- Industry data shows small molecules achieve 5–10% approval rates over 15–20 years; antisense oligonucleotides (“ASOs”) are shifting the odds through rational design.
- Six new antisense drugs gained FDA approval in 2023–2024, bringing total approvals above 20; evidence of accelerating regulatory momentum.
- Oncotelic Therapeutics’ OT-101 (Trabedersen) is the only TGF-β2-specific antisense in Phase 3 trials, targeting pancreatic cancer and other resistant malignancies.
The pharmaceutical industry has long faced sobering odds: about 90% of drug candidates fail before reaching market. For small molecules, approval rates hover at very low odds, often requiring up to two decades of development. In oncology, success rates fall to just 3%. These economics have created a bottleneck that leaves patients waiting years for new treatments that rarely arrive.
Antisense oligonucleotides, short synthetic strands of DNA or RNA that silence disease-causing genes, are beginning to rewrite those odds. With six new FDA approvals since 2023 and more than 50 candidates in active trials, ASOs are experiencing a long-anticipated breakout. Oncotelic Therapeutics Inc. (OTCQB: OTLC) aims to be at the forefront with OT-101 (Trabedersen), the only TGF-β2-specific antisense therapy in Phase 3 development, an important distinction after several high-profile failures from larger pharmaceutical peers targeting the same pathway.
The Rational Design Advantage
Unlike traditional drug discovery, which relies on screening millions of compounds, antisense therapeutics are rationally designed. Scientists identify a specific genetic sequence responsible for disease, then engineer a complementary molecule to silence it. This precision reduces much of the trial-and-error that slows and inflates the cost of small-molecule programs.
ASOs occupy a unique middle ground: small enough to penetrate tissues (roughly 5,000–7,000 daltons) but large enough for precise gene targeting. Between 2016 and 2024, the FDA approved 18 new antisense or siRNA therapies, compared to just two in the prior 18 years, underscoring the acceleration of RNA-based innovation.
Manufacturing is also more predictable. ASOs are produced using standardized solid-phase synthesis, bypassing the complex bioreactors required for biologics. This simplifies quality control, shortens timelines, and reduces regulatory risk.
Why TGF-β2 Matters
OT-101 (Trabedersen) is an 18-mer phosphorothioate antisense oligonucleotide designed to suppress TGF-β2, an immunosuppressive cytokine linked to tumor progression and treatment resistance. While TGF-β exists in three isoforms, only TGF-β2 consistently correlates with poor survival. In pancreatic cancer, patients with high TGF-β2 expression survive a median of just 15 months, less than half that of those with low expression.
Earlier industry attempts to block the broader TGF-β pathway have failed. Novartis’s NIS793 and Merck’s bintrafusp alfa were both discontinued after missing survival endpoints or poor performance relative to the benefit and risk. Both targeted all three isoforms indiscriminately, blunting immune response. OT-101, by contrast, isolates TGF-β2, the specific driver that converts tumor-fighting M1 macrophages into tumor-promoting M2 macrophages.
Clinical Validation and Phase 3 Pathway
Across seven completed studies involving more than 200 patients, OT-101 has demonstrated encouraging results. In a Phase 2b glioblastoma trial, the therapy achieved a 22% objective response rate, with responders living more than three times longer than non-responders. In pancreatic cancer, OT-101 produced disease control in 55% of patients, and those who subsequently received chemotherapy doubled median survival compared to immediate progressors.
These data underpin Oncotelic’s ongoing Phase 3 trial (NCT06079346) combining OT-101 with mFOLFIRINOX in metastatic pancreatic cancer. Preclinical work showed TGF-β2 inhibition synergizes with irinotecan, a key FOLFIRINOX component, but not with gemcitabine, the backbone of failed prior trials. With pancreatic cancer projected to become the second-leading cause of U.S. cancer death by 2030, even modest efficacy could represent a multibillion-dollar opportunity.
Platform Potential and Strategic Positioning
Beyond pancreatic cancer, OT-101 has received Rare Pediatric Disease Designation for diffuse intrinsic pontine glioma (“DIPG”), qualifying Oncotelic for a potential Priority Review Voucher worth $100–350 million. The company is also studying OT-101 in combination with PD-1 inhibitors. Bioinformatic analyses show that patients with low TGF-β2 expression experience median survival of 32.6 months on checkpoint inhibitors versus 14.5 months for those with high expression, suggesting OT-101 could enhance response to immunotherapy.
A Phase 1/2 trial pairing OT-101 with pembrolizumab in non-small-cell lung cancer is also in the works. Unlike most antisense companies focused on rare genetic disorders, Oncotelic is applying the platform to immuno-oncology, potentially unlocking far broader markets.
Regulatory Tailwinds and Economic Leverage
Regulators are increasingly receptive to RNA-based drugs. Six ASOs approved since 2023, including Qalsody for ALS and Izervay for geographic atrophy, demonstrate comfort with the modality across diverse diseases. Accelerated approval pathways and Orphan Drug incentives further de-risk development, granting up to seven years of market exclusivity and significant tax credits.
For Oncotelic, this convergence of science, regulation, and economics represents a rare alignment. OT-101’s late-stage status, selective mechanism, and combination potential position the company at the leading edge of antisense oncology. With a market capitalization below $50 million and an addressable market measured in billions, the asymmetry between valuation and opportunity is striking.
Oncotelic’s bet is clear: rational design is not just redefining how drugs are discovered; it’s reshaping what’s economically possible in cancer therapy.
For more information, visit the company’s website at www.Oncotelic.com.
NOTE TO INVESTORS: The latest news and updates relating to OTLC are available in the company’s newsroom at ibn.fm/OTLC
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