Ver­tex and CRISPR Ther­a­peu­tics un­veil more pos­i­tive gene ther­a­py da­ta, but busul­fan again casts a shad­ow over the field

Less than 12 hours af­ter re­veal­ing a flop on its sec­ond shot for al­pha-1 an­tit­rypsin de­fi­cien­cy, Ver­tex plowed ahead with an­oth­er da­ta drop from its part­ner­ship with CRISPR Ther­a­peu­tics. And though the topline proved pos­i­tive, con­cerns over con­di­tion­ing agents con­tin­ue to linger over the col­lab­o­ra­tion, as well as the en­tire gene ther­a­py space.

Pre­sent­ing da­ta from two tri­als at the Eu­ro­pean Hema­tol­ogy As­so­ci­a­tion an­nu­al meet­ing, the pair an­nounced that fol­low-up da­ta of at least three months for 22 pa­tients with ge­net­ic blood dis­or­ders in­di­cat­ed a “con­sis­tent and sus­tained” re­sponse to the ex­per­i­men­tal drug CTX001. All 15 pa­tients with trans­fu­sion-de­pen­dent be­ta tha­lassemia did not need fur­ther blood trans­fu­sions and all sev­en with se­vere sick­le cell dis­ease were pain free, the biotechs an­nounced.

There was one pa­tient not in­clud­ed in the da­ta cut­off of March 30, how­ev­er, who ex­pe­ri­enced a cere­bel­lar he­m­or­rhage less than three months af­ter be­ing treat­ed. The se­ri­ous side ef­fect was re­lat­ed to the busul­fan con­di­tion­ing gene ther­a­py pa­tients un­der­go be­fore re­ceiv­ing treat­ment, Ver­tex said, and has since re­solved.

Busul­fan has long proved tricky for com­pa­nies de­vel­op­ing gene ther­a­pies, with the chemo reg­i­men prov­ing a nec­es­sary but in­ten­sive process for pa­tients. It’s been linked in the past to can­cer and some have linked it to po­ten­tial cas­es of leukemia and myelodys­plas­tic syn­drome seen in blue­bird bio’s gene ther­a­py stud­ies.

Ad­di­tion­al­ly, as Ver­tex and CRISPR had pre­vi­ous­ly re­vealed, one be­ta tha­lassemia pa­tient ex­pe­ri­enced four se­ri­ous side ef­fects re­lat­ed or pos­si­bly re­lat­ed to CTX001. They all oc­curred with­in the con­text of an in­flam­ma­to­ry re­sponse and have al­so re­solved.

In the be­ta tha­lassemia study, in­ves­ti­ga­tors fol­lowed the 15 pa­tients for a range of four to 26 months, and the sick­le cell pa­tients from five to 22 months. Sev­en from across both stud­ies are more than a year out since re­ceiv­ing treat­ment. Fri­day’s re­sults are an up­date to a da­ta cut from De­cem­ber’s ASH con­fer­ence, which had on­ly in­clud­ed 10 pa­tients.

The gene ther­a­py in ques­tion, be­ing de­vel­oped joint­ly by Ver­tex and CRISPR, is an au­tol­o­gous ex vi­vo CRISPR/Cas9 treat­ment. Ver­tex teamed up with CRISPR back in 2015, but the pair ex­pand­ed on their part­ner­ship in April in a bid to de­vel­op the treat­ment more quick­ly.

In the ex­pan­sion, Ver­tex paid an ad­di­tion­al $900 mil­lion cash to take an­oth­er 10% of fu­ture sales from the gene edit­ing ther­a­py, with CRISPR hand­ing over re­spon­si­bil­i­ty for com­mer­cial­iz­ing CTX001 in the US. Along with oth­er re­cent changes to their part­ner­ship, the move ef­fec­tive­ly hands Ver­tex re­spon­si­bil­i­ty for man­u­fac­tur­ing the ther­a­py and stew­ard­ing it past reg­u­la­tors across the globe.

Should CTX001 be­come the first CRISPR-based ther­a­py to hit the mar­ket, that wa­ger would give Ver­tex a sig­nif­i­cant sales ad­van­tage over ri­vals like blue­bird. The Nick Leschly-run com­pa­ny has faced an up­hill climb for its gene ther­a­py pro­grams, ul­ti­mate­ly split­ting it­self in­to two com­pa­nies at the be­gin­ning of the year.

MedTech clinical trials require a unique regulatory and study design approach and so engaging a highly experienced CRO to ensure compliance and accurate data across all stages is critical to development milestones.

In­no­v­a­tive MedTech De­mands Spe­cial­ist Clin­i­cal Tri­al Reg­u­la­to­ry Af­fairs and De­sign

Avance Clinical is the Australian CRO for international biotechs providing world-class clinical research services with FDA-accepted data across all phases. With Avance Clinical, biotech companies can leverage Australia’s supportive clinical trials environment which includes no IND requirement plus a 43.5% Government incentive rebate on clinical spend. The CRO has been delivering clinical drug development services for international biotechs for FDA and EMA regulatory approval for the past 24 years. The company has been recognized for the past two consecutive years with the prestigious Frost & Sullivan CRO Best Practices Award and a finalist in Informa Pharma’s Best CRO award for 2022.

Mathai Mammen (Rob Tannenbaum, Endpoints News at BIO 2018)

Math­ai Mam­men makes an abrupt ex­it as head of the big R&D group at J&J

In an after-the-bell shocker, J&J announced Monday evening that Mathai Mammen has abruptly exited J&J as head of its top-10 R&D group.

Recruited from Merck five years ago, where the soft-spoken Mammen was being groomed as the successor to Roger Perlmutter, he had been one of the top-paid R&D chiefs in biopharma. His group spent $12 billion last year on drug development, putting it in the top 5 in the industry.

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Illustration: Kim Ryu for Endpoints News

Why non-opi­oid pain drugs keep fail­ing — and what's next for the field

In 1938, Rita Levi-Montalcini was forced to move her lab into her bedroom in Turin, as Mussolini’s facist government expelled Jewish people from studying or working in schools in Italy. Levi-Montalcini, then just a few years out of medical school and using sewing needles as scalpels in her makeshift lab, would soon discover nerve growth factor, or NGF, in chicken embryos.

Her discoveries formed the basis of our understanding of the peripheral nervous system and how cells talk to each other, and Levi-Montalcini went on to win the Nobel Prize in 1986. Much later, NGF was hailed as a promising target for new pain therapies, with some analysts quoting an $11 billion market. However, the latest anti-NGF candidate, Pfizer and Eli Lilly’s tanezumab, was rejected by the FDA last year because of a side effect that dissolved bone in some of its patients.

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Samantha Du, Zai Lab CEO

Any­one still look­ing for a CD47? Zai Lab shelves PhI pro­gram af­ter re­view­ing 'com­pet­i­tive land­scape'

Over the past few years, the promise of blocking CD47 — a “don’t eat me” signal co-opted by cancer cells — has sent drugmakers big and small into a frenzy. But one biotech is now bowing out.

Zai Lab is deprioritizing ZL-1201, its CD47 inhibitor, scrapping plans for a Phase II trial. It will now “pursue out-licensing opportunities,” the company said in its Q2 update. The decision was based on a review of the competitive landscape, it added, without going into further details.

Ted Love, Global Blood Therapeutics CEO

Up­dat­ed: Pfiz­er scoops up Glob­al Blood Ther­a­peu­tics and its sick­le cell ther­a­pies for $5.4B

Pfizer is dropping $5.4 billion to acquire Global Blood Therapeutics.

Just ahead of the weekend, word got out that Pfizer was close to clinching a $5 billion buyout — albeit with other potential buyers still at the table. The pharma giant, flush with cash from Covid-19 vaccine sales, apparently got out on top.

The deal immediately swells Pfizer’s previously tiny sickle cell disease portfolio from just a Phase I program to one with an approved drug, Oxbryta, plus a whole pipeline that, if all approved, the company believes could make for a $3 billion franchise at peak.

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Bernhardt Zeiher, outgoing Astellas CMO (Astellas)

Q&A: Astel­las' re­tir­ing head of de­vel­op­ment re­flects on gene ther­a­py deaths

For anyone who’s been following discussions about the safety alarms surrounding the adeno-associated viruses (AAV) commonly used to deliver gene therapy, Astellas should be a familiar name.

The Japanese pharma — which bought out Audentes Therapeutics near the end of 2019 and later built a gene therapy unit around the acquisition — rocked the field when it reported three patient deaths in a trial testing AT132, the lead program from Audentes designed to treat a rare muscle disease called X-linked myotubular myopathy (XLMTM).

When the company restarted the trial, it adjusted the dose and instituted a battery of other measures to try to prevent the same thing from happening again. But tragically, the first patient to receive the new regimen died just weeks after administration. The therapy remains under clinical hold, and just weeks ago, Astellas flagged another safety-related hold for a separate gene therapy candidate. In the process of investigating the deaths, the company has also taken flak about the way it disclosed information.

Big questions remain — questions that can have big implications about the future of AAV gene therapies.

Bernhardt Zeiher did not imagine any of it when he first joined Astellas as the therapeutic area leader in inflammation, immunology and infectious diseases. But his ascent to chief medical officer and head of development coincided almost exactly with Astellas’ big move into gene therapy, putting him often in the driver’s seat to grapple with the setbacks.

As Zeiher prepares to retire next month after a 12-year tenure — leaving the unfinished tasks to his successor, a seasoned cancer drug developer — he chatted with Endpoints News, in part, to discuss the effort to understand what happened, lessons learned and the criticism along the way.

The transcript has been lightly edited for length and clarity.

Endpoints: I want to also ask you a bit about the gene therapy efforts you’ve been working on. Astellas has really been at the forefront of discovering the safety concerns associated with AAV gene therapy. What’s that been like for you?

Zeiher: Well, I have to admit, it’s been a bit of a roller coaster. We acquired Audentes. Huge amount of enthusiasm. What we saw with AT132 — that was the lead program in XLMTM — was just remarkable efficacy. I mean, kids who went from being on ventilators, not able to eat for themselves, sit up, do things like that, to off ventilators, walking, you know, really — one investigator called it this Lazarus-like effect. It was just really dramatic efficacy. And then to have the safety events that occurred. So they actually occurred within that first year of the acquisition. So we had the three patient deaths. Me and my organization became very, very much involved. In fact, Ed Conner, who had been the chief medical officer, he left after some of the deaths, but I stepped in as the kind of acting chief medical officer, we had another chief medical officer who was involved, and then we had a fourth death, and I became acting again for a period of time.

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Steve Paul, Karuna Therapeutics CEO (Third Rock)

Karuna's schiz­o­phre­nia drug pass­es a close­ly-watched PhI­II test, will head to FDA in mid-2023

An investigational pill that combines a former Eli Lilly CNS compound with an overactive bladder drug was better than placebo at reducing a scale of symptoms experienced by patients with schizophrenia in a Phase III trial.

Karuna Therapeutics’ drug passed the primary goal in EMERGENT-2, the Boston biotech said early Monday morning, alongside quarterly earnings. The study is the first of Karuna’s four Phase III clinical trials to read out in schizophrenia and will provide the backbone to the biotech’s first drug approval application, slated for mid-2023.

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HHS Secretary Xavier Becerra (Patrick Semansky/AP Images)

US weighs new route of ad­min­is­tra­tion for mon­key­pox vac­cine as cas­es climb — re­port

Less than a week after HHS Secretary Xavier Becerra declared monkeypox a national health emergency, reports have emerged that the US plans to extend its vaccine supply by opting for a different route of administration.

Officials are expected to call for intradermal injection of Bavarian Nordic’s Jynneos vaccine — the only shot approved specifically for monkeypox in the US — as opposed to subcutaneous injection, unnamed sources told both the New York Times and Washington Post on Tuesday.

'Messy at best': Is the US re­peat­ing the same Covid mis­steps with mon­key­pox mes­sag­ing?

When Kyle Planck first suspected he might have monkeypox in late June, he went to the CDC website and found six photos of different types of lesions. And that was about it for general public information.

Planck, who is a sixth-year PhD pharmacology researcher at Weill Cornell, kept looking though and found a separate part of the CDC website meant for healthcare professionals. There he found a medical slide deck with more pictures, professional journal articles and more details about symptoms and diagnosis.

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