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Vivek Ramasmawy

Vivek Ramaswamy and his Alzheimer’s Drug Company

Dementia drugs that failed to delight.

Vivek Bursts into the Biotech Scene

In 2015, serial entrepreneur Vivek Ramaswarmy burst into the biotech scene with Riovant, a holding company through which he launched 6 other subsidiary companies. Each of these subsidiaries were created to launch experimental drugs. How they would do that was to purchase drugs that had been shelved by bigger phama companies.

  • Riovant
  • Dermavant
  • Myovant
  • Enzyvant
  • Urovant
  • Axovant

Vivek Bets on Alzheimer's

Axovant was purchased for a mere $5M and subsequently floated on the New York Stock Exchange, raising $360 million in the process. That was a 72x, which was a killing even by biotech standards.

Axovant’s star drug was called Intepirdine. Intepirdine was shelved by GSK because it had failed four clinical trials.

However, Vivek Ramaswarmy asserted that Glaxo Smith Kline did not cover all possible grounds and took the other side of the bet.

What Does Intepirdine Do?

Intepirdine was meant to be a holistic take on treating Dementia or Alzheimer’s. It did not target the traditional pathways leading to amyloid-beta and tau accumulation. Rather, it targeted an impaired serotonergic neurotransmitter system.

Intepirdine is a 5-HT6 receptor antagonist – it blocks out the 5-HT6 receptor in the brain. By doing so, the intended outcome was increased acetylcholine in the brain.

Vivek’s Alzheimer drug was effective on reversing learning deficits in rats, and Vivek had hoped it would also be helpful in treating humans. Unfortunately, the human trials bombed.

Intepirdine Results?

The intended effect of Intepirdine was for Alzheimer’s patients to remember better and also carry out daily tasks with less difficulty.

According to the clinical results, the patients in the clinical trial didn’t fare well on either of the cognitive tests.

  • For the ADAS-Cog test, there was a mere benefit of 0.36 points but with a p-value of 0.22 – in such a trial, you need p-values to be less than 0.05 for the result to be statistically significant!
  • For the ADCS-ADL test, the benefit was a measly 0.09 points with a p-value of 0.83 – this was even worse!

Why Focus On Acetylcholine for Alzheimer's?

The cholinergic hypothesis of Alzheimer’s disease postulates that destruction of cholinergic neurons in the CNS leads to decreased acetylcholine and declining cognitive function.

As we age, there is a natural decline in the number of cholinergic neurons (neurons that use ACh as a neurotransmitter) in the brain.

Cholinergic neurons are widely distributed in brain regions that play a role in cognitive functions.

Normal cholinergic signaling that relates to learning and memory is dependent on acetylcholine.

To maintain a balance, the body increases acetylcholinesterase activity to break down acetylcholine more rapidly, ensuring that the remaining ACh is used efficiently.

Acetylcholinesterase Inhibitors Don't Seem To Work

Acetylcholinesterase inhibitors, also known as AChEIs, go by the names Donepezil, Galantamine and Rivastigmine. These three drugs are called 2nd-generation cholinesterase inhibitors (ChEIs).

They can improve Alzheimer’s symptoms by preventing synaptic acetylcholine breakdown in the brain.

However, second-generation ChEI benefits are limited.

This is largely because peripheral cholinergic stimulation induces several side effects. This limits the dosage that can be given to the patient.

5HT Serotonin Antagonist For Alzheimer's - How Does It Work?

Targeting the serotonin (5-hydroxytryptamine) subtype 6 (5-HT6) receptor, which is located primarily in brain regions critical to memory and learning, has garnered significant interest as a therapeutic mechanism in AD.

Inhibition of the 5-HT6 receptor has been shown to increase neuronal release of acetylcholine, as well as other neurotransmitters that are dysregulated in AD, leading to cognitive improvement in preclinical models. 

Because the 5-HT6 receptor is located almost exclusively in the central nervous system, 5-HT6 antagonism has the potential to increase central acetylcholine release, while minimising peripheral side effects.

This mechanism is distinct and complementary to that of the AChEIs, supporting adjunctive use to enhance therapeutic benefit.

Why Interpiridine Failed To Treat Alzheimer's

Intepirdine (also called RVT-101) is a potent 5-HT6 receptor antagonist.

Intepirdine failed to reduce the symptoms of Alzheimer’s in a large trial. Patients treated with 35 mg of Intepirdine a day did not show significant signs of improvement. 

Vivek Ramaswamy had a reason for why Intepirdine did not work.

He argued that intepirdine would only work well when combined with an second generation ChEI like Aricept (brand name for Donezepil).

  • Aricept prevents the breakdown of a neurotransmitter critical for thinking called acetylcholine.
  • Intepirdine was aimed at making more acetylcholine by stimulating a cell receptor called 5HT6.

The last of these studies, Ramaswamy believed, actually showed a benefit. The study had missed statistical significance on one of its main endpoints. But on other measures of memory – the ones normally used in clinical trials – it seemed effective.

Vivek Leaves the Biotech Scene

Subsequently, after the terrible results from Intepirine’s clinical trials in 2017, Vivek handed the reins over to David Hung, the new CEO of Axovant. David Hung was a bigshot in the biotech world, having successfully built up a cancer biotech Medivation, which was later bought out for $14 billion by Pfizer.

Unfortunately, David Hung left Axovant in early 2018, only one year in taking over Axovant, with Pavan Cheruvu taking over as CEO.

Are These Drugs Worth the Effort? What Is The Moral Of This Story?

Dementia (including Alzheimer’s) is the looming health epidemic that is about to strike globally.

With an aging population worldwide, the tsunami that is Alzheimer’s will not impact only the person suffering from it; it will also place an enormous burden on caregivers and the healthcare system.

The story of Vivek Ramaswarmy’s Axovant tells us how difficult the journey has been for drug discovery for Alzheimer’s Disease.

All this while, these pharma companies have been creating drugs based on the cholinergic hypothesis of Alzheimer’s Disease.

The two approaches that have stood out are

  1. Acetylcholinesterase Inhibitors like Donezepil
  2. 5HT Serotonin Antagonists like Intepirdine

As standalone treatments, These two approaches do not seem to result in meaning benefit to Alzheimer’s sufferers.

Are we going down the right research path, or is the cholinergic hypothesis a dead end in Alzheimer drug discovery?