Teva Faces Laquinimod Setback After High Dose Linked To CV Events
This article was originally published in The Pink Sheet Daily
Executive Summary
Teva will discontinue higher doses of laqunimod in two ongoing studies for multiple sclerosis after cardiovascular events were experienced in eight patients. Trials will continue with a lower dose.
Teva Pharmaceutical Industries Ltd.’s attempt to produce greater efficacy with the investigational multiple sclerosis drug laquinimod by testing higher doses has backfired. The company revealed Jan. 4 that it will discontinue higher doses of laquinimod in two ongoing clinical trials after eight non-fatal cardiovascular events occurred.
The two trials, CONCERTO and ARPEGGIO, will continue testing the lower 0.6 mg dose, where no cardiovascular events have been identified, although with routine monitoring.
The changes were based on the recommendation of the data monitoring committee (DMC), which identified an imbalance in the number of CV events in the studies. Seven events were observed in patients receiving laquinimod daily at 1.2 mg for treatment of relapsing-remitting MS in the Phase III CONCERTO trial, while no events occurred in the 0.6 mg arm or placebo group. The study has 2,199 patients.
One event was observed in the Phase II ARPEGGIO trial in primary-progressive MS patients in a patient receiving the 1.5 mg daily dose. The trial has enrolled 191 patients.
The finding is the first time laquinimod has been linked to cardiovascular events despite the drug’s extended development. Teva, however, had studied the immunomodulator extensively at the lower 0.6 mg dose, not the higher doses.
The company doubled the dose in the most recent Phase III program as part of an effort to boost the efficacy profile of the drug, which fell short in the initial late-stage studies. The drug had demonstrated a strong safety profile at the lower 0.6 mg dose.
In an interview in October, Teva VP-Global Clinical Development, MS Volker Knappertz said the company felt it was “natural” to double the dose given the drug’s solid safety track record (Also see "Teva Pins Long-Term Hopes In MS On The Return Of Laquinimod" - Pink Sheet, 12 Oct, 2015.).
Laquinimod’s Future Tied To The 0.6 mg Dose
Laquinimod’s prospects are now tied to the drug’s performance at the 0.6 mg dose. Data from CONCERTO are expected to read out in the second quarter of 2017, and Teva has been eyeing a regulatory filing in 2018. The Phase II data from ARPEGGIO could read out around the same time. [See Deal]
The revised timeline is greatly delayed from the 2012 filing Teva had originally hoped for, back when the company expected to launch the drug around the same time as two other new oral entrants, Biogen Inc.’s Tecfidera (dimethyl fumarate) and Sanofi’s Aubagio (teriflunomide). Those drugs have both reached the market but laquinimod failed to demonstrate significant efficacy in its second pivotal trial, BRAVO, curbing its path to market.
Instead, Teva initiated the CONCERTO trial – a third Phase III trial – in 2012, incorporating a different primary endpoint. BRAVO relied on annualized relapse rate as the primary endpoint, a standard measure in MS trial, but laquinimod failed to show a statistically significant reduction in AAR (Also see "Disappointing BRAVO Data Raise Doubts About Laquinimod's Chances With FDA" - Pink Sheet, 1 Aug, 2011.). An earlier trial, ALLEGRO, did show a statistically significant effect on AAR, though efficacy was modest (Also see "No Homerun, But A Base Hit For Teva's Laquinimod" - Pink Sheet, 12 Apr, 2011.).
A statistically significant benefit was seen in BRAVO, however, after taking into account a pre-specified sensitivity analysis, and patients treated with the drug showed benefits on a secondary endpoint, reduced risk of disease progression.
Thus, in CONCERTO, Teva is relying on time to confirmed disability progression as measured by the Expanded Disability Status Scale (EDSS) as the primary endpoint, with the hope of a better efficacy result. If the results are positive, the data could also differentiate laquinimod from other marketed rivals; most of the drugs on the market for MS were approved based on clinical trials that used relapse rate as a primary endpoint.
Despite the increasingly crowded market for drugs to treat multiple sclerosis, Teva continues to believe laquinimod could be a valuable option for patients – and a solid commercial opportunity. But a strong safety record is an important part of the profile Teva is looking to establish for laquinimod, which would presumably be positioned as a modestly effective, but safe option for patients versus more efficacious alternatives with more side effects. Teva has also been hoping that laquinimod’s strong safety and differentiated mechanism of action would make it a candidate for combination treatment.
The company would like to have a successor to its blockbuster MS backbone Copaxone (glatiramer) and insists MS remains a cornerstone of its CNS franchise, despite headwinds ahead for Copaxone.
Evercore ISI analyst Umer Raffat said there is still hope for laquinimod in an email to investors the same day.
“Many investors have written off laquinimod entirely – perhaps given the low relapse rate reduction, and perhaps also given the superior efficacy of Gilenya and Tecfidera,” he said. “I will point out that Sanofi’s Aubagio has $1bn in sales despite not having Gilenya/Tecfidera-like efficacy and despite having a black box for liver tox and teratogenicity. Thus, I find it hard to put a zero on laquinimod.”