Tag: Medication

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Vertex Eyes Expansion Beyond Cystic Fibrosis with Planned $10B Crinetics Buyout

Vertex Pharmaceuticals has agreed to acquire Crinetics Pharmaceuticals for $10 billion cash, the companies said, in a deal that would expand the buyer’s rare disease portfolio beyond its anchor indication of cystic fibrosis (CF), by adding an approved treatment and a pipeline anchored by two Phase III candidates, all predicted to generate more than $5 billion in annual revenue.

Based in San Diego, Crinetics focuses on discovering, developing, and commercializing therapeutics for endocrine diseases. The company’s first marketed drug Palsonify® (paltusotine), an oral SST2 agonist, was approved by the FDA in September as the first and to date only once-daily oral therapy for adults with acromegaly, a debilitating condition which affects an estimated 20,000 Americans. Palsonify won European Commission approval in April and is under review by regulators elsewhere in the world.

Palsonify has enjoyed rapid uptake among acromegaly patients, with Crinetics reporting the drug generated net product revenue of $10.3 million during the first quarter, with 232 patients enrolling for treatment. Approximately 70% of patients treated with Palsonify at the end of Q1 were on reimbursed therapy—reflecting payers increasingly agreeing to cover the treatment, according to the company.

Within the first two quarters of its U.S. launch, Palsonify was prescribed by 263 unique healthcare providers.

Under its generic name paltusotine, the drug is in Phase III study for a second indication of carcinoid syndrome, a rare condition resulting from neuroendocrine tumors.

‘Excellent strategic fit’

Reshma Kewalramani, MD, Vertex Pharmaceuticals CEO and President

“Crinetics is an excellent strategic fit for Vertex, with its focus on serious diseases in specialty markets with significant unmet need, well-understood causal human biology, and potentially best-in-class medicines that could deliver transformative benefit to patients,” Reshma Kewalramani, MD, Vertex’s CEO and president, said in a statement. “We believe Vertex can build on the strong momentum of the Palsonify launch by applying our experience in commercializing medicines for rare genetic diseases.”

Crinetics investors agreed, roaring their approval of the pending acquisition as the company’s shares all but doubled in early trading Tuesday, zooming 99% to $83.54 as of 10:28 am ET from yesterday’s closing price of $42.03. Vertex shares dipped 2% to $516.48 from $529.59 at Monday’s closing bell.

Also in late-stage development is Crinetics’ lead pipeline candidate atumelnant, an oral adrenocorticotropic hormone (ACTH) antagonist now under development for congenital adrenal hyperplasia (CAH) and ACTH-dependent Cushing’s syndrome.

In classic CAH, a rare chronic genetic disease with 17,000 addressable patients in the U.S., atumelnant is in a pair of clinical trials. One is a Phase III study in adults with the most common cause of the disease, 21-hydroxylase deficiency (21-OHD). The study’s estimated primary completion date is May 2027 (NCT07144163). The other trial is a Phase II/III study in children ages one to <18, which has an estimated primary completion date of March 2030 (NCT07159841).

Earlier Phase II studies of atumelnant showed that patients treated with the therapy achieved near normalization of excess androgen levels on physiologic replacement doses of glucocorticoids—a therapeutic profile that Crinetics  has said positions atumelnant to become the leading treatment for people with CAH.

Atumelnant (formerly CRN04894) is also being developed for ACTH-dependent Cushing’s syndrome, and is under study in a Phase Ib/IIa open-label, multiple-ascending dose exploratory study (NCT05804669) designed to evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamic biomarker responses associated with the treatment.

‘Significant potential’

“We are also excited by the significant potential of atumelnant to transform the treatment landscape for CAH, setting a new standard of care where patients do not have to choose between managing their excess adrenal androgens and enduring the side effects of high-dose steroids,” Kewalramani said.

One analyst said a Vertex buyout would be good news for Crinetics.

“This is a solid outcome for CRNX, given stock pressure from the near-term Palsonify launch (generally slow and steady launch but (+) [positive] progress by CRNX so far) and the fact that key Phase III catalyst for CAH isn’t until late 2027/28,” Jefferies equity analyst Dennis Ding wrote today in a research note.

In a regulatory filing yesterday, Crinetix shared an email it sent to employees, stating: “We have always been confident in the ability of Crinetics to achieve our plan and were not actively looking to sell the company when Vertex approached us. However, after careful consideration, our board unanimously determined that the transaction is in the best interests of our shareholders.”

Crinetics’ pipeline of more than 10 disclosed candidates includes:

  • CRN09682, a Phase I nonpeptide drug conjugate candidate being developed to treat somatostatin receptor 2 (SST2) expressing neuroendocrine tumors and other SST2 expressing solid tumors.
  • Discovery-phase preclinical programs focused on endocrine targets that include thyroid stimulating hormone (TSH), parathyroid hormone (PTH), somatostatin receptor 3 (SST3), growth hormone (GH), glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP), as well as GPCR-targeted oncology indications.

Vertex said the deal was expected to contribute immediately to revenue growth via the ongoing launch of Palsonify, which the company says has blockbuster (greater than $1 billion in annual sales) potential in acromegaly. Longer term, Vertex says, atumelnant could also generate multiple billions of dollars in CAH, with additional revenue potential in Cushing’s syndrome.

$5B revenue forecast

R. Scott Struthers, PhD, Crinetics’ Co-founder and CEO

At peak year, Palsonify and atumelnant could deliver more than $5 billion in combined annual revenue, Vertex said, and thus contribute toward its goal of delivering sustained double-digit revenue growth, plus industry leading operating margins. The transaction is expected to add to non-GAAP operating income as of 2029.

Jefferies analyst Ding commented that atumelnant in CAH is expected to generate the largest share of the projected $5 billion, as in $2 billion to $3 billion, plus another $1 billion to $2 billion for Cushing’s syndrome–with the remaining $1 billion to be generated by Palsonify in acromegaly.

Scotiabank analyst Louise Chen told Reuters: “The deal ​adds a fifth vertical, endocrinology, which helps diversify VRTX’s concentration in CF.”

That concentration has proven lucrative for Vertex: During Q1, CF treatments generated $2.915 billion in total revenues, 98% of the company’s total revenue of $2.987 billion.

Vertex has agreed to acquire all outstanding shares of Crinetics common stock for $85 per share cash, in a deal valued at $8.8 billion net of estimated cash acquired. Vertex said it expects to finance the acquisition using a combination of cash on hand and debt, supported by $4.5 billion of fully committed bridge financing from Bank of America and Morgan Stanley Senior Funding.

Vertex finished the first quarter with cash, cash equivalents, and total marketable securities of $13 billion, up from $12.3 billion as of December 31, 2025. The company attributed the increase primarily due to cash flows from operating activities, partially offset by repurchases of Vertex’s common stock.

The transaction is expected to close in the third quarter subject to customary closing conditions, including receipt of regulatory approvals and approval by Crinetics shareholders.

“Nearly 18 years ago, we founded Crinetics with a clear goal of transforming the lives of patients living with endocrine-related diseases. Today marks a historic milestone as we embark on this next chapter with Vertex,” stated R. Scott Struthers, PhD, Crinetics’ co-founder and CEO. “Vertex’s global infrastructure and commercial footprint will serve to amplify the reach of our science and allow us to maximize the impact of Palsonify, atumelnant and our pipeline.”

The post Vertex Eyes Expansion Beyond Cystic Fibrosis with Planned $10B Crinetics Buyout appeared first on GEN – Genetic Engineering and Biotechnology News.

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New Clues to Inherited Heart Disease Point to Broader Role for Mavacamten

A targeted therapy already transforming treatment for hypertrophic cardiomyopathy (HCM) may be effective across a broader range of disease-causing genetic mutations than previously understood, according to new preclinical research published in Nature Cardiovascular Research.

The study identifies a previously unknown molecular mechanism underlying one of the most common inherited forms of HCM and demonstrates that the cardiac myosin inhibitor mavacamten—the first targeted therapy available for this condition—can reverse disease-associated changes, even when the underlying biology differs from that of the patients for whom the drug was originally developed.

HCM affects approximately one in 200 to 500 people and is the leading cause of sudden cardiac death in young adults and athletes. The disease is characterized by abnormal thickening of the heart muscle, impaired relaxation, and excessive contractility, which can ultimately lead to heart failure, arrhythmias, and sudden cardiac death.

Most inherited cases are caused by variants in either MYH7, which encodes the molecular motor myosin, or MYBPC3, which encodes cardiac myosin-binding protein C (cMyBP-C), an important regulator of cardiac muscle contraction.

While truncating mutations in MYBPC3 reduce levels of cMyBP-C and promote excessive myosin activity, much less has been known about how missense mutations—which preserve protein levels but alter protein function—drive disease.

To investigate this question, researchers generated a knock-in mouse model carrying the R502W missense mutation, one of the most common pathogenic MYBPC3 variants found in patients with HCM. Unlike mice lacking cMyBP-C, the R502W animals maintained normal amounts and localization of the protein yet still developed hallmark features of hypertrophic cardiomyopathy, including cardiac hypertrophy, fibrosis, impaired cardiac function, and hypercontractility.

“Our findings support that mutation-induced loss of interactions between the central domains of cMyBP-C and myosin is a molecular pathomechanism in HCM that can be targeted by myosin inhibitors,” the authors write.

Rather than reducing protein abundance, the mutation weakened the interaction between cMyBP-C and myosin, shifting more myosin molecules into an active structural state capable of generating contraction. The mutation also increased calcium sensitivity, together producing excessive contractile force.

Importantly, these abnormalities arose through a mechanism distinct from the loss-of-protein pathway associated with truncating MYBPC3 mutations.

Despite these divergent disease mechanisms, treatment with mavacamten significantly reduced pathological remodeling in both the R502W mice and animals lacking cMyBP-C. The drug also restored a more normal inactive structural state of myosin in mutant heart muscle and reduced excessive contraction in engineered human heart tissues carrying the same mutation.

“Hence, our data and evidence in the literature suggest that mavacamten is equally effective for carriers of any pathogenic variant in MYH7 or MYBPC3,” the authors conclude. The findings may help explain why genetic differences alone are unlikely to account for the variable clinical responses observed in patients receiving mavacamten.

The work also has implications beyond current therapies. Because some emerging gene therapies aim to replace cMyBP-C rather than correct mutant protein function, the authors suggest those approaches may be less effective for patients carrying missense mutations such as R502W. By contrast, gene-editing strategies capable of directly correcting single-base mutations may prove particularly promising.

The researchers also propose that the newly developed mouse model more closely resembles the relatively mild progression of human hypertrophic cardiomyopathy than previous models based on complete cMyBP-C deficiency, making it a valuable platform for testing future therapies and studying disease biology.

Looking ahead, the investigators suggest that most patients carrying pathogenic MYBPC3 variants could potentially benefit from myosin inhibition regardless of the mutation’s underlying molecular mechanism.

“Our preclinical data indicate that all carriers of pathogenic variants in MYBPC3, arguably the most common cause of HCM, may similarly benefit from myosin inhibition regardless of diverging specific pathomechanisms,” the authors conclude. They add that the limited effectiveness of mavacamten observed in some patients is “probably due to reasons other than the specific HCM variants they carry,” including disease stage, environmental influences, or other genetic factors.

 

 

The post New Clues to Inherited Heart Disease Point to Broader Role for Mavacamten appeared first on Inside Precision Medicine.

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STAT+: FDA approves Vera Therapeutics kidney disease treatment

The Food and Drug Administration on Tuesday approved a new medicine from the biotech company Vera Therapeutics for patients with a type of chronic autoimmune kidney disease.

The drug, called Trutakna, was cleared to treat IgA nephropathy, or IgAN, a disease caused by the buildup of immune antibodies in the kidneys. The condition leads to progressive loss of kidney function and potentially organ failure requiring dialysis.

“We’re extremely excited to bring Trutakna to patients,” Vera CEO Marshall Fordyce told STAT, in an interview conducted ahead of the FDA approval. 

Continue to STAT+ to read the full story…

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CRISPR-Engineered Treg Cell Therapy Clears IND for Solid Tumors

The U.S. Food and Drug Administration has cleared CoRegen’s Investigational New Drug (IND) application for CRG-150, allowing the company to initiate a first-in-human Phase I/IIa clinical trial of its autologous CRISPR-engineered regulatory T (Treg) cell therapy in patients with advanced solid tumors. The study will evaluate safety and preliminary efficacy in metastatic triple-negative breast cancer (TNBC), metastatic HR-positive/HER2-negative breast cancer, and metastatic prostate cancer at leading academic cancer centers.

The clearance advances into the clinic an immunotherapy strategy that differs fundamentally from existing cell therapies. Rather than engineering cytotoxic lymphocytes to recognize tumor antigens, CRG-150 uses CRISPR gene editing to reprogram regulatory T cells (Tregs), with the goal of reversing the immunosuppressive tumor microenvironment and restoring endogenous antitumor immunity.

The approach emerged from more than three decades of research at Baylor College of Medicine on steroid receptor coactivator-3 (SRC-3), a transcriptional regulator that sits upstream of numerous immune signaling pathways. According to CoRegen, CRISPR-mediated disruption of SRC-3 fundamentally alters Treg biology, removing one of the mechanisms tumors use to evade immune surveillance.

Suneet Varma - CoRegen
Suneet Varma, Chairman of the Board at CoRegen [Baylor College of Medicine]

“What was fantastic about this discovery was that it allowed us to engineer a regulatory T cell to knock out SRC-3,” said Suneet Varma, chairman of the board of CoRegen. “By knocking out SRC-3, we have essentially removed the cloak of invisibility that cancer was hiding behind. Once you remove that cloak of invisibility, the tumor is recognized by the immune system, and CD4-positive T cells, CD8-positive T cells, and natural killer cells flood the tumor.”

The company reports that preclinical studies in multiple murine solid tumor models demonstrated durable tumor eradication following treatment with SRC-3-disrupted regulatory T cells. Investigators subsequently rechallenged animals with the original tumor and observed rapid elimination consistent with immunologic memory. In additional experiments, mice challenged with different tumor types, including pancreatic cancer after initial treatment of triple-negative breast cancer, also mounted antitumor responses, suggesting that the mechanism may not depend on a single tumor antigen or histology. Those findings now await validation in humans.

“This is a new, never-been-done-before approach to immuno-oncology,” Varma said. “We’ve cured many, many mice. But we need to now treat and cure humans. There’s a lot of work between here and there.”

Reversing the biology of immune suppression

Since the identification of FOXP3 as the master transcription factor governing regulatory T-cell development more than two decades ago, Tregs have become recognized as essential regulators of immune homeostasis. By suppressing excessive immune activation, they prevent autoimmunity and maintain peripheral tolerance. The same biology, however, is frequently co-opted by cancer. Many solid tumors recruit or expand Tregs within the tumor microenvironment, where they suppress cytotoxic T lymphocytes and natural killer (NK) cells, limiting endogenous antitumor immunity and contributing to resistance against immunotherapy.

That dual biology has made Tregs both attractive and challenging therapeutic targets. Most clinical development in the field has focused on harnessing their suppressive properties. Multiple companies are developing autologous, allogeneic, and CAR-engineered Treg therapies for autoimmune diseases, inflammatory disorders, and transplantation, where augmenting immune tolerance is desirable. By contrast, relatively few cell therapy programs have sought to manipulate Tregs in oncology because selectively disrupting their immunosuppressive function without broadly compromising immune regulation has proven difficult.

For example, last week, the FDA approved Orca Bio’s Tregzi, an unmodified donor-derived cell therapy designed as an alternative to traditional matched-donor stem cell transplantation for blood cancer patients. The therapy uses three purified donor cell populations—including regulatory T cells, conventional T cells, and hematopoietic stem and progenitor cells—selected to preserve immune control while supporting blood system recovery. By leveraging naturally occurring immune-regulating cells, Tregzi aims to reduce complications such as chronic graft-versus-host disease, marking a key milestone for the broader effort to harness Tregs as a next-generation approach in cancer treatment.

Sonal Gupta - CoRegen
Sonal Gupta, MD, PhD, Chief Medical Officer at CoRegen [CoRegen]

CoRegen’s strategy is to alter Treg biology directly through CRISPR-mediated disruption of SRC-3, a steroid receptor coactivator that functions as a transcriptional regulator upstream of numerous immune signaling pathways. Sonal Gupta, MD, PhD, chief medical officer of CoRegen, explained that SRC-3 occupies a regulatory position upstream of numerous genes involved in immune signaling, including pathways associated with immune checkpoint regulation. “What we do is use CRISPR editing to knock out the SRC-3 gene,” Gupta told Inside Precision Medicine. “That changes the biology of regulatory T cells.”

She compares unmodified Tregs to “bouncers at a nightclub,” preventing immune cells from entering tumors. Following gene editing, the cells no longer maintain that suppressive phenotype, allowing endogenous immune cells to infiltrate the tumor microenvironment. Unlike checkpoint inhibitors, which interrupt individual inhibitory pathways such as PD-1/PD-L1 or CTLA-4, the company hypothesizes that reprogramming Tregs through SRC-3 disruption may produce broader remodeling of tumor immune suppression.

The therapy is also differentiated from CAR T cells. “CAR T cells directly kill the cancer cells by targeting something on the cancer cell, and, in our case, we genetically modify regulatory T cells,” said Gupta. “Regulatory T cells play a very important role in the tumor microenvironment. They basically do not allow the endogenous immune system to kill the cancer. When we gene-modify them the way we do, they allow the endogenous immune system to enter and kill the cancer cells.”

From laboratory discovery to first-in-human testing

The origins of CRG-150 trace back more than three decades to the laboratory of the late Bert W. O’Malley, MD, at Baylor College of Medicine. O’Malley, widely regarded as one of the founders of molecular endocrinology, spent much of his career studying steroid receptor coactivators (SRCs), proteins that regulate large transcriptional networks controlling cellular behavior.

According to Varma, bringing that body of work together with advances in regulatory T-cell biology transformed a long-running academic research program into a therapeutic platform. “Our goal was to take this tremendous body of evidence and receptor biology and move what was in an academic laboratory into a biotech environment where we could demonstrate the potential impact in patients,” he said.

CRG-150 begins with collection of autologous peripheral blood cells rather than bone marrow. Regulatory T cells are isolated, edited using CRISPR to disrupt SRC-3, expanded ex vivo, and then reinfused into the patient.

Gupta believes beginning with an autologous product provides the strongest opportunity to demonstrate proof of concept. “Autologous really is the gold standard,” she said. “Because the cells come from the patient, they’ve already been exposed to the tumor antigens.”

Another potentially important distinction is the absence of lymphodepleting chemotherapy prior to treatment. Current CAR T therapies typically require depletion of endogenous lymphocytes before infusion, adding toxicity and limiting outpatient administration. “Unlike CAR T cells, these patients do not have to undergo depletion and have their immune system knocked out before receiving therapy,” Gupta said. “There is potential for this therapy to actually be outpatient.”

Varma noted that because the therapy relies on a standard blood collection rather than more invasive procedures, the collection process should also be broadly accessible. “Not all autologous therapies are created equal,” he said. “We wanted the process to be as simple as possible and the vein-to-vein time as manageable as possible.”

The company has partnered with Lonza under a multi-year manufacturing agreement to support clinical production. Varma said manufacturing consistency formed an important component of the IND package reviewed by the FDA. “The FDA concurred that we had achieved what we needed to achieve to proceed,” he said.

Gupta added that recent advances in Treg manufacturing have substantially improved the feasibility of clinical development. “Being able to expand regulatory T cells to generate sufficient doses for patients has been a very important advance,” she said.

Testing a new therapeutic paradigm

Historically, novel oncology therapies enter clinical testing in heavily pretreated patients before moving into earlier treatment settings if efficacy is demonstrated. Varma believes CRG-150 may ultimately challenge that paradigm because its mechanism depends on mobilizing endogenous immunity. “We would really benefit from a healthier immune system, since that’s what we’re activating,” he said. “Scientifically, it suggests the therapy should ultimately be used earlier.”

The initial study, however, appropriately begins in advanced disease. The Phase I/IIa trial will use a dose-escalation and cohort-expansion design. Phase I will establish safety and identify the recommended Phase II dose, followed by expansion cohorts evaluating preliminary efficacy in metastatic TNBC, HR-positive/HER2-negative breast cancer, and metastatic prostate cancer. According to Gupta, the long-term objective is to generate sufficient data to support discussions with the FDA regarding a subsequent registration study.

The company reports strong interest from academic investigators participating in the study. “We’ve had more interest from clinical sites than we can currently support,” Varma said.

The FDA clearance positions CoRegen within a rapidly evolving landscape of engineered immune cell therapies. Most current Treg programs are directed toward restoring immune tolerance in autoimmune disease or transplantation, whereas oncology developers have largely focused on engineered effector cells such as CAR T cells, T-cell receptor-engineered T cells, and tumor-infiltrating lymphocytes. CRG-150 occupies a distinct niche by seeking to reprogram, rather than expand or eliminate, regulatory T cells within the tumor microenvironment.

The company is already exploring future iterations of the platform, including allogeneic products and in vivo approaches, as well as expansion into additional tumor types including pancreatic cancer, glioblastoma, melanoma, colorectal cancer, and non-small cell lung cancer. For now, however, the focus is on determining whether a strategy that has generated durable immune responses across multiple preclinical solid tumor models can safely translate into patients. The Phase I/IIa trial will provide the first opportunity to answer that question.

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STAT+: The crumbling employer-based health insurance system

You’re reading the web edition of D.C. Diagnosis, STAT’s twice-weekly newsletter about the politics and policy of health and medicine. Sign up here to receive it in your inbox on Tuesdays and Thursdays.

Cody Rhodes, a WWE star and friend of the trans community; and Triple H, former pro wrestler and son-in-law of Education Department Secretary Linda McMahon, helped kick off the return of the presidential fitness test. Send news tips and your favorite wrestling moves to John.Wilkerson@statnews.com or John_Wilkerson.07 on Signal.

U.S. workers and businesses are getting soaked

Today, Bob Herman launched a series on the crumbling employer-based health insurance system. He wrote about it for his Health Care Inc. newsletter, so with his blessing, I’m going to cut-and-paste some of that here. Enjoy.

Continue to STAT+ to read the full story…

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$10 Million Donation Boosts Treatment Development for Ultra-Rare Disease

The Clayco Foundation has gifted $10 million to researchers at the Perelman School of Medicine at the University of Pennsylvania to help them to development a potential treatment for the ultra-rare disease retinal vasculopathy with cerebral leukoencephalopathy (RVCL).

“This is a disease that affects so many organs across the body, so a typical targeted gene therapy doesn’t work,” said Jonathan Miner, MD, PhD, an associate professor of Rheumatology at Penn, who leads the work. “We have developed something that labels abnormal proteins—just like you would a package. The body’s cells can then read that label and ship the protein to a specific location in the cell for destruction.”

RVCL is an inherited, autosomal dominant disease caused by mutations in a gene called TREX1 that affects around 200 people across the world. The mutation causes DNA damage and premature death of the endothelial cells that line small blood vessels. Over time, the surrounding tissue receives less blood and oxygen and begins to malfunction or die.

People with the condition usually present in mid‑adulthood with slow vision loss from retinal vasculopathy and then develop stroke‑like episodes, cognitive decline, and psychiatric symptoms linked to white‑matter damage in the brain. There is no current disease-modifying treatment for the condition and people with the condition usually die in mid-late adulthood.

Miner directs the RVCL Research Center at Penn. He and his team are working on several potential therapies for this very rare disease including the one funded by this donation, a small molecule drug candidate that can degrade damaged TREX1 proteins in the body.

“In mice with the human mutation who get this disease, the degrader molecule saves their lives,” explained Miner in a press statement. “It stops organ damage and stabilizes them from further harms.”

The candidate therapy works by linking the faulty protein to an enzyme, an E3 ligase, that marks unwanted proteins so the cell can break them down. The damaged protein is then rapidly cleared by the cell’s disposal machinery, while normal proteins are spared.

The $10 million donation from the Clayco Foundation will help Miner and colleagues move this drug candidate closer to the clinic.

The Clayco Foundation is Chicago‑based and is closely linked to the design‑build firm Clayco, which was founded in the 1980’s by Bob Clark. Clark’s wife Ellen died of RVCL in 2010 and because of this the foundation has a strong focus on funding research that helps people with the condition.

Miner and colleagues are also working on a couple of genetic therapies for RVCL using CRISPR and prime-editing technology. They are also assessing if crizanlizumab, a P‑selectin–blocking monoclonal antibody currently approved to reduce sickle cell crises, could be repurposed to also treat RVCL.

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A New Development Playbook for PROTACs

Shanghao Li
Shanghao Li, PhD
International Marketing Associate Director, La, boratory Testing Division, WuXi AppTec

As proteolysis-targeting chimeras (PROTACs) mature from scientific breakthrough to clinical modality, a candidate’s degradation potency is no longer enough to justify its advancement. A strong degrader is not necessarily a strong drug candidate if liabilities in exposure, safety, selectivity, manufacturability, or dosing strategy emerge later. As the field advances, success will depend on whether sponsors can integrate chemistry, pharmacology, safety, manufacturability, and clinical strategy early enough to translate promising degraders into viable medicines.

PROTACs have helped redefine what may be possible in drug discovery. By harnessing the ubiquitin-proteasome system to eliminate disease-relevant proteins, rather than simply inhibiting their activity, they have expanded the scope of targets that may be therapeutically addressable. For the past several years, much of the excitement around PROTACs has centered on this breakthrough mechanism. The field has been driven by the promise of degrading previously “undruggable” proteins, improving selectivity, and potentially overcoming resistance mechanisms that limit traditional inhibitors. But as clinical programs progress and the modality moves closer to late-stage regulatory milestones, the central question is changing.

The issue is no longer whether targeted protein degradation works. It is whether promising degraders can be translated into clinically and commercially viable therapies.

That transition marks an important phase of maturity for PROTAC development. The next wave of progress will depend on translational discipline and the ability to balance potency with developability, pharmacology, safety, manufacturability, and clinical feasibility from the earliest stages of development.

Entering a new phase of maturity

Early PROTAC innovation was rightly focused on validating the modality itself. Demonstrating that a heterobifunctional molecule could recruit an E3 ligase, drive ubiquitination of a target protein, and induce selective degradation was a foundational scientific achievement. That early work established targeted protein degradation as part of a broader wave of transformational therapeutic modalities, alongside approaches such as RNA interference therapeutics and antibody–drug conjugates, that have expanded what drug developers can target and how they think about translation.

Today, however, the field is operating under a different set of expectations. As more candidates advance through clinical development, sponsors must show not just that a PROTAC can degrade a target, but that it can do so with an exposure profile, safety margin, formulation strategy, and manufacturing pathway appropriate for clinical applications. A potent degrader in vitro may still fail to become a viable development candidate if it cannot achieve sufficient intracellular exposure, is metabolically unstable, if its degradation profile extends beyond the intended target set, or if its chemistry introduces manufacturing and formulation complications that slow advancement.

In other words, the scientific novelty of a modality can carry a program only so far before technical feasibility must be addressed for a candidate to advance. For PROTACs, that moment has arrived.

Potency alone is an incomplete metric

Degradation potency remains important. Maximum degradation, degradation half-life, and related pharmacodynamic measures are essential for understanding whether a molecule is engaging its biology as intended. But potency on its own can be misleading, particularly when it becomes the dominant criterion for candidate selection.

PROTACs are not conventional inhibitors. Their event-driven, catalytic mechanism introduces complexities that make exposure-response relationships less intuitive than those seen with traditional small molecules. Biological effects may persist after plasma concentrations decline, while higher concentrations do not necessarily lead to greater activity. In some cases, excessive exposure may even reduce degradation efficiency because of saturation effects that limit productive ternary complex formation.

This means the “best degrader” in a screening cascade is not always the best drug candidate. A molecule may demonstrate impressive degradation in a cellular assay while carrying liabilities that emerge only later, such as poor permeability, limited oral bioavailability, rapid linker metabolism, high nonspecific binding, unstable analytical performance, or off-target degradation driven by ligase biology or ternary complex behavior. If those issues are not considered early, potency can create a false sense of confidence in a degrader’s potential for clinical use.

Development workflows fall short

One reason translational issues emerge so frequently in PROTAC programs is that many development workflows still reflect assumptions built around traditional small molecules. In those models, discovery, DMPK, bioanalysis, toxicology, and chemistry, manufacturing, and controls (CMC) often proceed in a staged or partially sequential manner, with each function evaluating modality-relevant properties within its own domain before handing it forward.

With targeted protein degraders, however, early chemistry decisions can directly influence permeability, intracellular exposure, metabolic clearance, assay reliability, biodistribution, and manufacturability. Linker design, ligand selection, and overall polarity are not simply medicinal chemistry concerns; they shape how the molecule behaves across the entire development continuum. Likewise, a bioanalytical challenge may obscure the interpretation of PK/PD relationships, complicate dose optimization, or delay confidence in candidate selection.

The same is true for safety. Because PROTACs eliminate proteins rather than transiently inhibiting them, the consequences of target engagement can differ meaningfully from those associated with conventional inhibitors. On-target toxicity may emerge when complete or prolonged degradation is not tolerated, even if partial functional inhibition is acceptable. Off-target effects may arise not only from target promiscuity, but also from E3 ligase recruitment and unintended ternary complex formation. These risks cannot be addressed effectively if safety is considered only after potency and exposure have been optimized.

Traditional workflows can also underweight manufacturability and CMC considerations. PROTACs are generally handled as small molecules, but their structural complexity can create multi-step synthesis challenges, impurity-control difficulties, and formulation constraints much earlier than teams may expect. When these issues are discovered late, promising programs can lose momentum for reasons that have little to do with biology.

The core issue is not organizational design alone. It is that PROTACs expose the limits of linear decision-making. They require earlier integration because the liabilities that determine success are tightly interconnected.

PROTAC-specific development

If PROTACs require a different development model, what would it look like?

First, a successful PROTAC development plan should begin with balanced optimization across parameters rather than sequential, single-parameter optimization. Candidate selection should account not only for degradation potency, but also for permeability, solubility, metabolic stability, intracellular exposure, selectivity, formulation feasibility, and synthetic tractability. Programs that rank candidates holistically are better positioned to recognize which molecules are genuinely translatable.

Second, the PK/PD strategy should be built around the biology of degradation. Because systemic exposure does not fully explain pharmacological effect, teams increasingly need direct measures of target degradation and recovery kinetics, not just plasma concentration data. Mechanistic PK/PD models can help connect degradation durability, protein resynthesis, and dosing schedule in a way that better reflects how PROTACs work in vivo.

Third, bioanalysis should be treated as a strategic enabler rather than a downstream technical function. PROTACs can introduce assay complications, including nonspecific binding, chromatographic artifacts, and instability across matrices. Robust analytical methods are essential not only for quantitation but for making reliable decisions about exposure, disposition, and translation across study systems.

Fourth, safety assessment must expand beyond conventional assumptions. Early proteomic profiling, tissue distribution analysis, and evaluation of degradation selectivity can help identify liabilities before they become entrenched in a program. For PROTACs, understanding where degradation occurs, how long it persists, and what unintended proteins may be affected is central to designing an acceptable therapeutic window.

Finally, CMC and manufacturability should be considered earlier than many teams may be accustomed to. A molecule with compelling pharmacology but limited synthetic scalability, poor solid-state properties, or unstable formulation behavior may not be a strong development candidate. Integrating these realities earlier supports smarter program prioritization and reduces late-stage surprises.

Taken together, these elements define a development playbook centered on translation. They signal a maturation of the field, in which the emphasis shifts from demonstrating biological power to establishing overall developability, recognizing that promising degraders must ultimately succeed as integrated therapeutic candidates, not just mechanistic innovations.

Sponsors can improve the odds

For sponsors advancing PROTAC programs, translation should be a design principle from the beginning. That starts with cross-functional alignment early in discovery. Chemistry, DMPK, bioanalysis, safety, and CMC teams should work together to shape candidate criteria, so that trade-offs are recognized early, and optimization reflects the realities of development rather than the priorities of any one function.

It also means adopting more realistic success metrics. Degradation data should remain central, but it should be interpreted alongside developability, not in isolation from it. Sponsors may also benefit from building translational assays and biomarkers earlier. The ability to directly measure target degradation and connect it to pharmacodynamic effect can strengthen decision-making throughout preclinical and clinical development. In a modality where traditional exposure markers may be incomplete, translational pharmacology can provide strategic direction.

Most importantly, teams should resist the temptation to force PROTACs into a conventional small-molecule framework. These candidates may be classified as small molecules for many regulatory purposes, but functionally, they behave as a distinct modality. Treating them as such allows the development strategy to evolve in step with biology.

The next phase of PROTAC success

PROTACs have already shifted the pharmacological landscape around drugability. Their next contribution may be just as important by forcing the industry to rethink what a good development strategy looks like for complex, mechanism-driven therapeutics. As the field matures, successful drug sponsors will be those who can translate degradation into a developable, manufacturable, safe, and clinically meaningful therapy. That requires a different playbook built on integration, balanced optimization, and translational discipline. For PROTACs, that is no longer a future concern. It is the central challenge of the present.

 

Shanghao Li, PhD, currently serves as international marketing associate director in the Laboratory Testing Division at WuXi AppTec.

The post A New Development Playbook for PROTACs appeared first on GEN – Genetic Engineering and Biotechnology News.

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Non-Suicidal Self-Injury (NSSI) presents a significant public health challenge; however, its underlying neurobiological mechanisms remain insufficiently understood, limiting the development of targeted interventions. Emerging evidence suggests that NSSI exhibits core addictive features, such as compulsive urges and tolerance, which may be driven by dysfunctions in the brain’s reward circuitry. This review synthesizes current research on the neural overlaps between NSSI and addiction, specifically focusing on the dysregulation of the ventral striatum and prefrontal cortex. Based on this mechanistic framework, we propose the potential of Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT)—a high-dose, functional connectivity-guided transcranial magnetic stimulation protocol—as a precision treatment for NSSI. By targeting specific reward network deficits, SAINT may offer a novel, rapid-acting therapeutic strategy for patients who do not respond to conventional pharmacological or psychological interventions.
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