Teva Stumbles, Actelion Rises In MS: Clinical Protocols Lost And Gained

FDA casts a vote of confidence in Actelion's Phase III trial design for its oral multiple sclerosis candidate ponesimod, while Teva loses its special protocol assessment for laquinimod after dosing changes. Plus more regulatory clinical trial news in brief.

Recent announcements by Actelion Pharmaceuticals Ltd., Athersys Inc., and Tracon Pharmaceuticals Inc. – and a cautionary example from Teva Pharmaceutical Industries Ltd. and Active Biotech AB – highlight the influential role regulators play in the design of clinical trials.

An FDA clinical hold placed on Alcobra Ltd.'s lead product also spotlights the power of the agency's safety oversight of clinical trials.

Actelion Will Test First All-Oral Combo For Relapsing MS In Phase III POINT Trial

Actelion obtained a (SPA) from FDA for the second Phase III trial of its oral multiple sclerosis candidate ponesimod, providing a regulatory vote of confidence in the design of the first major trial of an all-oral combination treatment regimen for relapsing multiple sclerosis (RMS).

The POINT trial will look for superiority of combination treatment with ponesimod, an oral sphingosine-1-phosphate receptor 1 (S1P1), and Biogen Inc.'s oral Tecfidera (dimethyl fumarate) when compared with Tecfidera alone in 600 adults with active RMS. Enrollment is expected to start by year-end 2016, Actelion said Sept. 29.

Combination therapy in RMS "has likely been limited due to the potential risks associated with the long duration of action of existing products," Actelion said. Ponesimod, in contrast, has a "short half-life and rapid reversibility." Preclinical data "suggests the combination of ponesimod and dimethyl fumarate can be beneficial while not compromising safety," the company said.

In POINT, patients who have received Tecfidera for at least six months will add either ponesimod 20mg or placebo to their drug regimen. They will be followed for an expected average of two years to determine if patients receiving ponesimod plus Tecfidera have reduced relapse frequency, measured by annualized relapse rate (ARR), as compared to Tecfidera/placebo patients.

Secondary endpoints will assess safety and tolerability of add-on ponesimod while looking at further efficacy parameters, including time to 12-week confirmed disability accumulation (CDA).

The ponesimod Phase III program started in April 2015 with the OPTIMUM trial, a 108-week study comparing the Actelion drug as a single agent with Sanofi's pyrimidine synthesis inhibitor Aubagio (teriflunomide). OPTIMUM is also looking for ponesimod to show superiority to the comparator in reducing relapses. Actelion expects to complete enrollment of 1,100 patients in OPTIMUM around the end of 2016.

Athersys Says Stroke SPA 'De-Risks' Stem Cell Therapy Development Pathway

Athersys has received an FDA SPA for the MASTERS-2 trial of Multistem treatment of ischemic stroke. "The SPA is important in clarifying and de-risking an accelerated development pathway for us," Athersys said in its Sept. 28 announcement, "because it means that the successful completion of the MASTERS-2 trial, together with other available clinical data, could enable us to apply for marketing approval in the US."

Multistem represents a new approach to stroke treatment. The biologic product is an "off the shelf" stem cell therapy based on the company's multipotent adult progenitor cell (MAPC) technology. Donor cells can "be expanded on a large scale for future clinical use and stored in frozen form until needed," according to the company.

MASTERS-2, which is expected to launch in 2017, will enroll 300 patients in North America and Europe who have suffered moderate to moderate-severe ischemic stroke. Within 18 to 36 hours of the stroke, patients will receive a single IV dose of either placebo or Multistem, in addition to standard of care.

The primary endpoint will use modified Rankin Scale (mRS) scores at three months to compare "the distribution, or the 'shift,' between the MultiStem treatment and placebo groups," Athersys reported. "The mRS shift analysis considers disability across the full spectrum, enabling recognition of large and small improvements in disability and differences in mortality and other serious outcomes, among strokes of different severities."

Key secondary endpoints in MASTERS 2 will look for patients with an "excellent outcome" on the mRS as well as two other clinical rating scales, the NIH Stroke Scale (NIHSS) and Barthel Index, at three months and one year.

The "excellent outcome" measure at one year was statistically significant for Multistem in a Phase II ischemic stroke study that did not meet its primary efficacy endpoint, Global Stroke Recovery Assessment at 90 days.

The Phase III trial's 18-36 hour dosing timeframe will be shorter than the Phase II study, which administered IV Multistem or placebo 24-48 hours after the stroke. Analysis of the Phase II data found better outcomes for patients who received Multistem within 36 hours.

A separate Phase III study is being readied in Japan, where Athersys has partnered with Healios KK. Japan's Pharmaceutical and Medical Devices Agency (PMDA) has accepted the companies' proposal for a placebo-controlled study of Multistem administered 18-36 hours after stroke, Athersys announced Sept. 12. The study will evaluate patient recovery at 90 days post-treatment, also using the "excellent outcome" measure.

Tracon Prepares For Adaptive Phase III Trial Of Carotuximab

US and European "separately determined the acceptability" of key elements of Tracon's proposed Phase III trial for the anti-endoglin antibody carotuximab (TRC105) in angiosarcoma, an ultra-orphan cancer indication with no specifically approved treatment, the company announced Oct. 3. The company intends to submit the protocol to FDA for an SPA later this year and expects to start enrolling patients before the end of 2016.

An end-of-Phase II meeting with FDA and a Protocol Assistance Meeting with the European Medicines Agency produced agreement on important aspects of the Phase III design, Tracon said. The company plans a total enrollment of 124 patients, but trial will use an adaptive design featuring an interim analysis "that allows for sample size re-estimation up to a maximum of 200 patients, as well as enrichment of more responsive patients based on the subtype of angiosarcoma, visceral or cutaneous."

The Phase III study will randomize patients to carotuximab in combination with Novartis AG's Votrient (pazopanib) or to Votrient alone. Patients will be stratified by treatment experience and will not have received a prior VEGF inhibitor.

The primary endpoint will be progression-free survival (PFS); overall survival (OS) will be a secondary endpoint. The trial "will provide at least 80% power to determine an improvement in median PFS from 4.0 to 7.3 months," Tracon said.

Teva Laquinimod CONCERTO Trial Loses SPA After Dose Change

FDA rescinded an SPA for the Phase III CONCERTO trial of Teva and Active Biotech's troubled oral multiple sclerosis candidate laquinimod because the companies did not seek agency approval before terminating two high-dose arms, Active Biotech reported Sept. 19.

Teva discontinued the higher dose arms in January after the data monitoring committee identified an imbalance in the number of cardiovascular events in CONCERTO, a 2,199-patient trial in relapsing remitting MS, and ARPEGGIO, a 191-patient Phase II trial in primary progressive MS . Seven CV events were seen in patients receiving laquinimod 1.2 mg in CONCERTO, while no events were reported in the 0.6mg or placebo arms; one ARPEGGIO patient receiving 1.5mg laquinimod daily had a CV event. (Also see "Teva Faces Laquinimod Setback After High Dose Linked To CV Events" - Pink Sheet, 4 Jan, 2016.)

Teva submitted an amendment to the CONCERTO SPA in February to account for the change, Active Biotech reported, but "the SPA was rescinded as all changes must be agreed to prior to implementation of the change." The company maintained that "this requirement could not be fulfilled in the current case, since the DMC recommendation triggered an immediate action to withdraw the 1.2mg dose … in the interest of patient safety."

CONCERTO is the third Phase III trial for laquinimod, initiated in 2012 after the Phase III BRAVO trial in RRMS failed to demonstrate significant efficacy on its primary endpoint, reduction in annualized relapse rate, a standard measure in MS trials. CONCERTO uses an endpoint of time to confirmed disability progression as measured by the Expanded Disability Status Scale. (Also see "Disappointing BRAVO Data Raise Doubts About Laquinimod's Chances With FDA" - Pink Sheet, 1 Aug, 2011.)

CONCERTO will continue as planned, Active Biotech said, with data expected in the first half of 2017. Teva still plans to use CONCERTO to support marketing applications in the US and Europe.

Alcobra Halts MDX Phase III MEASURE Trial In Adult ADHD

FDA's Division of Psychiatry Products has placed a full clinical hold on Alcobra's investigational new drug (IND) applications for its lead product, MDX, in attention deficit hyperactivity disorder and Fragile X syndrome, leading to a halt in the company's Phase III MEASURE trial in adult ADHD.

FDA told Alcobra that the hold would be placed "due to adverse neurological findings in a preclinical study." More information is expected from the written letter, expected about a week after the verbal notification, Alcobra President and CEO Yaron Daniely told a Sept. 28 investor call.

Alcobra presented FDA with a "comprehensive preclinical data package" before a March 2015 end-of-Phase II meeting on MTX, Daniely said, and FDA agreed the preclinical data supported moving into Phase III. He wondered why the clinical hold was being issued now. FDA "did not refer to any human clinical data from the ongoing MEASURE trial or any previous MTX clinical study," he emphasized.

The MEASURE trial has enrolled nearly 500 of an anticipated 750 patients, Daniely noted. The trial is a 10-week study comparing MDX, a proprietary once-daily dual-release formulation of the monoamine-independent GABA modulator metadoxine, with placebo. The trial had been expected to produce data by year-end 2016.

FDA had earlier agreed that positive efficacy results from MEASURE could allow an NDA for adult ADHD with a single Phase III study, Alcobra said. MEASURE implemented lessons from the company's first Phase III trial in adult ADHD, the ALO12 study, which failed to meet its primary endpoint. ALO12 showed an "unusually large" response variability, including significant placebo response, the company said; the larger MEASURE study introduced a double-blinded variable placebo period to exclude extreme placebo responders and extended treatment duration to "target reduction of placebo response."

The clinical hold also delays the company's plans to advance MDX in pediatric ADHD and Fragile X syndrome. In July, the company reported that its first pivotal pediatric ADHD MDX would start in 2016. FDA had also agreed to a development plan for adults and adolescents with FXS, an orphan condition where the drug holds fast-track status, based on a single pivotal trial.