What is PEN-221?

Tarveda Therapeutics is discovering and developing a new class of potent and selective precision oncology medicines for the treatment of patients with various solid tumor malignancies. Their strategy includes developing their own proprietary Pentarin miniature conjugates to enhance the effectiveness of promising anti-cancer payloads that have struggled without their selective targeting to solid tumors.  These medicines are known as ‘Pentarins’. PEN-221 is the lead candidate ‘Pentarin’ aimed at Neuroendocrine Cancer – PEN-221.

Somatostatin receptor 2 (SSTR2) is frequently overexpressed on several types of solid tumors, including neuroendocrine tumors and small-cell lung cancer. Peptide agonists of SSTR2 are rapidly internalized upon binding to the receptor and linking a toxic payload to an SSTR2 agonist is a potential method to kill SSTR2-expressing tumor cells. PEN-221 is a conjugate consisting of microtubule-targeting agent DM1 linked to the C-terminal side chain of Tyr³-octreotate. PEN-221 demonstrates in vitro activity which is both potent and receptor-dependent. PEN-221 targets high levels of DM1 to SSTR2-expressing xenograft tumors, which has led to tumor regressions in several SSTR2-expressing xenograft mouse models. The safety and efficacy of PEN-221 has been evaluated in human clinical trials (clinical trials information including Phase 1 data below).

The use of somatostatin analogues and somatostatin receptors to deliver the ‘payload’ would strongly indicate this is a targeted therapy.

What Makes this different to other NET treatments?

The trial is aimed at all types of Neuroendocrine Neoplasms including well and poorly differentiated types, e.g. small cell and large cell lung Neuroendocrine Carcinoma, pheochromocytoma, paraganglioma, medullary thyroid carcinoma and merkel cell carcinoma.  The use of somatostatin receptors is not new, this is currently the main route used by somatostatin analogues and also used in somatostatin receptor Theranostics (e.g. Ga68 PET an PRRT). However, Tarveda’s miniature drug conjugates are designed to maintain therapeutic properties while remaining miniature in size to enable rapid penetration into solid tumors.  The plasma circulation time of hours is designed to allow for penetration into the tumor but to limit the overall exposure to normal tissue. Tarveda’s miniature drug conjugates are designed to accumulate anti-cancer payloads in the tumor by targeting and minimize effects on healthy tissue. The conjugates’ payloads are designed to remain masked while in circulation within the body to reduce normal tissue toxicity with unmasking occurring when the payload is cleaved in the tumor.

The Clinical Trial for Neuroendocrine Cancer?

Protocol PEN-221 is an open-label, multicenter Phase 1/2 study evaluating PEN-221 in patients with SSTR2 expressing advanced gastroenteropancreatic (GEP) or lung or thymus or other neuroendocrine tumors or small cell lung cancer (SCLC) or large cell neuroendocrine carcinoma (LCNEC) of the lung. There’s also mention of Advanced paraganglioma, pheochromocytoma, medullary thyroid carcinoma, Merkel cell carcinoma, or high grade extrapulmonary neuroendocrine carcinoma having progressed after 1 or more lines of anticancer chemotherapy (unless no standard treatments available or such treatments are deemed not appropriate).  The exclusion and inclusion criteria are extensive and those interested should read this section of the clinical trial document very carefully (see below). The phase 1 trial route of administration appears to be a one-hour IV infusion every 3 weeks.

The trial locations incudes several sites in US plus 4 locations in the UK.

Clinical Trial results so far

Conclusions: PEN-221 appears well tolerated at 8.8 mg/m² q 3 weeks and has demonstrated efficacy exceeding its clinical efficacy goals with a CBR of 88.5% and a mPFS of 9 months. A randomized trial of PEN-221 in GI mid-gut NET patients is now in development. Clinical trial information: NCT02936323

Further Reading:

1. Tarveda Therapeutics website – click here

2. The clinical trial document – click here

3. ASCO Poster with Phase 1 data – click here

4. ASCO Poster with Phase 2 data – click here