The most commonly stated statistic about clinical trials is that for every one drug on the market, there are nine that failed. A look back through 2018 indicates there were a great many successes, but plenty of challenges as well. Here’s a look at 10 notable drug challenges of the year.
The most commonly stated statistic about clinical trials is that for every one drug on the market, there are nine that failed. A look back through 2018 indicates there were a great many successes, but plenty of challenges as well. Here’s a look at 10 notable drug challenges of the year.
#1. Takeda and Zinfandel and Alzheimer’s. On January 25, 2018, Takeda Pharmaceutical and its development partner Zinfandel Pharmaceuticals gave up on their five-year Phase III TOMORROW trial after an interim analysis. They were evaluating pioglitazone in mild cognitive impairment due to Alzheimer’s disease. The TOMMORROW trial was evaluating the genetic-based biomarker risk assignment algorithm (BRAA) in addition to the safety and efficacy of the drug. The safety was generally considered fine, but there was inadequate treatment effect.
#2. Boehringer Ingelheim and Alzheimer’s. Unfortunately, Alzheimer’s failures are the norm, rather than the exception. On February 9, 2018, Boehringer Ingelheim indicated it was abandoning its Phase II compound BI 409306 after it failed to meet its endpoints. The drug, a PDE9 inhibitor, being used to treat patients with cognitive impairment and memory dysfunction in schizophrenia and Alzheimer’s, failed to show superiority over placebo in cognition in two separate clinical trials.
#3. Merck & Co. and Alzheimer’s. Yes, well, it does seem like a theme. On February 14, Merck & Co. said it was halting protocol 019, its APECS Phase III clinical trial of verubecestat (MK-8931) in Alzheimer’s. An external Data Monitoring Committee (eDMC) had recommended ending it after an interim safety analysis, saying the likelihood of benefits didn’t outweigh the risks. Verubecestat is a BACE inhibitor, a precursor to amyloid-beta.
#4. Celgene and Multiple Sclerosis (MS). This particular failure was a bit of a surprise. On February 28, the U.S. Food and Drug Administration (FDA) hit Celgene with a Refusal to File letter over its New Drug Application (NDA) for multiple sclerosis treatment ozanimod. What was surprising was the Refusal to File was over the “nonclinical and clinical pharmacology sections” in the NDA, claiming they were insufficient for the agency to go ahead with the approval process. This was more than a bit unexpected for a company with the reputation and size of Celgene, suggesting that the application wasn’t really ready to go to the agency.
Several months later, in June, the company sort of admitted it was their fault, although at the same time, the company’s president of hematology and oncology, Nadim Ahmed, seemed to throw their Receptos unit under the bus, blaming them for the failure. Celgene acquired Receptos in 2015. The NDA for ozanimod was submitted toward the end of 2017, after it reported positive data from the second pivotal Phase III trial, RADIANCE, which was announced in May 2017.
On October 10, Celgene reported positive data from two post hoc analysis from the Phase III SUNBEAM and RADIANCE Part B trials, evaluating ozanimod in MS. The company indicates it plans to file again in 2019.
#5. Incyte and Melanoma. On April 6, Incyte Corporation revealed that its IDO1 drug in combination with Merck’s Keytruda did not meet its endpoints in a Phase III melanoma trial. The drug, epacadostat, did not improve rates of progression-free survival in the patient population compared to Keytruda alone.
#6. vTV Therapeutics and Alzheimer’s. On April 10, vTv Therapeutics announced its azeliragon failed to meet either co-primary efficacy endpoint in its Phase III STEADFAST clinical trial in patients with mild Alzheimer’s disease. It was made up of two independent, but identical double-blind, placebo-controlled trials, Part A and B. The group in Part A that received the drug showed a 4.4-point decline from baseline in the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) and a 1.6-point decline from baseline in the Clinical Dementia Rating Scale Sum of Boxes (CDR-sb) compared to declines in the placebo groups of 3.3 and 1.6, respectively. They were not clinically significant changes. Azeliragon is an orally active small-molecule antagonist of advanced glycation endproducts (RAGE).
#7. Roche and Exelixis and Colorectal Cancer. On April 11, Roche temporarily halted recruiting patients to its Phase II MODUL clinical trial for metastatic colorectal cancer after four patient deaths. The patients were receiving Tecentriq (atezolizumab) in combination with Exelixis’ MEK inhibitor Cotellic (cobimetinib). Then, in mid-May, the two companies’ IMblaze370 Phase III clinical trial of Tecentriq and Cotellic failed in a comparison to Bayer’s Stivarga (regorafenib) in colorectal cancer patients who had failed at least two rounds of chemotherapy.
#8. Johnson & Johnson and Alzheimer’s. On May 18, Johnson & Johnson’s Janssen division halted its clinical trials of atabacestat, a BACE inhibitor, for Alzheimer’s disease. It was ending the program over safety issues, rather than efficacy. Patients in the EARLY Phase IIb/III clinical trial with preclinical Alzheimer’s disease, as well as a Phase II long-term safety trial, had elevated liver enzymes. EARLY launched in 2015 and was scheduled to wrap in 2024.
#9. Sarepta Therapeutics and Duchenne Muscular Dystrophy (DMD). On September 21, the European Medicines Agency (EMA) rejected Sarepta’s application for Exondys 51 for DMD. What is most notable about this was that in September 2016, the FDA approved the drug after a contentious and dramatic battle that involved internal conflict at the agency, media coverage and members of Congress and panels of DMD experts sending public letters urging approval. The application to the EMA was based on two clinical trials in 12 boys with DMD between the ages of 7 and 13.
The European agency, in its negative opinion by the Committee for Medicinal Products for Human Use (CHMP), expressed doubts about the evidence, especially related to the studies’ small size, use of historical data, and lack of comparison data beyond 24 weeks. These were essentially the same controversies within the FDA.
Meanwhile, Exondys, approved in the U.S., has a yearly price tag, based on the patient’s body weight, of approximately $300,000.
#10. Alkermes and Depression—Stay Tuned! On November 2, two FDA advisory committees voted down the company’s NDA for ALKS-5461 for depression. In total, the committees voted 21 to 2 against recommending the drug. They also voted 20 to 3 that the company had not provided substantial evidence that supports the efficacy of ALKS-5461.
One of the committee members, Martin Kulldorff, a professor of population medicine and a biostatistician at Harvard Medical School, said, “I don’t think there’s evidence that this drug works.”
The drug has had a tumultuous history. The FDA accepted the NDA in April only a few weeks after initially rejecting it due to “insufficient evidence of overall effectiveness for the proposed indication.” In its Refusal to File letter, the FDA said the company would likely have to launch additional clinical trials in order to support a resubmission. But then the FDA changed its mind and Alkermes said it did not submit any additional data to the agency as was originally suggested.
The FDA is not required to follow the recommendations of its advisory committees, although with such a strong rejection by two Adcoms, it would be surprising if it did approve the drug. The agency has a target action date of January 31, 2019 for approval.
