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.

More than a year ago, hit by a surprise complete response letter from the FDA, Immunomedics bid its then-CEO, Michael Pehl, adieu and began a 15-month quest to resolve the manufacturing issues cited in the CRL and seek a new leader — all the while moving forward with a Phase III study on its lead drug for metastatic triple-negative breast cancer.

Today the biotech said their stars are finally aligning. Not only is Novartis Oncology vet Harout Semerjian coming on board as CEO to steer what they believe will be a smooth sail to a new PDUFA date in June, Immunomedics has also been informed that their late-stage trial can be stopped early due to “compelling evidence of efficacy.”

German drug discovery company Evotec — which has a thriving rolodex of biopharma partners such as Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, Pfizer, Sanofi, and Takeda — is now venturing into gene therapies.

The company swallowed Seattle-based Just Biotherapeutics, a company focused on reducing the cost of manufacturing protein therapies last year. It is now setting up a dedicated R&D site for gene therapies in Austria, in an effort to achieve a “modality-agnostic” repertoire — small molecules, biologics and now gene therapies.

Four months after an intercontinental merger, Menlo Therapeutics is counting yet another pair of trial failures — ones with significant consequences for the companies, their shareholders and the drug.

In two pivotal Phase III trials, Menlo’s lead drug serlopitant failed to treat pruritus associated with prurigo nodularis — basically itchiness from a particular skin disease that causes red lesions on a person’s arms or legs. Serlopitant has long been the company’s only drug and as recently as 2018, it looked promising enough to support a stock price of $37. In April of that year, a Phase II failure demolished the stock price overnight: $35 to $9. Other subsequent stumbles trickled the ticker down to just above $2.