Teva, Eisai, and GlaxoSmithKline all used the opportunity of this year's American Academy of Neurology Annual Meeting to showcase pooled analysis of their late-stage pipeline candidates. While not groundbreaking, the positive data for laquinimod (MS) and perampanel and Potiga (epilepsy) will bolster physician confidence and position the drugs well in their respective markets.
Teva: following last year's clinical trial setback, pooled analysis indicates benefit of laquinimod use in MS
Following the report of disappointing clinical trial results for the BRAVO study in August 2011, which showed that Phase III candidate laquinimod missed its primary endpoint of reducing annual relapse rate in multiple sclerosis (MS) (19%), Teva was keen to confirm the clinical use of the product in MS at the 64th American Academy of Neurology Annual Meeting (AAN 2012). The company announced new data from the pooled analysis of both the BRAVO and ALLEGRO Phase III clinical trials, highlighting the benefit of 0.6mg laquinimod on the reduction of annualized relapse rates, progression of disability, and brain atrophy, as well as its tolerable side-effect profile. In addition, the company used the meeting to present new trial data from the CombiRx trial that investigated the use of its established MS therapy Copaxone (glatiramer acetate) against and in combination with interferon beta 1a.
In a presentation by the company, it was conveyed that despite laquinimod missing its primary endpoint on annual relapse rates in the BRAVO trial, the pooled analysis showed an overall benefit of the treatment on annual relapse rates compared to placebo (20%). In addition, the numbers of gadolinium and T1 lesions in patients treated with 0.6mg laquinimod were significantly reduced compared to placebo (30% and 24%, respectively), and the percentage change in brain volume was 30% less than for placebo, with both reaching statistical significance. The data from the pooled analysis continue to show a strong effect of the drug on reducing disability progression at both three and six months (34% and 46%, respectively). The data support the clinical efficacy of laquinimod in the treatment of MS, and a spokesperson indicated that the company will be submitting applications for laquinimod to both the European and US regulatory bodies in the second half of 2012.
Datamonitor believes that the improvement in disability will be laquinimod's key differentiator in the MS market, and a lifeline for Teva when Copaxone succumbs to generic erosion in the US from May 2014. Due to its inferior efficacy profile, laquinimod is unlikely to impact upon the sales of Gilenya or BG-12, both of which have strong efficacy profiles. Teva would be well placed to conduct additional trials for the product exploring higher doses (investigations in Phase II trials indicate this is a viable approach) and its use in combination to gauge the potential success for laquinimod as an adjunctive therapy. Additional studies have the potential to identify further clinical advantages that the product may offer in the MS patient population.
Teva also presented new data from the CombiRx trial, a multicenter study comparing the combined use of Copaxone and interferon beta 1a against either therapy alone. In this three-year trial, patients were randomized to receive both Copaxone and interferon beta 1a, or placebo interferon and active Copaxone, or placebo Copaxone and active interferon beta 1a. It was reported that the combination of weekly interferon beta 1a and daily Copaxone was superior to either agent alone in reducing new lesion activity and total lesion volumes. While the positive trial data support the use of these compounds together, the inconvenience of more frequent dosing (once-weekly interferon beta 1a plus daily Copaxone) in addition to the sheer cost of MS therapies will be a great hindrance in using the combination of treatments in clinical practice.
Eisai: pooled Phase III data confirm efficacy of novel candidate in epilepsy ahead of expected Q3 2012 FDA decision
Eisai's perampanel is an orally available and novel selective alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist for the potential once-daily oral adjunctive treatment of partial-onset seizures. Most anti-epileptic drugs (AEDs) target ion channel activity, but perampanel uses a different approach and focuses on excitatory damage. Perampanel is currently pending approval for the adjunctive treatment of partial seizures in the US, with the FDA expected to issue an opinion in late October 2012. The regulator initially issued a Refusal to File letter in response to the company's New Drug Application (NDA) for perampanel in July 2011, due to a request that Eisai reformat and reanalyze some datasets in the dossier. Perampanel is also pending approval in the EU and remains under Phase III development in Japan for the adjunctive treatment of partial-onset epilepsy.
With the potential for perampanel to enter the epilepsy market by the end of 2012, Eisai took the opportunity to educate delegates at AAN 2012 on the safety and efficacy of its latest epilepsy offering via information presented across six posters. Two of these posters presented pooled Phase III data which focused upon responder rates, seizure freedom, and time to seizure recurrence associated with perampanel (2mg, 4mg, 8mg, or 12mg) use.
Perampanel (4-12mg/day) was reported to markedly and dose-dependently improve 50% and 75% responder rates and increase seizure freedom rates. It was also found to prolong time to baseline seizure rate and time to next seizure versus placebo, and the pooled Phase III data identified 4mg as the minimally effective dose.
In addition, a dose-response analysis from Phase III studies reported perampanel 12mg/day to demonstrate slightly improved efficacy over 8mg/day. The 12mg/day dose improved seizure-free rates versus 8mg/day (4.4% versus 2.5%). In a separate session at AAN 2012, Dr Jacqueline French presented research assessing the effect of concomitant AEDs on seizure frequency and responder rate in a pooled analysis of perampanel Phase III studies. Across the Phase III studies, 1,478 patients were randomized and treated and were taking an average of 2.2 concomitant AEDs. Results of the analysis found that perampanel (4-12mg/day) decreased seizure frequency and increased responder rates in patients concomitantly taking at least one of the four most common AEDs. The presence of another AED mechanism did not appear to reduce the efficacy of perampanel.
While the data are not groundbreaking, Datamonitor believes that Eisai's first-in-class AMPA receptor antagonist is well positioned to capture a decent share of the epilepsy market on account of its efficacy in treatment-resistant epilepsy, which remains an important unmet need in the treatment of the condition. The drug's novel mechanism of action and once-daily dosing are also likely to be positive factors encouraging physicians to use this product upon launch. Moreover, Eisai's well-established presence in the epilepsy market represents a key commercial advantage should the FDA grant approval of perampanel in October 2012.
GlaxoSmithKline/Valeant: integrated Phase III data for Potiga in epilepsy presented ahead of US launch
GlaxoSmithKline's and Valeant's ezogabine, known by the brand names Potiga in the US and Trobalt in Europe, is a first-in-class AED that reduces neuronal excitability by enhancing neuronal KCNQ (Kv7) potassium channel activity. Ezogabine is known as retigabine outside the US and Canada. In March 2011, European approval was granted for retigabine as an adjunctive treatment of partial-onset seizures with or without secondary generalization in adults. The product received FDA approval for the same indication in June 2011 and GlaxoSmithKline reported that US launch of Potiga would take place in late April 2012.
In spite of this, Valeant's and GlaxoSmithKline's presence at AAN 2012 was limited and there was no stand for Potiga in the exhibition hall. Datamonitor regards this as a missed opportunity for the companies to promote the product to US-based neurologists ahead of the drug's market entry. Nevertheless, the companies did present three key posters at the conference which examined ezogabine's efficacy and safety based on integrated datasets from three pivotal trials.
The first of these posters focused upon the efficacy of adjunctive use of ezogabine with traditional versus non-sodium channel blocker AEDs. Subjects receiving either traditional sodium channel blocker AEDs only or non-sodium channel blocker AEDs only were evaluated. Efficacy was evaluated by responder rate (greater than 50% reduction of baseline seizure frequency). Results found that efficacy was similar between subgroups, as measured by median percentage reduction in seizures over the double-blind treatment period and in responder rates during the maintenance phase. The study investigators concluded that the efficacy of ezogabine as adjunctive treatment is similar with either traditional sodium channel blocker AEDs or non-sodium channel blocker AEDs in adults with drug-resistant partial-onset seizures.
A related poster presented an evaluation of the safety and tolerability of ezogabine as adjunctive therapy with traditional sodium channel blocker or non-sodium AEDs using datasets from three pivotal trials. Results demonstrated that the safety and tolerability of ezogabine were generally similar as adjunctive therapy with only traditional sodium channel blockers or only non-sodium AEDs. Adverse events occurred in 72% (placebo) and 81% (ezogabine) of subjects taking traditional sodium channel blockers versus 81% and 85%, respectively, with non-traditional sodium channel blockers. Serious adverse events were reported for 7% (placebo) and 9% (ezogabine) of subjects taking traditional sodium channel blockers versus 3% and 9%, respectively, with non-traditional sodium channel blockers. Another poster presented by Dr Vanlandingham detailed an analysis of the potential for suicidality with ezogabine. The analysis concluded that the rate of suicidal thoughts and behavior reported in the pivotal controlled trials of ezogabine was similar to placebo, with no evidence of any increase in suicide, suicidality, or self-injurious behavior.
Although not groundbreaking, the data are positive and will serve to build physicians' confidence in this new entrant to the epilepsy market. Ezogabine has been shown to improve the treatment of refractory epilepsy, an important unmet need. Phase III RESTORE trials demonstrated impressive efficacy as an add-on therapy for drug-refractory partial-onset epilepsy patients, with ezogabine producing a 44% reduction in seizure frequency and a responder rate of 45% at the highest investigated dose. However, Datamonitor believes that ezogabine's three times-daily dosing schedule and relatively high discontinuation rate in the Phase III RESTORE studies offset this drug's promising efficacy and will preclude it from widespread use as a second-line therapy in the US. This is already the case in the UK, where Potiga is recommended in guidelines published by the National Institute for Health and Clinical Excellence (NICE) as a last-line treatment option for use when patients are dissatisfied with eight other AEDs.