Man­u­fac­tur­ing is­sues hob­ble Heron's quest to mar­ket its long-act­ing non-opi­oid painkiller

The C-suite at Paci­ra like­ly sighed in re­lief on Wednes­day, as their main ri­val, Heron Ther­a­peu­tics, was hand­ed an un­ex­pect­ed FDA re­jec­tion — re­lat­ed to man­u­fac­tur­ing con­cerns — for a com­pet­ing long-act­ing non-opi­oid painkiller for post-sur­gi­cal anal­ge­sia.

The health reg­u­la­tor has asked for ad­di­tion­al in­for­ma­tion re­lat­ed to Heron’s chem­istry, man­u­fac­tur­ing and con­trols and oth­er non-clin­i­cal da­ta — and has not iden­ti­fied any safe­ty or ef­fi­ca­cy is­sues, nor asked for ex­tra clin­i­cal stud­ies and da­ta analy­ses for the drug, HTX-011, Heron said.

Paci­ra in­vestors cheered the an­nounce­ment, lift­ing the com­pa­ny’s stock $PCRX more than 16% to $46.25 be­fore the bell. Mean­while, Heron shares $HRTX tum­bled more than 26% to $16.01 pre­mar­ket.

Heron plans to li­aise with the FDA to re­solve their con­cerns, and re­sub­mit its mar­ket­ing ap­pli­ca­tion as soon as pos­si­ble, chief Bar­ry Quart said in a state­ment.

The man­u­fac­tur­ing is­sues are like­ly solv­able, Cowen an­a­lysts wrote in a note, pre­dict­ing a new FDA de­ci­sion date in first half of next year.

As the US health reg­u­la­tor per­sists in its ef­fort to stem the tide of opi­oid abuse, over­dose and ad­dic­tion while the phar­ma­ceu­ti­cal ar­chi­tects of the pre­scrip­tion painkiller cri­sis face fierce scruti­ny, Heron Ther­a­peu­tics had de­signed the drug to take a bite out of the mar­ket that en­com­pass­es mil­lions of post­op­er­a­tive pa­tients who are can­di­dates for opi­oids. HTX-011 has shown in stud­ies to sub­due the need for opi­ates.

Heron is ini­tial­ly tar­get­ing rough­ly 13.5 mil­lion pa­tients who have un­der­gone the most painful pro­ce­dures (typ­i­cal­ly gen­er­al surgery, OB/GYN and plas­tic surgery). Many of these pa­tients are first giv­en a lo­cal anes­thet­ic like bupi­va­caine to dull the pain, but the ef­fects on­ly last about six hours or so, there­fore doc­tors tend to pre­scribe opi­oids to man­age se­vere pain that can last up to three days (de­pend­ing on the surgery).

HTX-011 is de­signed to slow­ly re­lease its two in­gre­di­ents: bupi­va­caine and the non-steroidal an­ti-in­flam­ma­to­ry drug (NSAID) meloxi­cam over a three-day pe­ri­od.

Bar­ry Quart

When you cut through tis­sue, and some­times bone, in­flam­ma­to­ry cy­tokines are re­leased. Apart from the in­flam­ma­tion that aris­es in re­sponse, these cy­tokines change the lo­cal PH of the in­ci­sion, mak­ing it more acidic (lo­cal anes­thet­ics tend to lose their po­ten­cy in acidic en­vi­ron­ments), and en­hance the sen­si­tiv­i­ty of nerve end­ings so even low lev­els of pain pro­duce a larg­er pain trans­mis­sion to the brain, Quart ex­plained in an in­ter­view with End­points News ahead of the FDA de­ci­sion.

“Adding a small amount of the NSAID meloxi­cam in­to our poly­mer for­mu­la­tion and re­leas­ing that si­mul­ta­ne­ous­ly over three days al­lowed us to block enough of that in­flam­ma­to­ry process,” Quart said. “We can show clear pain re­duc­tion for the full three days that the drug (HTX-011) is be­ing re­leased. It’s the first time — that we know of — that an ex­tend­ed-re­lease lo­cal anes­thet­ic of any kind re­gard­less of how its de­liv­ered has been able to beat bupi­va­caine so­lu­tion as stan­dard-of-care in large Phase III tri­als.”

Com­bin­ing HTX-011 with two over-the-counter oral anal­gesics (ac­eta­minophen and ibupro­fen) has yield­ed im­pres­sive re­sults in help­ing post-op pain pa­tients re­main opi­oid free in two stud­ies pub­lished by Heron this year.

In a 63-pa­tient study, 90% of pa­tients re­ceiv­ing HTX-011 with the OTC anal­gesic reg­i­men did not re­quire opi­oids to man­age their post­op­er­a­tive pain through 72 hours post her­nia surgery, com­pared to 51%, 40% and 22% of pa­tients re­ceiv­ing HTX-011, bupi­va­caine and a place­bo, Heron re­vealed in Jan­u­ary. Fol­low up af­ter 28 days showed 81% of pa­tients re­mained opi­oid-free.

Biren Amin

“We con­sid­er these re­sults as com­pelling, and sup­port­ing a best-in-class pro­file in post-op pain based on sig­nif­i­cant­ly more opi­oid-free pa­tients and sub­stan­tial­ly low­er opi­oid use. HTX-011 could of­fer the on­ly op­tion of opi­oid-free pre­scrip­tion at dis­charge, which re­mains a high pri­or­i­ty in the bat­tle against opi­oid abuse,” Jef­feries’ Biren Amin wrote in a note that month.

Apart from bupi­va­caine, HTX-011 will com­pete with Paci­ra Phar­ma­ceu­ti­cals’ J&J-part­nered, long-act­ing post-op painkiller Ex­par­el, which gen­er­at­ed net sales of about $331 mil­lion last year. Ex­par­el’s main in­gre­di­ent is al­so bupi­va­caine and the drug has been ap­proved by the US reg­u­la­tor since Oc­to­ber 2011 as a treat­ment for post­sur­gi­cal anal­ge­sia.

In a note pub­lished in March, SVB Leerink an­a­lysts wrote that while “Ex­par­el does a good job re­duc­ing opi­oid use for post-op pain; HTX-011 could do this bet­ter,” cit­ing a KOL sur­vey. “…it (Ex­par­el) has done a good job in re­duc­ing opi­oid use and hos­pi­tal­iza­tion time in its post-op­er­a­tive pa­tients, the du­ra­tion of ef­fi­ca­cy is in the 24-36 hour range. As such, this KOL be­lieves the longer po­ten­tial du­ra­tion of ef­fi­ca­cy and the in­stil­la­tion method of HTX-011 will re­sult in ini­tial use of the prod­uct. But up­on avail­abil­i­ty of both prod­ucts, this KOL be­lieves hos­pi­tals will run their own pi­lot stud­ies in var­i­ous sur­gi­cal mod­els to see how they com­pare to one an­oth­er.”

Over half the pa­tients Heron is tar­get­ing are re­ceiv­ing bupi­va­caine, and about 4% are get­ting Ex­par­el — the rest are get­ting var­i­ous “caines” such as li­do­caine, Quart said. “While we ob­vi­ous­ly ex­pect to take a cer­tain part of Ex­par­el mar­ket share…our pri­ma­ry tar­get is the 96% of pa­tients who are re­ceiv­ing…short-act­ing lo­cal anaes­thet­ics.”

Paci­ra, which un­veiled plans to swal­low a com­pa­ny that makes a sys­tem that us­es in­tense­ly cold ther­a­py on a spe­cif­ic nerve to re­lieve pain to com­ple­ment its flag­ship Ex­par­el treat­ment and for­ti­fy its pain fran­chise in March, is set to re­port is first-quar­ter re­sults on Thurs­day.

Year-on-year Ex­par­el rev­enue growth for 2019 is es­ti­mat­ed at 23%, Jef­feries an­a­lysts pre­dict­ed in a note last week. “(D)es­pite the strong re­cent (Ex­par­el) re­sults…cur­rent pen­e­tra­tion rates re­main very low…and the mar­ket is cer­tain­ly large enough to ac­com­mo­date two or more play­ers. In fact, we think the ad­di­tion­al voice of an­oth­er mar­ket­ing team rais­ing aware­ness for non-opi­oid post-sur­gi­cal pain op­tions ar­guably helps all mar­ket par­tic­i­pants. And per­haps most im­por­tant­ly, we view the sit­u­a­tion as less like ‘Coke vs Pep­si’ and more to the point that if un­bundling and ac­cess con­tin­ue to im­prove, all com­peti­tors in the seg­ment ben­e­fit.”

Biotech Half­time Re­port: Af­ter a bumpy year, is biotech ready to re­bound?

The biotech sector has come down firmly from the highs of February as negative sentiment takes hold. The sector had a major boost of optimism from the success of the COVID-19 vaccines, making investors keenly aware of the potential of biopharma R&D engines. But from early this year, clinical trial, regulatory and access setbacks have reminded investors of the sector’s inherent risks.

RBC Capital Markets recently surveyed investors to take the temperature of the market, a mix of specialists/generalists and long-only/ long-short investment strategies. Heading into the second half of the year, investors mostly see the sector as undervalued (49%), a large change from the first half of the year when only 20% rated it as undervalued. Around 41% of investors now believe that biotech will underperform the S&P500 in the second half of 2021. Despite that view, 54% plan to maintain their position in the market and 41% still plan to increase their holdings.

NYU surgeon transplants an engineered pig kidney into the outside of a brain-dead patient (Joe Carrotta/NYU Langone Health)

No, sci­en­tists are not any clos­er to pig-to-hu­man trans­plants than they were last week

Steve Holtzman was awoken by a 1 a.m. call from a doctor at Duke University asking if he could put some pigs on a plane and fly them from Ohio to North Carolina that day. A motorcyclist had gotten into a horrific crash, the doctor explained. He believed the pigs’ livers, sutured onto the patient’s skin like an external filter, might be able to tide the young man over until a donor liver became available.

UP­DAT­ED: Agenus calls out FDA for play­ing fa­vorites with Mer­ck, pulls cer­vi­cal can­cer BLA at agen­cy's re­quest

While criticizing the FDA for what may be some favoritism towards Merck, Agenus on Friday officially pulled its accelerated BLA for its anti-PD-1 inhibitor balstilimab as a potential second-line treatment for cervical cancer because of the recent full approval for Merck’s Keytruda in the same indication.

The company said the BLA, which was due for an FDA decision by Dec. 16, was withdrawn “when the window for accelerated approval of balstilimab closed,” thanks to the conversion of Keytruda’s accelerated approval to a full approval four months prior to its PDUFA date.

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Marty Duvall, Oncopeptides CEO

On­copep­tides stock craters as it pulls can­cer drug Pepax­to from the mar­ket

Shares of Oncopeptides crashed more than 70% in early Friday trading after the company said it’s pulling its multiple myeloma drug Pepaxto (melphalan flufenamide) from the US market after failing a confirmatory trial. The move will force the company to close its US and EU business units and enact significant layoffs.

The FDA had scheduled an adcomm meeting next Thursday to discuss Pepaxto, which first won accelerated approval in February and costs about $19,000 per course of treatment. The committee was to weigh in on whether the confirmatory trial demonstrated a worse overall survival in the treatment arm compared to the control arm.

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How to col­lect and sub­mit RWD to win ap­proval for a new drug in­di­ca­tion: FDA spells it out in a long-await­ed guid­ance

Real-world data are messy. There can be differences in the standards used to collect different types of data, differences in terminologies and curation strategies, and even in the way data are exchanged.

While acknowledging this somewhat controlled chaos, the FDA is now explaining how biopharma companies can submit study data derived from real-world data (RWD) sources in applicable regulatory submissions, including new drug indications.

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Pfiz­er pitch­es its Covid-19 vac­cine for younger chil­dren ahead of ad­comm next week

Pfizer will present its case to the FDA’s vaccine adcomm next week, seeking authorization for a lower-dose version of its Covid-19 vaccine for kids ages 5 through 12, which the Biden administration said will likely begin rolling out early next month.

Two primary doses of the 10 µg vaccine (the dose for those ages 12 and up is 30 μg) given 3 weeks apart in this group of children “have shown a favorable safety and tolerability profile, robust immune responses against all variants of concern including Delta, and vaccine efficacy of 90.7% against laboratory-confirmed symptomatic COVID-19,” the company said in briefing documents ahead of next Tuesday’s meeting of the FDA’s Vaccines and Related Biological Products Advisory Committee.

Jay Flatley, new Zymergen CEO

Fol­low­ing Au­gust melt­down, Zymer­gen hints at sal­vage plans — cut­ting jobs and rene­go­ti­at­ing loans

Two months after a spectacular implosion that saw its founding CEO leave his post amid customer reports its only product didn’t work, Zymergen provided the first peek behind the curtain for its plans moving forward.

In an SEC filing Wednesday, Zymergen told regulators it would slash about 100 jobs and had renegotiated a $100 million loan from Perceptive that loomed like a storm cloud over the company, moving up the maturity date 18 months to June 30, 2022. Jed Dean, one of Zymergen’s three co-founders and VP of operations, will also step down at the end of the month.

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Sanofi, Re­gen­eron etch out an­oth­er PhI­II vic­to­ry for Dupix­ent, eas­ing se­vere itch and clear­ing le­sions

Sanofi and Regeneron can boast of another inflammatory disease where Dupixent has proven effective.

The best-selling drug, which targets both IL-4 and IL-13, has delivered a clean sweep in a Phase III trial for prurigo nodularis, a chronic disease characterized by itch so intense that it can affect patients’ sleep and psychology. Thick skin lesions can cover most of the body.

On the primary endpoint, 37% of patients taking Dupixent saw a clinically meaningful reduction in itch compared to 22% of those on placebo (p=0.0216) at week 12. All secondary endpoints were also met, including clearance of skin lesions and improvement in quality of life.

David Lockhart, ReCode Therapeutics CEO

Pfiz­er throws its weight be­hind LNP play­er eye­ing mR­NA treat­ments for CF, PCD

David Lockhart did not see the meteoric rise of messenger RNA and lipid nanoparticles coming.

Thanks to the worldwide fight against Covid-19, mRNA — the genetic code that can be engineered to turn the body into a mini protein factory — and LNPs, those tiny bubbles of fat carrying those instructions, have found their way into hundreds of millions of people. Within the biotech world, pioneers like Alnylam and Intellia have demonstrated just how versatile LNPs can be as a delivery vehicle for anything from siRNA to CRISPR/Cas9.

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