Last week, I wrote an article detailing Titan Pharmaceuticals' (OTC:TTNP) history and made an argument that the company's current market cap of $125 million presents an enticing investment opportunity. Today I would like to make the argument for Probuphine's future success. It is important to note that Probuphine is not intended to be a miracle cure for those battling their addiction, but it is an effective treatment that provides numerous advantages over Suboxone, the current standard of care in addiction treatment. While some may view the clinical data from Probuphine's Phase III trials as disappointing, when compared to the real world efficacy of Suboxone, it is important to analyze Probuphine's clinical trial data in comparison to the clinical trial data used to support the FDA approval of Suboxone. Through a true apples to apples comparison, it is easy to see that Probuphine has the potential to become a revolutionary treatment for those suffering from opiate addiction. In order to assess the true potential of Probuphine, we must first compare the clinical results of Probuphine to those of Suboxone.
Probuphine completed an initial Phase III trial (Pro 805) that demonstrated that Probuphine is statistically superior to placebo as a maintenance treatment for opiate addiction. During the first Phase III trial, Probuphine was compared to placebo to determine if Probuphine is an effective treatment for opiate addiction. To determine this, both Probuphine and placebo patients were required to submit to thrice weekly drug tests to determine if they had used illegal opiates during the specified time frame. Of the 72 tests taken, the Probuphine group had a mean 36.6% of negative urine samples. Furthermore, the results show that 71 out of 108 patients (65.7%) on Probuphine completed the trial. Of those patients, 62 were allowed to participate in an additional six months of treatment. Of those patients, 46 (74%) completed the trial.
Titan then ran another Phase III trial (Pro 806) for Probuphine in which the drug was tested to determine statistical superiority over placebo and non-inferiority to Suboxone. During the study, Probuphine demonstrated statistical and clinical superiority over placebo during the 24-week treatment with 36% of urine tests coming back negative for opiates. Compared to the 35% of negative urine samples for Suboxone, Probuphine was found to be non-inferior to Suboxone. Similar to the first trial, 73 of the 114 (64%) patients treated with Probuphine completed the entire 6 months of treatment. It is important to note that this retention rate was identical to the retention rate in the Suboxone arm. Like the first trial, patients had the option of completing an additional 6 months of treatment. A total of 81 patients elected to undergo the additional treatment. Of those who elected to undergo the additional treatment, 67 (79%) completed the trial.
Below is a chart showing the percentage of patients treated with Probuphine who had negative urine samples for specified lengths of time:
While these results leave one wondering if Probuphine is an appropriate treatment for opiate abuse, it is important to compare Probuphine to the current standard of care, Suboxone, to determine if the results presented for Probuphine are as poor as some would lead you to believe. Below is an analysis of the data submitted by Reckitt Benckiser (RB) to support the New Drug Application (NDA) for Suboxone.
To support the Suboxone NDA, RB submitted data from 2 Phase III trials demonstrating the statistical superiority of Suboxone over placebo.
The first study was a 4-week trial that tested Suboxone against both placebo and Subutex, which lacks the abuse deterrent Naloxone. The study found that the Suboxone group presented negative urine samples 17.8% of the time:
Each patient was tested a total of 12 times over a 4-week period. Below is the breakdown of the percentage of patients who tested negative for opiates over the twelve test period:
As you can see, 48% of patients in the Suboxone group, indicated here as "combination," failed to submit at least one urine sample that was negative for illegal opiates.
A second Suboxone study tested various doses (8,12,and 16mg) of Suboxone against a standard 1mg dosage over a sixteen week period. The study found that the highest dosage of Suboxone tested, 16mg, had a patient group who submitted negative urine samples 32.6% of the time. Furthermore, the study demonstrated that the 16mg patient group had a retention rate of 60.8%. The results of the study are presented below:
Probuphine vs. Suboxone
Based on these results, one could easily argue that neither treatment is suitable for treating those who are addicted to opiates. However, it is important to put the results from both drugs into perspective. During the clinical testing, if a patient dropped out of the trial or was deemed a clinical failure, the remaining drug tests that would have been submitted by those patients were automatically treated as being positive. Considering the fact that most of the trials saw an average retention rate of 60%, it is easy to see why the drop outs in each study could skew the negative urine sample data in a meaningful way.
For Suboxone, there are results that show that these disappointing numbers do not hold up in real world treatment, but that is not the case for Probuphine. In Probuphine's case, the drug is being compared to the standard of care as it operates in the real world. While this comparison is inevitable, it does not demonstrate the true clinical comparability of the two drugs. When compared side by side, in a similar setting, it is easy to see that Suboxone has produced negative urine samples in patients 18-35% of the time. In comparison, Probuphine has produced negative urine samples 36-37% of the time. Are these results spectacular? Of course they aren't, but they also aren't a true reflection of how the drugs have or will perform in a real world setting. Given the fact that Suboxone and Probuphine have a comparable clinical profile, it can easily be argued that Probuphine will experience the same success that Suboxone experiences in real world treatment. Probuphine offers a patient the ability to ensure that they receive continuous, around the clock, treatment for their addiction. As the clinical results highlighted, there is a large number of patients who battle their addiction on a daily basis. For these patients, there is a real fear that one slip up could undo the progress that has been made in treating the addiction. This is a fear that patients on Probuphine simply do not have to worry about. Combine that with the fact that Probuphine is an abuse proof treatment that exposes a patient and their families to significantly less sublingual Suboxone, and it is easy to see why the clinical data of Probuphine, when combined with the other treatment benefits of the drug, has the potential to gain a significant share of the $1.5 billion addiction market.
Based on the clinical information provided for both Probuphine and Suboxone, it is easy to see that Probuphine is a treatment that offers a similar efficacy profile to the current standard of care. While some may wish that the clinical trials for Probuphine provided better results, it is a fact that those results show that Probuphine is a safe and effective treatment for opiate addiction. Furthermore, Probuphine offers a treatment option that is significantly safer for both patients and their families due to the reduction of sublingual Suboxone associated with the treatment. While a small amount of sublingual Suboxone may be needed for some patients, it is a far less amount than the pills needed if a patient is on a sublingual treatment alone. Though some may point to the need of sublingual Suboxone as a failure of Probuphine, I believe that it is important to look at it from another perspective. One of the other concerns raised in regard to Probuphine treatment is that a patient will not have the motivation needed to continue to make the monthly doctor visits necessary to track the patient's progress. However, if a patient is allotted 5-10 pills per month of rescue Suboxone during the initial stages of treatment, the doctor would have the carrot needed to ensure that a patient continues to attend regularly scheduled office visits. From the perspective of a patient, the use of a small amount of sublingual Suboxone allows a patient to "control" an aspect of their treatment. It has often been argued that patients new to addiction treatment have a psychological need for control over their treatment. The use of a small amount of sublingual Suboxone gives a patient the ability to control a portion of their treatment that can slowly be reduced over time. As the patient progresses in their treatment, the need for sublingual Suboxone reduces dramatically, as demonstrated by the fact that only a small percentage of Probuphine patients required sublingual Suboxone during their second six months of treatment. This transition from the oral form of the drug, to a treatment comprised of Probuphine alone, benefits both the doctor, who has an assurance that the patient will maintain monthly visits, and the patient, who will retain a small, but important, amount of physical control over their treatment.
Another issue raised is that patients may not have the money needed to pay for Probuphine's treatment regime. It is important to note that 80% of patients receive insurance coverage for their treatment. However, even if that were not the case, an addiction patient would most likely have the financial means necessary to pay for the treatment out of their own pocket. Presented below is data from the Suboxone NDA that shows that the average patient spent between $90-100 a day on their addiction:
While this is a small and outdated sample size, it is in line with national statistics that show that the average opiate user spends $150 a day on their drug habit. If an addict can afford to pay $90-150 a day on their addiction, it would be hard to argue that they couldn't afford the $150-300 bill associated with a monthly office visit. While it may be difficult, the patient population has demonstrated that they have the disposable income needed to afford the treatment.
Based on the clinical data presented, it is easy to argue that the concerns over Probuphine's efficacy are significantly overblown. Had Probuphine's development taken place during the same period as Suboxone's, this most likely would not even be a concern. The problem is that Probuphine is compared to the real world use of Suboxone. Based on that comparison, it is not hard to see how the clinical results for Probuphine are considered by some to be disappointing. However, it is important to note that is not an apples to apples comparison. If Titan's commercialization partner, Braeburn Pharmaceuticals, is able to effectively demonstrate this fact to treatment providers, it isn't hard to envision the $300-500 million in peak sales that are estimated for Probuphine. Assuming Probuphine can live up to its potential, it is still easy to argue that Titan Pharmaceuticals presents an enticing investment opportunity.