No sooner did Moderna (MRNA) and Merck & Co. (MRK) announce additional positive data for their cancer vaccine candidate, a messenger RNA (mRNA)-based individualized neoantigen therapy (INT), than Moderna investors rushed to buy on the good news.

Shares of the mRNA vaccine pioneer, best known for its COVID-19 vaccine, jumped 10% in the three trading days that followed the companies’ announcement of positive Phase IIb data for a combination of their personalized cancer vaccine (PCV)—which Moderna calls mRNA-4157 and Merck calls V940—and Merck’s cancer immunotherapy blockbuster Keytruda® (pembrolizumab).

The companies on Wednesday morning trumpeted their latest follow-up data from the Phase IIb KEYNOTE-942/mRNA-4157-P201 trial (NCT03897881), assessing the vaccine in combination with Keytruda in the primary endpoint of recurrence-free survival (RFS) in patients with stage III/IV melanoma following complete resection.

At a median planned follow-up of approximately three years, adjuvant treatment with mRNA-4157/V940 plus Keytruda reduced the risk of recurrence or death by 49%, and the risk of distant metastasis or death by 62%—results that, according to Moderna and Merck, showed that the combination “continued to demonstrate a clinically meaningful improvement.”

“These data add another positive analysis to the multiple endpoints and subgroups previously assessed in this study,” Kyle Holen, MD, Moderna’s senior vice president and head of development, therapeutics and oncology, said in a statement.

Data from the trial’s primary analysis has been submitted for publication in a peer-reviewed journal, Moderna and Merck said.

In July, Moderna and Merck launched a Phase III trial, V940-001 assessing the combination as an adjuvant treatment in patients with resected high-risk (Stage IIB-IV) melanoma. The trial is designed to enroll approximately 1,089 patients at more than 165 sites in over 25 countries. The Phase III trial’s primary endpoint is RFS, and secondary endpoints include distant metastasis-free survival (DMFS), overall survival (OS), and safety.

“DMFS is an interesting endpoint and could be used to file for accelerated approval [if it] showed more in-line benefit at three-year follow up with a 62% benefit vs 65% benefit at two years,” Yee added.

Earlier this year, researchers presented earlier data showing mRNA-4157/V940 achieved RFS in April at the American Association for Cancer Research (AACR) Annual Meeting, followed in June by presenting data showing the vaccine met KEYNOTE-942’s secondary endpoint of DMFS at the American Society of Clinical Oncology (ASCO) Annual Meeting.

Investors flocked to Moderna shares, lifting them from $78.04 the day before the data was announced, to $86.01 at the close of trading Friday, before shares dipped on Monday.

Celebrate too soon?

Did Moderna and Wall Street celebrate too soon?

The stock surge that followed reflected investor confidence that the data was strong enough for Moderna and Merck to discuss pursuing a faster-than-anticipated approval track for mRNA-4157/V940.

“The question then becomes if they can file for accelerated approval. We think [that is] unlikely given this is only a Phase II and FDA might want data from Phase III to get a better sense on the benefit given some baseline imbalances in the Phase II,” Michael Yee, an equity analyst with Jefferies, wrote in a research note, dampening investor enthusiasm.

Those imbalances, Yee wrote, relate to the number of patients in the combo therapy arm including 13 with circulating tumor DNA (9%), vs. only two such patients (4%) in the Keytruda monotherapy arm.

“The combo arm still outperformed those on monotherapy on RFS and there was a clear separation of the curves. The ctDNA- KM curves clearly show the benefit with the ctDNA-[combination] arm near flat-lined w/ few progressors,” Yee added. (“KM” stands for Kaplan-Meier estimator, which is used for measuring the fraction of subjects living for a certain amount of time after treatment).

Bill Maughan, PhD, equity research senior analyst-biotechnology with Canaccord Genuity, expressed surprise at the Moderna surge—as well as a smaller 7% surge, from $97.18 to $103.95, on Thursday in shares of another mRNA and COVID-19 vaccine pioneer, BioNTech (BNTX)—“given the widespread conviction in the cancer vaccine already and remaining questions about additional tumor types and ultimate addressable market.”

Maughan said the cancer vaccine’s potential market opportunity in treating melanoma accounted for $1/share to Canaccord Genuity’s 12-month price target of $82, “with a 50% likelihood of success–all of which we maintain on the news today.”

As a result, he said, Canaccord Genuity was maintaining its “Hold” rating on Moderna shares.

mRNA-4157/V940 consists of a synthetic mRNA coding for up to 34 neoantigens that is designed and produced based on the unique mutational signature of the DNA sequence of the patient’s tumor. When administered into a patient, the algorithmically derived and RNA-encoded neoantigen sequences are endogenously translated and undergo natural cellular antigen processing and presentation, which the companies note is a key step in adaptive immunity.

Individualized neoantigen therapies are designed to train and activate an antitumor immune response by generating specific T-cell responses based on the unique mutational signature of a patient’s tumor.

Yee concluded that while the latest data represented an incremental positive for Moderna, investors are still skittish on the company given its 2024 sales guidance, which showed only about $4 billion in total sales (vs. guidance of $6 billion to $8 billion for this year, lowered by November to “at least $6 billion”). Nearly all ($3.8 billion) of the 2024 projected sales reflects its COVID-19 vaccine Spikevax®, with another $200 million estimated for Moderna’s respiratory syncytial virus (RSV) vaccine set to launch next year (following an expected approval decision in April).

Another factor in investor skittishness on Moderna is rival COVID-19 vaccine developer Pfizer’s declining sales guidance for the coming year—about $5 billion in 2024, vs. $11.5 billion guidance offered for this year. (Pfizer co-markets Comirnaty® with BioNTech).

The 2024 Pfizer forecast “is much lower than Street was expecting and signals even decreased demand in 2024,” Yee added.

Leaders & laggards

  • C4 Therapeutics (CCCC; C4T) shares nearly quintupled, leaping 367% between December 11 and Wednesday, from $1.18 to $5.51, after the company announced that it entered into an up-to-$2.5 billion exclusive license and collaboration agreement with Merck & Co. (MRK) to combine C4T’s TORPEDO® platform with Merck’s antibody-drug conjugation expertise to develop degrader-antibody conjugates (DACs), designed to selectively target and neutralize disease-causing proteins in cancer cells. Merck agreed to pay C4T $10 million upfront and partner with C4T to develop DACs directed to an initial undisclosed oncology target. For DACs directed to that initial target, Merck agreed to pay C4T up to approximately $600 million tied to achieving milestones, plus tiered royalties on future sales. Merck has the option to extend the collaboration to include three additional targets, which could yield option exercise payments as well as potential milestones and royalties.
  • Checkpoint Therapeutics (CKPT) shares nosedived 45% on Monday, from $3.32 to $1.81 as of 3:34 pm, after the company acknowledged receiving a Complete Response Letter from the FDA for its BLA for cosibelimab as a treatment for metastatic or locally advanced cutaneous squamous cell carcinoma (cSCC) who are not candidates for curative surgery or radiation. Checkpoint said the CRL only cited findings that arose during a multi-sponsor inspection of Checkpoint’s undisclosed third-party contract manufacturing organization as approvability issues to address in a resubmission. The CRL did not state any concerns about the clinical data package, safety, or labeling for the approvability of cosibelimab, Checkpoint emphasized. “We believe we can address the feedback in a resubmission to enable marketing approval in 2024,” said James Oliviero, Checkpoint’s president and CEO.
  • Icosavax (ICVX) shares jumped 49.5% on December 12, from $10.49 to $15.68, after the Seattle-based developer of protein virus-like particle vaccines—profiled by GEN Edge in 2021—agreed to be acquired by AstraZeneca (AZN) for $1.1 billion. The deal is designed to build on the buyer’s expertise in respiratory syncytial virus (RSV), strengthening AstraZeneca’s Vaccines & Immune Therapies late-stage pipeline with Icosavax’s lead vaccine candidate IVX-A12, a Phase III-ready, combination protein VLP vaccine which targets both RSV and human metapneumovirus (hMPV). The deal price is a 91% premium to Icosavax’s closing market price on December 11, and a 130% premium to the 60-day volume-weighted average price of Icosavax shares.
  • Reneo Pharmaceuticals (RPHM) shares cratered 83% on Thursday, from $7.75 to $1.34, after the company acknowledged that its pivotal STRIDE study (NCT04535609) of mavodelpar in adults with primary mitochondrial myopathies (PMM) did not meet its primary efficacy endpoint, the change from baseline in the distance walked during the 12-minute walk test (12MWT) at week 24. The study also missed its secondary efficacy endpoint of the change from baseline in the PROMIS® Short Form Fatigue 13a score. Reneo also announced it would carry out immediate cost savings initiatives, including suspending all mavodelpar development activities and eliminating about 70% of its workforce—about 34 jobs, based on its workforce of 48 employees as of March 21.
  • Shattuck Labs (STTK) shares more than tripled, zooming 230% between Wednesday and Friday, from $2.11 to $6.96, after the company announced initial topline dose-expansion data from its ongoing Phase Ia/Ib trial (NCT05275439) of SL-172154 in combination with azacitidine (AZA) in frontline higher-risk myelodysplastic syndrome (HR-MDS) and TP53 mutant (TP53m) acute myeloid leukemia (AML) patients. SL-172154 plus AZA showed a 79% objective response rate (ORR) in frontline HR-MDS patients, primarily with TP53 mutations, plus an initial complete response (CR)/marrow complete response (mCR) rate of 64%. Researchers also reported seeing a 27% initial CR/complete response with incomplete hematologic recovery (CRi) in frontline TP53m AML patients, while 5 of 11 evaluable patients achieved stable disease with decreasing blast counts and peripheral blood count improvement; these patients continue on treatment.

Alex Philippidis is Senior Business Editor of GEN.

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