Btobioinnovation.com

Author: Jean-Claude Muller, 穆卓Executive Editor at BtoBioInnovation  jcm9144@gmail.com

SPECIAL REPORT #45

2019 Major Pivotal Clinical Trials Failures

Pivotal Phase 3 clinical trials are of utmost importance for the registration and the launch of a new drug, a new indication or of a combination of drugs for the treatment of a given disease. In many cases such pivotal studies request investments in the range of hundreds of millions of dollars and may last up to five years. In spite of existence of more and more predictable early stage studies, bringing a project from first-in man through registration, there are still far too many failures at this late stage of development.  Relying on recent reports from Fierce Biotech we have selected to describe some of the most significant 2019 failed pivotal studies in areas of unmet medical need: Alzheimer’s disease, glioblastoma, NASH, “diastolic” heart failure and respiratory syncytial virus infection.

Alzheimer’s disease

Elenbecestat, a BACE inhibitor designed to interfere with the beta amyloid cascade and the formation of the characteristic amyloid plaque, was stopped by Biogen and Eisai in September when the sponsors were facing an “unfavourable risk-benefit ratio” in the phase 3 MISSION AD trials.

Umibecestat, a selective BACE1 inhibitor from Novartis saw also its development stopped earlier in the year.  In spite of many recent setbacks several scientists still speculate that BACE inhibition, in combination with other targeted drugs, might be useful in the treatment of Alzheimer’s disease.

Aducanumab’s resurrection came as a massive surprise when Biogen and Eisai announced that the futility analysis announced earlier in the year was incorrect and that the ENGAGE study, where patients were treated longer and with higher doses, was strong enough to consider a submission to the US FDA. The worrying discrepancy between the ENGAGE and the EMERGE groups has triggered controversial positions of various analysts close to the file. Some feel that the evidence of efficacy and the cumulative data fall far from the FDA standards. Biogen remains bullish on the new data, insisting that they represent the first time that any drug has been able to show a statistical improvement on a clinical dementia scale. The incoming FDA commissioner, Stephen Hahn, will be scrutinised on the rationale of the decision of the agency.

Glioblastoma

High grade gliomas (HGCs) are, with pancreatic cancer, the toughest tumours to treat and at least three drugs have failed to reach a positive outcome in this highly aggressive form of brain cancer. Right now, newly diagnosed glioblastoma patients are treated with surgery and chemotherapy and radiotherapy, with average survival time of 12-18 months and less than 5% patients still alive five years after diagnosis.

Depatux-M, formerly ABT-414, a depatuximab payloaded with mafodotin, targeting EGRF astrocytes was unsuccessful in the phase 3 INTELLANCE-1 trial aimed at treating patients with glioblastoma multiform (GBM), a subcategory of HGC, known to be the fastest growing and most malignant form. The trial compared Depatux-M to placebo on top of standard treatment with radiotherapy and chemotherapy in patients diagnosed with EGRF overexpression. The drug showed no benefit on survival and an independent data monitoring committee recommended AbbVie to abandon the trial.  Two years ago, Depatux -M already failed in the INTELLANCE-2 trial when the drug was tested in combination with temzolomide in relapsed patients. Temzolomide, a cytotoxic agent was, back in 2005, the last approved drug to treat HGC.

Opdivo, Bristol-Myers Squibb’s checkpoint inhibitor also failed in the CheckMate-548 trial to improve on progression free survival (PFS) when given on top of standard of care treatment with chemo and radio therapies in selected patients with a specific marker named MGMT used to determine the best approach for treating GBM.  CheckMate-548 is BMS third missed trial for Opdivo in GBM.

Toca 511/Toca FC, is a combination of gene therapy drug, with a prodrug of 5-fluorocytosine (5-FC) which missed its primary endpoint of overall survival compared to standard-of-care as well as its secondary endpoint. Toca 511 is an injectable retroviral replicating factor directly delivered to cancer cells encoding a prodrug activator enzyme named cytosine deaminase (CD). Toca FC is a chemotherapy prodrug (5-FC) that is inactive until catalysed by CD. The rationale behind the approach is that only cancer cells expressing CD would activate the chemotherapy prodrug without affecting healthy tissues. Tocagen claimed that in a small subgroup, they saw a doubling of survival in patients with an IDH1 mutation. The company is still continuing a phase 2/3 trial in newly diagnosed GBM patients.

Non-alcoholic Steatohepatitis (NASH)

NASH, a form of non-alcoholic fatty liver disease characterised by fibrosis and inflammation, is now estimated to affect almost 1 billion people. NASH has been the focus of many biopharmaceutical companies but there has not been a single drug approved as of yet. So far only Intercept Pharma obeticholic acid has shown activity in late stage clinical trials and the file has been submitted to the US FDA, in spite of major safety concerns associated with the treatment.

Emricasan, a pan-caspase inhibitor developed by Conatus and Novartis, was not superior to placebo in the phase 2b ENCORE-LF trial, on primary endpoints looking at survival, new decompensating events or liver disease progression. In addition, the drug was no better than placebo at improving mean hepatic venous pressure gradient.

Selonsertib, an ASK1 inhibitor, is one of the three NASH drug candidate Gilead has in its clinical pipeline.  The STELLAR-4 trial showed Selonsertib, to be no better than placebo at improving fibrosis in NASH patients and the STELLAR-3 readout indicated that the drug did worse than placebo at reducing scarring in patients with bridging fibrosis. Gilead has still two NASH clinical candidates in its pipeline: Cilofexor a FXR agonist and Firsocostat, an ACC inhibitor, but both are threatened by fierce competition in the field. In 2018, Takeda/Shire stopped SHP626 (volixibat) its apical sodium-dependent bile acid transporter inhibitor for the NASH indication.

One of the difficulties of running large late stage NASH clinical trials is directly linked with the necessity to perform several painful liver biopsies. On November 10, Genfit announced results from a study demonstrating NIS4, an innovative non-invasive diagnostic blood test designed to diagnose NASH in people with type 2 diabetes,  could potentially be replacing biopsy with a single blood test.

Heart failure with preserved ejection fraction (HFpEF) or “diastolic” heart failure.

Heart failure is a common disease, the cause of major impairment and often of death. There are two types of left ventricular heart failure: heart failure with reduced ejection fraction (HFrEF) or “systolic” heart failure where the heart muscle is not able to push rich oxygen blood efficiently around the body and heart failure with preserved ejection fraction (HFpEF) or “diastolic” heart failure where the heart pushes the right amount of blood but where a series of factors including how the blood can carry oxygen are involved.

Entresto, a fixed combination of sacubitril and valsartan, has been approved since 2015 as a treatment for HFrEF and has become a blockbuster with sales far above $1 billion. Novartis has expected that Entresto might also be effective in HFpEF, which accounts for more than half the population affected by heart failure, in particular women and older people. The PARAGON-HF trial of Entresto in HFpEF was unsuccessful and missed its main goal of reducing deaths and emergency hospitalisations.  A new study called PARADIGM-HF that includes mainly women and people with structural changes in the left ventricle of the heart is in progress and Novartis already announced “profound effects” in such patients. A series of other trials including PARALLAX -HF are ongoing.

Praliciguat, a soluble guanylate cyclase (sGC) stimulator from Cyclerion Therapeutics did not prove active in heart failure patients with HFpEF and diabetic kidney disease. The drug, which is thought to work by fixing nitric oxide and increase vasodilatation was unable to improve exercise capacity. Cyclerion intends to pursue the diabetic kidney disease indication. Merck & Co and Bayer have reported positive phase 3 results for their sGC stimulator vericiguat (MK-1242) in the phase 3 VICTORIA trail for HFrEF but have not yet initiated large studies in HFpEF.

Respiratory syncytial virus (RSV) infection

There is currently no approved RSV vaccine to combat the estimated more than 60 million people infected by the virus each year. Three years ago, ResVax from Novavax failed in a placebo-controlled study of nearly 12,000 adults aged over 60 years, where the vaccine did not protect against the RSV lower respiratory tract. At the time Novavax indicated that it would focus its effort to test the vaccine in infants with a $89 million in backing from the Bill and Melinda Gates Foundation. In February of this year the company had to concede that the four-year study of 4,600 pregnant women with ResVax administered in the third quarter of pregnancy did not support the hypothesis that immunity would be passed to new-borns in the first 90 days of life. The vaccine only had a 39% protective effect against RSV related lower tract infections and a 44% reduction of RSV related hospitalisations, which means that at least one additional study will be requested for US FDA approval. European regulatory authorities are not keen to give a conditional approval based on these results and may also request an additional trial. Several other companies, including GlaxoSmithKline, Merck/Moderna and Sanofi/AstraZeneca are developing late stage clinical candidate vaccines to treat RSV infections. At one point, analysts had projected that ResVax, Novavax’s RSV vaccine could be become the world top-selling candidate of all time. On December 10, Sanofi’s CEO Paul Hudson presented Nirsevimab “as the first prophylaxis vaccine against RSV which has the potential to cover all infants through a single injection”. Nirsevimab received US FDA breakthrough submission therapy designation and EMA Priority Review with an expected submission in 2023.

We wish all our subscribers and readers a Merry Christmas and a Prosperous Year 2020

December 18, 2019

This document has been prepared by btobioinnovation and is provided to you for information purposes only.  The information contained in this document has been obtained from sources that btobioinnovation believes are reliable but btobioinnovation does not warrant that it is accurate or complete. The views presented in this document are those of btobioinnovation’s editor at the time of writing and are subject to change.  btobioinnovation has no obligation to update its opinions or the information in this document.