Questionable Road to Approval
The FDA’s recent approval of Biogen’s drug, aducanumab, for Alzheimer’s disease finally brought hope for a memorable future. However, there are also quite a few critics due to the seemingly lack of data that the drug actually works. So what is the fine line between rejecting it due to not having enough data and giving it a chance to be used in more people? Whether it is due to safety, efficacy, or sample size, the reasons for not getting FDA’s approval can go on. Although the FDA has specific criteria that has to be met for drug approval, this line still seems unclear to most. Aducanumab’s approval brought out the question, “Are there any other questionable drugs that may not be approved by the FDA?” These three controversial drugs below are currently in, recently completed, or ready to start phase 3 clinical trials.
1. NurOwn – by BrainStorm Cell Therapeutics (NASDAQ:BCLI)
Amyotrophic lateral sclerosis, known as ALS, is a life-changing disease where the neurons (cells) in the brain and spinal cord degenerate and die. As a result, muscles lose control, involuntarily twitch, and progressively weaken. ALS patients may experience difficulty walking, speaking, swallowing, and even breathing. Therefore, the average survival rate of ALS from diagnosis is three to five years. The exact cause of ALS is unknown, which is why it is so hard to treat this disease. There is no treatment available that stops or reverses progression of ALS. However, four medications have been FDA approved to slow progression of ALS symptoms and prevent further complications.
Currently, there are over 160 pipeline ALS drugs in both non-clinical and clinical stages. A drug that stands out is NurOwn, which relies on the patient’s own cells for treatment. Cells are collected from the patient’s very own bone marrow and grown in the lab. They become cells that ultimately help the neurons grow and survive. Then, they are injected back into the patient’s spine.
In one of its phase 3 trials, patients with rapidly progressing ALS were studied. In this patient population, 34.7% of patients treated with NurOwn experienced slower disease progression, whereas 27.7% of the placebo group (without medications) experienced the same effect. Unfortunately, this difference was so trivial that the FDA dismissed the results as being most likely due to chance.
In another phase 3 trial, patients with earlier stage ALS were studied. The results were comparably much better in this patient population. The progression of ALS slowed down in 34.6% of patients treated with NurOwn, in contrast to the 15.6% of the placebo group. For ALS patients and their loved ones, this data could be very meaningful because any chance is worth taking if this worsening reality could be forestalled. However, many scientists take a dim view of the data because the results were not statistically significant. In addition, the mean change in ALSFRS-R (ALS Functional Rating Scale) score was also not statistically significant between the NurOwn group and the placebo group.
What does it mean when data is “not statistically significant”? It simply means that the data turned out the way it did due to chance or luck. Therefore, if the exact same study were to be replicated, the researchers would not get the same results. Statistical significance is a great way for people to measure whether the data is worth believing in.
The good news is that NurOwn significantly increased the neurotrophic factors that support the growth and survival of neurons. In addition, it decreased the ‘bad’ degenerative and inflammatory factors in the brain, so it will ultimately lead to a longer survival of neurons. These beneficial effects were not seen in the placebo group.
Not all hope is lost for BrainStorm Therapeutics as it is still looking for a path to get FDA’s approval. Although the data was statistically insignificant, the severity of ALS had an impact on the efficacy of NurOwn. Therefore, more work needs to be done in specifically defining its intended patient population. The increase in ‘good’ factors and decrease in ‘bad’ factors also prove that NurOwn may serve a therapeutic purpose. In addition, BrainStorm Therapeutics is also exploring other ways to utilize NurOwn, including as therapy for Parkinson’s disease, Huntington’s disease, and autism spectrum disorder.
2. Vadadustat – by Akebia Therapeutics (NASDAQ: AKBA)
More than 1 in 7 adults in the US have chronic kidney disease (CKD), where the kidneys cannot filter blood normally due to damage. A common complication of CKD is anemia, a condition where the lack of healthy red blood cells cannot deliver enough oxygen throughout the body. Side effects of anemia include feeling tired and weak. As CKD worsens, anemia also worsens. When severe, anemia can lead to heart problems because the heart has to work extra hard to pump red blood cells and oxygen throughout the body.
Vadadustat is one of the pipeline medications for treating anemia associated with CKD. It is in the HIF-PHI (hypoxia-inducible factor prolyl-hydroxylase inhibitor) class that works by stimulating erythropoietin formation. Erythropoietin is a hormone that increases production of red blood cells when there is a decreasing level of oxygen in tissues. After completing phase 3 trials, Akebia Therapeutics submitted a New Drug Application (NDA) to the FDA, which was accepted on June 1, 2021 for official review. However, vadadustat is quite controversial due to its questionable data.
One of the first-line medications for anemia due to CKD is currently darbepoetin alfa. It is an erythropoiesis-stimulating agent (ESA) that stimulates the production of red blood cells. In phase 3 trials, when compared with darbepoetin alfa, vadadustat was non-inferior in correcting and maintaining hemoglobin (protein that transports oxygen) concentrations. ‘Non-inferior’ means that vadadustat was ‘just as good as’ darbepoetin alfa.
However, vadadustat was associated with much higher heart complications compared to darbepoetin alfa, which already leads to some heart problems. There is also not enough data on efficacy because darbepoetin alfa was the only medication in the ESA class that vadadustat was compared to. Not all ESAs are the same, so more research needs to be done to compare the efficacy of vadadustat and other ESAs.
Although there are definitely gaps to fill in the data and study design, vadadustat does still have a chance of FDA approval because it is non-inferior to darbepoetin alfa. If approved, Akebia Therapeutics estimates a $2 billion opportunity for vadadustat in the market.
3. BXCL501 – BioXcel Therapeutics (NASDAQ: BTAI)
BXCL501 is a thin film version of dexmedetomidine that is dissolved under the tongue, which allows the drug to work quickly in the body. BXCL501 is versatile in that it is being investigated to treat agitation associated with a variety of diseases such as schizophrenia/bipolar disorders, dementia, and delirium. It is also being studied to treat opioid withdrawal symptoms.
Opioids are a class of drugs (e.g., morphine and oxycodone) used to treat pain. Due to its highly addictive nature, substance abuse is very common. When people stop taking opioids, they experience withdrawal symptoms. These symptoms may include anxiety, inability to sleep, and even seizures and hallucinations if severe. To combat these withdrawal symptoms, the patient may need additional drugs. This is when BXCL501 would come in.
Compared to placebo, BXCL501 successfully increased retention rates (the percentage of patients that remain in treatment for substance abuse). A higher retention rate means a lower chance of relapse. Although BXCL501 prevented patients from falling back into opioid abuse by treating withdrawal symptoms, these results were not statistically significant. The retention rates were 42% for 120 microgram group, 52% for the 180 microgram group, compared to the 24% for the placebo group. Because this improvement could have been from luck, it is questionable whether it is worth the wait for BXCL501 to complete phase 3 trials. Regardless, there is still hope for BXCL501 as it could be used for other indications besides opioid withdrawal symptoms.
These three medications are currently controversial in their data. But that does not mean that all the money, research, and hard work must go to waste. Whether it is by modifying the drug or discovering another condition that it can treat, there is still some potential for FDA approval in the future. However, the road to approval is quite questionable. Investing in any of these stocks would not be the best option for the faint of heart.