Will the FDA approve Vitaros? – A look into Apricus Biosciences’ (APRI) quest.

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BACKGROUND WISDOM

Apricus Biosciences’ (Ticker: APRI) Vitaros is set for potential approval by the FDA on February 17th, 2018.

Vitaros is the brand name for a cream that contains alprostadil. Alprostadil, the active ingredient, is a synthetic version of a naturally occurring biochemical called prostaglandin E1 (PGE1). It is designed to treat erectile dysfunction (impotence) in men 18 years of age and over. It works because PGE1/alprostadil helps engorge the penile tissues with blood; maintaining a firmer erection as a result.

Numerous different formulations of alprostadil have been in use for quite some time, including direct injections into the penis. Vitaros is an alternative delivery mechanism. It’s a cream that is delivered over the very tip of the penis.

One of Vitaros’ secondary ingredients is known as DDAIP (dodecyl-2-N,N-dimethylaminoproprionate). This is an excipient. An excipient is supposed to be an inert/inactive substance that serves to change certain qualities associated with a drug. In this case, it appears that DDAIP helps the body absorb alprostadil more effectively.

WHY DID THE FDA REJECT VITAROS?

In 2008, the FDA rejected Vitaros (then marketed as Alprox-TD by NexMed, APRI’s former name). As stated in a press-release at the time, the main concern in the FDA’s complete response letter (CRL) appeared to be the potentially carcinogenic (cancer-causing) effects of DDAIP observed in 2002.

The DDAIP in question is a major component of something Apricus Biosciences calls “NexAct”, which is still found in the current version of the Vitaros. NexAct appears to help the drug penetrate into the body better than it would on its own.

Despite the carcinogenic concerns raised by the FDA over DDAIP, Vitaros (or a similar drug of a different name) has gone on to be approved in many parts of the world; most notably in Canada and in some parts of Europe.

In Canada, it was approved in 2010, but not before it had received a NOD (Notice of Deficiency) and a NON (Notice of Non-compliance) during the evaluation process. Despite approval, Vitaros has encountered concerns about its shelf-life stability in Canada.

Vitaros was also approved in Europe/UK (2013), where it was temporarily withdrawn from the market due to a quality control issue in Germany. A recall was also issued in the UK due to a batch distribution mistake.

More notably and recently, Vitaros’ application for approval in Australia was voluntarily withdrawn due to numerous unaddressed concerns in 2016 just as, not surprisingly, the regulatory body there was recommending it be rejected anyways. This was partly as a result of the sponsor’s inability to adequately answer pertinent questions or provide adequate data to mollify their numerous concerns.

While Vitaros’ worldwide approval is a good sign, the FDA (contrary to some popular belief) is known to be generally more stringent in its approval process than most of the nations where Vitaros has been approved.

DOES VITAROS CAUSE CANCER IN PATIENTS?

3 killer T-cells (in green) surround a cancer cell (blue-center) and are about to kill it with various biochemicals (red).

3 killer T-cells (in green) surround a cancer cell (blue-center) and are about to kill it with various biochemicals (red).

The more important question is whether or not the FDA’s specific carcinogenic concerns about DDAIP have been addressed scientifically and adequately enough since the CRL.

Several animal studies have investigated the connection between DDAIP and cancer. None conclusively prove that DDAIP causes cancer in rodents, let alone people.

At worst, one study points to the potential that DDAIP leads to the formation of benign, wart-like, tumors called papillomas. This occurs in a very specific subset of genetically modified mice. In this specific case, such an animal model and the findings thereof are unlikely to correlate well with their relevance to humans for numerous reasons. For the sake of brevity, these reasons are not discussed herein.

The other studies, albeit not all are directly related to Vitaros’ exact formulation or method of use, have shown no such cancer-causing potential when used in non-genetically modified rodents.

This held true for comparable exposures to DDAIP over a much longer period of time than in the papilloma study. Furthermore, studies modeling human tissues have failed to reproduce the carcinogenic potential of DDAIP that was seen in the papilloma mice.

WHAT’S THE CONCLUSION ABOUT THE POTENTIAL FOR CANCER IN MEN?

As for the bad news: most of this animal-based evidence is old news and the FDA temporarily stopped a phase III clinical trial of the drug as a result of this same evidence (and issued the CRL).

The other partially bad news is that the Canadian and European approvals shouldn’t be seen as a major boon to the chances of FDA approval. This is because their respective regulatory bodies approved Vitaros in spite of the FDA’s concerns for carcinogenicity, not as a result of newer findings to the contrary.

There is a light at the end of the tunnel however. In the time after the Canadian/European approval, a small amount of additional data regarding this general point was released and none found any connection between Vitaros/DDAIP and cancer. Moreover, the FDA has already approved drugs containing compounds that are at least as “concerning” in their cancer-causing potential and mechanisms as Vitaros (albeit this was also true before the CRL as well).

All of this leads us to believe that if the sole criterion for the CRL was the potential for its carcinogenicity in the user/patient, then it’s quite likely Vitaros will be approved this time around given certain labeling and post-approval concessions on the part of APRI. The evidence for its carcinogenicity is simply too scant otherwise.

FURTHER CONCERNS

Unfortunately, the CRL contained other concerns. These included:

  1. Inadequate information regarding the amount of DDAIP transferred to a sexual partner and the potential risk of cancer to sexual partners as a result.
  2. The potential risk that DDAIP could, in addition to helping the body absorb alprostadil, also facilitate the transfer of sexually transmitted infections/diseases (STIs/STDs).
  3. The potential that the risks associated with the drug may not outweigh the benefits.

We address these in order.

CAN VOTAROS CAUSE CANCER IN PARTNERS?

Initial animal-based studies of the genetically modified mice showed that both male and female mice are susceptible to papillomas. So, in theory, both male and female sexual partners could be at risk of developing cancer upon exposure. At the same time, a study of Vitaros in rabbits failed to show signs of carcinogenicity when it was administered into the vagina.

Furthermore, a post-CRL study utilizing a primate-based model failed to find any cancer-related changes to the vaginal tissue of monkeys exposed to Vitaros. The study assumed a full dose of the medication would be transferred to the sexual partner, which is extremely unlikely in the real world.

In actuality, it’s estimated that less than 18% of the total amount of DDAIP found in Vitaros will transfer from a man to his partner (without a condom). This number drops to about 4% of total with the use of a condom.

Combined with the prior discussion on carcinogenicity, this leads us to believe that sexual partners are at a very small risk of developing cancer as a result of their partner’s use of Vitaros.

Studies conducted on this topic with respect to anal sex and oral sex are lacking; which is a concern raised by regulatory authorities.

Overall, we believe this concern has been adequately addressed especially if the sponsor commits to clear warnings on its labels and adequate post-approval strategies.

CAN DDAIP FACILITATE THE TRANSFER OF STIs/STDs?

It’s unlikely that DDAIP itself somehow directly facilitates the transfer of infectious organisms from one sexual partner to another. However, DDAIP is a potential irritant. Irritation leads to inflammation and this breaks down the protective outer layers of the reproductive tract. This, in turn, can allow for infectious organisms to make it into a person’s body more easily than before.

Data from studies unrelated to Vitaros suggest that it is very likely that local irritation/inflammation of the reproductive tract in general, regardless of cause, can facilitate the transmission of STDs/STIs. This is a concern, and there is no evidence to the contrary.

So this is indeed a major issue. This problem may be just as true, if not more valid, for oral and anal sex (again, for which studies are painfully lacking).

Unless Apricus pulls a scientific rabbit out of a hat that shows that none of this is pathophysiologically applicable to DDAIP, it may alternatively provide strong post-marketing data from other countries that indicate little such risk in real-world use. Or it may try to appease the FDA circuitously by offering clear warnings about this potentially major threat to consumers and the need to wear a condom.

Wearing a condom also reduces other potential concerns associated with the ingredients in Vitaros; such as the potential for toxicity to an embryo and causing a pregnant woman to go into premature labor.

DO THE BENEFITS OUTWEIGH THE RISKS?

The other major problem the FDA had with Vitaros was whether or not the gains Vitaros provides are worth the risks to the patient and sexual partners. This meant we had to examine all the pieces of available evidence regarding the efficacy and safety surrounding Vitaros.

After doing so, we concluded that the gains Vitaros provides with respect to patient-important sexual function is, at best, modest for the average patient (in line with the thoughts of European regulators).

That being said, Australian regulators came to a different conclusion not long ago in that the benefits do not outweigh the risks due to a long list of issues. These issues included qualitative and quantitative concerns with respect to the sponsor’s studies, drug efficacy, DDAIP-related risks, and general safety that the FDA had raised itself a decade ago.

It’s highly unlikely the FDA is unaware of the relatively recent concerns and conclusions raised by the Australian authorities. These are issues they’ll have to overcome in their resubmission of the NDA.

WILL THE FDA APPROVE VITAROS?

Consequently, it appears Apricus Biosciences only has a couple major outs here with respect to gaining FDA approval:

  1. Apricus has conducted higher quality and longer-term studies that addressed these numerous qualitative and quantitative concerns. In its re-submission presentation, Apricus hinted that it provided some studies that address these concerns.

But whether or not they will be of high enough quantitative and qualitative strength for the FDA and whether or not they address the FDA’s specific concerns directly (as opposed to tangentially) is our major worry based on the recent experiences of Australian authorities.

  1. If few or no such adequate studies were completed, Apricus may push for approval by voluntarily including more numerous and more explicit warnings about its numerous potential risks to male users and their partners in the product labeling; as well as clear commitments to post-approval strategies to address these issues. This strategy can potentially allay a wide swath (but not all) of the FDA’s concerns.

While this is the easiest route to take, the FDA may not be satisfied given the risk-benefit ratio the FDA was concerned about to begin with. There is, however, an out here as well.

Apricus “admits defeat” and, instead of trying to get Vitaros approved for all adult males with erectile dysfunction (ED), narrows its market to only men with severe ED or those who cannot tolerate sildenafil (Viagra). Barring newer evidence to the contrary, the latter have the best known risk-benefit profile for Vitaros compared to men with mild to moderate ED.

If Apricus is willing to limit its market indications to this specific subset of users, then it stands a far higher chance of gaining FDA approval assuming #1, #2, or both are also true. The downside of doing this is the cost of potentially significant losses of market share and revenue from men with mild to moderate erectile dysfunction who will be advised against using Vitaros as a result.

Read our article disclaimer.

Published: 2/5/2018

Updated on: 2/15/2018 – the article’s content was not altered; only the article disclaimer was modified on this date.

Author: Artem Cheprasov

No one associated with this article has any financial stake in, or ties to, APRI.

2018-10-03T11:32:55+00:00