Inside five innovative research companies driving progress in oncology and neurology

BIO-Europe Spring 2023's therapeutic focus this year is on the latest innovation in oncology and neurology. Leading international life science venture capital firm TVM Capital Life Sciences has multiple investments in these areas. The firm continues to build its portfolio with new investments from its Life Science Innovation II fund.

September 21, 2024

9 Min Read
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This article is a contributed piece from MC Services first published on 20 March 2023.

BIO-Europe Spring 2023 in Basel, Switzerland, featured a therapeutic focus on the latest innovation in oncology and neurology. Leading international life science venture capital firm TVM Capital Life Sciences has multiple investments in these areas. The firm continues to build its portfolio with new investments from its Life Science Innovation II fund.

TVM pursues an innovative two-pronged investment strategy with its funds. It invests directly in novel medical technologies with commercial proof-of-concept and late clinical-stage therapeutics while also financing early-stage therapeutics by setting up a Project-Focused Company, PFC—an independent company formed around a single asset. These assets are usually first- or best-in-class product candidates with strong scientific rationale, a clear differentiation from competition and the potential to become standard of care. The PFC model allows for lower overhead costs and for more of the money invested to go directly into R&D. TVM’s experience with this model has shown that, PFC drug candidates can reach Phase II proof of concept (POC) much quicker than a typical biotech.

The firm’s two-pronged strategy has been validated through successful exits including AurKa Pharma, Inc. and Acanthas Pharma, Inc. TVM is currently applying this strategy with the following assets in the CNS / ONCO space.

Ovarian cancer in the era of immune checkpoint inhibitors

According to research published by Doo DW, Norian LA and Arend RC in June 2019, "ovarian cancer is the deadliest gynecologic malignancy, and relapse after initial treatment is frequently fatal. Although incremental advances in the treatment of this disease have been made, major breakthroughs are lacking. Given the success of checkpoint inhibitors in the treatment of other malignancies, there has been an attempt to replicate these results in ovarian cancer clinical trials.“

Despite their progress in other tumor types, the researchers said, “clinical use of checkpoint inhibitors in ovarian cancer has thus far been disappointing and any successes have yet to be translated to the clinical realm. Whether this is because the drug class is truly ineffective in ovarian cancer, or simply because the research is lacking is unclear. Either way, it is evident that preclinical data on the use of checkpoint inhibitors is woefully deficient in ovarian cancer and more research is urgently needed to inform the translation of immune checkpoint blockade into successful clinical use. “

TVM portfolio company, Esperas Pharma Inc. has a clinical stage program for ESP-01 in a well-defined group of ovarian cancer patients for whom nothing is available. With an injection of funds received in February, Esperas will conduct a POC study in a genetically selected sub-population of high-grade serous ovarian cancer (HGSOC).

The new trial will assess the efficacy of lead drug candidate ESP-01 in combination with low-dose gemcitabine in patients with HGSOC and tumors expressing defined genetic profiles. In a first proof-of-concept study in HGSOC, ESP-01, combined with low-dose gemcitabine, showed a significant rate of disease control (59.3%).

Prexasertib from Acrivon Therapeutics/SOM Biotech has shown some efficacy in HGSOC (33% in BRCA wild-type). What is more interesting is that the response rate increases to 42% in BRCA wild-type subjects with CCNE1 upregulation. Unfortunately, every responder experienced significant safety and tolerability issues from prexasertib. ESP-01 has been shown to be safe and well tolerated with manageable side effects, not only in HGSOC patients but in over 100 patients with advanced and metastatic cancer. Further, due to the mechanism of action, it is expected that ESP-01 + low-dose GEM should have a response rate similar to that of prexasertib in HGSOC with wild-type BRCA and high copy numbers of CCNE1 tumors.

There is no approved treatment for HGSOC tumors which fail PARP (poly-adenosine diphosphate ribose polymerase) inhibitors. These tumors are normally BRCA wild-type as the presence of BRCA mutations is a predictor of response to PARP inhibitors. Although the response rate of prexasertib in this patient population was good, safety and tolerability are major issues with prexasertib. ESP-01 may have a major advantage with safety and tolerability.

With the rising incidence of ovarian cancer, it is no surprise that the list of main players in the field reads like the who’s who of the pharma world and ranges from AstraZeneca, Roche, Tesaro, Clovis Oncology, Boehringer Ingelheim, Merck, Amgen, GlaxoSmithKline, La Roche, Bristol-Myers Squibb to Eli Lilly and Company - just to name a few. Roche for example, just recently signed a worldwide agreement with Repare Therapeutics for the development and commercialization of camonsertib (RP-3500), an oral small molecule ATR inhibitor in Phase I/II trials.

Innovation in reproductive health

TVM portfolio company Ixchelsis was developing cligosiban, an oxytocin receptor antagonist, for the treatment of Premature Ejaculation (PE). After a positive clinical POC study, a dose ranging Phase 2b study was conducted which failed to demonstrate efficacy, as such the development in PE was halted. Three hundred and forty-seven men have been exposed to single or multiple doses of cligosiban up to 2400mg daily and the tolerability profile has been consistently similar to placebo across studies with no serious or severe adverse events related to study drug.

Ixchelsis has also undertaken a range of pre-clinical work demonstrating the potential utility of cligosiban in benign prostatic hypertrophy and prostate cancer to a point where the next step would be to conduct clinical POC studies in these indications.

Recently published academic pre-clinical and clinical work has demonstrated the potential utility of an OTra in the treatment of mesothelioma, narcolepsy/cataplexy and a range of women’s health indications that include endometriosis, pre-term labor and IVF.

The following is a list of companies working in some of the therapeutic areas detailed above: BPH and PCr: Amgen, Aspire Pharma, Astellas, Boehringer Ingelheim, GSK, Lilly, Merck, Novartis, Pfizer.

Taxanes – nano-formulation to overcome drug resistance

 Soon to be in the clinic with its novel taxane formulation addressing the one major cancer type—colorectal cancer—where taxanes have not yet seen much progress, is Recurv Pharma. The company received funds from TVM in February 2023 to breathe some new life into this well-established class of chemotherapy agents.

Recurv is developing a new chemical entity, RP-001 delivered through a nano-emulsion formulation that focuses the drug delivery on the tumor, sparing healthy organs. The molecule has demonstrated the ability to kill tumors even in multi-drug resistant cancers, with strong efficacy in various pre-clinical tumor models, including non-small cell lung, breast, ovarian, prostate, pancreatic and colorectal cancers.

It has also been proven in preclinical models to cure tumor types that are resistant to current taxane treatments. The data have shown that RP-001 can effectively kill cancer stem cells, the cells that trigger recurrence, and toxicology studies suggest a potentially superior safety profile compared to taxanes currently on the market. Additionally, RP-001 was demonstrated to be synergistic with immune checkpoint inhibitors in a pancreatic cancer model.

Many big pharma companies have clinical research programs which could benefit from this novel taxane in combination with other, already approved cancer drugs. Recurv has published data showing the synergy of RP-001 with immuno-oncology agents including checkpoint inhibitors. There is now significant potential to assess these combinations in the clinic. The long list of companies in the taxane market includes Genentech (Roche), Merck, BMS, Sanofi, GSK and Novartis.

Progress in treating KRAS mutations

As the most frequently mutated oncogene, Kirsten rat sarcoma viral oncogene homologue (KRAS) has attracted substantial attention. According to a paper published by Huang, L., Guo, Z., Wang, F. et al.  in May 2021, “the understanding of KRAS is constantly being updated by numerous studies on KRAS in the initiation and progression of cancer diseases. Resistance to drugs targeting specific KRAS mutations is currently one of the greatest challenges in the treatment of KRAS cancers.“

Current targeted therapies are effective only in a minority of patients and hampered by the development of drug resistance. Auricula Biosciences is developing a drug candidate, SDV-1001, that is a pan-KRAS therapeutic approach, designed to target all KRAS mutations and overcome resistance mechanisms of conventional inhibitors.

This conjugate targets macropinocytosis, a unique feature of cancer cells harboring KRAS mutations.

Auricula plans to develop the first in class conjugate to a clinical POC study in KRAS mutant cancers. KRAS is found commonly in pancreas, colorectal, lung and urogenital cancers. The mutation confers a poor prognosis as current targeted therapies are effective in a minority of patients and hampered by the development of drug resistance. The conjugate to be developed by Auricula has been designed to by-pass such resistance.

The main players in the KRAS space include Amgen, Mirati, Novartis, J&J, Roche, Eli Lilly and Pfizer. Pfizer recently made an investment deal with Cardiff Oncology and acquired US-based Seagen - Adcetris. KRAS G12C inhibitors have been a triumph of drug discovery against a target that had been defying all efforts for decades, however they are effective only in a minority of patients and hampered by the development of drug resistance. Amgen’s Lumakras (sotorasib) was the first ever approved KRAS inhibitor, followed by Mirati’s Krazati (adagrasib). Several companies including Novartis, J&J, Roche, Eli Lilly have KRAS G12C inhibitors currently in the clinic and inhibitors for other KRAS mutations, G12D and G12V, as well as pan-KRAS inhibitors are also being developed opening a new set of untapped possibilities for the patients.

Treating CNS disorders with human antibodies

Specializing in the central nervous system space is the TVM portfolio company AL-S Pharma, with a focus on Amyotrophe Lateralsklerose (ALS), also known as Lou Gehrig’s disease. This rare neurodegenerative condition has no established cure and is frequently fatal within two to five years as patients experience a rapid functional decline in their abilities to move, talk, swallow, and breathe. The mainstay of ALS disease management is focused on timely intervention to effectively manage symptoms, optimize function, and help ensure quality of life.

There are currently six drugs approved by the U.S. Food and Drug Administration (FDA) to treat ALS and its symptoms: RELYVRIO (approved in 2022), Radicava, Rilutek, Tiglutik, Exservan and Nuedexta. Most of these drugs have very limited efficacy and can only treat symptoms of the disease.

AL-S Pharma is developing a human antibody, AP-101, that has the promise of being a disease modifying drug targeting misfolded superoxide dismutase 1 (SOD1) which is considered a cause for ALS. AP-101 selectively binds to misfolded and aggregated forms of SOD1 with the goal to neutralize and remove these abnormal proteins.

The key players in ALS are Sanofi (Rilutek), Mitsubishi (Exservan), Isis and Avanir (Nuedexta) and Biogen (Tofersen). Tofersen did not meet the primary endpoint in Phase 3 but could still be approved later in 2023. BMS and Lilly have also shown interest in the indication and could be larger movers in the future. Most ALS drugs have been licensed at a very early stage, so no very large deals in the field were announced recently.


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