ASH23 Recap; 2-Year Review of ADC BD Deals | |
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CAR-T, bispecifics, and sickle-cell disease took the central stage
ASH’s annual meeting featured several updates from CAR-T therapies and bispecifics, and sickle cell disease took center stage with the FDA’s landmark approvals for two gene therapies.
Bristol Myers Squibb’s KarMMa-3 trial showed no OS benefit for Abecma in 3-5L multiple myeloma (HR 1.01 vs. standard therapy), while the updated PFS data remained strong (51% reduction in the risk of progression or death). To explain the wide gap between PFS and OS, BMS and the presenter pointed to a 56% crossover rate, plus an imbalance of early deaths and bridging therapies between the two arms. The FDA is slated to dissect the OS data at an upcoming ODAC.
A new study examined adverse events reported for three BCMA therapies—Abecma, J&J/Legend’s Carvykti and J&J’s Tecvayli—in the FDA’s FAERS database. Abecma had the highest proportion of CRS in its total reported events, Carvykti showed the most Parkinsonism cases, whereas Tecvayli had a “notably higher” rate of infections. An expert also explained to Fierce Pharma why he’s not convinced that a recent CAR-positive T-cell lymphoma case reported from Carvykti’s CARTITUDE-4 trial is a smoking gun of CAR-T’s secondary cancer risk, which is the focus of an ongoing FDA investigation.
Also in the CAR-T field, Gracell offered an update from a single-center study in China for its CD19/BCMA CAR-T using the company FasTCAR tech. Among 22 treatment-naive MM patients, GC012F achieved a 95% stringent complete response rate. Acknowledging the small patient size, analysts at Leerink Partners called the results “impressive” and noted that the study enrolled very high-risk patients.
Regeneron provided updates for its two T-cell engagers. First up, BCMAxCD3 bispecific linvoseltamab showed 71% ORR and 46% CR or better among myeloma patients who had received a median five prior lines of therapy, according to 11-month follow-up of a phase 1/2 trial. The data looked better than J&J’s Tecvayli by cross-trial comparison, but the Regeneron drug had 14 (12%) deaths due to treatment-related adverse events.
As for Regeneron’s CD20xCD3 candidate odronextamab, updated phase 2 data showed its ORR/CR at 51%/31%, with mDOR/mDOCR lasting 10 months/18 months, in relapsed/refractory diffuse large B-cell lymphoma. Its ORR/CR rates were lower than but not materially different from AbbVie/Genmab’s Epkinly and Roche’s Columvi. In follicular lymphoma, the Regeneron drug’s ORR/CR numbers were 80%/73%. The drug has an FDA PDUFA on Mar. 31, 2024.
Besides longer-term follow-up for its fixed-duration bispecifics, Roche offered a glimpse at early front-line DLBCL data for its Columvi-Polivy-R-CHP combo, which entered phase 3 in September. In a phase 1b trial, the combo showed a 12-month PFS rate at 91.5%, which was better than the 80.1% by Columvi-R-CHOP. The readout gives Roche confidence in the phase 3 SKYGLO trial compared with competitor phase 3 regimen that adds a bispecific on top of R-CHOP rather than Polivy-R-CHP, Dr. Charlie Fuchs, Genentech’s head of oncology and hematology global product development, told Fierce Pharma.
With the approvals for Vertex/CRISPR’s Casgevy and bluebird bio’s Lyfgenia, the FDA fired the starting gun on competition of gene therapies in sickle cell disease (SCD). Bluebird offered longer follow-up, showing 30 of 33 patients (90.9%) who received Lyfgenia had complete resolution of vaso-occlusive events between 6 and 18 months after treatment, and 32 (97%) saw no severe VOEs. One KOL interviewed by Barclays predicted an initial 50/50 share between the two gene therapies at her facility despite Casgevy’s lower list price and lack of black box warning. Lyfgenia’s longer durability data partly contributed to her prediction. A second KOL also didn’t view Lyfgenia’s boxed warning as a problem but noted the importance of price. This KOL also said he would likely use both therapies upon contracting.
Editas updated early-phase data for its gene-editing therapy reni-cel (EDIT-301). All 11 SCD patients were free of VOEs at the data cutoff. Doctors expect no major differences in data from reni-cel versus existing options, the first KOL told Barclays.
Pfizer offered a preliminary look at GBT601, a sickle hemoglobin polymerization inhibitor the New York pharma got from the acquisition of Global Blood Therapeutics. The first KOL expected greater use of the Pfizer med in children and considered it unsuitable for patients with kidney dysfunction, according to Barclays.
Also at ASH23, J&J’s Darzalex-VRd combo set a new standard of care in newly diagnosed multiple myeloma with a 58% PFS improvement over VRd and a four-year PFS rate of 84.3%. Meanwhile, AbbVie and J&J’s Imbruvica had a positive readout for an Imbruvica-Venclexta combo versus Imbruvica monotherapy in mantle cell lymphoma. But a recent Imbruvica market withdrawal may pose a hurdle in the U.S. Elsewhere, AstraZeneca’s China spinout Dizal Pharmaceutical reported high ORR/CR data for its peripheral T cell lymphoma candidate golidocitinib. Because of the FDA’s recent requirement to have a confirmatory trial under way before an accelerated approval, Dizal is currently talking to the agency to decide on a phase 3 design. — Angus Liu
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Review of 2-year ADC BD deals
In just one month, my previous top 25 #ADC deals analysis requires major updates (https://lnkd.in/eHqXeWuV). Of note, the largest #ChinaBiotech BD deal measured by #upfront payment happened last week between SystImmune and Bristol Myers Squibb. Based on the largely complete 2-year data set, a few additional observations have emerged from the analysis:
🔔 In the past 2 years, all major #biopharma with significant footprint in #oncology, except for Roche, have done #ADC deals. Indeed, Merck, Bristol Myers Squibb, Gilead Sciences, Merck KGaA, Darmstadt, Germany, GSK, Pfizer, AstraZeneca, Johnson & Johnson, AbbVie, and Takeda have done #BD or #MergersAndAcquisitions deals. This strong reliance on external innovation is consistent with the recent finding from Atlas Venture annual review, which shows that ONLY ~12% of the 300+ approved drugs in from 2015 to 2021 came from top-20 pharmas' internal R&D (https://lnkd.in/ewA75NEJ).
🔔 #AsianBiotech(s) have become the primary source of early stage #ADC assets for biopharmas via #BusinessDevelopment deals, while Western biotechs such as such as Seagen, ImmunoGen, Inc., and Immunomedics provided most commercial stage #ADC to biopharmas via M&A.
🔔 The total sum of upfront payment of #ChinaBiotech(s) ADC out-licensing deals in 2023 increased by ~4x vs 2022 (~$5.7bn vs ~1.2bn), and the sum of deal value increased by ~0.8x vs 2022 (~$47.0 vs ~$25.9), an impressive jump!
The question is, would this #ADC BD boom continue in 2024? I believe it will continue into 2024 or even beyond. Here is why:
📢 Given #ADC is seen by many drug developers and physicians as simply "fancy chemo", only a small fraction of chemo therapies have been or are being replaced with ADC. Indeed, my conversations with colleagues from biopharma's BD team all suggest their ADC arsenal is far from being completed.
📢 Recall the most successful PD-1 combo strategies proves to be PD-1/chemo combo in the previous PD-1 frenzy? Well, the recent approval of #Padcev/#Keytruda (https://lnkd.in/eqUJizNG), and the encouraging data of #Opdivo/#Adcetris/chemo combo in classical Hodgkin's lymphoma prove the great potential of PD-1/ADC to "upgrade" PD-1/chemo combo.
📢 The recent SystImmune/Bristol Myers Squibb deal of an EGFRxHER3 ADC shows the biopharma's vote of confidence in the next-gen ADCs that are based on bispecific antibody backbone. In addition to antibodies, next-gen ADCs have shown differentiating features in innovative payloads such as immune-agonist, siRNA, molecule glues, or even gene-editing payloads; different conjugation methods; or innovative linkers.
It is an exciting time for ADC companies that are developing innovative ADCs, and I expect ADC will continue to be the hottest area in oncology in 2024 and even beyond. — Leon Tang's LinkedIn post.
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Global Biotech News
2023-12-13: Vertex’s non-opioid painkiller VX-548 significantly decreased pain in people with people with painful diabetic peripheral neuropathy (DPN) in a Phase 2 trial. The news sent Vertex stock (VRTX) up 13% on Wednesday, elevating the market cap of the company to over 100 billion dollars.
The trial tested VX-548, a selective Nav1.8 inhibitor, over 12 weeks in ~160 patients with painful DPN. The primary endpoint was pain intensity measured by an 11-point scale, Numeric Pain Rating Scale (NPRS), with 10 being the “worst pain imaginable.” High, mid, and low doses of VX-548 reduced average pain intensity by 2.26, 2.11, and 2.18, respectively. (Figure below, source: Vertex investor presentation). For context, the trial also included an active reference arm, in which patients were treated with Lyrica (pregabalin), a non-opioid therapy commonly used as the first-line treatment for painful DPN. Lyrica (Pregabalin) reduced average pain intensity by 2.09 over 12 weeks. VX-548 was generally well-tolerated at all doses, and that the majority of adverse events were mild or moderate. Based on the Phase 2 data, Vertex plans to advance VX-548 into a pivotal program following discussions with regulators.
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2023-12-14: Obesity is thought to cause type 2 diabetes, heart disease, arthritis, fatty liver disease, and certain cancers. In the US, about 70% of adults are affected by being overweight, and in Europe that number is more than half. By Chinese BMI classification, 34.8% were overweight and 14.1% were obese. Now, GLP-1 drugs are reshaping medicine, popular culture, and even global stock markets. The mechanism of weight loss is by inhibiting gastrointestinal peristalsis and delaying gastric emptying through binding to GLP-1 receptors in the gastrointestinal tract, and by enhancing satiety and suppressing appetite through binding to central GLP-1 receptors. Surprisingly, clinical trials have found that they also cut symptoms of heart failure, lower the risk of heart attacks and strokes, and delay the progression of kidney disease, the most compelling evidence yet that the drugs have major benefits beyond weight loss itself. Moreover, Scientists are also testing them for AD and PD. Therefore, Science has named GLP-1 drugs the Breakthrough of the Year, which was well-deserved. However, remarkable discontinuation rebound phenomena and serious gastrointestinal adverse effects beg the question of whether GLP-1 agonists “forever” drugs that people have to take indefinitely to preserve weight loss?
All in all, these new therapies are reshaping not only how obesity is treated, but how it’s understood-as a chronic illness with roots in biology, not a simple failure of willpower. — Amber Wang
2023-12-15: This week, a significant milestone was achieved as the first gene-edited B cell therapy, ISP-001, was dosed to a patient in a P1 trial for Mucopolysaccharidosis type I (MPS I), a rare fatal genetic disease. The developer, Immusoft, reprogrammed this MPS I patient's B cells to continuously produce the missing enzyme, alpha-L-iduronidase (IDUA), addressing the root cause of the disease vs. the conventional enzyme infusion treatment for life (Press Release).
Compared to approved engineered stem cell therapy (e.g., Vertex's Casgevy ) or engineered T-cell therapy (e.g., CAR-Ts like Kymriah), engineered B cell therapy is unique in its capability to produce large quantities of various proteins, including enzymes, antibodies, structural proteins, and signaling proteins. B-cell therapy has several advantages: 1) It has a broad application for any disease with the need for different kinds of therapeutic proteins. 2) It eliminates the need for pre-conditioning or immunosuppression, which enables outpatient treatment and/or repeated dosing possibility. Despite the promising outlook, challenges exist in manipulating B cells compared to other cell types, and safety concerns, including the secondary cancer risk that the FDA is investigating in approved CAR-Ts (see our newsletter), must be addressed.
Immusoft holds FDA Orphan Drug Designation and Rare Pediatric Disease Designation for ISP-001 in MPS I. Moreover, the company has already entered into a deal with Takeda for rare diseases with a total value of over $900M in 2021 (Press Release). The first administration of its ISP-001 in human patients marks a major advancement in cell therapy, providing hope for patients with MPS I and potentially paving the way for the application of engineered B cell therapy in treating various diseases beyond MPS I. — Jiamin Zhuo
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BioVerse Webinar, Where Science Sparks Business | |
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🎉 BioVerse, a monthly webinar series by SAPA-GP (Sino-American Pharmaceutical Professionals Association -Greater Philadelphia) & InScienceWeTrust Community (ISWT), has just concluded its last episode in 2023. Seasoned investor Les Funtleyder shared his views on current capital winter in the context of big #biotech #investment cycle.
Here are the key takeaways:
1️⃣ This capital winter is global but could end in 2024. Historically, we typically see the bottom 3-6 months before the first rate cut in the US. Current consensus expects rate cuts to begin in 2024. The global nature of this winter, election year, and IRA pressure could delay the recovery, but the speaker was quite optimistic and assured the audience about the cyclical nature of the healthcare industry and expected to see #IPO and M&A deals to return to normal, but another bubble is unlikely.
2️⃣ Investing in Chinese biotech. US investors view Chinese biotechs with skepticism due to transparency concerns. Chinese biotech companies face challenges in accessing North American markets, but partnering with local firms can help. The best advice to executives is to be available and be part of the #ecosystem where #innovations and #transactions emerge.
3️⃣ Data comes first. Despite the economic difficulties, companies should focus on conducting high-quality #clinicaltrials and producing meaningful data, which is seen as the base for any capital raise, BD and M&A deals. — SAPA-GP LinkedIn post
Episode 005 is scheduled on Jan 11th, 8 PM EDT. We will have a panel discussion chat with Tong Zhang, CBO& co-founder of VelaVigo; Jing Yang, CSO of BaseCure Therapeutics; and two more panelists to be annouced to review the outlook of 2024 right after JP Morgan Healthcare Conference. Check our website for more information.
Review the previous episodes on YouTube here.
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Special thanks to guest contributors Devin Chen & Amber Wang
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