Prospects for Roche’s Kadcyla were badly damaged by news released Dec. 19 that its MARIANNE trial failed to show the new drug performed better than Herceptin in first-line treatment of advanced HER2-positive breast cancer.

The Phase III study is testingKadcyla (ado-trastuzumab emtansine) and Perjeta (pertuzumab) in combination compared to Herceptin (trastuzumab) and chemotherapy in a first-line setting. The trial has three different arms: Kadcyla plus Perjeta, Kadcyla alone, and Herceptin plus taxane chemotherapy. All three arms performed about the same on the primary endpoint of progression free survival, but Roche said neither Kadcyla-containing treatment arm significantly improved PFS compared to Herceptin and chemotherapy.

Kadcyla is an antibody-drug conjugate that combines the active ingredient used in Herceptin with a potent cytotoxic agent delivered directly to the tumor. Roche had hoped Kadcyla would eventually trump Herceptin as the standard of care for HER2+ breast cancer ahead of biosimilar competition, which could potentially hit in 2016 Also see "Roche’s Breast Cancer Strategy Paying Off, But Diversification Difficult" - Pink Sheet, 15 April, 2014.. The MARIANNE trial results have dashed those aspirations.

“We had hoped to show improvement in progression-free survival without the use of traditional chemotherapy in the first line treatment of patients with advanced HER2-positive breast cancer,” Sandra Horning, Roche’s chief medical officer and head of global product development said in a statement. “While MARIANNE didn’t achieve this result, we will continue to study these medicines, as well as investigational treatments for other types of breast cancer.”

Kadcyla Stays Late-Stage Now

Analysts said the trial results were a surprise and mean Kadcyla will probably now stay a late-stage drug.

“This is an unexpected negative,” Bernstein analyst Tim Anderson said. He noted that while Kadcyla is now selling well and growing in the second-line breast cancer setting, its prospects in the first-line setting “are now probably nil.” Sales projections for the drug will therefore need to be slashed.

“In our 2020 estimates, we have Kadcyla reaching sales levels of CHF3 billion ($3.1 billion) versus consensus of CHF3.6 billion ($3.7 billion); this may have to be cut down to perhaps CHF1 billion,” Anderson said in a note to investors.

Emphasis at Roche will now probably move to Perjeta, whose usage will be mainly with Herceptin now rather than Kadcyla. Analysts at Berenberg said their forecasts already assume Perjeta becoming the leading HER2 drug in Roche’s franchise, with relatively little weight on Kadcyla.

But to hit that target “we need to see the combination of Perjeta and Herceptin prove effective in the adjuvant setting. This will be determined by the outcome of the APHINITY study, with data expected in 2016,” Berenberg analysts Alistair Campbell and Louise Pearson said.

Gantenerumab Setback

Roche the same day announced a second Phase III setback, that one in trialing gantenerumab in prodromal Alzheimer's patients.

The SCARLET-ROAD study with gantenerumab – an investigational, fully human, monoclonal antibody designed to decrease levels of beta amyloid in the brains of people with Alzheimer’s – was terminated early for lack of efficacy. The decision was based on the results of a pre-planned futility analysis and a recommendation by the independent Data Monitoring Committee. No new safety signals for gantenerumab were observed in this analysis and the overall safety profile was similar to that seen in the Phase I trial.

Roche’s Sandra Horning voiced disappointment about that trial outcome as well, noting that it was the first Phase III trial to evaluate a potential disease-modifying medicine in the early prodromal stage of Alzheimer’s disease. But she stressed they “remain committed to investigating new medicines for this devastating illness.”

Alzheimer’s disease has been notoriously tricky for drug developers due to uncertainty about causes of the disease, as well as poor procedures for diagnosing patients early.

Gantenerumab came out of an antibody engineering pact with MorphoSys AG Also see "Roche's CNS Drug Pipeline Matures: More Investment, More Promise" - Pink Sheet, 6 June, 2011.. The German biotech in a statement noted that the discontinued SCarletRoAD study enrolled 799 pre-symptomatic patients with so-called prodromal Alzheimer's disease.

Two additional clinical studies are currently ongoing. The Marguerite RoAD trial is a Phase III study evaluating gantenerumab in around 1,000 patients with mild Alzheimer's disease. The second trial, run by the Dominantly Inherited Alzheimer Network, assesses the safety, tolerability and biomarker efficacy of gantenerumab in individuals who have a genetic predisposition for Alzheimer's disease.

Similar anti-amyloid beta antibodies include Eli Lilly & Co.’s solanezumab, currently in Phase III, Roche’s crenezumab, which is expected to enter Phase III soon, and Biogen Inc.’s BIIB037, which will soon begin Phase III.

Roche Says Kadcyla Fails To Better Herceptin In First-Line Breast Cancer

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