In October of 2014 a patient died of pulmonary (lung) blood clots. The Food and Drug Administration (FDA) placed a partial clinical hold on the trials, and now the manufacturer experienced trials in other senses of the word, from challenges to tribulations. The company had to step up its safety game, and choose participants unlikely to suffer adverse reactions.
But in January of 2015, another patient died from the same cause as the first one — despite having been extensively screened. The FDA responded by placing a complete hold on Zafgen’s operations, and ordered an investigation which, as journalist Sy Mukherjee suggested, might “doom any hopes the investigational compound had for regulatory clearance.” He also wrote,
It’s important to note that a direct link between the drug and the blood clots/deaths has not been incontrovertibly established — but the fact that several patients in studies involving beloranib have reported blood clots isn’t encouraging.
A month later, the same reporter caught up on the story:
The data that was released on Wednesday stems from 74 patients who had completed the phase 3 trial before the FDA’s hold and another 27 who had completed at least three-quarters of the trial. Specifically, the data showed significant body weight reductions (9.45% weight loss at a 2.4 mg dose and 8.2% loss at 1.8 mg) and reduced the urge to overeat associated with Prader-Willi syndrome.
[T]he company will have to convince the FDA that the screens and risk mitigation strategies are stringent enough to ensure patient safety.
Zafgen tweaked the formula, and the focus changed to diabetes, which is a much larger market, and pretty well saturated already by anti-diabetes drugs that can be taken orally. Beloranib needs to be injected, and although subcutaneous is not quite as bad as intramuscular, an awful lot of people would rather swallow a pill than puncture themselves.
Halfway through 2017, Science Translational Medicine writer Derek Lowe referenced the original mission and noted:
The benefits of going after an unusual population like Prader-Willi patients is that they are easy to identify and there is no medical treatment available. You will be the first to ever help them, and demonstrating that benefit should be a pretty straightforward proposition, clinically. Diabetes, on the other hand, is trickier.
[T]here’s a lot of competition — a whole list of drugs and a whole list of different mechanisms. It’s a crowded field with plenty of options, and making one’s way in it is going to be a lot harder (and a lot more costly) than it is in a rare disease.
This new iteration of beloranib was problematic because anti-diabetes drugs have especially high standards, and testing for cardiovascular outcomes is very costly. The drug did not have a good thrombotic safety profile, and the FDA “cited the possibility of cardiovascular safety risk.” Reporting for FierceBiotech, Nick Paul Taylor write,
The FDA has placed a clinical hold on Zafgen’s ZGN-1061. Zafgen has spent the past year putting that idea to the test in a phase 2 trial of ZGN-1061 in patients with Type 2 diabetes. The brief statement from Zafgen offers few clues about how long the clinical hold will be in place.
Things got up and running again, but the researchers tried out another compound that had a toxic effect on muscle tissue that had not shown up in previous formulations. Also, Lowe wrote,
There’s not much clarity on how (or if) the clinical hold on ZGN-1061 could be resolved, and it may in fact be unresolvable… [T]hey have quite a hole to climb out of at this point.
Your responses and feedback are welcome!
Source: “CORRECTED — New entrant in obesity drug race targets body, not the mind,” Reuters.com, 08/26/13
Source: “UPDATE: FDA places complete hold on Zafgen obesity med trials after 2nd patient death,” BioPharmaDive.com, 12/03/15
Source: “After patient deaths, new Zafgen obesity med data revives approval hopes,” BioPharmaDive.com, 01/21/16
Source: “Zafgen’s Second Act,” ScienceMag.org, 05/08/17
Source: “FDA hits Zafgen’s beloranib successor with clinical hold,” FierceBiotech.com, 11/26/18
Source: “Zafgen: Will There Be a Third Act?,” ScienceMag.org, 03/14/19
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