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RU58841/PSK3841/HMR3841
RU58841 - part of 2 patents
Date of Patent : May 1997
Inventors: Martine Gaillard-Kelly, Francois Goubet, Daniel Philibert, Jean-Georges Teutsch.
Assignee: Roussel Uclaf /FRANCE
NAME OF THE PATENT**:** PHENYLIMIDAZOLIDINES HAVING ANTIANDROGENIC ACTIVITY
One of the most notable and controversial issues faced by Roussel Uclaf was RU486 (mifepristone), an abortion pill, the drug faced significant opposition from various groups, including political, religious, and social organizations. In some countries, the drug faced legal barriers and delays in approval, affecting Roussel Uclaf’s ability to market and distribute the medication effectively.
These legal issues contributed to the financial and reputational strains, leading to the eventual disappearance of the brand as an independent entity.
- Acquisition and Integration
Roussel Uclaf was acquired by Hoechst AG, Hoechst later merged with RhĂ´ne-Poulenc to form Aventis.
After the acquisition and integration, Aventis received 245 patents for anti-androgenic imidazolidines, RU58841 included.
Aventis(the world’s fifth-largest pharmaceuticals company by total sales at the time) didn’t make use of this patented compounds until the spin-off.
- The spin-off
- This osteoporosis research unit will later become ProSkelia, Aventis will hold a 42% stake in the new company and will become an important factor in the development of RU58841.
- Nick Lowcock, managing director of Warburg Pincus’ London office, says that the spinoff consumed 15 months and was a “long and complicated process. You have to trust the other side and have the same goals for it to work.”-the other side being Aventis
- Warburg(holding 58% stake) was particularly attracted to ProSkelia because the spinout already had three products in clinical development. It might take a startup six years to reach such a milestone. “For most drug development companies, it is a 10 to 15 year process, with a high risk of failure at any point,”
- For Warburg, the most intriguing aspect of ProSkelia was that it essentially represents a small segment of Aventis rebranded as an independent company, and this segment appears to be golden.
- ProSkelia assumed all bone R&D activities of Aventis, plus intellectual property and an 80-person staff. ProSkelia specializes in bone biology and is making strides in a $5 billion osteoporosis drug market that is growing 16% annually and is expected to rise as the population ages. Lowcock said “28 million Americans either have osteoporosis or are at risk. A 50-year old woman, he adds, would have more than a 40% chance of incurring an osteoporosis fracture in her lifetime. Although not as widely reported, men are also at risk.”
- The patents on the anti-androgen have been assigned to Proskelia by Aventis. The US patents expire on 2 May 2012 and 6 May 2014, while the patents in the EU expire on 8 January 2012 and in Japan on 28 May 2013.
- In 2002, Proskelia raised € 60 million, the largest European venture capital funding in that year, experts suggesting that these funds will sustain the company through to approximately 2005 or 2006.
In a French publication, when asked about the company’s mission and objectives, the director of Proskelia declared:
- "Proskelia’s strategy is to develop products in the field of bone - in particular, but not only, in osteoporosis - until the proof of concept in humans, i.e. phase IIa clinical trials. The next step will be to find an industrial partner to take the product to the market. However, the company reserves the right to go beyond phase IIa on its own, “for niche products,” says Roland Baron
However, this strategy was set to change as Aventis had different plans for Proskelia.
- THE DEVELOPMENT OF RU58841
In July 2002, the company announced that it had three molecules currently in development.
PSK 3841(RU58841) was announced to be in the Phase I/IIa clinical trial stage, with the market potential for this product estimated to exceed $300 million per year. This revenue was not solely from alopecia but also included earnings from treating acne. The company anticipated the launch date to be in 2006.
Before entering clinical trials, the R&D department declared that their new compound demonstrated promising pre-clinical results and showed potential for treating the targeted condition effectively. They highlighted key attributes such as its mechanism of action, efficacy in pre-clinical models, and favorable safety profile, which supported the decision to advance to clinical trials.
Remember that pre-clinical pharmacology studies are not conducted on humans, the findings may not fully translate across species.
Aventis expressed interest in two drugs that were in development at Proskelia
- SERM PSK 3471
- PSK 3841 [RU58841]
1.This SERM is the same compound featured in other documents outlining drugs at various stages of development, Proskelia renamed SERM 4371 to SERM PSK 3471.
It seemed that the Phase I trial yielded promising results, prompting Aventis to take action. By securing the right of first refusal, Aventis ensured they had the exclusive opportunity to acquire SERM PSK 3471 before it was offered to other companies. Aventis gained the advantage of negotiating licensing terms based on the outcomes of the ongoing trial (Phase IIa), if the drug continued to show positive results, they would have the first opportunity to secure it, potentially leading to significant returns on their investment.
Unfortunately for Aventis, the Phase IIa trials for SERM PSK 3471 did not succeed. During this stage, significant safety concerns emerged regarding the endometrium, which is crucial for menstruation and pregnancy. These issues were serious enough to halt further development of the compound for treating osteoporosis in women who had not undergone a hysterectomy (removal of the uterus).
2.PSK 3841 [RU58841] first clinical trial
Before we dive into what happened, let’s break down how a Phase I clinical trial works.
Phase I typically involves the following practices:
- Single and multiple dose studies
- Single Dose: Initially, a single dose of the drug is administered to participants to observe its effects and identify any immediate adverse reactions. This helps establish the safety profile and identify any potential side effects.
- Multiple Dose: Once single-dose studies are completed, participants receive multiple doses over a period to assess the drug’s safety, tolerability, and pharmacokinetics (how the drug is absorbed, distributed, metabolized, and excreted). This phase helps determine how the drug behaves in the body over time and at different doses.
- Progressive dosing
- In Phase I studies, the dose of the drug is gradually increased in a controlled manner. This dose escalation helps identify the maximum tolerated dose or the highest dose that does not cause unacceptable side effects.
- Participants are closely monitored at each dose level for adverse effects, and the data collected guides the next dose level adjustments.
- Pharmacokinetics and pharmacodynamics
- Pharmacokinetics: The study investigates how the drug is absorbed, distributed, metabolized, and excreted by the body. This involves measuring drug levels in blood at various times after administration.
- Pharmacodynamics: This involves assessing how the drug affects the body, including its mechanism of action and any biological effects.
- Safety assessments:
- Events: Researchers track and document any adverse effects or side effects experienced by participants. This helps in evaluating the drug’s safety profile.
- Vital signs and laboratory tests: Participants undergo regular monitoring of vital signs (e.g. heart rate, blood pressure) and laboratory tests (blood tests) to detect any potential issues.
- Early signs of efficacy:
- Although Phase I primarily focuses on safety, any early signs of efficacy observed (such as changes in biomarkers or symptoms) are noted.
PHASE I
- “A double blind, randomized, vehicle-controlled, safety and tolerance study of topical PSK 3841 solution at 5% administered twice daily over four weeks to healthy Caucasian males with androgenetic alopecia”
The study involved 60 participants.
Study hypothesis
- To assess the systemic and local safety and tolerance of 5% PSK 3841 solution versus vehicle (70% ethanol) when administered topically twice-a-day over 4 weeks on the scalp of Caucasian males with androgenic alopecia.
Safety and tolerability based on pharmacodynamic endocrine profile (gonadotropins, steroids) on day 1, 15 and 28 of treatment.
Additionally, the study aimed to characterize the pharmacokinetics of PSK 3841 and its metabolites. (Pharmacokinetics involves studying how the drug is absorbed, distributed, metabolized, and excreted in the body, helping to understand its overall behavior and effectiveness)
Aventis had been keeping a close eye on this drug, monitoring its progress carefully,
Aventis carefully reviewed the report and made a strategic decision -Right of First Negotiation Agreement-
The right of first negotiation agreement held specific implications for both Proskelia and Aventis:
For Proskelia:
- It meant that if Proskelia decided to move forward with licensing or selling the drug, they were obligated to negotiate with Aventis first. This provided Proskelia with a serious potential partner early in the drug development process.
- The agreement assured Proskelia that Aventis, a major player in the pharmaceutical industry, had a vested interest in their drug, potentially leading to a lucrative deal if the negotiations succeeded.
For Aventis:
Aventis gained the advantage of being the first and only company to negotiate a deal for the drug before Proskelia could consider other potential buyers or partners.
CONFLICT OF INTEREST CONCERNS
When a company like Aventis holds a significant ownership stake in another company, such as the 42% stake in Proskelia, concerns about a conflict of interest can arise. The worry is that Aventis might influence Proskelia’s decisions or the outcomes of drug trials in ways that benefit Aventis, potentially compromising the integrity of the research.
Why it didn’t matter in the drug trials:
Regulatory Oversight:
- Drug trials are subject to rigorous oversight by regulatory bodies such as EMA (in Europe). These agencies ensure that trials are conducted according to strict ethical and scientific standards, regardless of any ownership interests. This oversight helps prevent any potential bias from affecting the trial outcomes.
Independent Data Monitoring Committees:
- Many clinical trials involve independent data monitoring committees (DMCs) that review the data and progress of the trial. These committees are composed of experts who are not affiliated with the companies involved in the trial, ensuring impartial assessment of the trial’s safety and effectiveness. This independence helps mitigate any influence Aventis might have due to its ownership stake.
Market and Legal Consequences:
- Any perceived or actual manipulation of trial results due to a conflict of interest could have severe consequences for both companies. This includes damage to their reputation, loss of trust from investors, potential legal action, and rejection by regulatory bodies. The high stakes involved act as a strong disincentive against unethical behavior.
The final clinical study report appeared to declare PSK 3841 safe. By confirming its safety, all the points discussed earlier (in the section where we covered how a Phase I trial is conducted) were validated. This means the drug successfully passed the safety and tolerability assessments, showed consistent pharmacokinetic and pharmacodynamic profiles, and demonstrated no significant adverse effects at the tested doses. With these criteria met, the drug was considered ready to move forward to the next phase of development.
PHASE IIa
When researchers begin a Phase II clinical trial, they rely heavily on the data gathered from the Phase I trial. This data provides a critical foundation for conducting Phase II. Here’s what they use:
Safety and Tolerability Data:
- Adverse Effects: Researchers review the types, frequencies, and severities of any adverse effects observed in Phase I to determine safe dosage levels for Phase II.
- Maximum Tolerated Dose: The highest dose that was well-tolerated in Phase I without causing severe side effects is used to guide dosing in Phase II.
- Half-Life and Steady-State Concentration: Steady-state and half-life are critical for planning dosing frequency in Phase II.
Dosing Information:
- Dose-Response Relationship: Data on how different doses affected participants in Phase I helps in selecting the most effective and safest doses to test in Phase II.
- Dose Escalation: The patterns of dose escalation in Phase I help in refining the dosing strategy for Phase II, ensuring that the doses used are both safe and potentially effective.
“A multi-center, double-blind, randomized, vehicle-controlled study for a quantitative estimation of hair re-growth in male subjects with androgenic alopecia treated over 6 month with two ethanolic PSK 3841 solutions (2.5% and 5%)”
The study involved 120 participants.
Study hypothesis
- Once-daily treatment with PSK 3841 solution at 5% was to result in a significant increase in hair growth, when compared to daily treatment with vehicle
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- There should be a difference between the two active treatments (2.5% and 5% once-a-day)
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- Treatments should be safe and well tolerated in men with male pattern baldness
The data guiding Phase II reflects the findings of Phase I.
By analyzing the information gathered for Phase II, we can already infer what occurred in Phase I such as the identification of safe and effective dosing ranges, the intervals at which the drug should be administered, and the highest dose that participants could tolerate without significant adverse effects.
In Phase I, researchers experimented with administering a 5% dose twice daily. However, Phase II data reveal that the maximum safe dose was adjusted to 5% once daily. This indicates that the twice-daily dosing did not meet the required safety profile and was deemed unsuitable for patient health.
At this point, the situation regarding the drug begins to become ambiguous.
According to a press release, the Phase IIa study was scheduled to conclude in June 2003.
In 2003, Philippe Ballero, a media representative for Proskelia, announced that PSK 3841 was progressing through Phase IIA and was expected to advance to Phase IIB before the end of the year. The company projected that registration, and launch would occur in 2007.
By the time Phase IIa concluded, the deal with Aventis -expiring in February 2004-was still active.
Proskelia declared the Phase II trial of PSK 3841 a success.
"It has demonstrated similar efficacy after 6 months treatment as that observed with current oral therapy for alopecia after twelve months, based on the increase in net hair count. Again, no systemic anti-androgenic effect was observed (n=90).
This product is available for licensing."
Although Aventis did not report Phase II as a failure, the deal was not finalized.
Reasons Why PSK 3841 Was Unsatisfactory for Aventis and how the challenging financial situation at Proskelia prevented the drug from reaching the market
- After completing the clinical trials, acne was removed from the treatment scope. Proskelia had previously estimated the global market for the drug, combining both alopecia and acne treatments, to be around $300 million per year. The exclusion of acne from the drug’s therapeutic scope significantly diminished its market potential, leading to a sharp decline in its projected value.
- When Aventis secured the right of first negotiation, they were already well aware of Proskelia’s precarious financial situation, given that they held a 42% stake in the company.
- If Aventis had exercised its right of first negotiation and taken the license, they would have been responsible for further developing, conducting any necessary additional clinical trials, obtaining regulatory approval, and eventually marketing and selling the drug. This would have made Proskelia’s financial situation irrelevant to the drug’s future, as Aventis had the resources to carry it forward independently.
- At the time, Aventis was the fifth-largest pharmaceutical company in the world, with the financial resources and manufacturing capabilities to fully develop and bring the drug to market. In 2003, Aventis reported net sales of approximately €16.8 billion. After the sharp decline in projected sales when acne was removed from the drug’s indications, it appears that for a major pharmaceutical company like Aventis, the drug was no longer worth the investment of time and resources.
The challenging financial situation at Proskelia
Since Aventis decided not to take the drug to market, Proskelia would need to either manage the development independently or continue searching for another partner.
Unfortunately, the post has become quite lengthy, so I will briefly summarize why the drug stagnated after the end of Phase IIa:
The drug development stalled because Proskelia lacked both the financial resources and the development capabilities to advance the drug further.
Detailed financial figures for Proskelia are not necessary here, as the crucial factor is that the time between the conclusion of the drug trials and Proskelia’s merger with another company, which subsequently had the means to advance drugs through Phase III and bring them to market, was very short.
The integration of Proskelia into Strakan, resulting in the formation of ProStrakan
The proposed merger between Strakan and Proskelia was announced on June 8, 2004, approximately one year after the completion of the Phase II clinical trials for RU58841
The newly formed company, ProStrakan, engaged a consulting firm called Bridgehead to review their drug candidates and assess the financial risks associated with each. However, RU58841 was not included in the list of evaluated candidates.
By this time, ProStrakan had the capability to pursue Phase III trials, but primarily within Europe rather than on a global scale. Evidence shows that around that time, all their products that advanced to Phase III were registered and launched exclusively in Europe.
ProStrakan continued to seek opportunities to out-license RU58841, but its limited market potential and the need for global distribution to be profitable made it an unattractive option for potential partners. With the patent set to expire in 2012, and considering the lengthy process required for trials, regulatory approval, and market launch, the opportunity to profit from the drug became increasingly narrow.
While it seems that RU58841’s failure to reach the market was primarily due to its marketability issues, it is also crucial to note that, without approval, there is no long-term safety data available.
Fighting hair loss is a long-term commitment, and without evidence demonstrating the drug’s safety over several years or detailed data on its behavior in the body, RU58841 is not a viable option for extended use.
Additionally, the drug’s acquisition method presents its own risks. Since RU58841 was not commercialized, detailed information on its formulation and delivery methods is limited. This lack of standardization raises concerns about the reproducibility of clinical results and the potential for variability in the drug’s safety.
- A less discussed aspect of RU58841 is its potential allosteric effects
An AR antagonist blocks the androgen receptor by fitting into its binding site without activating it, preventing androgens like DHT from producing their effects.
In addition to blocking the primary binding site, some AR antagonists can also influence the receptor’s function through allosteric effects.
When an allosteric AR binds to a different site on the receptor (the allosteric site), it can alter the activity of the receptor, enhancing the overall efficacy of the antagonist or changing the receptor’s response.
If the drug goes systemically, the allosteric effects become important. When an allosteric modulator binds to the receptor, it can alter the receptor’s overall function and how it interacts with other molecules.
This means that the drug’s effects might not be restricted to just blocking androgen activity. The changes in receptor behavior could lead to side effects or impacts on other physiological processes.