Teva Pins Long-Term Hopes In MS On Return Of Laquinimod
This article was originally published in Scrip
After missing out on the initial wave of oral multiple sclerosis drugs, Teva Pharmaceutical Industries Ltd. still has its eye on the oral immunomodulator laquinimod as a future pillar for the firm in multiple sclerosis. Teva is hoping for a launch in 2018 after a third and final Phase III trial reads out in 2017.
"We remain very excited about the prospects of laquinimod," Global CNS Head Mike Derkacz said in an interview with Scrip's sister publication, "The Pink Sheet". "We will remain focused and expect Copaxone to remain the leading product as it is today up until that point when laquinimod is expected to launch in 2018."
Copaxone (glatiramer) has been the Israeli company's only specialty blockbuster; it generated $4.24bn in sales in 2014, nearly half of Teva's $8.56bn in specialty revenues. But Novartis AG's Sandoz unit launched Glatopa, the first generic version of Copaxone, in June, putting pressure on the company and worrying investors.
Teva has managed to limit the impact of Glatopa by successfully switching the majority of patients taking Copaxone to a new 40 mg version that is dosed just three times a week compared to once-daily dosing for the original 20 mg dose.
About 76% of patients on Copaxone have switched to the 40 mg version, Derkacz said. Glatopa, meanwhile, appears to have plateaued at a 20% share of the Copaxone 20 mg business, he said.
Teva views multiple sclerosis as a long-term cornerstone of its CNS strategy, despite the headwinds facing Copaxone, and laquinimod is considered an important piece of that future.
A Phase III trial testing laquinimod in relapsing-remitting multiple sclerosis called CONCERTO is expected to read out in the second quarter of 2017, and a Phase II study in patients with primary progressive MS is also on track to read out around the same timeframe.
But laquinimod has a long development track record. Teva originally planned to file the drug in 2012, with the expectation it would reach the market around the same time as Biogen Inc.'s Tecfidera (dimethyl fumarate) and Sanofi's Aubagio (teriflunomide). But laquinimod failed to demonstrate significant efficacy in a second pivotal trial, curtailing those plans.
CONCERTO was initiated in 2012, after the BRAVO study that read out in 2011 showed patients treated with laquinimod failed to show a statistically significant reduction in annualized relapse rate (ARR) – a standard measure in MS trials – compared with placebo after 24 months of treatment.
Statistically significant benefits were seen, however, after taking into account a prespecified sensitivity analysis, and patients treated with the drug also showed benefits on a secondary endpoint – reduced risk of disease progression. An earlier trial, ALLEGRO, did show a statistically significant effect on ARR, though efficacy was modest.
Teva believes it has landed on the key to unlocking better trial results with laquinimod this time around: a different primary endpoint, time to confirmed disability progression as measured by the Expanded Disability Status Scale (EDSS). FDA agreed to the disability endpoint under a Special Protocol Assessment.
The new endpoint could yield better efficacy results in CONCERTO and also differentiate laquinimod from marketed rival orals. Almost all of the drugs currently on the market for MS were approved based on clinical trials that used relapse rate as a primary endpoint; Biogen's Avonex (interferon-1b) is an exception, approved based on a trial that used disability progression as an endpoint.
Volker Knappertz, Teva VP-Global Clinical Development, MS, said disability progression is the more difficult endpoint to reach and could be more appropriate for laquinimod based on its differentiated mechanism of action.
"I think it is in everybody's mind the more important endpoint, and the reason people went to relapse is because there is a great marker for relapse, suppression of lesions," he said.
One reason laquinimod might perform better on the disability endpoint is because of the way it works. It is believed to modulate the inflammatory response of astrocytes, which could represent a novel protective effect on neurodegeneration; most of the marketed drugs for MS work by blocking or destroying lymphocytes from entering the brain, Knappertz said.
Teva has taken another step to amplify the efficacy in CONCERTO. The company is studying a higher 1.2 mg dose of laquinimod in addition to the original 0.6 mg dose and placebo. The drug has demonstrated a strong safety profile in earlier studies, and thus, Knappertz said, "It was natural to double the dose."
Laquinimod's safety profile thus far and its differentiated mechanism of action could make it an ideal candidate for combination treatment with other therapies. Teva is already evaluating its potential in combination, but has not announced plans to initiate any clinical studies.
In addition to laquinimod, Teva is continuing to evaluate other opportunities in MS, including some internal but as yet undisclosed programs and external collaborations.
"We believe MS is the centerpiece of our CNS strategy and we will do whatever is possible to help advance the treatment of MS," Derkacz said.
Nonetheless, Teva can expect to be playing in an increasingly competitive and changed market if and when laquinimod is finally approved.
Rival drug manufacturers are continuing to make inroads with novel approaches to treating MS. Several companies presented interesting data at the European Committee for Treatment and Research in Multiple Sclerosis Oct. 7-10. Sanofi unveiled long-term data on Lemtrada (alemtuzumab) showing that patients treated with the drug maintained the benefit they saw out to five years after just two initial courses of therapy.
Roche, meanwhile, appears poised to bring the first drug to market for primary progressive multiple sclerosis, a rarer form of the neurological condition that can be severely debilitating. The company detailed positive Phase III data testing the CD20 antibody ocrelizumab in patients with PPMS and RRMS at ECTRIMS and said it plans to file the drug with global regulators in early 2016.
This article has also been published in "The Pink Sheet". Scrip Intelligence brings selected complementary coverage from our sister publications to our subscribers.