Over the next year, a series of clinical milestones and regulatory decisions—what companies and investors like to call “inflection points”—will set for years to come the direction of what has been until now the fledgling biotech segment focused on genome editing.

Yet this week, investors received a reminder that in genome editing, inflection points don’t always lead to big stock gains: Beam Therapeutics (BEAM) shares skidded 12% in early trading, reaching a new 52-week low as it slid from $20.80 to $18.36, after the company announced a restructuring and reprioritization of its pipeline of base editing therapies that will include elimination of about 100 jobs—some 20% of its workforce.

Beam said it will prioritize development of its ex vivo and in vivo sickle cell disease programs—including BEAM-101, which applies the company’s Engineered Stem Cell Antibody Paired Evasion (ESCAPE) non-genotoxic conditioning strategy, and in vivo delivery to hematopoietic stem cells (HSCs).

Beam also said it will:

• Prioritize development of its in vivo base editor BEAM-302 for the treatment of alpha-1 antitrypsin deficiency (AATD).

• Conduct an initial clinical trial in the U.S. assessing BEAM-301 as a treatment for glycogen storage disease 1a (GSD1a).
• Seek partnerships for BEAM-201 and other potential ex vivo CAR-T programs, including ongoing research to create next-generation allogeneic cell therapies with multiplex base editing. For BEAM-201, Beam plans to generate a focused clinical dataset in T-cell acute lymphoblastic leukemia (T-ALL).
• Focus near-term spending on research and platform applications that apply Beam’s in vivo editing capabilities in the liver, targeting both rare genetic and common disorders, as well as select opportunities in hematology and immunology/oncology.
• Pause its hepatitis B virus program and seek for it a partner “given the requirement of specialized development and commercial capabilities.”

“From the beginning, Beam’s strategy has been to develop base editing technology broadly across a diverse portfolio of programs and delivery modalities, and our science and pipeline continue to progress across the board,” Beam CEO John Evans stated. “In this challenging market environment, however, we need to make the difficult decision to focus our resources on those clinical programs and research areas we believe have the highest potential for near-term value creation, while continuing to build a strong company for the future.”

Intellia Therapeutics (NTLA) shares fell about 3% on Wednesday from $29.05 to $27.96, and dipped another 3% on Thursday, to $27.10, despite the company sharing more positive news.

Intellia’s NTLA-2001 became the first first-ever investigational in vivo CRISPR-based gene editing therapy cleared to enter late-stage clinical development when the FDA cleared the company’s Investigational New Drug (IND) application for NTLA-2001 for the treatment of transthyretin (ATTR) amyloidosis with cardiomyopathy. The decision paves the way for a global Phase III study of NTLA-2001 that is expected to start by year-end 2023.

In a statement, Intellia president and CEO John Leonard, MD, said the company will share details about that pivotal trial on its third-quarter earnings call with analysts, set for November 9.

“Details on trial design at 3Q call Nov 9 should clarify next steps and further move the stock. We expect (+)ve [positive] readthrough to other editing cos [companies] too,” Jefferies equity analyst Maury Raycroft, PhD, wrote Wednesday in a research note. “The bar for FDA has been unclear, and NTLA now sets precedent for others to follow.”

He said Intellia had noted to him that while global trial start-up activities will start, “actual dosing may begin early ’24 depending on how fast things move.”

Raycroft added that he and other Intellia watchers will be seeking more specifics about the size and duration of the Phase III trial compared to the pivotal trials for other non genome-edited therapy developers of ATTR amyloidosis-caused cardiomyopathy treatments.

Pfizer (PFE) crossed the proverbial finish line first when it won FDA approval in 2019 for its wild-type or hereditary ATTR amyloidosis treatments, Vyndaqel^® (tafamidis meglumine) and Vyndamax^® (tafamidis). Each uses a different form of active ingredient tafamidis (micronized meglumine salt and free acid form, respectively), and each is taken a different dosage.

The Pfizer drugs are expected to be joined soon by treatments being developed by other companies—a group that includes Anlylam Pharmaceuticals (ALNY), BridgeBio Pharma (BBIO), and the tandem of Ionis Pharmaceuticals and AstraZeneca (IONS/AZN). Those treatments “pose substantial headwinds” to Intellia’s NTLA-2001, observed David Nierengarten, PhD, managing director and head of equity research focusing on biotech for Wedbush Securities, according to Investor’s Business Daily.

However, whatever headwinds Alnylam posed to Intellia have been significantly stilled.

As Raycroft commented, Alnylam saw a setback to development of patisiran for cardiomyopathy of ATTR amyloidosis on October 9 when the FDA refused to approve Alnylam’s supplemental NDA for the RNA interference (RNAi)-based therapy already marketed as Onpattro^® for polyneuropathy of hereditary ATTR amyloidosis in adults. Instead, the agency sent Alnylam a Complete Response Letter stating that data from the company’s Phase III APOLLO-B trial (NCT03997383) had not established the clinical meaningfulness of patisiran’s treatment effects in ATTR amyloidosis. Alnylam responded by saying it was no longer pursuing the additional indication in the U.S.

Earlier this year, BridgeBio and Ionis/AstraZeneca announced positive Phase III results for their ATTR amyloidosis candidates—acoramidis and eplontersen, respectively.

Intellia is among a half-dozen genome editing therapy developers with key clinical and regulatory inflection points to watch in coming months. Following is a roundup of those companies, their anticipated events, and recent actions by analysts covering the company:

Beam Therapeutics (BEAM)

Inflection Points: BEAM restructured operations and reprioritized its pipeline on Thursday (see above), listing first its ex vivo and in vivo sickle cell disease programs, which include BEAM-101—for which the company anticipates reporting initial data in 2024 on multiple patients from its Phase I/II BEACON trial (NCT05456880) assessing BEAM-101 in severe SCD.

In August, BEAM said it anticipated having enough currently consented patients to fill a three-patient sentinel cohort and launch an expansion cohort. Beam will continue adding additional patients to the BEACON trial through the end of year and beyond, until it reaches a total target of 45 treated patients. The trial has an estimated primary completion date of February 1, 2025.

Significance: BEAM-101 is an ex vivo therapy that produces base edits designed to potentially alleviate the effects of SCD by mimicking genetic variants seen in individuals who have hereditary persistence of fetal hemoglobin.

Other catalysts: BEAM is also prioritizing development of BEAM-302 in AATD, saying in August it expected to submit a regulatory filing in the first quarter of 2024 to begin a clinical trial. A similar filing is expected in the first half of 2024 for BEAM-301 in GSD1a, with BEAM saying Thursday that an initial clinical trial is still planned.

BEAM-301 is a liver-targeting lipid nanoparticle (LNP) formulation of base editing reagents designed to correct the R83C mutation—the most common mutation responsible for causing GSD1a. BEAM-302 is a liver-targeting LNP formulation of base editing reagents designed to correct the PiZ allele, the most common gene variant associated with severe AATD.

However, BEAM is seeking a partner for BEAM-201, for which it dosed the first patient with BEAM-201 in a Phase I/II trial (NCT05885464) assessing the CD7+ relapsed/refractory T-ALL/T-LL (T-cell lymphoblastic leukemia) in August. The trial has an estimated primary completion date of December 2031. BEAM-201 is, according to Beam, the first quadruplex-edited, allogeneic CAR-T cell therapy candidate in clinical-stage development, and the first treatment with a base editing candidate in the U.S.

Analyst action: Cantor Fitzgerald’s Rick Bienkowski on Tuesday lowered his firm’s 12-month price target on Beam shares 43%, from $56 to $32, but maintained its “Overweight” rating.

Caribou Biosciences (CRBU)

Inflection Point: CRBU expects to begin patient enrollment in the Phase I AMpLify trial by mid-2024. AMpLify is designed to assess the safety and tolerability of a single administration of CB-012 for relapsed or refractory acute myeloid leukemia (r/r AML) at dose level 1 (25×10⁶ CAR-T cells). The FDA has cleared Caribou’s IND for the trial, the company said Wednesday.

Caribou said it is beginning Part A of AMpLify, a 3+3 dose escalation design that will evaluate the safety and tolerability of CB-012 at ascending dose levels to determine the maximum tolerated dose and/or the recommended doses for expansion. Part B, the dose expansion portion, has as its primary objective determining antitumor response, assessed by overall response rate (ORR), after a single dose of CB-012. AMpLify will include patients who have not responded to or relapsed after standard treatment and will exclude patients who have been treated with more than three prior lines of therapy and patients with proliferative disease.

Significance: According to CRBU, CB-012 is the first allogeneic CAR-T cell therapy with both checkpoint disruption through a PD-1 knockout, and immune cloaking through a B2M knockout and B2M–HLA-E fusion transgene insertion.

Analyst action: Nothing since July 26, when HC Wainwright’s Robert Burns lowered his firm’s price target 8%, from $25 to $23, but maintained its “Buy” rating.

CRISPR Therapeutics (CRSP) and Vertex Pharmaceuticals (VRTX)

Inflection points: The FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee will meet October 31 to recommend how the agency should act on exagamglogene autotemcel (exa-cel), the companies’ autologous, ex vivo CRISPR/Cas9 gene-edited for severe sickle cell disease (SCD) and transfusion-dependent beta thalassemia.

The FDA, which typically heeds the advice of its “adcomms,” has set for December 8 its Prescription Drug User Fee Act (PDUFA) target action date on the companies’ biologics license application (BLA) for exa-cel in SCD. In beta thalassemia, the agency has set a PDUFA date of March 30, 2024.

Significance: If approved, exa-cel would be the first CRISPR-Cas9 gene-edited therapy to win FDA approval.

Other catalysts: Cardiovascular candidate CTX310, which applies in vivo editing of the ANGPTL3 gene, is expected to enter the clinic by year’s end; Atherosclerotic cardiovascular disease candidate CTX320 is expected to begin clinical trials in the first half of 2024.

Analyst action: Cantor Fitzgerald’s Eric Schmidt on Tuesday downgraded CRSP shares from “Overweight” to “Neutral.” Mizuho’s Salim Syed, however, initiated coverage of CRSP on September 27 with a “Buy” rating.

Editas Medicine (EDIT)

Inflection Point: Editas’ EDIT-301, an ex vivo autologous CRISPR gene edited gene-edited CD34+ hematopoietic stem and progenitor cell therapy candidate, received the FDA’s Regenerative Medicine Advanced Therapy (RMAT) designation on Monday. EDIT-301 is on track to dose 20 total sickle cell disease (SCD) patients in the Phase I/II RUBY trial (NCT04853576), and deliver a clinical update on the study, by the end of this year, the company said in August.

In June, Editas presented positive initial clinical safety and efficacy data from the RUBY trial in an oral presentation at the European Hematology Association (EHA) Hybrid Congress in Frankfurt, Germany, and in a company-sponsored webinar.

Significance: In EDIT-301, patient-derived CD34⁺ hematopoietic stem and progenitor cells are edited at the gamma globin gene (HBG1 and HBG2) promoters, where naturally occurring fetal hemoglobin (HbF) inducing mutations reside, by a highly specific and efficient proprietary engineered AsCas12a nuclease. Red blood cells derived from EDIT-301 CD34⁺ cells have shown a sustained increase in fetal hemoglobin production, which according to Editas could provide a one-time, durable treatment benefit for people living with severe SCD and TDT.

The RUBY trial marked the first time that a novel type of CRISPR gene-editing technology—CRISPR/CA12—was used in a human clinical study to alter the defective gene, according to the scientists.

Other catalysts: SCD is one of two indications for which Editas is developing EDIT-301; the other is transfusion-dependent beta thalassemia (TDT), for which Editas also has a clinical update planned by year’s end, from the Phase I/II EDITHAL trial (NCT05444894). Editas presented positive initial clinical safety and efficacy data from the first EDITHAL patient in June, in a company-sponsored webinar.

Analyst action: J.P. Morgan’s Brian Cheng on Wednesday upgraded his firm’s rating on EDIT stock from “Underweight” to “Neutral,” and announced a price target of $8 a share. However, Cantor Fitsgerald’s Eric Schmidt downgraded EDIT on Tuesday from “Overweight” to “Neutral.” Last month, Stifel’s Dae Gon Ha upgraded the stock from “Hold” to “Buy” and nearly doubled his firm’s price target, from $9 to $17.

Intellia Therapeutics (NTLA)

Inflection Point: Intellia said Wednesday its NTLA-2001, being co-developed with Regeneron Pharmaceuticals (REGN), won FDA clearance of its IND application for a trial assessing the in vivo CRISPR-based therapy as a treatment of transthyretin (ATTR) amyloidosis with cardiomyopathy. The decision paves the way for a global Phase III study of NTLA-2001 that is expected to start by the end of this year. In a statement, Intellia President and CEO John Leonard, MD, said the company will share details about that pivotal trial on its third-quarter earnings call with analysts, set for November 9.

Significance: NTLA-2001 is the first first-ever investigational in vivo CRISPR-based gene editing therapy cleared to enter late-stage clinical development when the FDA cleared. If approved by the agency, it could potentially be the first single-dose treatment for ATTR amyloidosis, according to Intellia.

Other catalysts: NTLA-2002, an in vivo CRISPR-based treatment candidate for hereditary angioedema, earlier this month was granted the European Medicines Agency (EMA)’s Priority Medicine (PRIME) designation. NTLA-2002 is set to start a global pivotal Phase III trial as early as Q3 2024 “subject to regulatory feedback,” Intellia said in August, following release of positive Phase I data including extended data announced in June. According to Intellia, NTLA-2002 is the first single-dose investigational treatment being explored in clinical trials for the potential to continuously reduce kallikrein activity and prevent attacks in people with HAE.

Analyst action: Nothing since September 13, when Cantor Fitzgerald’s Rick Bienkowski maintained his firm’s “Overweight” rating and $65 a share price target on the stock.

Prime Medicine (PRME)

Inflection Point: PRME expects to submit an IND in 2024 for its first clinical candidate to the FDA, the company’s co-founder, prime editing and base editing pioneer David R. Liu told an investor conference earlier this month.

While the company has not identified that candidate, its pipeline shows only one of its 18 programs has reached the phase of IND-enabling studies—a blood-targeting candidate for chronic granulomatous disease (CGD), designed to be administered ex vivo. Additional IND filings are anticipated in 2025, Prime Medicine said in a company presentation to investors last month.

Significance: If Prime wins FDA clearance for its IND, it could be the first drug developer to bring a base edited therapy into the clinic. By contrast, base editing technology, first disclosed in 2016 by Liu’s lab—is under investigation in six ongoing clinical trial.

Other catalysts: Three other programs in Prime’s pipeline are in lead optimization phases—a Wilson’s disease candidate targeting liver tissue and using lipid nanoparticle (LNP) delivery; a retinitis pigmentosa/rhodopsin candidate targeting eye tissue and using adeno-associated virus (AAV) vector delivery; and a neuromuscular tissue targeting candidate for Friedreich’s ataxia also delivered via AAV. The rest of Prime Medicine’s programs are in preclinical discovery phases.

Analyst action: BMO Capital’s Kostas Biliouris initiated coverage of PRME on October 9 with an “Outperform” rating and a price target of $19 a share. A month earlier on September 6, JonesTrading’s Justin Walsh initiated coverage with a “Buy” rating and a price target of $20 a share.

Leaders & Laggards

• Aldeyra (ALDX) shares plunged 66% on Monday, from $5.43 to $1.83, after it disclosed that according to minutes of a late-cycle review meeting with the FDA, the company “needs to conduct an additional clinical trial to satisfy efficacy requirements for reproxalap as a treatment for signs and symptoms of dry eye disease. Aldeyra quoted from the minutes: “[i]t does not appear that you have data to support the clinical relevance of the ocular signs to support your dry eye indication.” As a result, Aldeyra acknowledged, “the FDA may not be in the position to approve the NDA [New Drug Application] for reproxalap on or about the Prescription Drug User Fee Act (PDUFA) target action date of November 23, 2023 or afterwards, and it may issue a Complete Response Letter.”
• Assembly Biosciences (ASMB) shares rocketed 71%, from 73 cents to $1.25, after the company announced a 12-year partnership with Gilead Sciences (GILD) to advance R&D of novel antiviral therapies, focusing initially on herpes, hepatitis B, and hepatitis D viruses. Gilead agreed to pay Assembly Bio an initial $100 million consisting of $84.8 millionupfront and a $15.2 million equity investment. Gilead also agreed to pay at least $45 million per program after clinical proof-of-concept is achieved to opt into exclusive rights for each of Assembly Bio’s current and future programs,. If Gilead opts-in to any program, it will pay Assembly Bio up to $330 million per program tied to achieving regulatory and commercial milestones, plus royalties. Assembly Bio is also be eligible to receive three separate $75 million collaboration extension payments toward funding future R&D. Gilead shares rose 2% from $79.20 to $80.48.
• Evelo Biosciences (EVLO) shares plummeted 59% on Tuesday, from $2.91 to $1.20, after the company acknowledged that it had begun exploring strategic alternatives after its moderate psoriasis candidate EDP2939 failed the Phase II EDP2939-101 trial. EDP2939 missed the study’s primary endpoint of achieving a statistically significant difference in the proportion of patients who achieved an outcome of a 50% improvement from baseline in Psoriasis Area and Severity Index (PASI) score (PASI-50) between EDP2939 and placebo after 16 weeks of daily treatment. Evelo added that EDP2939 went from being inferior to placebo at week 16 (19.6% vs 25%) to being superior at the week 20 follow-up visit (33.9% vs. 26.9%).
• Nkarta (NKTX) shares more than doubled, zooming 112% on Tuesday from $1.48 to $3.14, after the company said the FDA had cleared its IND application to evaluate NKX019, its allogeneic, CD19-directed CAR NK cell therapy for lupus nephritis (LN). The company plans to launch a multi-center, open label, dose escalation clinical trial designed to assess the safety and clinical activity of NKX019 in patients with refractory LN. The study is designed to enroll up to 12 patients, with the first patient expected to be enrolled in the first half of 2024. Nkarta also disclosed plans to eliminate 18 jobs—about 10% of its workforce—among cost containment measures designed to extend its projected cash runway by one year into 2026.

Alex Philippidis is Senior Business Editor of GEN.

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Carl C. Icahn has launched the next phase of his campaign for change at Illumina through a lawsuit filed this week in Delaware against former CEO Francis deSouza and board members.

Icahn’s lawsuit alleges that deSouza and board members breached their financial duty by directing Illumina’s three-year effort to acquire cancer blood test developer Grail, as well as the company’s defense of the $7.1 billion deal in the face of opposition from U.S. and European regulators.

The lawsuit comes four months after deSouza resigned as CEO following a proxy challenge from the activist investor that was partly successful. Shareholders of the sequencing giant ousted a deSouza ally as chair and elected to the board one of three allies nominated by Icahn.

The lawsuit was filed Tuesday in Delaware Chancery Court. However, the complaint on which the suit is based is not public and will not be until next week. The court allows complaints to be kept confidential pending potential redactions to be proposed by lawyers for Icahn and the defendants.

Illumina spokesman David McAlpine told GEN today that Illumina was reviewing the complaint.

Illumina investors appeared somewhat fazed by news of Icahn’s lawsuit. Shares of Illumina fell nearly 6% today, from $131.87 to $124.45. Shares of Icahn’s publicly-traded Icahn Enterprises stayed flat, inching up 0.5%, from $17.77 to $17.86.

Icahn disclosed his lawsuit yesterday during a “fireside chat at the 13D Monitor Active-Passive Investor Summit, a conference focused on shareholder activism; corporate governance; environmental, social, and governance (ESG) concerns.

“Throughout my long, long career as an activist, I have never found it necessary, until today, to sue a board of directors in this manner,” Icahn told the conference, according to Bloomberg News. “I continue to believe in the company’s long-term potential and I have full faith in Illumina’s new CEO, and its employees.”

In a statement Wednesday, Icahn said he decided to pursue the lawsuit because of “the board’s unconscionable and egregious actions relating to closing the acquisition of Grail without regulatory approval, thus putting Illumina, a great company, in harm’s way.”

Icahn has voiced public support for deSouza’s successor Jacob Thaysen, PhD, who became Illumina’s CEO effective September 25. While some market watchers questioned Thaysen’s lack of past CEO experience, Icahn posted on X, formerly Twitter:  “I think he will do an excellent job and he has my full support.”

deSouza’s resignation marked the second victory for Icahn in his effort to change the direction of Illumina’s management by reshaping its board. The first came in May, when Illumina shareholders ousted chairman John W. Thompson, who had ties to deSouza, and instead elected to Illumina’s board Andrew J. Teno, a portfolio manager at Icahn’s investment management firm Icahn Capital since October 2020.

Icahn’s case for change

During more than two months of open letters to Illumina shareholders—and in an exclusive interview on GEN’s “Close to the Edge” video series, Icahn and Teno stated their case for change at Illumina. That case rested on three key arguments:

• Illumina drained itself of resources by acquiring Grail and challenging regulators.
• Illumina’s stock price had shrunk to the point where the company had lost some $50 billion in market capitalization—the share price times the number of outstanding shares of a public company.
• Illumina’s board nearly doubled deSouza’s total compensation last year, to almost $27 million, with much of that increase based on stock options.

Speaking with GEN in April, Icahn cited an instance of what he considered a breach of duty by Illumina’s board—its decision to increase its insurance protection to board members before they approved the purchase to what he has termed an unprecedented level. That decision, Icahn concluded in March, reflected board reluctance to support the Grail acquisition absent additional personal liability protection above existing protections.

“This board realized—they must have—how crazy this was. So, they’re supposed to use their business judgment, their duty of loyalty, their duty of care. They didn’t use it,” Icahn said.

“If they were really lax to do a business judgment, and so if that is found, insurers may not cover them. But the board doesn’t seem to care,” Icahn lamented. “It’s a very, very interesting and strange situation. I’ve never seen one as bad as this, and I’ve been around a long time.”

Potential conflicts

Icahn has also raised the question of potential conflicts by deSouza and Illumina’s board between their duty to shareholders and their actions in the Grail acquisition—potential conflicts that he told shareholders on May 8 justified requesting a fairness opinion from an independent financial expert.

Icahn cited as one example deSouza’s years of personal friendship and professional relationships with John W. Thompson, a Grail shareholder who served as Illumina’s board chair from 2021 until he was ousted by shareholders in May.

Another example was Goldman Sachs’ role as Illumina’s financial advisor after having served as a lead underwriter for Grail in an attempted initial public offering (IPO) that it aborted when Illumina agreed to buy the company in 2020, saying the deal would accelerate the commercialization of its Galleri blood detection test, then being planned for launch in 2021.

In his May 8th letter, Icahn also introduced the possibility of a lawsuit: “We believe there are likely many more red flags [emphasis in original] that will be revealed if and when the members of Team Francis are forced to sit for depositions.”

During the GEN interview, Teno contrasted deSouza’s relationships with Thompson and the presence on the board of other deSouza allies with the traditional separation of powers between CEOs and board chairs: “Francis is picking the people he wants to be on the board and pushing them through his committee.”

Asked if the moves constituted too close a link between chairman and CEO, and thus a breach of fiduciary duty, Teno replied: “If you hired your friend of 20 years, you’ve known someone for 20 years, do you think they treat them a little differently than you treat someone you don’t know? I think the answer is absolutely. That’s why they have the separation of powers.”

Alex Philippidis is Senior Business Editor of GEN.

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Anurup Ganguli was finishing up his PhD at the University of Illinois at Urbana-Champaign, reading bioRxiv preprints on CRISPR-based molecular detection from the labs of Nobel laureate Jennifer Doudna, PhD, and the Broad Institute’s Feng Zhang, PhD, when he realized that every molecular detection platform has relied on DNA amplification since the advent of PCR in 1983.

“This is also true for the other CRISPR-based platforms developed by Sherlock and Mammoth Biosciences,” Ganguli told GEN Edge. “They are all doing a pre-amplification step, such as LAMP (Loop-Mediated Isothermal Amplification), before going to CRISPR.”

Ganguli argues that DNA amplification creates limitations, including the ability to massively multiplex and the time to result. He began looking for a solution that eliminates the need for a DNA amplification step typically required for molecular detection.

Today, VedaBio, co-founded by Ganguli, emerged from stealth mode and unveiled its Cascade molecular detection platform. Ganguli, who is CEO, said that this CRISPR-based technology has the best accuracy in its class, can detect molecules at room temperature, and gives results almost instantly without the need for target amplification. This is how Veda, which means “the creation of knowledge” in Sanskrit, was able to raise more than $40 million and get support from OMX Ventures, the company’s lead investor.

Ganguli’s work began in the lab of Rashid Bashir, PhD, professor of bioengineering, and currently Dean of the Grainger College of Engineering at the University of Illinois at Urbana-Champaign. Bashir is also a co-founder at VedaBio.

Creating a cascade of success

The Cascade platform is aptly named as it is essentially a positive feedback loop. It starts with a CRISPR complex called RNP1, which consists of an enzyme paired with a sequence that complements a target. When RNP1 binds to the target sequence, it cuts a reporter molecule, which sends out a fluorescent signal and gives RNP2 a place to go. RNP2 cuts the reporter molecule when it binds to this target sequence and turns on, just like RNP1. This releases a fluorophore and additional RNP2 target sequences, triggering an exponential cascade effect that creates a strong, easily detectable signal almost instantly.

Ganguli said that this approach has many advantages over DNA amplification systems, in part because of the use of primers and probes. Pooling of these primers results in false positives because the primers cross-react. But with the CRISPR-based approach, this cross-reactivity can be avoided because of the specificity of the guide RNA in RNP1, which cleaves different reporter molecules.

Cascade’s sensitivity is comparable to PCR, claimed Ganguli, going down to just a few copies of a target molecule.

“That’s the beauty of it—you can get rid of the amplification step while capturing state-of-the-art gold standard accuracy, and that’s what we will leverage for our first product and our application pipeline,” said Ganguli.

Behind this technology, Ganguli said that Veda is pursuing two core narratives. The first is to build and launch an initial flagship product, which he is still keeping under wraps. The second is to demonstrate the platform’s power in multiple application areas.

“We believe that, given the fundamental nature of the breakthrough, it can be applied to research use, industrial applications, diagnostics, and therapeutics,” said Ganguli. “We have solidified the core platform over the last two years. Being in stealth allowed us to focus a lot on our IP portfolio and strategy and to generate content and data for our publications.”

To do this, Ganguli moved the company and seven staff from Chicago to San Diego. In the past year, the company has grown to about 25 people. “We are growing quite quickly. San Diego has a lot to do with it, given the innovation hub here,” said Ganguli.

Although Cascade is amenable to most DNA purification methods, Ganguli said Veda’s growth will also support the development of its own proprietary sample prep methods that are catered toward its first product.

“For the first product, we are building a fit-for-purpose solution for a specific market,” said Ganguli. “If you look from an IP standpoint, [Veda has] a very broad portfolio. It goes beyond just CRISPR IP—we have engineering IP, and some of that ties back to sample prep.”

A league of their own

While CRISPR-based molecular detection platforms aren’t new, some prominent companies have yet to establish themselves with a commercial product.

The FDA gave Mammoth Biosciences, co-founded by Doudna, an early use authorization (EUA) in January 2022 for their CRISPR-based SARS-CoV-2 molecular assay. Since then, the company has expanded in other areas, including therapeutics and protein discovery. At ASGCT 2023, Janice Chen, PhD, co-founder and CTO, presented data showing that their ultra-compact NanoCas can perform robustly in vivo editing in mice, supporting one-and-done precision editing approaches to unlock new therapies.

Similarly, Sherlock Biosciences, co-founded by Zhang and others in 2018, announced in August that it had purchased a Cambridge-based manufacturing facility to support the production of five million diagnostic devices, with the capacity to grow as the company approaches commercialization. But to Ganguli’s point, even though Sherlock has gained U.S. rights to a patent for diagnostic use of a CRISPR system based on the smaller Cas12 enzyme, the CRISPR diagnostics developer marries amplification and detection through patents licensed to the company and the Broad Institute.

Then there’s Paragraf, which acquired Cardea Bio, a CRISPR-Chip company, earlier this year to pursue novel detection of both protein and RNA biosignals on a single graphene-based biosensor. Together with DARPA, the U.S. Army, and Siemens, Paragraf is creating a mass-market version of their SARS-CoV-2 RNA and protein detection platform.

It is not out of the question that Veda can make a splash in CRISPR-based molecular diagnostics. As the company provides updates in the coming months on its first product, we should get a better sense of whether they will be directly nipping at the heels of Mammoth and Sherlock or wading into uncharted territories.

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Over the past decade, single-cell biology and spatial biology have revolutionized how researchers understand biological processes. Single cell has made, according to an editorial in Molecular Systems Biology, important contributions to our understanding of cell types, cell states, cell–cell interactions, and tissue architecture—while spatial biology also promises to transform biology and especially pathology by measuring physical tissue structure and molecular characteristics at the same time, as a recent review article in Science has noted.

Playing leading roles in the development of both technologies have been 10x Genomics and its co-founder and CEO, Serge Saxonov, PhD, who discusses his career in genomics and science on GEN’s Close to the Edge.

After discussing how he developed a lifelong interest in genomics and science, Saxonov shares how as founding architect and director of R&D at 23andMe, he defined the initial conception of its product, built many elements of the technology, and drove strategy and execution of R&D functions as the direct-to-consumer genetic testing company scaled.

As VP of applications at QuantaLife, which Bio-Rad acquired in 2011 for $162 million, Saxonov was responsible for building content, driving new applications, and identifying key diagnostics opportunities for the core droplet digital PCR (ddPCR) technology.

In 2012, Serge co-founded 10x Genomics with Ben Hindson and Kevin Ness. As the company’s CEO, Saxonov defined 10x’s vision and strategy, contributed to core inventions, and has led the company since its inception. In 2016, Saxonov was honored as one of Goldman Sachs’ 100 Most Intriguing Entrepreneurs of the Year.

Alex Philippidis is senior business editor of GEN. Jonathan Grinstein, PhD, is senior editor of GEN.

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Carlsbad, CA—Durhane Wong-Rieger, PhD, president and CEO of the Canadian Organization for Rare Diseases and chair of a global alliance for patient organizations called Rare Diseases International, recalled a recent conference where he found himself speaking between panels with a patient advocate from Zimbabwe.

The woman, whom Wong-Rieger regards as one of the smartest and most involved patient advocates he knows, told him she would not go to any more sessions on cell and gene therapy because she didn’t want to hear about therapies that she or her patients would never get.

Wong-Rieger immediately realized the truth in her statement: many people who are in dire health conditions have no access to what may be a life-saving treatment.

“We really don’t have any rules for [cell and gene therapies] as we’re all saying this is the most amazing breakthrough in terms of therapies—truly lifesaving therapies,” said Wong-Rieger. “But the problem is we can’t give them to everybody. Unfortunately for us in this whole space, how do we get to doing what is the right thing?”

While Wong-Rieger doesn’t have the answer, he thinks that evolving ethics are at the heart of what will allow the field of cell and gene therapy get there.

A North Star

Ethics often gets a bad rap for being prohibitive, but for J. Benjamin Hurlbut, PhD, associate professor, School of Life Sciences, Arizona State University, that’s just plain wrong. Hurlbut believes that ethics is primarily about innovation and limits themselves can be sources of creativity and innovation.

“This is a domain where lives are at stake, and it makes this industry a different kind of industry than other industries because the stakes associated with the work, how the work is done, what the work means, and the name of the public goods the work has undertaken have a greater significance than in the automobile and smartphone industries,” said Hurlbut.

Tim Hunt, JD, CEO of the Alliance for Regenerative Medicine (ARM), has been mulling over the ethics of cell and gene therapy for months because, ultimately, this is the business of permanently altering people’s DNA or irreversibly transplanting cells.

“For too many of our patients—millions of people around the world—the status quo represents death or serious disability,” said Hunt. “No one runs out and takes gene therapy, a gene editing regimen, or cell therapy because they feel great and healthy. Patients are in difficult shape.”

Rob Perez, operating partner at the global growth equity firm General Atlantic, feels similarly about ethics, which he defines as a set of moral principles that helps one navigate challenging problems and situations.

“If we can have more conversations and come to more alignment on what an ethical code or ethical standards could be for the industry, it can help to be a north star on how we want to operate and how we want to make those very difficult decisions,” said Perez. “That’s always been a really important part of how I can deal with the most challenging questions, the most challenging decisions, and the most challenging complexities in operating a business.”

Value and accessibility

While the goal of many cell and gene therapies is to cure diseases and completely return a patient to full health, an incremental change in the patient’s health, which also can greatly affect a whole family, is understated. Somebody having to walk or sit for the rest of their time can be incredible in terms of that benefit.

Tay Salimullah, vice president, Global Head of Value and Access, Novartis Gene Therapies, was part of the team that led the first FDA-approved cell therapy, Kymriah, and is currently on a team working on a treatment for spinal muscular atrophy. He says defining patient success happens before one even begins to define value and economics.

“You have to actually understand the journey—the days, weeks, months, years—it takes families to try and get care,” said Salimullah. “It’s like a diagnostic odyssey where they can’t even actually then find out who’s going to treat them in what center. And that’s before even getting to the transaction of buying a gene therapy!”

For Salimullah, it’s all about democratizing access to gene therapies. Salimullah thinks carefully about how polarizing cell and gene therapy can be, especially regarding pricing.

“How can you have a $2-million gene therapy and leave babies to die?” asked Salimullah.

He believes in a self-imposed responsibility that looks for ways to find new opportunities where patients worldwide get access not only in the United States but in Europe and other environments. Salimullah thinks that the theme of democratizing access is dependent on finding the right people who can reinvent a playbook. But who is going to set that up? Will anyone take responsibility and apply it globally?

Janet Lambert, former CEO of ARM and now a consultant at The Densmore Group, believes the global democratization of cell and gene therapies will rely on public-private partnerships. That is a steep hill to climb.

“We’ve had such trouble successfully commercializing advanced therapies, and it is my view that getting it right and getting the economic base that’s necessary from the U.S. and Europe for these therapies is going to be absolutely essential to succeeding in global reach,” she said. “And we have a lot of work left to do there.”

The failed system of responsibility                             

Hurlbut thinks that it’s important to address whether the way of doing innovation in health for the public good is suited to the kind of innovation that is happening in cell and gene therapy. If it isn’t going to serve people as well as it can, then it’s no good.

“All the different stakeholders engage with the sector to ask pretty hard questions about whether the way business as usual is playing out is the best way for that business to play out,” said Hurlbut. “And if things change, some businesses may get broken. But that’s the way things should go if the question is about the broader purpose of this domain, which is to heal people, to treat people.”

According to Hurlbut, an obvious issue to address is pricing, because the sticker shock is so profound that it’s easy for people to protest such steep prices and blast the entire industry of cell and gene therapy as useless.

As he is not a health economist, Hurlbut doesn’t claim to have the answer. However, he said if the regimen is unsustainable for the long run such that society cannot benefit from the good things that its investments have produced, then it’s a failure. Hurlbut said that thinking about these kinds of questions—such as whether cell and gene therapy is economically sustainable—has ethical stakes.

“Is the right way to ask questions about that life in terms of healthcare costs saved, future economic productivity, or to count the various beings and pile them up and say, look, there’s value here?” said Hurlbut. “Maybe that’s the way that one has to convince some set of actors, but maybe that’s the wrong way to ask questions about children’s lives.”

Hurlbut goes one step further, suggesting that, depending on a particular society or government, the decision on whether to get treated or not could be taken completely out of the hands of the patient at the earliest of life stages, even before birth, for all sorts of reasons like cost-savings—the more people who are “cured,” the less of an economic burden on that society. Hurlbut brings up a situation for which he has unique insight—that of He Jankui and the IVF embryos that he gene-edited—noting that one of the central arguments for this infamous experiment that was undertaken in China a few years ago is that it’s a lot easier and a lot cheaper to do it in one cell than to do it in many.

Hurlbut thinks that thinking through this ethical problem highlights that with the system that gets put in place—the drug makers, the regulators, the insurance companies, the health systems—no singular actor is responsible, but instead, it’s the collective actions of the community put in place—and that’s where things can go wrong because it results in failures of responsibility, compassion, and recognition of what is at stake.

After all, there is a dark side to gene therapy, and not every company working on cell or gene therapy is thinking about how their technology may contribute to applications that they would never endorse and, even, abhor, such as genetic cleansing.

Changing the path of humanity 

Even in a world where accessibility and economics for cell and gene therapies get worked out ethically, there’s another set of questions lying in wait that are top of mind for Lambert. For example, if a person chooses to get treated with gene therapy and it reaches the germline, genetic changes will be made in the patient and possibly in their children and generations to come.

Similarly, who is responsible for whether a child with a disease will get gene therapy? Does it fall into the hands of the parents?

“One of the most profound conversations I had in my time at ARM was with a mom who had signed her child up for a safety study,” said Lambert. “And even though this was a very well-educated mom, she felt profound guilt about having done that and that her child was, therefore, ineligible to get a therapeutic dose, which in that particular case turned out to be different than the safety trial dose.”

When it comes to gene editing, Lambert thinks that a major challenge in deciding what is a disease, what’s worth preventing, and what needs to be prevented.

At the end of the day, cell and gene therapy is not about eliminating or customizing people—it’s about treating patients.

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Novo Nordisk (NVO) continued its year-long stock surge this week when it halted a Phase III trial early due to undisclosed efficacy results suggesting that its blockbuster adult type 2 diabetes drug Ozempic^® (semaglutide)—which shares the same active ingredient as its obesity drug Wegovy^® (semaglutide injection)—is also an effective treatment for chronic kidney disease (CKD).

Novo Nordisk announced an early halt to its Phase III FLOW trial (NCT03819153), designed to compare semaglutide with placebo in the progression of renal impairment in people with type 2 diabetes and chronic kidney disease. The company cited a recommendation from the study’s independent Data Monitoring Committee (DMC) following results from an interim analysis that were not shared in a press release announcing Novo Nordisk will begin closing the trial.

Results from FLOW are expected to be read out during the first half year of 2024, Novo Nordisk said.

Launched in 2019, FLOW enrolled 3,534 patients and has been conducted at more than 400 investigator sites in 28 countries. According to baseline data published August 31 in Nephrology Dialysis Transplantation, enrolled participants had a baseline mean age of 66.6 years, haemoglobin A1c of 7.8%, diabetes duration of 17.4 years, an estimated glomerular filtration rate (eGFR) of 47.0 ml/min/1.73 m2 (SD 15.2) and median urine albumin-creatinine ratio (uACR) of 568 mg/g (range 2‒11 852), with 68.2% of patients at “very high risk” for CKD progression.

The CKD market is projected to grow from $32 billion as of last year to $47.9 billion by 2032, at a compound annual growth rate of 4% from 2023 to 2032, Allied Market Research has projected.

Acing the Phase III trial helped Novo Nordisk maintain a rising stock price, with shares on Nasdaq Copenhagen climbing 5% on Wednesday, from DKK 650.10 ($92.49) to DKK 681.80 (an even $97), then another 4% on Thursday, to DKK 710.20 ($100.47). Novo’s American depositary receipts (ADRs) on Nasdaq in New York rose 6% Wednesday from $93.01 to $98.84, and another 1.5% on Thursday as of 12:49 p.m. ET, to $100.29.

Novo Nordisk has seen its shares rise 13% since October 3, when they closed at DKK 625.70 ($89.04), a day after the company won FDA approval for another drug with a kidney-related indication—Rivfloza^TM (nedosiran) injection, a once-monthly subcutaneous RNA interference (RNAi) therapy designed to lower urinary oxalate levels in children ages nine and older and adults with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function.

Novo’s ADRs have risen 14% from $87.78 on October 3.

Near doubling year-over-year

More impressively, however, Novo Nordisk shares have surged 45% since January, when they began the year trading at DKK 471 ($67.04)—and have soared 71% over the past 12 months, from DKK 398.60 ($56.73) on October 11, 2022. That surge has transformed Novo Nordisk market capitalization—the product of the share price and the number of outstanding shares—into the second highest in Europe behind Nestle, according to Morningstar. Based on that market cap, Novo Nordisk topped GEN’s A-List of Top 25 Biotech Companies of 2023, published in May.

U.S. investors have been even more bullish on Novo Nordisk as its ADRs year-over-year have nearly doubled, rocketing 88.5% from $52.19 on October 11, 2022.

The ADR and stock surges reflect growing patient demand for drugs indicated for diabetes—and especially weight loss, since semaglutide is also the active ingredient in Novo Nordisk’s obesity drug Wegovy.

Investors apparently agree with Novo Nordisk’s apparent conclusion that Ozempic, as with other GLP-1 receptor agonists, have “therapeutic benefits far beyond their original intended purpose, according to Emily Field, director, head of European Pharmaceuticals Equity Research with Barclays, as reported by Reuters.

During the first half of this year, sales of Ozempic jumped 58%, from DKK 26.384 billion (about $3.758 billion) to DKK 41.741 billion ($5.945 billion), after zooming 77% last year, to DKK 59.750 billion ($8.509 billion) from DKK 33.705 billion ($4.8 billion) in 2021.

Also benefiting from Novo Nordisk’s good Ozempic news is Eli Lilly, whose stock has increased 6% earlier this week, from $571.76 on Monday to $605.28 on Wednesday. Lilly markets the type 2 diabetes drug Mounjaro^® (tirzepatide), to which the company is working to add an approval as a treatment of adults with obesity, or overweight with weight-related comorbidities. Lilly has a rolling submission to the agency for approval of the obesity indication, and has reported positive results earlier this year from three Phase III trials: SURMOUNT-2 (NCT04657003), SURMOUNT-3 (NCT04657016) and SURMOUNT-4 (NCT04660643).

Mounjaro has already reached blockbuster status, with January–June 2023 sales of $1.548 billion, multiples of the $16 million racked up in the first half of last year (all of it in June 2022, the month Mounjaro was commercially launched). For all of last year, Mounjaro generated $482.5 million in sales according to Lilly.

Morningstar has projected that sales of Ozempic will rise to earn $19.3 billion in 2027 and about $20 billion in 2030. Lilly’s Mounjaro^® (tirzepatide) future sales have been pegged even higher at $21.2 billion in 2027, while Wegovy, a next-gen once-weekly injection version of semaglutide approved in 2021, is projected to earn $12.5 billion in 2027.

Dodging a Bullet

Novo Nordisk dodged a proverbial bullet October 2 when the U.S. Patent and Trademark Office (USPTO)’s Patent Trial and Appeal Board (PTAB) denied an inter partes review (IPR) request by Mylan Pharmaceuticals, a generic drug company owned by Viatris, challenging Novo’s two key composition of matter patents for semaglutide, Nos. 8,129,343 and 8,536,122.

IPRs are designed to review the patentability of one or more claims in a patent based on two of the three patentability criteria, novelty and non-obviousness. In challenging the patents of Novo Nordisk, Viatris hopes to accelerate the arrival to market of the first generic version of Ozempic.

“VTRS’s arguments against the patents appeared weak, & we expected NVO to win,” Jefferies equity analyst Akash Tewari and colleagues wrote October 2 in a research note.

Two days later, however, the PTAB granted a separate IPR request to review the patentability of 10 claims within a third semaglutide patent, No. 10,335,462, covering dosing regimens: “We are persuaded that Petitioner has demonstrated a reasonable likelihood that it would prevail with respect to at least one claim challenged in the Petition,” according to the decision, written by Administrative Patent Judge Susan L.C. Mitchell.

While Novo Nordisk has vowed to vigorously defend the ‘462 patent, Tewari said the setback for the company isn’t as significant as it could have been.

“We don’t think this is a key patent as it only covers Ozempic, & the key claim is treating T2DM pts [type 2 diabetes patients] with a dose of 1.0 mg weekly,” Tewari and colleagues noted, citing the dosage of up to 2.4 mg weekly used in another clinical study—the Phase III SELECT trial (NCT03574597), a placebo-controlled, 17,609-participant study designed to assess whether semaglutide can reduce the risk of cardiovascular events in patients who are overweight or obese, with prior cardiovascular disease.

Two other challenges remain for Ozempic. Novo Nordisk is seeking to stop compounded versions of Ozempic as well as Wegovy from reaching the market. The company has sued four compounding pharmacies led by Brooksville Pharmaceuticals in U.S. District Court for the Middle District of Florida, Tampa Division, arguing that the compounded versions were never approved by the FDA. U.S. District Judge William F. Jung dismissed the suits on October 5, but Novo Nordisk has said publicly it plans to refile them.

Another challenge looming is Medicare drug-price negotiation, with Cantor Fitzgerald analyst Louise Chen telling CNBC in August that the drug may be among those chosen by the federal agency for discussions: “Ozempic is going to be the biggest one that people are going to watch really closely in the second round of negotiations.”

Leaders & Laggards

• Akero Therapeutics (AKRO) shares have plunged 70% over two days after the company disappointed investors with results from its Phase IIb SYMMETRY trial (NCT05039450) assessing lead product candidate efruxifermin (EFX) in patients with compensated cirrhosis (F4) due to NASH. EFX missed the study’s primary endpoint of achieving a one-stage or better improvement in liver fibrosis without worsening NASH, following 36 weeks of treatment with EFX vs. placebo. However, Akero cited a positive trend of 22% and 24% of the 28mg and 50mg EFX-treated groups, respectively, experiencing at least a one-stage improvement, vs. 14% for placebo. “We believe EFX has the potential to show additional improvements for patients after the long-term follow-up period is complete at Week 96,” Akero president and CEO Andrew Cheng, MD, PhD, stated. Shares plummeted 63% from $48.54 to $18.15 on Tuesday, and fell another 19% on Wednesday, to $14.68.
• Tempest Therapeutics (TPST) shares soared into the stratosphere, zooming more than 4,000% from 24 cents to $9.77 on Wednesday, after the company released updated positive results from an ongoing global Phase Ib/II clinical trial (NCT04524871) in which the lead program of the peroxisome proliferator-activated receptor alpha (PPAR⍺) antagonist TPST-1120 showed clinical superiority in multiple endpoints when combined with Tecentriq^® (atezolizumab) and Avastin^® (bevacizumab) in a randomized comparison to the two Roche (Genentech) marketed cancer drugs in the first-line treatment of patients with unresectable or metastatic hepatocellular carcinoma (HCC). Data showed a confirmed objective response rate of 30% for the TPST-1120 triplet arm versus 13.3% for atezolizumab and bevacizumab. Duration of response has not yet been reached.
• Teva Pharmaceutical Industries (TEVA) American depositary shares rose 2.5% over two days while its shares traded on the Tel Aviv Stock Exchange inched up about 1%, from ILS 3,608 ($909.03) to ILS 3,631 ($914.87) Wednesday, after the Israeli-headquartered drug developer said Tuesday it did not foresee a “meaningful” impact from Israel’s war against Hamas. Teva said its revenues in Israel last year accounted for approximately 2% of its $14.9 billion in global revenues, while production in Israel constituted less than 8% of its total global production in U.S. dollars. Production remains “largely unaffected,” the company added. “As an Israeli company we condemn this appalling assault and Teva stands with Israel in this time of great loss and challenge,” Teva declared.
• Ventyx Biosciences (VTYX) shares nosedived 37% over 2–1/2 trading days despite reporting positive results from a Phase II trial (NCT05156125) assessing the oral S1P1 receptor modulator VTX002 in moderate-to-severely active ulcerative colitis (UC). Ventyx reported that 28% of patients on the 60 mg dose and 24% of patients on the 30 mg dose achieved the trial’s primary endpoint of clinical remission at Week 13 compared to 11% of placebo But investors appeared unimpressed since Ventyx is trying to compete with Bristol-Myers Squibb, whose UC drug Zeposia^® (ozanimod) won FDA approval in 2020, and Pfizer, whose UC candidate etrasimod is under FDA and European Medicines Agency review. Shares skidded 26% Tuesday, from an even $30 to $22.22, slipped 9% on Wednesday, to $20.25, and fell another 7% to $18.84 Thursday as of 12:30 p.m.

Alex Philippidis is Senior Business Editor of GEN.

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Carlsbad, CA—The timing of the Cell & Gene Meeting on the Mesa appears to have been prearranged with the help of a crystal ball. Members of the cell and gene therapy field are anxiously awaiting the FDA’s review of three submissions before the end of 2023: two treatments for sickle cell disease—exa-cel (Vertex and CRISPR Therapeutics) and lovo-cel (Bluebird)—as well as Bristol Myers Squibb and 2Seventy Bio’s Abecma for earlier multiple myeloma.

The sector is at an inflection point. There’s a lot of excellent science and exciting clinical results. Still, it remains to be seen whether that will translate into commercial success—a major focus of this week’s Alliance for Regenerative Medicine (ARM) conference. 

Regulatory approval

All eyes, therefore, are on Nicole Verdun, MD, the new permanent director of the FDA’s Office of Therapeutic Products (OTC), which is within the Center for Biologics Evaluation and Research (CBER). Verdun’s plate has a healthy serving of cell and gene therapy clinical trials for rare and serious diseases, which typically do not fit the testing paradigm of a randomized clinical trial. According to Verdun, who will be working hand in hand with CBER director Peter Marks, MD, PhD, the key to the approval of cell and gene therapies for conditions with just a handful of patients is a mix of communication and regulatory flexibility.

“We have INDs open for diseases where there are 11 patients in the United States,” said Verdun. “There needs to be increased communication earlier on in the development process, and there has to be consideration for the disease, the benefit-risk for how rare it is, and we have to do what we can to partner to get more of these therapies to patients that need them.”

To get right at this, Verdun highlighted the “Support for clinical Trials Advancing Rare disease Therapeutics” (START) Pilot Program. Three chosen START participants must be sponsors of cell and gene therapies for rare diseases and serious conditions currently in clinical trials under an active Investigational New Drug Application (IND). These participants will be able to receive regular advice and ad hoc communication with FDA staff to talk about product-specific development issues, such as clinical study design, choice of the control group, and fine-tuning the choice of the patient population. START will begin accepting applications between January 2 and March 1, 2024. 

Manufacturing and commercialization

 As more cell and gene therapies begin to move into the clinic, there is growing attention on manufacturing, which may be the major bottleneck for creating commercialized products.

Automation and artificial intelligence (AI) will be major disruptors to the manufacturing and commercializing cell and gene therapy. The efforts made by Cellares with its Cell Shuttle to integrate batch processing and automation into the assembly process serve as evidence of this. But automation and AI will not be enough.

According to Ann Lee, PhD, chief technical officer at Prime Medicine, there are three key factors to developing commercial-grade manufacturing. The first is picking the right people, because getting a cell and gene therapy program into the clinic requires a breadth of expertise that will likely not be found in a single individual. The second is data infrastructure, because to generate data that will be submitted for an IND or BLA submission, processes need to be in place where it is retrievable, tracked, and analyzed. Third, Lee said that regardless of going the internal or external route, the process needs to be transparent because no cell or gene therapy will be approved if the manufacturing process is a black box.

Some key factors go into choosing to partner with an external CDMO for manufacturing or bringing it in-house, often touted as the best way to control one’s destiny. While many have approached the manufacturing of cell and gene therapies with the view to putting all their manufacturing capabilities into the hands of partner CDMOs, some have decided to take this on to various degrees to gain increased control of their medicine’s destiny.

For cell therapies, some of this may come down to whether a company’s approach uses allogeneic or autologous cells. Sumit Verma, senior vice president of Global Strategic Manufacturing at Iovance Biotherapeutics, said that, while there is a lot of allogeneic work being done and CAR T having that success rate, autologous cell therapy has its place as a potentially unrivaled personalized medicine but is incredibly challenging from a logistics side. “For the patient’s benefit, being able to manufacture [an autologous cell therapy] batch is a key concept that I think you’re going to see a lot more maturity next year,” said Verma.

With two autologous cell therapy, using patient-specific tumor-infiltrating lymphocytes and peripheral blood lymphocytes (PBL), Iovance has taken an approach to investing in both their own manufacturing capabilities, as evidenced by their recent investment in establishing the Iovance Cell Therapy Center (iCTC)—a 136,000-square-foot facility in Philadelphia.

While Intellia Therapeutics will also be opening a new manufacturing facility in Waltham, Massachusetts, in 2024, chief business officer Derek Hicks said that in this market environment, he wouldn’t be surprised if there are more deals featuring a shared partnership between manufacturing and smaller biotechs.

“When you think about manufacturing, it’s not just that shared risk,” said Hicks. “It is how can you work with someone that actually helps you accelerate because we’re trying to get these products to patients. The research is moving very quickly, so how do you ensure that manufacturing doesn’t stop you from bringing things forward? These are the things that we all need to think about.”

Healthcare systems

Bob Smith, senior vice president of the Global Gene Therapy Business at Pfizer, said a lot of his concern for getting cell and gene therapies commercialized is related to the healthcare systems in the U.S. and abroad.

“A lot of healthcare systems have a negative innovation bias in the way that they evaluate and value the innovations that our sector is developing,” said Smith. “No individual company is going to be able to overcome this, and I think we need to think about how we communicate not just with the healthcare systems and how they evaluate not just the regulatory aspects, but now really the value of what we’re bringing to patients.”

For example, Smith points to some European markets where sometimes there isn’t a price approval for a year and a half after the regulatory approval.

“Think about the burden that is on small midsize companies that don’t have a balance sheet like [Pfizer does],” said Smith. “We can absorb that financial hit, but it’s going to put a tremendous financial strain on capital-intensive companies, and we need to really think through how we can change that paradigm to be much more efficient, principally for the benefit of patients but also, quite frankly, for the sustainability of the sector.”

Phil Cyr, senior vice president at Precision Value & Health, said that historically, a lot of payers and health technology organizations have been very focused on cost-effectiveness, but that they’ll also be looking at the budget impact and affordability, especially as cell and gene therapy begin to move into more prevalent diseases, which he believes will happen. Cyr thinks that the way to overcome this is by developing an evidence base to discourage people from thinking about sticker price and more towards long-term value.

“How do you go to a payer with a three to four-year window and make them understand that [gene therapy] will benefit them?” said Cyr. “I can think of one payer that actually built a model to figure out how long they needed to keep that member in their plan to recoup the money.”

For these reasons, organizations like Express Scripts and Cigna’s Embarc will play a key role in the future of gene therapies by helping protect customers from the high cost of gene therapy drugs and ensure access for those who need them.

 Expectations for 2024

Much is riding on the cell and gene therapy submissions that are due to be reviewed by the FDA before the end of this year. If they are successful, its possible that there will be a change in sentiment within the investor community—not to mention patients.

Next year, the Cell and Gene Therapy Meeting on the Mesa will move to Phoenix, Arizona, as the conference has maxed out its current capacity at the Park Hyatt Aviara Resort in northern San Diego. If the FDA approves these initial submissions, the new venue will likely be filled in 2024. But what if they’re not approved? All it takes is one bad batch that will reflect poorly on the entire industry.

As regulatory submissions and clinical data trickle in, there has to be a high standard. But standardization will not be achievable by a single business entity or the FDA alone. This new and evolving field will require organizations like ARM to unite different voices. That’s exactly what’s happening right now at the Cell and Gene Meeting on the Mesa.

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Carlsbad, CA—Across the board, biotech investing in 2023 has seen a retraction from the high levels seen the past three years: venture investment has dropped and companies large and small have lost value. However, that doesn’t mean that biotech investors have lost interest or abandoned ship. In fact, with the FDA reviewing submissions for three cell and gene therapies in Q4, investors are looking beyond the discovery and development phase and into the manufacturing and commercialization of these potentially revolutionary medicines—a theme that has taken hold at the 2023 Cell and Gene Meeting on the Mesa.

To get there, cell and gene therapy companies will have to do more than fly by on the seat of their pants, hoping to just live another day. Instead, there’s a sentiment amongst investors that now is the time to show a vision for the long run if biotech hopes to have financial support to carry them through until the headwinds die down and into the tailwinds for smooth sailing. 

Is this the new normal?

According to Dynamk Capital’s market analysis, the size and count of deals—mergers and acquisitions (M&A) and initial public offerings (IPOs)—have dropped from the 2020 to 2022 levels through the pandemic. But with three quarters complete in 2023, their analysis shows that the industry numbers are on par with 2018 and 2019 levels, perhaps even higher. Beyond some outliers such as Danaher’s acquisitions of Aldevron and Cytiva as well as the Thermo-PPD deal, Daniella Kranjac, founding partner and managing director at Dynamk Capital, said the trend for deals is pretty healthy.

While recent transactions aren’t pulling in deals of 20x revenue as seen during the pandemic, they’re also not at the 3–6x revenue multiples seen in 2018–2019. The industry is at the “new normal,” she said, which is in the 10–15x range.

Valerie Dixon, managing director at Morgan Stanley, says it is less a “new normal”, and more of a reversion to the historical mean. It is foolish to hope for the same “irrational exuberance” of the market to return to pandemic levels and that things won’t change back to how they were in 2020 and 2021, she said.

“They’re not going to be saved by a white knight and get 15x as much revenue for their company. That’s not happening!”

Kicking the can down the road

While some investors, board members, and founders have been trying to stay afloat in the turbulent economic climate, Dixon said the perception that they can just kick the can down the road and stretch their cash for another two to four quarters is irrational, even in the context of recent geopolitical events—Russia and Ukraine and now Israel and Palestine.

“You can’t manage your balance sheet anticipating World War III,” said Dixon. “You need to be managing your own business for a two to three-year timeframe, not for next quarter or making that month’s quota.” Instead, Dixon believes that managing a biotech business today requires creating long-term, enduring, profitable growth. That’s what funders think is most credible.

“When you can tell a story about how you’re investing for long-term growth, then [the investors] will be there for your expansion capital or your growth capital when you need it,” said Dixon. “If they take that long-term mindset with you, that means that you can have confidence that they’re going to have capital that’s going to grow with you along the way. It’s not growth at any cost; it’s making sure you’re doing responsible growth and you’re hitting… milestones that will get you to that next inflection point.”

While Sean Mackay, Operating Partner at Casdin Capital, is excited about the numerous companies with great products in great markets, he won’t invest in a company if they can’t support their own operating expenses. For Mackay, it comes down to the return on investment from capital.

Consistency is key, Mackay insisted. He wants to know that a prospect’s revenue isn’t random and that a particular move is devoted to a big market that the company is creating or disrupting, which is harder to do. A company’s capital-raising process has to increase the number of shots on goal and, thus, increase the probability of raising the money. To succeed, Mackay says companies need to be creative and expand their funnel instead of just hopping to the next shiny thing.

To IPO or not IPO

Although there have been signs of life for investing in healthcare and biotech—nine deals so far in 2023 (eight in biotech)—today, only three are trading around issue price. Some 2021 biotech IPOs, Dixon notes, are trading as low as 85% below the original issue price.

“Just because you’re going public doesn’t mean everything’s great,” said Dixon, who has led Morgan Stanley’s efforts in life sciences tools and diagnostics. “You still have to pay attention to aftermarket performance… and not just be the first one out of the gate. Be consistent in execution and a good steward of the capital that you raise. Maybe they [went] public too early, took their eye off the ball, or any number of factors—all those things play into the success of an IPO.”

Kranjac’s guidance to founders trying to get term sheets done in this market environment and the near future is to make sure they are thinking about who they bring to the table— board members and investors who understand the market and can be helpful in terms of forging additional relationships, whether for investments, operations, or talent.

There is no magic wand to secure a deal sheet for financing, but Kranjac shared the advice she can give the founder of an early-stage company: although they may have the luxury of being pre-revenue and not having reportables on a monthly or quarterly basis, they should be raising as much money as possible.

“In this environment, the guidance that we’re giving our portfolio companies, and even companies that we’re looking at going forward, is don’t wait,” said Kranjac. “There were a number of folks that early in the year said, ‘We’re going to wait until the fall when the market’s better or until [JP Morgan] 2024, when things are going to be great. Don’t wait!”

As to how to value a company, Mackay said that during the 2019 and 2022 period, research analysts might have understood the liquidation value for a sale. But when there’s no M&A activity, that number is more difficult to calculate. The huge push by big pharma to invest in new therapeutic modalities like cell and gene therapies is evidence, according to Mackay, that the industry’s “tailwinds” appear to be very strong.

Dead cells don’t cure cancer

A major early theme of the 2023 Meeting on the Mesa has been manufacturing and commercialization. Along these lines, while the panelists are all excited about the development of cell gene therapies and the enabling tools that go along with them, they’re keeping a close eye on companies involved in manufacturing and commercialization.

Kranjac agreed that bioproduction is exciting because there are going to be many such medicines. And those are exactly the types of companies, like RoosterBio, Curi Bio, and CellFE, that Dynamk has been adding to its portfolio.

“You can’t take your eyes off the ball on the manufacturing process and the tools that help with potency, stability, purity, and quality control—dead cells don’t cure cancer,” said Dixon. “When there are huge acquisitions with outsourced manufacturing and you start seeing the Thermo Fishers and Danahers making multi-billion-dollar acquisitions in the space to have capacity for cell gene therapies, that’s a wake-up call.”

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NEW YORK—David R. Liu, PhD, the genome editing pioneer whose Broad Institute lab developed both base editing and prime editing technologies over the past decade, told an audience of investors that prime editing is on track to join base editing in human clinical trials in less than a year.

“Likely the first clinical trial will be in 2024,” Liu said, speaking via video at the Chardan 7^th Annual Genetic Medicines Conference, held this week in New York City. “Prime editors, we anticipate, will be in the clinic next year.”

Liu is a co-founder of Prime Medicine, the publicly traded company formed to commercialize prime editing by developing treatments based on applying the technology’s “search and replace” approach to genome editing.

In releasing second-quarter results in August, Prime Medicine conveyed the possibility of a first trial for its gene editing technology next year by publicly including among its anticipated upcoming milestones: “Complete first IND filing as early as 2024.” Additional IND filings are anticipated in 2025, Prime Medicine said in a company presentation to investors last month.

By contrast, base editing technology, first disclosed in 2016 by Liu’s lab—is under investigation in six ongoing clinical trials.

Prime Medicine has not yet released which of its 18 pipeline programs will be selected as its first clinical-phase candidate.

IND-enabling candidate

According to Prime Medicine’s presentation last month, only one of its programs has reached the phase of IND-enabling studies—a blood-targeting candidate for chronic granulomatous disease (CGD), designed to be administered ex vivo.

Three other programs are in lead optimization phases—a Wilson’s disease candidate targeting liver tissue and using lipid nanoparticle (LNP) delivery; a retinitis pigmentosa/rhodopsin candidate targeting eye tissue and using adeno-associated virus (AAV) vector delivery; and a neuromuscular tissue targeting candidate for Friedreich’s ataxia also delivered via AAV.

The rest of Prime Medicine’s pipeline programs are in preclinical discovery phases.

During the conference, Liu noted that AAV has fallen out of favor with some gene therapy developers, concerned about harm to patients from needed redosing, as that will often induce high-titer neutralizing antibodies that make it difficult for a second AAV dose to be effective. That’s less likely to be a problem in genome editing, Liu asserted, as long as the editing therapy is effective enough to be a one-time treatment.

“If you look at some of the new generation AAVs that have liver detargeting, that go to previously challenging organs like the brain or muscle or lung, even in primates in some cases, I actually think those AAVs are going to be powerful tools for the delivery of these gene editing agents, especially because we anticipate that we will only need to deliver them once to effect a permanent benefit for the patient,” Liu said.

Both prime and base editing are designed to engineer precise base substitutions while avoiding double-stranded DNA breaks (as occurs in CRISPR-Cas9 gene editing). As a postdoctoral fellow in Liu’s lab, Alexis Komor, PhD, spearheaded the development of the first base editing technology, which could install specific base substitutions (C to T or G to A) without cleaving DNA. Eighteen months later, her colleague Nicole Gaudelli, PhD, developed a complementary adenine (A to G) base editor. Both base editing approaches were detailed in separate papers published in Nature.

In 2019, Liu, former postdoc Andrew Anzalone MD, PhD, and colleagues detailed prime editing in Nature. In prime editing, the desired edit is supplied in an extension to the guide RNA, which is then converted to DNA using the enzyme reverse transcriptase. The technology can introduce targeted insertions, deletions, and all 12 possible base-to-base conversions.

Generating positive results

In May, Liu and colleagues published in Nature Biotechnology a paper entitled “Efficient prime editing in mouse brain, liver and heart with dual AAVs”, in which they sought to address bottlenecks limiting AAV-mediated prime editing in vivo by developing AAV-PE vectors with increased PE expression, stability of prime editing guide RNA, and modulation of DNA repair.

The study detailed how two dual-AAV systems were developed—v1em and v3em PE-AAV. They generated positive results by enabling therapeutically relevant levels of prime editing in mouse brain (up to 42% efficiency in cortex), liver (up to 46%) and heart (up to 11%).

The group declared that the results represented “the first prime editing in postnatal brain and heart and substantially higher AAV-mediated in vivo prime editing efficiencies than have been previously reported in the liver.”

The dual-AAV systems were also used to install the rare Apolipoprotein E Christchurch (APOE3 R136S) variant in vivo for Alzheimer’s disease in astrocytes, and the dominant variant of proprotein convertase subtilisin/kexin type 9 (PCSK9) Q152H (mouse Pcsk9 Q155H), associated with a reduction in low-density lipoprotein (LDL) cholesterol levels and protection from coronary artery disease in hepatocytes.

“Our results advance the potential of prime editing for basic research and therapeutic applications and establish optimized PE-AAV systems as an effective in vivo PE delivery method,” Liu and colleagues concluded in the study.

Correcting CGD mutation

Also in May, Prime Medicine researchers presented updated preclinical data showing the potential of prime edited cells to correct the causative mutation of chronic granulomatous disease (CGD) at the American Society of Gene and Cell Therapy (ASGCT) 26^th Annual Meeting, held in Los Angeles.

In an abstract, “Prime Editing of Human CD34+ Long-Term Hematopoietic Stem Cells Precisely Corrects the Causative Mutation of p47phox Chronic Granulomatous Disease and Restores NADPH Oxidase Activity in Myeloid Progeny,” the researchers reported greater than 90% prime editing in CD34⁺ cells from four donors—a finding they said showed their technology to be highly reproducible.

“These data show that prime editing precisely corrects the ΔGT mutation at NCF1 in p47phox CGD patient CD34+ cells and restores NADPH oxidase activity and myeloid cell function in progeny of these PE-corrected cells, thus representing a potential curative approach for p47phox CGD patients,” the Prime Medicine researchers concluded.

Earlier data showed the ability of prime editing to correct a CGD causative mutation in CD34⁺ cells ex vivo, with the prime edited CD34⁺ cells engrafting long-term in vivo and editing levels greater than 92%.

During the ASGCT conference—which featured a presidential symposium keynote address by Liu—Prime Medicine highlighted its Prime Editing Assisted Site-Specific Integrase Gene Editing (PASSIGE) platform, showcasing its potential application to generate multiplex-edited chimeric antigen receptor (CAR)-T cells for the treatment of some cancers and immune diseases, without the use of viruses.

Liu co-founded Prime Medicine with Anzalone, currently the company’s head of the prime editing platform. Anzalone detailed his creation of prime editing and career in genome editing earlier this year in an exclusive interview on GEN Edge’s video interview series “Close to the Edge”, and published in our sister journal GEN Biotechnology.

Genome editing methods

Base and prime editing, Liu told conferees, were two of three different ways that have emerged for editing the genomes of human cells currently that meet the criteria of reasonably efficient and reasonably specific, used by hundreds of laboratories, and well-validated. The third, he said, was using CRISPR nucleases, which can result in gene disruption and creation of indels.

There are three base-editing candidates now in clinical trials:

• BEAM-101: Beam Therapeutics—co-founded by Liu with Feng Zhang, PhD, and Keith Joung, MD—is assessing BEAM-101, delivered via autologous bone marrow transplant, to treat severe sickle cell disease in adults in the Phase I/II BEACON trial (NCT05456880). Beam said in August it had enough consented patients to fill its sentinel cohort and begin an expansion cohort. Beam expects to report initial patient data from BEACON in 2024.
• BEAM-201: Beam last month dosed the first patient in a Phase I/II trial (NCT05885464) evaluating BEAM-201, a multiplex base-edited CAR-T cell therapy for the treatment of relapsed/refractory T-cell acute lymphoblastic leukemia and lymphoma (T-ALL/T-LL).
• VERVE-101: Verve Therapeutics is studying VERV-101—the first in vivo base editing therapy to reach the clinic—to treat heterozygous familial hypercholesterolemia (HeFH) in the Phase Ib heart-1 trial (NCT05398029), enrolling patients in New Zealand and the U.K. Verve expects to complete patient enrollment outside the U.S. after the FDA placed a hold on its IND application pending additional data.

The progression of base and prime editing from research papers to preclinical to clinical trials have both been swift, Liu observed. “These are breathtakingly fast transitions from academia to actual clinical applications,” Liu said, paying tribute to numerous laboratories advancing these technologies. “There are, for example, more than 1,000 research papers published on base editors and prime editors,” he said.

“Our lab has not published most of those,” Liu quipped, drawing laughs. “And it’s something that has really helped establish the robustness of the technology, de-risk it, improve it, and given us and the patient communities some confidence that it can be deployed in ways that are useful for helping patients.”

Alex Philippidis is Senior Business Editor of GEN.

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An analyst and an influential American investor appeared to hold more sway over the price of Nvidia (NVDA) shares over the past week than French authorities investigating the Silicon Valley-based microprocessing giant with a growing presence in the life sciences, judging by recent stock activity.

Investigators from France’s Autorité de la Concurrence—the French Competition Authority—raided Nvidia’s French offices at dawn on September 27 on suspicion that it may carried out “anticompetitve practices” in the “graphics cards” sector.

The authority’s statement did not spell out the practices being investigated, or the company raided. However, numerous news outlets including Reuters and The Wall Street Journal cited Nvidia by name, after the French business magazine Challenges earlier reported that Nvidia was the target of the raid.

The authority emphasized in a statement that dawn raids like the “unannounced inspection” carried out last week “do not pre-suppose the existence of a breach of the law,” but as a step toward a complete investigation of competitive practices within a given industry.

Nvidia has declined to comment.

Nvidia was not among companies mentioned in a French government report issued June 29 that outlined concerns over a lack of competition in the sector—although the report did mention other companies, such as Amazon Web Services, Google Cloud, and Microsoft Azure.

The authority’s action had no apparent effect on Nvidia shares, which rose 1% the day of the raid, from $419.11 to $424.68. Shares continued to climb 5% through Monday, reaching a high for the week of $447.82 before declining 3%, to $435.17, then rebounding 3% over two days, to $446.88 at the close of trading Thursday.

Monday’s rise came after Toshiya Hari, lead semiconductors sector analyst with Goldman Sachs Research, added Nvidia’s stock to the firm’s “Conviction List” of top picks—although Hari did not change Goldman’s “Buy” rating or 12-month price target of $605 a share.

However, the French raid has led the European Commission to begin “informally” examining potential unfair practices related to the graphics processing units (GPUs) used for artificial intelligence (AI) applications, Bloomberg News reported, citing unnamed sources.

Stock selloff

Also on Monday, the influential electronic transfer fund ARK Genomic Revolution ETF (ARKG) had sold 8,983 shares of Nvidia stock, shrinking its holding in the company from 88,223 to 79,240 shares as of Tuesday, according to ARKG’s chart detailing its Nvidia holdings. That stake dipped further when ARKG sold another 499 shares on Wednesday, then another 15,696 shares on Thursday, bringing its stake in Nvidia to 63,045 shares with a total market value of about $28.2 million.

The fund’s ownership in Nvidia carries a “weight” of 1.7% of the 39-company portfolio, according to the website of ARKG parent ARK Investment Management (ARK Invest), whose chief investment officer and portfolio manager is Catherine D. (Cathie) Wood.

ARKG is an electronic transfer fund concentrating on healthcare and other sectors “expected to substantially benefit from extending and enhancing the quality of human and other life.”

Over the past year, ARKG has shed about two-thirds (66.5%) of its 12-month high of 188,160 shares held on November 18, 2022. Since August 24, when ARKG held 134,323 Nvidia shares, the ETF has sold off a combined 71,278 shares in six transactions, including the three that took place this week.

In January another ARK ETF, its flagship ARK Innovation ETF (ARKK), sold off 800,000 Nvidia shares in January—thus missing practically all of the company’s stock surge in the first half of this year, as investors jumped on the AI bandwagon.

As GEN reported in June, Nvidia shares rocketed 180% between January 3 and May 30 (when it finished at $401.11), then climbed another 5.5%, finishing on June 30 at $423.02 or up 196% from $143.15 at the start of 2023 trading on January 3.

“$NVDA is priced ahead of the curve,” Wood posted on Twitter (now X) May 25, when Nvidia’s stock price stood at 25x its expected revenue for this year.

On September 1, Wood promoted an ARK paper about potential opportunities stemming from investment in AI by posting on X her fund’s current thinking—namely that AI growth won’t be limited to giants like Nvidia: “Since 2014, our analysts have been dissecting the AI revolution. While big benchmarks highlight mega tech, we think AI’s true potential lies beyond them in focused, agile companies.”

Demand stays high

CapEdge cited a possible reason why Nvidia shares didn’t dip further this week: Demand for the company’s GPUs remains high despite rising costs reflected in a 16% hike last month in the price of Nvidia’s H100 GPU set by a sales partner, GDEP Advance.

The H100 now costs ¥5.44 million (just over $36,550), up ¥700,000 (about $4,700), according to a report in Nikkei Asia, in which GDEP blamed the price hike on the declining value of the Japanese yen. Another news report pegs the cost of H100 at about $40,000, with Nvidia spending only $3,320 on manufacturing the GPU.

The AI boom explains why this week one analyst raised his firm’s 12-month price target on Nvidia shares: John Vinn, a managing director and senior research analyst covering the semiconductor industry for KeyBanc Capital Markets, increased its target 12%, from $670 to $750, while maintaining KeyBanc’s “Overweight” rating on the stock.

Headquartered in Santa Clara, CA, Nvidia revolutionized gaming by inventing the GPU more than two decades ago. By 2021, as GEN reported, Nvidia doubled down on expanding its presence in AI-based drug discovery through a trio of partnerships.

Earlier this year, Nvidia announced initiatives that included BioNeMo, a generative AI cloud-based service designed to enable faster discovery and design of drugs; Tokyo-1, in which Nvidia and Mitsui & Co., are partnering to develop Japan’s first generative AI supercomputer for that nation’s pharma industry; and Clara, an AI-based platform used by more than 100 healthcare enterprises worldwide.

And in July, Recursion Pharmaceuticals (RXRX) agreed to accelerate development of its AI foundation models for biology and chemistry by using the cloud services of Nvidia, after it invested $50 million in Recursion.

Leaders & laggards

• ALX Oncology (ALXO) shares surged 56% on Tuesday, from $4.81 to $7.51, after the company announced positive prespecified interim data from its Phase II ASPEN-06 trial (NCT05002127) showing a confirmed overall response rate of 52% for the combination of its CD47 inhibitor evorpacept with Eli Lilly’s Cyramza^® (ramucirumab) and paclitaxel, compared to 22% for control treatment. The randomized multi-center international study assessed the combination as a treatment for patients with HER2-positive gastric/gastroesophageal junction (“GEJ”) cancer. ALX said it will release a final analysis from the trial in Q2 2024, and plans to launched the Phase III portion of ASPEN-06 in late 2024.
• Apellis (APLS) shares rose 5% on Thursday, from $37.62 to $39.64, after the company projected preliminary U.S. net revenue of approximately $74 million in the third quarter for its Syfovre^® (pegcetacoplan injection) for geographic atrophy (GA) secondary to age-related macular degeneration (AMD), and approximately $160 million from its launch in March through September 30. Apellis said demand has stayed strong, with more than 100,000 vials (commercial and sample) distributed to date. Apellis also reported that growth in week-over-week demand resumed in August following a decline linked to safety concerns that touched off a 73% share price plunge and was cited by a short seller last month.
• Ginkgo Bioworks Holdings (DNA) shares fell 5.5% on Monday, from $1.81 to $1.71, after its Zymergen subsidiary filed for Chapter 11 bankruptcy in U.S. District Court for the District of Delaware. In a regulatory filing, Ginkgo disclosed that it entered into an agreement with Zymergen to be the “stalking horse” bidder to acquire exclusive rights to substantially all of Zymergen’s intellectual property assets and “other assets that are relevant to Ginkgo’s business going forward.” Ginkgo’s bid includes $5 million cash and assumption of up to $77 million of potential future liabilities, including a lease, employee compensation, and severance costs. Ginkgo insisted that it and its other subsidiaries “will continue to operate their businesses as usual.”
• POINT Biopharma Global (PNT) shares nearly doubled, leaping 85% on Tuesday from $6.68 to $12.36 after the radiopharmaceutical drug developer agreed to be acquired by Eli Lilly for approximately $1.4 billion. The company’s pipeline of radioligand therapies to treat cancer is led by two late-phase candidates. One is PNT2002, a prostate-specific membrane antigen targeted radioligand therapy for metastatic castration-resistant prostate cancer (mCRPC) after progression on hormonal treatment, set to release topline data from the Phase III SPLASH trial (NCT04647526) later this quarter. The other is PNT2003, a somatostatin receptor (SSTR) targeted radioligand treatment for gastroenteropancreatic neuroendocrine tumors (GEP-NETs).The deal is expected to close near year’s end, subject to customary closing conditions.
• Nuvalent (NUVL) shares jumped 36% on Wednesday, from $42.42 to $57.51, after the company announced preliminary data from the Phase I dose-escalation portion of its ongoing ALKOVE-1 Phase I/II trial (NCT05384626) assessing NVL-655 in patients with advanced ALK-positive non-small cell lung cancer (NSCLC) and other solid tumors. Data showed partial responses to NVL-655 in 45% of response-evaluable patients with ALK-positive NSCLC who received the drug at doses ranging from 15–150 mg once daily (15 of 33 patients, with eight patients pending confirmation). An objective response rate (ORR) of 65% (11 of 17 patients) was seen in patients with baseline ALK resistance mutations, and an ORR of 41% (12 of 29 patients) was seen patients receiving third-generation ALK tyrosine kinase inhibitor lorlatinib, including cases with compound resistance mutations.
• Standard BioTools (LAB) shares tumbled 22% on Wednesday, from $2.70 to $2.10, after it agreed to merge with SomaLogic (SLGC) in an all-stock deal creating a combined company valued at more than $1 billion, to retain Standard’s name and be run by its CEO Michael Egholm, PhD. The new company expects to generate $80 million in “synergies” by 2026—but will have more than $500 million in estimated cash and cash equivalents upon closing. The deal is set to close in the first quarter of 2024 subject to conditions that include shareholder approval and expiration of the Hart-Scott-Rodino waiting period. Standard (formerly Fluidigm) raised its 2023 revenue guidance to $100–105 million, while SomaLogic reaffirmed its 2023 revenue guidance of $80–84 million. SomaLogic shares fell 10%, from $2.30 to $2.07.

Alex Philippidis is Senior Business Editor of GEN. 

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