Pharma Strategy Blog

"These phase II results suggest that RVD is a highly
effective combination, with a pre-ASCT ORR of 100% and high rates of CR/nCR, and encouraging time-to-event analyses to date. RVD
was well tolerated, with limited rates of grade 3 peripheral neuropathy and DVT/PE despite
prolonged use of bortezomib and lenalidomide." 

A new generation proteasome inhibitor, carfilzomib (PX-171), has been generating consistent results in the bortezomib refractory setting.  An ongoing phase II study presented at ASH looked at carfilzomib monotherapy in myeloma patients with relapsed or refractory disease following 1–3 prior therapies, ie a heavily pre-treated population.  Updated data for the bortezomib-treated cohort were reported at ASH and the authors concluded that:

"18% ORR (CBR 30%) is notable for this steroid- and
anthracycline-sparing regimen. Single-agent carfilzomib is well tolerated, even
in patients with renal insufficiency, and both myelosuppression and peripheral neuropathy
are uncommon." 

Carfilzomib was originally developed by Proteolix, who have just been acquired by Onyx.  This should ensure more solid funding for the development of the phase III program, which looks promising in the relapsed, refractory setting.

Perifosine (Keryx) modulates Akt, and a number of other signal transduction pathways,
including the JNK and MAPK, all of which are associated with programmed cell death, cell growth, cell
differentiation and cell survival.  Updated data from a phase I/II study in 84 patients who were heavily pre-treated with a median of 5 prior lines of therapy (range 1-13), showed that the overall response rate (ORR) was 41%, for the bortezomib relapsed group, 65%, and for the bortezomib refractory group, 43%. 

Approximately 60% of patients
demonstrated progression (or stable disease (SD) for 4 cycles) at some point in their
treatment and received 20 mg dexamethasone, four times per week, in
addition to perifosine plus bortezomib.  Responses occurred both with
patients taking perifosine in combination with bortezomib and with
patients receiving the combination plus dexamethasone.  The ORR for the perifosine plus bortezomib arm was 25%, with an increase to 38% when dexamethasone was added.  Survival data in the 73 evaluable patients was 6.4 months for PFS and 25 moths for overall survival (OS).

Another exciting new compound in development is MLN4924 from Millennium, the novel mechanism of which was recently described in detail (see article below) and was the also subject of a Nature article.  The compound works very differently from proteasome inhibitors, which target the proteasome substrate.  MLN4924 is involved with neddylation rather than direct ubiquination. 

Neddylation activating enzyme (NAE) is the E1-activating enzyme for the ubiquitin-like protein Nedd8. 
NAE catalyzes the first step in the neddylation cascade leading to
modification of cullin-based ubiquitin ligase activity.  This results in
specific protein substrates, with important roles in cancer cell
survival, being targeted for degradation as shown the diagram below:

Source: Soucy et al., 2009

The end result is that MLN4924 inhibits neddylation by disrupting the cullin-RING ligase-mediated protein turnover, leading
to apoptotic death in human tumour cells by a new mechanism of action,
the deregulation of S-phase DNA synthesis.

A phase I dose escalation study in myeloma and NHL patients with MLN4924 was reported at ASH.  The primary objectives were to determine the maximum
tolerated dose (MTD) and safety profile of MLN4924, as well as describe the
pharmacokinetics (PK) and pharmacodynamics (PD) in blood.  Among the 22 patients enrolled to date, the median age was 65 years, 14 had myeloma and 8 had NHL. 

The results showed that NEDD8-Cullin levels in peripheral blood myeloma cells (PBMCs) were inhibited and Nrf-2 target gene
transcripts in whole blood were higher vs. baseline after MLN4924
administration, which is indicative of NAE inhibition.  Cdt-1 and Nrf-2 levels in skin increased above baseline following the
second dose of MLN4924, which is indicative of NAE inhibition in peripheral
tissue.  These results are promising and provide early proof of concept for the role of neddylation in myeloma.

Overall, this was a good meeting on the myeloma front with lots of promise for triple and quadruple combinations, as well as new agents being developed in both the newly diagnosed and refractory settings that augers well for the future, both in terms of improved survival and also more tolerable regimens.

Soucy, T., Smith, P., & Rolfe, M. (2009). Targeting NEDD8-Activated Cullin-RING Ligases for the Treatment of Cancer Clinical Cancer Research, 15 (12), 3912-3916 DOI: 10.1158/1078-0432.CCR-09-0343

Soucy, T., Smith, P., Milhollen, M., Berger, A., Gavin, J., Adhikari, S., Brownell, J., Burke, K., Cardin, D., Critchley, S., Cullis, C., Doucette, A., Garnsey, J., Gaulin, J., Gershman, R., Lublinsky, A., McDonald, A., Mizutani, H., Narayanan, U., Olhava, E., Peluso, S., Rezaei, M., Sintchak, M., Talreja, T., Thomas, M., Traore, T., Vyskocil, S., Weatherhead, G., Yu, J., Zhang, J., Dick, L., Claiborne, C., Rolfe, M., Bolen, J., & Langston, S. (2009). An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer Nature, 458 (7239), 732-736 DOI: 10.1038/nature07884