Lipocine’s lat­est at­tempt at se­cur­ing ap­proval for its oral testos­terone drug has fiz­zled yet again.

The Utah-based drug de­vel­op­er on Mon­day said the FDA has spurned its mar­ket­ing ap­pli­ca­tion, in­di­cat­ing that some ef­fi­ca­cy da­ta on the drug, Tlando, was not up to scratch to treat male hy­pog­o­nadism, a con­di­tion char­ac­ter­ized by low pro­duc­tion of the hor­mone testos­terone, which is re­spon­si­ble for main­tain­ing mus­cle bulk, bone growth, and sex­u­al func­tion.

Shares of the Salt Lake City com­pa­ny $LPCN cratered more than 69% to 84 cents in morn­ing trad­ing.

Testos­terone treat­ments such as skin patch­es, short-act­ing in­jec­tions, and top­i­cal gels are cur­rent­ly on the mar­ket. The space is well cov­ered by in­sur­ers and is grow­ing, gen­er­at­ing some 7.2 mil­lion pre­scrip­tions last year, ac­cord­ing to Cowen an­a­lysts. But their pop­u­lar­i­ty in the ag­ing male de­mo­graph­ic has be­come a prob­lem for some biotechs in the field, with reg­u­la­tors re­ject­ing a num­ber of ap­pli­ca­tions in re­cent years.

In­tra­mus­cu­lar in­jec­tions are of­ten the first-line testos­terone re­place­ment ther­a­py (TRT) modal­i­ty due to the fact that they have long been gener­ic, be­fore grad­u­at­ing to the brand­ed top­i­cal prod­ucts (or even the gener­ic top­i­cals, which car­ry on­ly mod­est dis­counts to brand­ed An­dro­Gel), the Cowen an­a­lysts wrote in April. “The top­i­cal prod­ucts such as Ab­b­Vie’s An­dro­Gel and Lil­ly’s Ax­iron ap­pear to be read­i­ly ac­cessed, de­spite their brand­ed/brand­ed gener­ic pric­ing.”

Tlando is de­signed to avert the is­sues that plague the ex­ist­ing top­i­cal and in­jectable prod­ucts. Lipocine’s big ri­val, Clarus Ther­a­peu­tics, in March, won FDA ap­proval for its oral prod­uct, Jaten­zo. Lipocine and Clarus have been locked in lit­i­ga­tion re­lat­ed to in­tel­lec­tu­al prop­er­ty as­so­ci­at­ed with their re­spec­tive ther­a­pies.

Months ago, Lipocine said a tri­al is set to be­gin in Au­gust 2020 as part of its patent in­fringe­ment law­suit against Clarus’s Jaten­zo, re­lat­ing to six of Lipocine’s U.S. patents.  In the mean­time, Lipocine plans to seek a per­ma­nent in­junc­tion for Clarus’s al­leged in­fringe­ment.

Lipocine has been scarred time and time again in its bat­tle to bring Tlando to mar­ket. The com­pa­ny re­ceived its first re­jec­tion from the FDA in 2016, about a year af­ter the agency tight­ened its scruti­ny of TRT prod­ucts in gen­er­al. The reg­u­la­tor in March 2015 asked man­u­fac­tur­ers to tweak their la­bels to re­flect that TRT prod­ucts are on­ly ap­proved for men with cer­tain med­ical con­di­tions, and not for ag­ing-re­lat­ed low testos­terone; and that da­ta sug­gest TRT use leads to an in­creased risk of heart at­tacks and strokes.

In 2016, the agency in­di­cat­ed it was not com­fort­able with the Tlando dos­ing al­go­rithm. “The pro­posed titra­tion scheme for clin­i­cal prac­tice was sig­nif­i­cant­ly dif­fer­ent from the titra­tion scheme used in the Phase 3 tri­al lead­ing to dis­cor­dance in titra­tion de­ci­sions be­tween the Phase 3 tri­al and re­al-world clin­i­cal prac­tice,” Lipocine cit­ed the FDA say­ing in a state­ment.

Lipocine re­sub­mit­ted a mar­ket­ing ap­pli­ca­tion in 2017. In an FDA staff re­view that fol­lowed in 2018, the agency said it had rec­om­mend­ed that the com­pa­ny con­duct a new Phase III tri­al that tests the dose titra­tion scheme pro­posed for mar­ket­ing. In­stead, Lipocine chose to con­duct two new sin­gle-arm late-stage tri­als, each test­ing a dif­fer­ent dose of Tlando (150 mg thrice-dai­ly and 225 mg twice-dai­ly) with­out titra­tion. The 150 mg tri­al failed, but the 225 mg dose made the cut.

FDA pan­elists al­so ex­pressed oth­er con­cerns, in­clud­ing that the orig­i­nal late-stage tri­al up­on which Lipocine had based its ap­pli­ca­tion on did not meet one or none of the three sec­ondary end­points that as­sess for un­ac­cept­ably high max­i­mal ex­po­sures to testos­terone; the drug’s im­pact on the pa­tient’s blood pres­sure and heart rate; and whether Tlando was def­i­nite­ly restor­ing testos­terone and its ma­jor metabo­lites in­to nor­mal range.

Days lat­er, an in­de­pen­dent pan­el of ad­vi­sors to the FDA al­so sug­gest­ed their dis­com­fort with the drug. Over­all, thir­teen pan­elists vot­ed against the ben­e­fit/risk pro­file of Tlando, while six vot­ed in fa­vor. Un­sur­pris­ing­ly, the FDA hand­ed Lipocine an­oth­er re­jec­tion.

So Lipocine con­duct­ed an­oth­er study, a small 24-pa­tient tri­al to de­fin­i­tive­ly show that the drug was de­fin­i­tive­ly restor­ing testos­terone lev­els, us­ing tri­al pro­to­col the FDA was look­ing for. But on Mon­day, the FDA’s CRL flagged a prob­lem the com­pa­ny had failed to deal with from the start: that the orig­i­nal ef­fi­ca­cy tri­al failed to show the drug clear­ing three sec­ondary end­points for max­i­mal testos­terone con­cen­tra­tions.

The com­pa­ny plans to meet with the agency to fig­ure out its next steps.

Four years ago, when Arena CEO Amit Munshi cut its ties to a troubled weight drug and doubled down on the pipeline, a cannabinoid receptor 2 agonist figured prominently in the biotech’s future. On Tuesday evening, however, Munshi’s high hopes for the drug took a nasty hit after it failed a Phase IIb study for patients with irritable bowel syndrome pain.

Put through a randomized pace with 273 patients, researchers said it flat failed the primary endpoint among the large group with abdominal pain. But they quickly went on to highlight subgroup data, always a tricky and controversial ploy, where they spotlighted a positive p value for patients with moderate to severe pain who received the high dose of the drug — one of 3 provided in the study.

As the superbug crisis heats up around the world, Scynexis says it has new data from two interim analyses that prove its antifungal has the potential to treat a broad range of infections.

“The need for new anti-infectives capable of fighting the most resistant pathogens has never been more urgent as we confront the ongoing COVID-19 global pandemic,” CEO Marco Taglietti said in a statement.

When Takeda spun out a pipeline of experimental psychiatry drugs to Neurocrine in a $2 billion deal amid a post-merger shakeout, R&D chief Andy Plump described the therapies as “very interesting but still difficult.”

On Tuesday, we got some idea of how difficult.

San Diego-based Neurocrine revealed that one of the three spotlight clinical programs they’d acquired failed the primary endpoint in a Phase II trial for schizophrenia, registering a negative outcome on the change from baseline in the positive and negative syndrome scale/negative symptom factor score (PANSS NSFS).

Merck took a big gamble when it opted to jump into the Covid-19 vaccine race late, and made an equally momentous decision to back out in late January. Now, looking to chip in on the effort, Merck reportedly agreed to team up with one of the companies that has already crossed the finish line.

President Joe Biden on Tuesday is expected to announce a partnership between drugmakers Merck and Johnson & Johnson to jointly produce J&J’s recombinant protein Covid-19 vaccine that received the FDA’s emergency use authorization Saturday, the Washington Post reported.

FibroGen will likely have to delay its US rollout for roxadustat once again.

In an unexpected move, the FDA is convening its Cardiovascular and Renal Drugs Advisory Committee to review the NDA in an advisory committee meeting. The date is yet to be confirmed.

Just a few weeks ago, SVB Leerink analyst Geoffrey Porges predicted that the roxa approval could come ahead of the PDUFA date on March 20 — effusive despite already being let down once by the FDA’s extension of its review back in December. AstraZeneca, which is partnered with FibroGen on the chronic kidney disease-related anemia drug, disclosed regulators had requested further clarifying analyses of clinical data.