Necessary Ventures’ Biotech Watch List

Introduction

2023 was a challenging year for the biotech sector with the XBI index dramatically underperforming compared to the broader market. However, with falling interest rates the New Year seems set to bring good news for the biotech industry. As the Wall Street Journal reported, with declines in Treasury yields in recent weeks, XBI is up 20% in the past 30 days. 


KRAS

Kirsten rat sarcoma viral oncogene homologue is the most frequently mutated oncogene; especially common in pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC) and non small cell lung carcinoma (NSCLC). KRAS mutations tend to be single base missense mutations primarily found at codon 12. 

It was previously considered an ‘undruggable’ target but the recent discovery of a new allosteric site of KRAS (G12C) has enabled the development of irreversible covalently binding inhibitors of KRAS. Examples include Sotorasib which was approved after the phase III Lumakras clinic trial in NSCLC. The FDA has approved several tests to check for the G12C mutation including Qiagen’s therascreen KRAS RGQ PCR kit. 

However, the excitement has been tempered by the development of several forms of resistance which are being targeted in trials that combine KRAS inhibitors with inhibitors of horizontal or vertical signaling pathways.

Biological Pathway

KRAS is activated by most growth factors, cytokine and immunological receptors. The canonical downstream signaling pathway of KRAS is RAS-RAF-MEK-ERK. Activated KRAS-GTP recruits RAF from the cytoplasm to the plasma membrane and induces conformational changes in RAF, which subsequently binds to and activates MEK1/2. MEK1/2 activates ERK1/2 which phosphorylates RSK, ETS and ETS like-1 protein to regulate the transcription and translation of target genes as demonstrated in the figure above.

Current and emerging trends in KRAS therapeutics

Over the last decade, several different strategies for targeting oncogenic KRAS signaling have been developed including direct inhibitors, RNA interference and targeting of downstream effectors. The first KRAS inhibitor to be approved was sotorasib in 2021 for patients with NSCLC harboring the G12C mutation. Following this news, Bristol Myers Squibb acquired Mirati for adagrasib, another G12C inhibitor which secured accelerated approval in December 2022 for NSCLC. 

Exciting therapeutics in the pipeline include Revolution Medicines’ KRAS inhibitor RMC-6236 is the first macrocyclic glue-like inhibitor which acts beyond KRAS-G12C. It is able to inhibit KRAS in its active state by ‘gluing’ to the chaperone protein cyclophilin A. Phase I data was promising; the drug was well-tolerated and amongst the forty patients with NSCLC who were evaluable for efficacy, the objective response rate was 38% (3% (n=1) complete response and 35% (n=14) with partial responses), These responses were noted in tumors harboring G12D, G12V and G12R mutations. 

Additionally, Boehringer Ingelheim began a phase I trial for BI-3706674 which inhibits wild type amplifications of KRAS and G12V mutations. It is a non-covalent inhibitor that binds preferentially and with high affinity to the inactive state of KRAS with selectivity from NRAS and HRAS. Other selected assets of interest are shown in the table below.

Drug Company Market Value Differentiation Factors
Sotorasib (Lumakras) Amgen Has been prescribed to more than 3,700 patients making $75 million in Q322. FDA approved in 2021 for lung cancers with G12C mutation.  Analysis of 174 patients with NSCLC in the phase I and II parts of the CodeBreaK trial demonstrated a 1-year OS of 50.8% and a 2 year OS of 30.3%.
RMC-6236 Revolution Medicine Public company. Market cap is just over $4 billion. First pan-KRAS inhibitor; set the first clinical benchmark beyond KRASG12C. Oral; able to inhibit KRAS in active state. Currently in phase I/Ib.
Adagrasib (MRTX84) Mirati Therapeutics Acquired by Bristol-Myers Squibb for $4.8 billion in October 2023. Oral small molecule inhibitor optimized to sustain target inhibition as the KRASG12C protein regenerates every 24 to 48 hours. Phase III trials with the readout expected in Q124. FDA accelerated approval
BBO-8520 BridgeBio In vivo stage filing for IND Modifies both GTP and GDP forms of KRASG12C with the hypothesis that targeting the GTP form can improve efficacy by allowing rapid signal inhibition.
GDC-6036 Roche Roche is very interested in this space, paying Hookipa $25 million for HB-700 which can induce responses against cells that carry the five most common KRAS mutations G12D, G12V, G12R, G12C and G13D.  Phase 1a NCT04449874 in NSCLC. KRAS G12C inhibitor. Being tested alone and in combination with other therapeutics including the SHP2 inhibitor GDC-1971.
BI-3706674 Boehringer Ingelheim -- Phase I in advanced cancer of the stomach and esophagus (recruiting) NCT06056024

The potential of KRAS inhibitors is very exciting but has been far from curative, largely due to the development of resistance to monotherapy. Consequently, combination approaches are being developed but challenges remain. A study utilizing deep-RNA and whole-exome sequencing found numerous mechanisms for KRAS resistance in one patient’s mutant NSCLC. Some tumor areas showed reactivation of MAPK signaling whilst others had decreased KRAS G12C expression, and other evidence of epithelial-mesenchymal transition, highlighting the need for further exploration of resistance.

Epidermal growth factor

Epidermal growth factor was first identified in 1978 by Stanley Cohen, for which he was awarded the Nobel Prize. EGFR mutations are a common oncogenic driver found in 2.8% of all cancers. It is especially common in glioblastoma and non-small cell lung cancer (NSCLC). 

EGFR signaling is activated by the binding of various ligands including epidermal growth factor (EGF), TGF-α and betacellulin. Downstream signaling includes RAS/RAF/MEK, PI3K and the JAK/STAT pathways as demonstrated in the figure below:

Current and Future development of EGFR inhibitors 

The first generation of EGFR inhibitors were developed in the early 2000s, showing rapid and deep initial tumor responses. However, acquired resistance quickly developed. The most common mechanism was the development of the T790M mutation. This spurred the development of second and third generation EGFR TKIs. The most commonly used of these was osimertinib, a third generation irreversible TKI, capable of targeting exon 19 or 21 mutations and T790M-driven acquired resistance. 

However, despite its efficacy, acquired resistance still remains a challenge including C797S mutations. Osimertinib covalently binds to the cysteine 797 in EGFR and thus EGFR C797S mutations have been identified in 10–26% of patients with disease progression on second-line osimertinib.

Consequently, several fourth generation EGFR inhibitors are currently in development. Selected assets are highlighted in the table below. Other approaches include combination therapy with chemotherapy and immunotherapy. 

Drug Company Funding or Market Value Differentiation
BDTX-1535 Black Diamond Therapeutics for glioblastoma multiforme and NSCLC The market cap is $120.57 million currently. Phase I; oral EGFR inhibitor that can cross the blood-brain inhibitor and produce sustained inhibition of EGFR signaling. Believed to be a MasterKey inhibitor.
Sunvozertinib Dizal Pharmaceutical In 2020, raised $100 million in financing from names like Sequoia Capital and Trinity. Effective in over 30 different types of exon 20 insertions as well as EGFR activating mutations
THE-349 Theseus Pharmaceuticals Market cap just over $169 million. 4th generation, small molecule designed to inhibit all major classes of EGFR activating and resistance mutations with wtEGFR selectivity.
BLU-945 Blueprint Medicines In 2022 collaborated with Sixth Street and Royalty pharma for up to $1.25 billion in financing. CNS-penetrant wild-type EGFR-sparing four generation TKI. It is able to inhibit the triple mutant EGFR (harbouring a EGFR L858R mutation or exon 19 deletion, T790M, and C797S).

APRIL

A proliferation-inducing ligand (APRIL) is a member of the TNF superfamily of cytokines and has a physiological role in the regulation of B-cell mediated immune responses. It acts through two receptors: TACI and BCMA, and the former helps to mediate IgA class switch recombination. 

APRIL has significant therapeutic potential in IgA nephropathy. IgAN is the most common primary glomerular disease worldwide. Genome-wide association studies demonstrated a strong association between TNFSF13, the gene encoding APRIL, and IgAN development. In a study of over 400 IgAN patients, those with the highest APRIL plasma levels had a 10-fold greater risk of developing kidney failure. IgA nephropathy murine models treated with anti-APRIL mAb also showed a decrease in serum IgA and amelioration of glomerular lesions.

APRIL Therapeutic Development Pipeline

The most developed therapeutic so far is the monoclonal antibody sibeprenlimab which is currently in phase III (NCT05248646). The complete results of the phase II ENVISION clinical trial were recently presented at the ASN Kidney Week. ENVISION involved 155 patients with IgAN at high risk of disease progression, who were randomly assigned into either three different doses of sibeprelimab or placebo. At 12 months, sibeprelimab had significantly reduced the 24 hour urinary protein-to-creatinine ratio (uPCR) and decreased serum levels of APRIL and galactose-deficient IgGA1 (gdIgGA1). Whilst the effect on uPCR was maintained at 5 months, it was not for APRIL and gdIgGA1, suggesting that continued treatment is likely required. 

The table below includes selected assets of note.

Drug Company Clinical Trial Results Differentiation Factors
Sibeprelimab (IV) Otsuka Pharmaceuticals and Visterra for IgA nephropathy Placebo reduced 24-hour uPCR from baseline by 20.0% with 4 mg/kg by 58.8% and 8 mg/kg by 62.0%. Phase III to be completed Q42026.
Povetacicept (previously ALPN-303) Alpine Immune Sciences Phase Ia/IIb RUBY-3 ongoing. In IgAN, there was a 53.5% reduction from baseline in UPCR observed at 24 weeks. Completion expected in 2026. Dual inhibitor of BAFF and APRIL.
Zigakibart (IV/SC) Novartis (previously Chinook Therapeutics before acquisition) Acquired for $3.2 billion upfront. Is currently enrolling in phase 3 BEYOND clinical trial. Estimated primary completion is 2025. NCT05852938 Humanized IgG4 mAb.
Telitacicept Remegen Phase II: after 24 weeks of treatment the average 24-hour urine protein level was reduced by 49% compared to baseline which was statistically significant compared to the placebo group. Phase III clinical trial (NCT05799287) with primary completion estimated to be in 2025. Approved for active SLE in China.
Atacicept Vera Therapeutics The magnitude of proteinuria reduction was considered to be disappointing but still pushed to phase 3. April and Blys inhibitor. In phase III in IgAN and lupus nephritis. Recombinant fusion protein that targets the soluble TACI receptor that binds to cytokines BLyS and APRIL.

Thymic stromal lymphopoietin (TSLP)

Thymic stromal lymphopoietin (TSLP) is a cytokine which acts on several cell lineages including T cells, B cells and neutrophils affecting their maturation and survival. It is very important in promoting type 2 immune responses associated with allergic and eosinophilic inflammation. 

TSLP is a paralogue of IL-7 and signals through TSLPR that activates JAK1 and JAK2, which in turn activate STAT5A and STAT5B, driving the production of IL-4, IL-5, IL-9 and IL-13. In combination with the other epithelial cell-derived cytokines, IL-25 and IL-33, which are known collectively as ‘alarmins’, it helps drive asthma, atopic dermatitis and food hypersensitivity.

TSLP in asthma

Drug development has largely focused on the value of TSLP inhibition in asthma, for which there is a strong evidence base. In mouse models, overexpression of TSLP leads to severe airway inflammation and hyper-responsiveness. Asthmatic patients have high TSLP levels and this is correlated with future asthma exacerbations. This has further been supported by the development and approval of Tezpire (tezepelumab), a monoclonal antibody that prevents TSLP from binding to its receptor and reduces eosinophilic inflammation.

In the phase III NAVIGATOR trial, tezepelumab significantly reduced asthma exacerbations, including in those with low eosinophil levels. It however failed to meet the primary endpoint in  phase II trial of atopic dermatitis. Regardlessly, the results in asthma are very promising and analysts expect peak sales to reach US$1.4 billion. Other TSLP candidates have gained notable attention from investors with selected assets of note listed in the table below.

Drug Company Funding or Market Value Differentiation
Tezepelumab (Tezpire) Amgen and AstraZeneca for asthma $1.4 billion peak sales. Phase III trial for asthma led to FDA approval; failure of phase II trial in atopic dermatitis
CSJ117 Novartis for asthma Has been put up for partnering by Novartis Phase II trial. Inhaled antibody fragment
BSI-045B Biosion for atopic dermatitis 200 million RMB preB+ financing round Phase II in atopic dermatitis for monotherapy and combination therapy for Dupixent
UPB-001 UpstreamBio in asthma $200 million series B in June 2023. Phase 1b interim results were released which seemed to support progressing into phase 2 following completion. They are trialing dosing every 12 weeks and every 24 weeks.
AIO-001 Aiolos for asthma (phase II). Also future considerations for beginning trials in COPD and urticaria. Just recently came out of stealth with $245 million series A funding. Long acting mAb. Six-monthly administration schedule with extended half-life demonstrated pre-clinically

Targeting TSLP may still have significant future potential beyond atopic disease. Its role in the development of several cancers including solid tumors and in chronic inflammatory diseases such as idiopathic pulmonary fibrosis and COPD is an area of ongoing investigation.

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