Lutetium lu 177 vipivotide tetraxetan (pluvicto) Radioligand Therapy for PSMA+ mCRPC

Prostate Cancer

Epidemiology

2nd most common cause of cancer in men globally

2nd leading cause of cancer related death among men in the USA. 3rd leading cause in Europe.

Pathophysiology -mCRPC

Localised Prostate Cancer

Surgical

Radiological therapy

Androgen Depletion Therapy (ADT)

Metastatic Prostate Cancer (mPC)

Androgen Depletion Therapy is continued

ADT highly effective- elicits a PSA response

10/20% of patients become castration resistant within 5 years

5 year survival = 30%

90% of patients with mCRPC develop bone metastasis

Castration Resistant Prostate Cancer Therapeutics

>50% die within 3 years with historical standard therapies

Tax and based chemotherapy

Chemotherapy side effect profile

Limited options failure of chemotherapy

NCCN,ESMO,APCCC

No proper sequence for delivery

None have been proven to prolong survival

Pharmacodynamics

Target

PSMA

PSMA is a transmembrane glycoprotein involved in various cellular functions, such as cellular uptake of folate, cell migration, and cell survival. While PSMA is expressed at low levels in normal prostate epithelium, it is overexpressed (up to 1000 times higher) in 90–95% of prostate cancers. In contrast to benign prostatic epithelium where PSMA resides in the cytoplasm, PSMA is in the luminal epithelium of prostatic ducts in prostate cancers and presents a large extracellular binding domain . PSMA expression is positively correlated with more aggressive disease, including high PSA, high Gleason scores, and early recurrence. The highest levels of PSMA expression are found in metastatic and castrate-resistant disease Due to its overexpression on the surface of PC cells, PSMA remains a useful protein target for targeted diagnostic processes and radionuclide therapy in PC

>80% of patients with prostate cancer express PSMA

Therapeutic Indications/ eligibility

PET scan performed to check PSMA+ for Pluvicto eligibility

Androgen deprivation therapy, in adults previously treated with androgen receptor pathway inhibitors and taxes.

Administered with androgen deprivation therapy

Taxanes

Androgen receptor pathway inhibitors

Mechanism of Action

Targeted Radioligand therapy

Targeted RLT offers the possibility to treat prostate cancer lesions in a specific and tumour selective manor by exploiting the cell surface proteins mainly expressed on maligant cells.

PSMA-617 (precursor molecule)

Therapeutic radiation can be delivered via PSMA while minimising radiation related side effects. PSMA -targeted RLT uses a radiolabelled small molecule ligand (PSMA617) that binds with high affinity to PSMA, resulting in internalisation and retention within the targeted PC cell.

PSMA-617 complexed with radionucleotide Lu-177

Physical 1/2 life

6.64 days

Path length of B particles

medium length B emitter

shorter B length- better irradiation for small tumours

direct energy to tumour than surrounding tissue

Maximal tissue penetration

2mm

Intra tumoral half life

60/160 hours

Pharmacokinetics

Dosage

Supplied: 30 mL single dose vial. Pluvicto solution for injection contains : 7.4 GBq (200 mCi) of radioactivity (at time of use). Slow IV injection (1-10 mins)/ infusion

e4EM

Administered every 6 weeks for up to 6 treatments.

Administered by a healthcare professional, certified in radio pharmacotherapy.

Blood tests preformed pre and during treatment to monitor PSMA levels.

Absorbtion

Whole body and organ radiation dosimetry collected in a subgroup of patients the phase 3 vision trial. n=29

Radiation absorbed doses [mean calculated absorbed dose for 6 x 7.4 GBq (44.4 GBq cumulative activity)

Organs with highest radiation absorbed: Lacriminal glands, salivary glands , large intestine (left colon, rectum, right colon,kidneys, urinary bladder wall).

Maximum penetration of lutetium-177 in tissue is ≈ 2 mm (mean penetration is 0.67mm)

The 6-cycle cumulative estimated absorbed dose in the blood-based red marrow was 1.5 Gy.

After Iv admin- mean blood concentration 6.58ng/mL

Distribution

Volume of distribution : mean = 123 L

Within 2.5hr administration - Gastrointestinal tract, liver, lungs, kidneys, heart wall, bone marrow, salivary glands.

Metabolism

60-70% bound to human plasma proteins.

Substrates - not a substrate of CYP450 enzymes or of transporters OAT1,OAT3, OCT2.

Clearance

Primaly excreted via the kidneys

Exposure of drug to kidneys increases with decreasing creatinine clearance.

No dose adjustment rec-ommeded - kidney imparimeny- risk of toxicity

Effects of more severe kidney impairment or end stage kidney disease has not been investigated.

Safety Information

Contributes to long-term cumulative radiation exposure.

Administration precautions

Principles of ALRA (as low as reasonably achievable).

Minimise effects of radiation by :

Minimise close contacts

Potential adverse/ adverse drug events

Potential averse effects/ clinically relevant

Life threatening myleosupression

Infertility

Severe renal toxicity

Embryo-fetal toxicity

Most Frequent

5 year survival = 30%

90% chance of developing bone metastasis (fractures, spinal chord compression)

No therapeutic options remaining

Pluvicto: OS =15.3 months (4 months > then BSOC)

Estimated 38% reduction in risk of death

Quality of life

Pharmacoeconomics

Novartis bought Pluvicto in its $2.1 billion deal for Endocyte

predicting Pluvicto could eventually earn over $2 billion a year

However

Production limits mean demand is greater than supply

$45,657 for a supply of 1 solution

Manufacturing/ handling

manufacturing

2 different stable isotopes: Leutium 177- PSMA 176 + ligand

Complex to make

Supply

Struggled to produce/ source enough radioactive material to meet demand

Manufacturing halted last May to sort out supply issues- resumed

Storage/ Handling

Shelf life

120 hours (5 days)

Storage

Store below 30 do not freeze

Disposal

In accordance with local radiation safety federal laws.

Consult the product batch release certificate to identify the source of stable isotopes used- appropriate management for different types of isotopes

FDA Approval

USA

2nd of March 2022

Following VISION trial

Approval in the EU

13 October 2022

Pharmacovigilance

ongoing

Vison Trial

Trial Characteristics

Prospective open labelled trial

Best standard of care - as chosen by physician throughout the trial

Results

Primary end point

Median Overall Survival 15.3 months-11. 3 months

Radiographic Free Survival 8.7 months- 3.4 months

Secondary end point

Significant increase in Overall Response Rate (ORR)

PSA Decline 46% vs VS 7% 46% of patients who received Pluvicto (BSOC) PSA decline ≥ 50% VS 7%B SOC alone

Adverse effects

Myleosupression

15% grade 3 /4 ↓ hemoglobin ↓ 9% platelets ↓ 7% leukocytes ↓ 4.5% neutrophils

Fatal events (n=5)

1.1% grade ≥3 pancytopenia occurred (including 2 fatal events)

2 deaths (0.4%) - intracranial hemorrhage and subdural hematoma in association with thrombocytopenia.

1 death due to sepsis and concurrent neutropenia.

Renal toxicity

3% - Grade 3 or 4 acute kidney injury.

0.9% - ↑ creatinine

Benefit/ risk balance

Safety Profile

>safety risks than current BSOC

Efficacy profile

Efficacy profile outweighs safety profile according to European Medicines Agency