Editor’s Note: This article is being done in conjunction with a balance sheet partner.
Intra-Cellular Therapies holds itself out to both patients and investors as a fast-growing, lab coats-to-riches story.
In the telling, Intra-Cellular is a scrappy band of researchers whose single-minded pursuit of original treatments for long-vexing neurological conditions like schizophrenia and Parkinson’s Disease is paying off.
And certainly the New York City-based pharmaceutical developer has had some recent successes.
Lumateperone, Intra-Cellular’s sole drug, obtained Food and Drug Administration approval in December 2019 to treat adult schizophrenia. Two years later, in December 2021, the FDA signed off on the drug’s use in treating adult Bipolar depression. (The drug is marketed as Caplyta.)
The FDA’s blessing have sent both Intra-Cellular’s revenues and its share price arcing north.
But the truth of Caplyta – and perhaps even the drug’s future – may be much cloudier than Intra-Cellular is letting on.
That’s because Caplyta’s users are making themselves heard across the internet regarding their experiences with a particularly toxic side effect.
Almost from the moment Caplyta became commercially available in early 2020, a chorus of current and former Caplyta users have taken to website forums to weigh in on the drug.
And many of them have a lot to say about a specific Caplyta side effect whereby they become uncomfortably hot after taking their first dose.
Last May, one ex-Caplyta user at Drugs.com wrote that her “neck was burning hot (but on the inside),” and in January, an askapatient.com commenter wrote of a sensation akin to “being boiled alive.”
This WebMD poster last November, complained she “couldn’t regulate my body temperature,” among a host of other claimed effects. (To be fair, apart from the burning sensation, many of the side effects she described are listed as potential side effects for Caplyta’s class of drug.)
Another Drugs.com poster last April also framed what happened as a problem with “temperature regulation,” and said she had, “flu like symptoms.”
Most often this body temperature side effect is referred to in terms of being a burning sensation, but some – like this reddit poster from the r/bipolar forum last December — experience it as a fluctuation between the extremes of burning heat and icy chills.
More troublingly, a subset of the posters describing this body temperature regulation issue also dealt with the occasional swelling of hands and feet, as well as paresthesia, or pins and needles.
Even fans of Caplyta who have experienced the body temperature regulation side effect admit it was difficult to experience. Like a reddit commenter, who wrote in late December that after navigating, “the most uncomfortable feeling I’ve ever had with a medicine,” Caplyta wound up helping with her depression. Similarly, in January an askaptient.com poster related how the depression is “easing up.”
FAERS data suggests something is up
Where this side effect is most visible is in the FDA’s own adverse events reporting system, or FAERS.
For Caplyta, Storm King Reports found it referenced in 7 percent, or 102 of the 1,447 total FAERS entries made between 2020 and 2022.
To obtain that figure, we searched the reaction column of FAERS’ case listings for the years 2020-2022. Four search terms were used: Burning sensation, body temperature, paresthesia, and peripheral neuropathy. (Occurrences of each term were checked by hand to eliminate duplicates.)
In order to eliminate false positives, we searched for terms that could contribute to elevated body temperature independent of Caplyta.
For example, results that mentioned pyrexia or fever were culled, on the view that an infection may have been present before the drug was administered.
Also chopped: Results with thermal burn, temperature regulation disorder, Stevens-Johnson syndrome, a skin disorder caused by mood stabilizers, and neuroleptic malignant syndrome, a quite rare but serious (and possibly fatal) reaction to antipsychotic drugs.
Strikingly, a survey of three of Caplyta’s long-established competitors revealed that body temperature regulation is largely absent from their FAERS data.
For example, only four of Risperdal’s 2,234 adverse event reports last year mentioned body temperature discomfort. (Admittedly, Risperdal’s data required some effort to isolate those entries in which the user was primarily claiming a reaction to the drug, as opposed to other medications.)
Abilify and Seroquel, respectively, came in at .03 percent, or 5 out of 1,450, and 1.5 percent, or 10 out of 672. (Seroquel’s data suggests the possibly neuropathic reports came from only three users.)
A brief aside: Adverse event reports are a tabulation of submitted entries describing patient responses to a drug. They can range from the relatively mild, such as the temporary loss of appetite, to the deadly serious, like the onset of respiratory difficulties or cardiac arrest. The reports are unverified and are not designed to replace a formal investigation or autopsy. This completely voluntary reporting system allows for a wide array of filers, and with family members, caregivers and trained medical professionals able to make submissions, the level of accuracy and detail can vary. Finally, many medical professionals have suggested that because this documentation is voluntary, a majority of incidents involving newer drugs are not reported to FAERS.
One Caplyta user’s experience
An ex-Caplyta user named Madison, 28, who asked that her last name not be used, told Storm King Reports that shortly after taking her first dose of Caplyta 10 months ago: “I experienced a real burning sensation on my skin and my insides. Nothing I did to cool off worked.”
Finally, in desperation, during a frigid spell in her part of the northeast, “I went outside in the [December] snow in a t-shirt and shorts to try and get relief.” She reports she felt cooler, but after a few minutes her skin “was turning red and purple.”
“Later that day,” she continued, “I began to cool down a little and tried to sleep. Then I developed the worst chills. I had to wear a sweat shirt and socks to bed with extra blankets but my shaking wouldn’t stop.”
Madison said she was so desperate to come out of a bipolar depressive episode that she tolerated the temperature swings for six days before getting off Caplyta. Other than for brief periods, and to use the bathroom, she said, she was confined to bed for that time.
The experience was so consuming, Madison said, that she lost 13 pounds.
Her story has an unhappy coda: Despite going off Caplyta before the first week was complete, Madison said she still had intermittent “icy hot” sensations for much of the following month.
(Storm King Reports spoke to 11 ex-Caplyta users who related their experience on the drug, including several who posted on the websites listed above. Madison, however, is the only one who consented to use her name.)
An expert weighs in
According to Dr. David Healy, an expert in psychopharmacology, the fact that people are speaking up about these experiences is a great thing. (Dr. Healy, it should be said, has also attracted attention for his pointed criticism of what he contends was the pharmaceutical industry’s inaccurate disclosures of the risks of suicidal ideation in marketing antidepressants.)
Dr. Healy said that accounts of body temperature problems strongly suggested to him that the Caplyta users had experienced peripheral neuropathy, or the presence of neurotoxins that over time may kill nerve endings. Part of that process, he said, often includes the temperature swings Madison and others described above.
Confident that Caplyta’s chemical framework was behind these reactions, Dr. Healy narrowed his assessment to drug induced peripheral neuropathy.
“[Neuropathic] effects over time are bad enough for anyone,” Dr. Healy said. But since Caplyta belongs to a class of drug called an atypical antipsychotic, he said many users have been conditioned to think that before any therapeutic benefits can take hold, substantial side effects must be absorbed. As a function of this dynamic, many bipolar or schizophrenic patients are exposed to prolonged neuropathic adverse reactions.
“That can open the door to a patient’s possible longer-term nerve damage,” said Dr. Healy.
Even worse, Dr. Healy argued, is neuropathy’s risks for pregnant women. He said in those instances, the medical provider would need to immediately discontinue the drug because of the threat [body temperature swings] pose to healthy fetal development.
A side effect’s roots go back decades
What these Caplyta users almost certainly don’t know, however, is that the outline of this problem can be detected in a little noticed June 2005 press release.
The release is a boilerplate recounting of Bristol Myers Squibb’s sale of a series of working neurological disorder compounds to the-then embryonic Intra-Cellular Therapies for a $1 million payment and royalties.
While changing the gloss on Intra-Cellular’s own backstory, the sale itself was also a very curious transaction.
That’s because neurology disorders have long been an incredibly lucrative field for pharmaceutical companies, as a chart of Caplyta rival Seroquel’s revenues from that period demonstrates.
Add to that how even developing a working schizophrenia compound is no light task. Undoubtedly Bristol Myers Squibb’s scientists spent several years on the project, and at the cost of many millions of dollars.
Yet this publicly-traded company – with a multi-decade record of bare-knuckled business practices that have regularly caught the eye of a diverse set of regulators – readily surrendered the prospect of billions of dollars a year in sales revenue in order to sell the marketing rights to the product for a steep loss.
Large pharmaceutical companies are often accused of many things, but rejecting commercial opportunities is not one of them.
A more rational hypothesis is that Bristol Myers Squibb’s scientists, after analyzing lumateperone’s preclinical data, saw something that prompted them to abandon the project.
But what specifically troubled them remained unclear until nearly a dozen years later.
A Bristol Myers Squibb spokesperson did not reply to an email seeking comment.
What the FDA saw
On May 1, 2017, Intra-Cellular put out a press release that put Bristol Myers Squibb’s 2005 actions into context.
The crux of the press release reads: “The FDA has raised questions, however, relating to certain findings observed in nonclinical animal toxicology studies of lumateperone and has requested additional information to confirm that the nonclinical findings are not indicative of a safety risk associated with long term exposure in humans.”
To be sure, the press release’s subsequent paragraphs had Intra-Cellular denying in full throat that lumateperone posed any risk to humans.
Still, the plainest reading of the FDA’s request to Intra-Cellular for additional data is that the agency’s researchers saw a data signal that should not have been there.
(It’s worth noting that the FDA has been analyzing and reviewing antipsychotic drug clinical data since the 1950s. It is a safe assumption the agency is keenly aware of an atypical antipsychotic’s standard side effect profile.)
What the FDA observed in Caplyta’s clinical trials, as laid out deep in its label, was a very serious neurotoxicity signal. Specifically, that a percentage of dogs that were given the drug over nine months experienced brain cell death, or neuronal necrosis, as well as the beginning of brain tumors.
Before a drug is approved, the FDA’s Center for Drug Evaluation and Research performs what it calls, “a multi-discipline review.” The CDER review of Caplyta concluded the unidentified pigmented material in the brains of the subject dogs and rats was correlated to neuropathy.
Moreover, the CDER’s discussion of Caplyta’s clinical trial history shows the deep roots of FDA concern over the drug’s neurotoxicity signal. In fact, the FDA noted it came close to taking the unusual step of placing the clinical trials on hold.
But crucially for Intra-Cellular, the FDA concluded that the drug’s aniline compound — which triggered the troubling neural degeneration present in the laboratory animals — wasn’t readily observable in human subjects.
Oddly, despite the ongoing adverse event report volume linked to neuropathy, Caplyta’s two clinical trials recorded just one case of peripheral neuropathy.
Conscientious medical professionals looking to Caplyta’s label for guidance won’t be alerted in a material way to the risks of body temperature regulation. Buried within boilerplate atypical antipsychotic risks is a brief warning about body temperature dysregulation. The more frequently consulted list of leading adverse reactions in the clinical trials — for both schizophrenia and bipolar depression — has no mention of the issue.
Dr. David Healy, asked why a gulf exists between the clinical trial data, where there is no experience of neuropathy, and Caplyta’s users, who are registering an exceedingly clear signal, did not hesitate with an answer.
The fact that Caplyta’s clinical trials have no participant experiencing these symptoms suggested to Dr. Healy that the trial is flawed.
“There should not be an entire category of side-effect” that becomes visible to [medical professionals] after the drug is approved,” Dr. Healy said. “That is why we have clinical trials, to establish these things.”
Intra-Cellular was emailed this set of questions prior to the article being published. Should they respond, their answers will be featured prominently within the article.