929 251 Libretto-001 NCT03157128
Blueprint BLU-667 245 75 Arrow NCT03037385
Source: EvaluatePharma sellside consensus sales by indication.

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