“WOW！”

On June 8th, analysts from Leerink Partners responded to the clinical data released by Tango Therapeutics using the aforementioned term. On that day, the stock price of this biotechnology company, which had not yet launched a product, surged by 53%.

It is Tango's core pipeline, a PRMT5 inhibitor called vopimetostat, that has delivered 92% of the data of remission rate in pancreatic cancer related indications.

If the timeline is stretched, this is not the first time Tango has created a "WOW" moment.

Two years ago, a $80 million private equity financing and endorsement of a partnership with pharmaceutical giant Gilead led to a 126% surge in Tango within three days. At that time, the market believed that milestone payments of up to $6 billion were enough to support a future. However, the reality took a sharp turn for the worse - the cooperation was terminated early in 2025, and Tango's strategic contraction at the beginning of this year caused a daily drop of 11% in stock prices.

Tango and its PRMT5 inhibitor have experienced ups and downs over the past three years, and the ups and downs on this track are far more than just the story of one company.

PRMT5， This target, which was once highly anticipated by the industry as the 'next PARP', is now standing at a brand new crossroads after nearly a decade of twists and turns.

01、The temptation of the target
 

PRMT5 is a fascinating target, and MTAP gene deletion is the core biomarker that exerts the synthetic lethal effect of this target.

MTAP deletion accounts for about 10% – 15% of all human tumors and up to 40% of pancreatic cancer. The deletion of this gene can cause the continuous accumulation of metabolic product MTA in cancer cells, which in turn makes tumor cells highly sensitive to the inhibitory effect of PRMT5, forming a typical synthetic lethal effect. That is, when PRMT5 is inhibited, cells carrying normal MTAP are less affected, while tumor cells lacking MTAP will be significantly impacted in proliferation and survival.

Due to its clear biomarkers and broad-spectrum potential, PRMT5 was once highly anticipated by the industry as the 'next PARP'. But the first generation of PRMT5 inhibitors dealt a heavy blow to the industry.

As one of the earliest companies to establish a presence in this field, GSK participated in the development of the first generation PRMT5 inhibitor GSK3326595, which ultimately failed in clinical development due to dose limiting hematological toxicity. In February 2022, GSK terminated its cooperation with Epizyme and returned all rights related to the target project.

In fact, these early candidate drugs have repeatedly failed in clinical trials due to dose limiting hematological toxicity. The root of the problem lies in these drugs indiscriminately blocking PRMT5, which is an essential gene for regulating the differentiation and maintenance of hematopoietic stem cells. This has resulted in multiple first generation drugs being difficult to achieve effective anti-tumor doses in the early clinical stages, making it impossible to further validate the concept.

The industry has realized that in order to achieve selectivity for MTAP deficient tumors, inhibitors must 'utilize' the synergistic effect of MTA rather than 'bypass' it.

The second generation of MTA co inhibitors was born, which specifically targets the PRMT5-MTA complex and achieves maximum or even complete PRMT5 inhibition in MTAP deficient tumor cells, while sparing normal cells of MTAP wild-type.

This concept transforms PRMT5 inhibitors from "comprehensive inhibition" to "state selective inhibition", becoming a common starting point for all subsequent players. For example, Tango's vopimetostat, BMS's navlimitostat (MRTX1719), and IDEAYA's IDE892 all follow this design philosophy.

The second generation design addresses security issues, but research and development uncertainties remain significant. Although the proportion of MTAP deletion in pancreatic cancer is high, more than 90% of pancreatic cancer patients carry RAS mutations. Relying solely on PRMT5 inhibition to synthesize lethal tumor cells still has limited activity in solid tumors.

That is to say, PRMT5 inhibitors require a 'partner'.

02、RAS cornerstone

Tango's chosen partner is Daraxonrasib from Revolution Medicines. This is an oral, non covalent pan RAS (ON) selective inhibitor that can cover multiple RAS mutation subtypes (including G12X, G13X, Q61X) and wild-type RAS, breaking through the limitations of traditional single site inhibitors.

In April 2026, Revolution announced that the Phase III RASolute 302 trial of daraxonrasib for second-line treatment of metastatic pancreatic ductal adenocarcinoma (PDAC) had successfully reached the primary survival endpoint. Data shows that daraxonrasib extended the median overall survival of patients from 6.7 months of chemotherapy to 13.2 months, almost doubling. Currently, the drug is being evaluated in four global phase III registered trials.

The impressive single drug clinical data of Daraxonrasib has laid a solid foundation for its combination therapy strategy, and the combination with Tango's PRMT5 inhibitor vopimetostat has achieved groundbreaking therapeutic effects.
The relevant efficacy data comes from an ongoing Phase I/II clinical trial aimed at evaluating the efficacy and safety of vopimetostat in combination with two RAS inhibitors from Revolution Medicine, daraxonrasib and zoldonrasib, for the treatment of PDAC or non-small cell lung cancer (NSCLC) patients with MTAP deficiency and RAS mutation.

According to recent trial results disclosed by Tango, the vopimetostat combined with daraxonrasib regimen achieved a 92% objective response rate (ORR) and a 100% disease control rate (DCR) in the queue of metastatic PDAC patients with MTAP deficiency and RAS mutation. In addition, the overall tolerability of the experimental group was good, with no discontinuation due to adverse events and no grade 4 or 5 adverse events.

Malte Peters, CEO of Tango, said on the conference call that these results strengthened the company's belief that the RAS inhibitor combination program based on vopimetastat might become a chemotherapy free treatment path for patients with pancreatic cancer without MTAP.

03、Joint Competition

Based on the breakthrough clinical data presented by vopimetostat and daraxonrasib, Tango has achieved landmark results in the second-generation PRMT5 inhibitor race. Looking at the entire industry, it can be seen that the competition in this race has already surpassed the simple competition of single molecule efficacy.

IDEAYA's IDE892 is currently one of the most distinctive competitors in terms of differentiation strategy on the track. This is an MTA synergistic PRMT5 inhibitor, positioned by IDEAYA as a potential best in class, with its core advantage being extremely high selectivity.

Preclinical data shows that IDE892 has a selectivity for MTA binding PRMT5 that is approximately 1400 times higher than SAM binding, aiming to maximize the treatment window and minimize toxic side effects on the hematopoietic system. The single drug phase I dose escalation study has cleared multiple dose cohorts and has not yet reached the maximum tolerated dose. The single drug expansion study is expected to commence in the third quarter of 2026.

Combination therapy is the core layout direction of IDEAYA. Phase I/II trial of IDE892 combined with self-developed MAT2A inhibitor IDE397 has completed the first case of inclusion on June 15, 2026, targeting non-small cell lung cancer and pancreatic cancer with MTAP deletion.

In June 2026, IDEAYA reached a clinical collaboration with Roche to evaluate the combination of IDE892 and Roche pan RAS inhibitor RG6505 in the treatment of pancreatic ductal adenocarcinoma with MTAP deficiency and RAS mutation. IDEAYA serves as the sponsor for the clinical trial, while Roche is responsible for supplying RG6505. Both parties reserve all commercial rights to their respective compounds, and with mutual approval, the development of IDE892, RG6505, and IDE397 triple therapy can be promoted.

BMS's navlimitostat (formerly known as MRTX1719) is currently the fastest progressing PRMT5 inhibitor and has entered phase II/III, with multiple late stage clinical trials including metastatic NSCLC starting in 2026. AstraZeneca's AZD3470 takes a different approach, focusing on classic Hodgkin's lymphoma (MTAP epigenetic silencing rate exceeding 80%). Against the backdrop of intense competition for solid tumors, hematological tumors may become a breakthrough for PRMT5 inhibitors.

The Chinese PRMT5 inhibitor race is emerging intensively.

At present, the ABSK131 of Heyu Pharmaceutical is in Phase I/II clinical stage. This highly selective MTA co PRMT5 inhibitor has shown significant anti-tumor activity and good selectivity in preclinical studies (such as lung cancer and pancreatic cancer models with MTAP deficiency), and has shown synergistic effects with KRAS inhibitors, EGFR inhibitors and other drugs.

BeiGene's BGB-58067 is also a synergistic inhibitor of MTA and PRMT5. Currently, it has undergone phase Ia/Ib studies in China, entered phase I clinical trials in the United States, and conducted phase 0/2 trials in newly diagnosed MTAP deficient glioblastoma.

The CS08399 of Microchip Biotech was approved by NMPA IND in March 2026, with its core differentiation advantages being brain permeability and independent research and development of the "AI+chemical genomics" platform. As an oral MTA synergistic PRMT5 inhibitor, it can specifically target PRMT5-MTA complexes, selectively induce MTAP deficient tumor cell apoptosis, and has potential advantages in the treatment of brain metastases or primary brain tumors.

GH56 from Qinhao Pharmaceutical obtained dual IND approval from NMPA and FDA in January 2025, and has started Phase I clinical trials in China. It is a novel MTA synergistic PRMT5 inhibitor, and its therapeutic potential has been highlighted in clinical trials; The MAT2A inhibitor GH31 has also been approved, and the combination therapy of GH56 and GH31 is expected to produce synergistic effects in the future.

The PRMT5 inhibitor race is currently in a critical window period for clinical validation, but the challenges of scientific uncertainty, capital patience, and regulatory barriers are still ongoing.

Tango's 92% relief rate is a shining moment in this long race, far from the end.

Reference articles: 

1. 2026 ASCO | pancreatic cancer treatment ushers in a new dawn; Medicine Intelligence Network
2 Tango Therapeutics Stock Soars 53% After ’Unprecedented’ Data on Pancreatic Cancer Treatment； Barron’s
3. Death, project cuts, bankruptcy wave: Will gene therapy still work?; Same freehand brushwork
4. Company News Announcement