By Alex Philippidis
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.
Verve Therapeutics (VERV)
Inflection Point: VERV plans to hold an investor event November 12 in conjunction with its presentation of interim data from its ongoing Phase Ib heart-1 trial (NCT05398029) assessing VERVE-101 for patients with high-risk heterozygous familial hypercholesterolemia (HeFH). The data is being presented in a late-breaking science presentation at the American Heart Association’s (AHA) Scientific Sessions 2023, set for November 11-13 in Philadelphia. Verve said last month it expects to report initial safety and pharmacodynamic data, as well as blood PCSK9 and blood LDL-C levels, from patients across four single ascending dose cohorts.
[The FDA has lifted a clinical hold placed last year, and cleared Verve’s IND application to conduct heart-1 in the U.S., the company announced October 23.]
In a study published in January by Verve researchers, VERV-101 showed itself well tolerated in nonhuman primates, leading to 83% lower blood PCSK9 protein and 69% lower low-density lipoprotein cholesterol with durable effects up to 476 days after dosing. These results, according to the researchers, supported initiation of a first-in-human clinical trial in patients with HeFH and atherosclerotic cardiovascular disease.
Significance: VERV-101 was the first in vivo base editing therapy to reach the clinic when the first patient was dosed in the trial last year. If approved by the FDA and other regulators, VERV-101 would be the first in vivo base editing therapy to reach the market.
Other catalysts: VERVE-102, an in vivo base editing candidate that aims to inactivate the PCSK9 gene in a similar way to VERVE-101, is expected to begin a Phase Ib trial in patients with HeFH in the first half of 2024. Preclinical development began in early 2022, with studies in mice and non-human primates demonstrating effective in vivo liver gene editing and significant PCSK9 protein reduction. VERVE-102 uses Verve’s proprietary GalNAc-LNP delivery technology
VERVE-201, an in vivo base editing therapy also designed to treat homozygous familial hypercholesterolemia (HoFH), is expected to begin a Phase Ib trial in the second half of 2024. Delivered as a one-time intravenous infusion, VERVE-201 is designed to inactivate the ANGPTL3 gene in liver cells, turning off liver production of blood ANGPTL3 and thereby durably reducing low-density lipoprotein cholesterol (LDL-C) and triglyceride-rich lipoproteins (TRLs).
Analyst action: [Updated October 23: William Blair’s Myles R. Minter, PhD, reiterated his firm’s “Outperform” rating, adding: “We see the removal of the clinical hold on VERVE-101’s IND in the U.S. as a best-case scenario for the company ahead of initial data from the heart-1 study.] On September 13, Cantor Fitzgerald’s Rick Bienkowski last reiterated his firm’s “Neutral” rating and maintained its price target of $22 a share, as he did on August 29. The last movement occurred August 15, when Guggenheim’s Seamus Fernandez lowered his firm’s price target about 2%, from $56 to $55, but maintained its “Buy” rating.
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. This report was updated to include Verve Therapeutics.