By John Vandermosten, CFA
Lipocine (LPCN) distributed a press release yesterday announcing the completion of the Ambulatory Blood Pressure Monitoring (ABPM) clinical study and providing topline results. The study enrolled 144 male hypogonadal subjects that received four months of Tlando treatment of 225 mg, twice per day. Blood pressure measurements were taken at baseline and at end of study with 118 subjects providing evaluable ABPM data.
Results of the ABPM demonstrated a mean change of systolic blood pressure (SBP) of +3.82 mm Hg and diastolic blood pressure (DBP) of +1.20 mm Hg over the course of the study. When broken down by subjects with SBP above 140 mm Hg at baseline, 32% of the subjects were 140 mm Hg or below by the end of the study (n=25). Subjects with SBP of 140 or below at the beginning of the study, 9.7% of the subjects were above 140 mm Hg at the end of the study (n=93). Referencing back to the SOAR study, about 1% of subjects needed a change in their blood pressure medication after a year of Tlando treatment.
The FDA did not outline any predetermined thresholds that it wanted to see from the ABPM, but based on discussions held at the FDA’s February 4th pressor workshop, the important factors to consider are informing physicians and patients of the risk on increased blood pressure and adjusting medication to compensate for any changes in blood pressure. There is also an intensified focus on those with higher blood pressure, as a unit increase for those in the high category contributes more to negative cardiovascular events as the same unit increase for someone in the low category.
We note that in clinical trials Antares’ (ATRS) Xyosted observed a 4 mm HG increase in SBP after 12 weeks and one year of treatment in its study. Jatenzo saw a slightly larger increase of 4.9 mm Hg in SBP after four months in its ABPM study. Based on our interpretation of the FDA’s concerns, we believe that the agency is more concerned with an increase in blood pressure for higher baselines due to the correlation of higher blood pressure and negative cardiovascular events, which will be reflected in the label. Both Xyosted and Jatenzo have the same black box warnings and we expect Tlando will carry it as well.
View Exhibit I - Xyosted Black Box Warning
We see the results from the ABPM study as positive as they are lower than levels reported by Xyosted and Jatenzo, both of which were approved. We think that the FDA has a better understanding of the risk profile of testosterone replacement therapy and is open to approving Tlando based on the results of the numerous trials which have been conducted. Lipocine plans to resubmit its NDA in the second quarter of 2019, which suggests a PDUFA or target action date in the fourth quarter.
Tlando Recent History
After completing the Advisory Committee meeting in January 2018 and suffering the 6 to 13 unfavorable vote from its members, Tlando received a CRL from the FDA in May. The agency identified several deficiencies in its response and identified the following requirements:
‣ determine the extent, if any, of clinically meaningful ex vivo conversion of testosterone undecanoate (TU) to testosterone (T) in serum blood collection tubes to confirm the reliability of T data;
‣ obtain definitive evidence pre-approval via an ABPM study as to whether Tlando causes a clinically meaningful increase in blood pressure in hypogonadal men, which is a surrogate marker of predicting cardiovascular outcomes;
‣ verify the reliability of Cmax data and provide justification for non-applicability of the agreed-upon and pre-specified Cmax secondary endpoints for Tlando; and,
‣ determine the appropriate stopping criteria that can reproducibly and accurately identify those patients who should discontinue use of Tlando
The CRL identified additional comments that were not considered approvability issues and not discussed. Following a Post Action meeting with the FDA, two additional trials were designed: the definitive phlebotomy study and ABPM which were designed to determine any clinically meaningful conversion of TU to T and to identify whether or not a clinically meaningful increase in blood pressure was associated with Tlando.
Lipocine reported the successful completion of its phlebotomy study on the last day of 2018. It measured testosterone concentrations in blood samples in plain serum separation tubes at there and five hour intervals after collection. There were 24 observations from 12 patients who were dosed a single oral 225 mg dose of TLANDO. Concentration levels at the indicated intervals were compared to immediately processed concentrations to determine any observed variation. The mean percentage difference of testosterone concentrations was -1.0% with a standard deviation of 9.2%. The difference was not statistically significant, demonstrating that there was no significant ex vivo TU to T conversion over the time period observed. Recall that this concern was raised by the advisory committee as a result of Clarus’ use of special tubes for blood collection for its AdCom in January of 2018 rather than a specific concern over TU to T conversion for Lipocine’s data collection. We believe that the results of the study will put to rest this concern that was raised in last year’s AdCom.
The ABPM study was launched in June following the Post Action meeting and completed enrollment in November. Topline results were reported on March 27, 2019 and discussed above. The FDA has a broad concern over the risks of increasing blood pressure and has held public workshops on the topic1 for all medications, with particular focus on high risk categories.
FDA Approval of Jatenzo
On March 27, 2019, the FDA approved Jatenzo for testosterone replacement therapy in adult men. We see the approval as a significant positive for the likelihood of approval for Tlando. In their press release, Clarus expects Jatenzo to be available in the United States before year end.
The results reported by Lipocine for its two follow-up studies suggest that Tlando is within the parameters for approval. While the FDA has not identified what constraints it requires for approval, the 3.8 mm Hg increase in SBP was lower than that reported for Xyosted and Jatenzo, both of which were approved. The approvals of these two competitors suggests that the FDA has a better understanding of the risks and benefits of TRT and will be open to granting approval to Tlando. The timeline going forward suggests a 2Q:19 resubmission of the NDA and a target action date prior to year-end.
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1 On February 4, 2019, the FDA held a public workshop entitled, “Evaluating the Pressor Effects of Drugs & Ambulatory Blood Pressure Monitoring Studies”. The purpose of the workshop was to bring together the stakeholder community, including company sponsors, FDA, and key opinion leaders, to discuss the premarketing assessment of a drug’s effect on blood pressure. Topics discussed by the FDA included: study design considerations to definitively assess a drug’s effect on blood pressure and appropriate regulatory action; the need to raise physician and patient awareness via labeling or risk mitigation strategies based on blood pressure effects and associated increased cardiovascular risks; the assessment of clinical meaningfulness of blood pressure changes based on findings; appropriately identifying the population at risk; and, a drug’s benefit risk analyses.
By John Vandermosten, CFA