Upcoming events – Crowded markets ahead for TG and Redhill

Welcome to your weekly digest of approaching regulatory and clinical readouts. TG Therapeutics is due to report initial data in the third quarter from its phase III chronic lymphocytic leukaemia trial, testing a combination of the anti-CD20 MAb ublituximab and the PI3K inhibitor umbralisib. CLL is a crowded space, and TG will have its work cut out to make a mark with the combo.

Phase III data are also expected with Redhill Biopharma’s RHB-104 in Crohn’s disease before the end of the month. RHB-104 looks to target the bacteria that could lie behind the condition; however, Humira remains the mainstay for treatment while other monoclonal antibodies head up the rest of the market.

TG’s combination

The phase III Unity-CLL trial tests ublituximab plus umbralisib, together known as TG-1303 or U2, versus Roche’s Gazyva plus chlorambucil in 420 CLL patients, 60% of whom were front line and 40% relapsed/refractory.

Overall response rate data, a secondary endpoint, are due in the third quarter. Progression-free survival, the primary measure, will not report until next year, but if the combination proves superior on ORR an accelerated filing is likely. However, it is still unclear whether the FDA approve based on a surrogate endpoint, especially given the availability of other treatments.

Unity-CLL is 90% powered to show a 15-point absolute improvement in ORR. The trial anticipates a blended ORR of 84-88% versus 67-71% for Gazyva plus chlorambucil.

CLL is a crowded space, and ublituximab will need to differentiate itself from other anti-CD20 MAbs like Roche’s Rituxan, which is also facing biosimilar rivals, not to mention the efficacious small molecules Imbruvica and Venclexta.

Moreover, umbralisib is a PI3K inhibitor, a disappointing class; Gilead’s Zydelig is the only marketed PI3K inhibitor for CLL, but carries warnings about liver, gastrointestinal and other toxicities. Umbralisib is said to have a better safety profile.

TG’s shares are up over 61% this year; Jefferies reckons that the Unity-CLL data could bolster shares by another 60%, or decrease TG’s value by 40%, depending on the absolute difference in ORR. TG has $109m in cash, sufficient to fund it through mid-2019.

Three in one

Meanwhile, data are due with Redhill’s RHB-104 in its lead indication, Crohn’s disease, from the phase III MAP US trial.

The theory behind using RHB-104, a combination of the antibiotics clarithromycin, rifabutin and clofazimine in a single capsule, is that the chronic inflammation seen in Crohn’s is caused by a bacterium, Mycobacterium avium paratuberculosis.

MAP US enrolled 331 moderate to severe patients, defined as those with a Crohn’s disease activity index (CDAI) score of 220 to 450, given five oral capsules twice a day of RHB-104 or placebo.

The primary endpoint is remission at week 26, defined as a CDAI score of less than 150. One of the secondary measures is response at week 26 – a reduction of CDAI score by a minimum of 100 points. The study is 80% powered to demonstrate a treatment effect of 15%.

Redhill hopes that, once the bacteria have been eradicated and the patient is in remission, patients could come off medication. This would make treatment with RHB-104 different from the standard of care, chronic therapy with anti-TNF MAbs like Abbvie’s Humira. As well as only treating the symptoms of autoimmune disorders, anti-TNFs are linked with side effects including infection and cancer due to their effect on the immune system .

Despite these issues Humira’s stronghold on Crohn’s disease is set to continue, according to consensus from EvaluatePharma, which sees the product’s 2024 sales reaching $4.4bn. The other top four spots are all taken by MAbs, making the market tough to crack.

Redhill has said that additional clinical studies are likely to be required to support an NDA for RHB-104. An open-label extension trial called MAP US2 is ongoing, and includes patients with a CDAI score of greater than 150 at 26 weeks; subjects are eligible for up to one year of treatment.

To contact the writer of this story email Joanne Fagg in London at joannef@epvantage.com or follow @ByJoFagg on Twitter