The FDA has accepted a new drug application (NDA) for Verastem’s duvelisib, and earlier this week granted it priority review. The application seeks full approval for duvelisib to treat relapsed/refractory chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) and also seeks accelerated approval in relapsed/refractory follicular lymphoma (FL).

While duvelisib’s Priority Review designation in the US is an important milestone that reflects the unmet needs for efficacious therapies in relapsed/refractory FL and CLL/SLL, particularly those CLL/SLL patients with the high-risk 17p deletion, US experts interviewed by GlobalData have expressed a pessimistic view for duvelisib’s future use in CLL if it gains FDA approval due to its substantial toxicity profile.

Duvelisib, which was given Fast Track designation for patients with CLL/SLL that have received at least one prior therapy, successfully achieved the primary endpoints in the Phase III DUO trial for CLL/SLL. In the DUO study, duvelisib monotherapy improved progression-free survival (PFS) by 3.4 months over the comparator ofatumumab (Arzerra) (hazard ratio [HR] 0.52; p = 0.0001) in relapsed/refractory patients.

However, this contrasts to the Phase III RESONATE study for Imbruvica (ibrutinib) in relapsed/refractory CLL, where the median PFS was not reached with Imbruvica compared to 8.1 months with Arzerra (HR 0.22). The DUO trial did not meet investor or physician expectations, due to the design of the clinical study in which Arzerra is a weak comparator arm in addition to the side effects observed. The most severe adverse events (grade 3 or worse) reported in the DUO study were neutropenia (30%), diarrhoea (15%), pneumonia (14%), anaemia (13%), and colitis (12%). In 5% of patients, diarrhoea or colitis led to treatment discontinuation, while 1% of patients died from treatment-related adverse events. Experts interviewed by GlobalData expressed their concern in particular with diarrhoea, which was especially elevated in comparison with marketed drugs for relapsed/refractory CLL, such as Imbruvica.

Duvelisib will compete with a number of other drugs already on the market, namely Imbruvica, Zydelig (idelalisib), and Venclexta (venetoclax). Duvelisib’s main competitor will be the PI3Kδ inhibitor Zydelig, which shares a mechanism of action with the agent but has the benefit of first-to-market advantage. Despite its challenges, an advantage duvelisib has is its convenience as an oral agent in monotherapy as opposed to the combined administration of the oral drug Zydelig with Rituxan, which must be given either subcutaneously or intravenously. Furthermore, as a dual δ/γ-specific inhibitor of the PI3K enzyme, duvelisib’s inhibition of multiple isoforms may prove more efficacious than Zydelig’s single inhibition of the PI3Kδ protein, and this may explain duvelisib’s activity as a monotherapy. Duvelisib’s toxicities, however, will limit its possibilities in combination therapies with other drugs and thus possibly confine its usage to single-agent treatment.

Duvelisib’s significant limitations are a driver of physicians’ negative view of the drug, and many would be reluctant to prescribe the single agent when other more viable options are already available on the market. With so many shortcomings, it seems duvelisib will likely become an insignificant player in CLL even if granted FDA approval. Upon first regulatory approval, Verastem will have to pay the bulk of the agreed-upon $28M, but given that Zydelig’s 2017 sales totaled $149M down from peak year sales of $168M in 2016, it is nonetheless possible that Verastem will recoup their investment despite duvelisib’s flaws.

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GlobalData (2018). Chronic Lymphocytic Leukemia (CLL) – Opportunity Analysis and Forecasts to 2027, to be published

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