Bellicum: An ASH Review

Overview:

Disclosure: The fund I work for, Aju IB Investment, was a private investor in Bellicum before its IPO and invested further in the IPO. The firm continues to hold all of the shares it has purchased in Bellicum. I wrote this article myself and it expresses my own opinions. It does not reflect the views of my employer. I am not receiving any compensation for this blog post. I have no business relationship with any company whose stock is mentioned in this article. This is not a recommendation to buy any security.

Bellicum’s ASH data were well received. If the data continue on this trajectory, BPX-501 enabled HSCT has a strong case to be the standard of care for allogeneic HSCT, initially for orphan blood disorders and subsequently for hematologic malignancies. To be clear, the numbers in the BPX-004 trial need to be larger for certainty and an approval, but it very much looks like BPX-501 enabled haploHSCT has the best outcomes across the allogeneic HSCT literature — and that includes matched related donor HSCT.

In my recap of the main ASH poster (here), I discuss initial thoughts on what the data mean from a market perspective. I’ll revisit the market potential in more detail in my next post on valuation but the last one did some high level market sizing.

A quick review of the Data

Below is a review of the mortality and morbidity vs. controls in the BP-004 trial. Keep in mind if you reduce mortality enough and all other morbidity is the same, you have a valuable drug. BPX-501 appears to not only improve mortality but also improve morbidity rates.

Mortality: In the BP-004 trial, non-relapse mortality / transplant related mortality (NRM/TRM) was 0% vs. ~10% in the T cell depleted control group and around 13% with the current standard of PostCy treatment (discussed later). All else being equal, this reduced mortality rate would make BPX-501 very competitive for allogeneic HSCTs across the board assuming disease related mortality is unchanged or improved, specifically in malignant patients.

Morbidities: BPX-501 patients had lower infection rates and full immune reconstitution was 40 days (~33%) sooner than control for non-malignant patients. Moreover, it was exciting to see that several patients with primary immunodeficiencies, or PIDs, and with active, life threatening infections who got an HSCT with BPX-501 were cleared of their active infections post HSCT, not to mention also cured of their PIDs. With only Grades I-II acute GvHD, the BPX-501 group was slightly lower compared to a T cell depleted control (19% vs 23%). It is too early to compare chronic GvHD, which occurs after 100 days and can present a bit differently. Engraftment rates were similar and relapse rates for malignant populations were not disclosed, which follows my earlier prediction that the data would not be mature enough to understand. The BPX-501 patients also had 45% shorter hospital stays (26.5 vs. 48 days for the control) as well as lower readmission rates of 17% vs. 53% for the control. Longer term follow-up is needed but length of stay and re-admission rates together are an important indicator of low morbidity and also total procedure cost.

There is also reason to be hopeful in relapse rates given the GvL effect in haploHSCT and some of the measures being incorporated into the BP-004 protocol going forward, which I discuss later in this post.

Overall, when you look at the outcomes for all other allogeneic HSCT alternatives, whether it is matched unrelated (55% of procedures in 2012) or matched related (37% of procedures in 2012), the results for BPX-501 enabled haploHSCT appear better. Also, haploHSCT addresses those patients considered not to have a suitable match and who currently never get an HSCT, representing 40% of patients who need an allogeneic HSCT. BPX-501 can (theoretically) be incorporated into a matched related donor (MRD) but not a MUD, per MUD protocol.

Questions from ASH

Despite the well-received data, there were a few questions that were brought up during and post-ASH that this post seeks to address:

1. Why are the patients having a lower rate of GvHD than expected?

2. With no high grade GvHD, why do you need the CaspaCIDe switch?

3. What was the reason for showing mostly orphan data and omitting more detailed malignant data?

4. Is GvHD prophylaxis (“PostCy” in T cell replete HSCT) a sufficient alternative to BPX-501?

I promised to do a valuation of Bellicum and I will. But I think these are some of the immediate questions that should be addressed before building the market case.

Why the Low Rate with BPX-501 of High Grade GvHD in the BP-004 Trial?

The main question on twitter before and after the poster presentation by Locatelli was — why is there such a low rate of high grade GvHD? In the control arm, Alpha/Beta T cell and CD19+ B cell depleted haploHSCT, the rate was low but remember these patients were given an HSCT depleted of mature T cells and none were added back. So the GvHD rate was expected to be low in the control group — but the infection rate and transplant related mortality (TRM) was untenable at near 10%.

Despite the add-back of mature T cells (with the switch, in the form of BPX-501), the acute GvHD rates were slightly lower than the control group, 19% vs. 23%. Locatelli, in his presentation after ASH, said that the use of retrovirus for gene transduction of T cells has been associated with the change in the representation of T cells. It is also possible that the overall culture conditions may affect the activation state of the cells while in culture thus reducing the initial GvHD; the transduction step itself may or may not contribute. Nevertheless, we do see a lower level of alloreactivity, which is a better outcome if the infection rates remain relatively low.

So How Important is the CaspaCIDe Switch?

If GvHD rates remain low, some have said the need for the switch seems less critical. To address this concern, one needs to ask only one key question: in what context would a parent or physician deny a child this safety measure, along with the overall benefits of BPX-501, which include lower infection, mortality, GvHD and readmissions?

While the control group (T cell depleted) gives you low GvHD it affords little protection from life threatening infection. One cannot separate the totality of the benefits and then exclude the switch, as some have wondered. Is the theory that someone take out T cells and treat them a certain way to get the same reduced alloreactive effect and forego the switch? It seems like a lot of effort for an inferior end product. The risks posed would likely prevent physicians from trying it.

Notably, for malignant patients Bellicum is planning to escalate the dose of BPX-501 cells administered, from 1x10^6 to 2x10^6 and then 4x10^6. With this increase in dose we might expect a higher rate of aGvHD, including grades III and IV.

Case Study: Use of the CaspaCIDe Switch in BP-004 Trial

In the BP-004 trial the switch was activated in one BPX-501 patient. This 15-month old girl had a rare immunodeficiency called interferon gamma receptor 1 immunodeficiency (IFNGR1). As an aside, her brother had been transplanted for the same rare condition, dying after his second transplantation post-graft failure.

This patient was successfully transplanted (engrafting by day 14) but developed a severe infection on day 7. The physician administered BPX-501 earlier than usual due to this infection. On day 50 the patient developed grade II GvHD, which the doctors tried unsuccessfully to control with topical steroids. IV steroids would be the next step but the treating physician felt this was a risk due to the patient’s severe micro-bacterial infection.

To address the refractory GvHD (and to prevent progression), the physician administered rimiducid and the results were consistent with the prior trial in BPX-501 (here, here). The picture shows the clear resolution of GvHD symptoms. Notably, the switch has been shown to only eliminate the alloreactive T cells, leaving sufficient T cells alone to fight infection, as was shown in the prior trial.

Why Didn’t The Investigators Show More Leukemia Data?

The Company didn’t show much new data on malignant patients. Presumably, the number of patients is too small and the relapse time is long enough that they don’t have the proper follow up. The ASH abstract had more specific data on relapse rates, indicating that 2 of 7 (29%) patients with malignancies had a relapse, which is far too small to tell but PostCy and MUD have relapse rates of 44–48% and 39–40%, respectively while one small study on Alpha/Beta T cell Depleted haploHSCT had a 75% leukemia free survival rate. It would be expected that adding back T cells would improve on this rate, which is already superior to the noted MUD and MRD rates.

Locatelli, the lead investigator, discussed several ways his group and Bellicum are looking at improving the GvL effect:

· In BP-004, the protocol will be amended to escalate the dose of BPX-501, as discussed above.

· Physicians will evaluate adding zoledronic acid (ZOL), which potentiates Vδ2 killing against leukemia blasts.

The expectation is that the initial regulatory pathway will be for non-malignant orphan blood disorders and that malignant disorders will follow as outcomes take longer to assess.

Is GvHD Prophylaxis (“Post-Cy”) as Good as BPX-501?

Currently in the United States, the widely adopted “Hopkins Protocol” involves a T cell replete HSCT followed by administration of high dose cyclophosphamide (“PostCy”) for GvHD prevention. In effect, PostCy GvHD prophylaxis works a lot like T cell depletion but does it in vivo with cyclophosphamide, a chemotherapy used since the 1960s. PostCy takes advantage of the differential susceptibility to cyclophosphamide of proliferating, alloreactive T cells that cause GvHD (as well as fight infection and assist in engraftment, among other things) over non-proliferating, non-alloreactive T cells. Owing to the drug’s stem cell sparing effects, this strategy seeks to optimize GvHD prophylaxis while allowing for immune reconstitution over time.

One doctor tweeted that T cell replete HSCT with PostCy is “easier and widely adopted.” This is true. However, a review of the most recent literature on haploHSCT with PostCy vs. the preliminary data on BPX-501 from ASH, suggests that PostCy prophylaxis would not bein the best interest of patients vs. BPX-501. Indeed, the literature suggests no difference between haploHSCT with PostCy vs. HLA-matched HSCT in terms of acute GVHD, non-relapse mortality, and overall survival. But the data from ASH indicate that BPX-501 enabled HSCT is better than both haploHSCT with PostCy and HLA-matched HSCT.

The following papers cover mostly HSCT with PostCy for hematologic malignancies. It turns out that the data support haploHSCT with PostCy as being as good as MUD and nearly as good as MRD. But preliminary data on BPX-501 suggests it is materially better than PostCy. See below for a relatively comprehensive review of papers on haploHSCT with PostCy GvHD prevention regimens.

Transplant related (or non-relapse) mortality is much higher for Post-Cy, as is the acute GvHD rate. An (unscientifically) distilled table of this long list of papers is below. When juxtaposed against the BPX-501 early data, these results highlight that PostCy currently looks to be inferior in terms of non-relapse mortality and GvHD.

It should be noted that there is less literature on haploHSCT with PostCy in non-malignant disorders. One would assume that most of the TRM is related to infection and therefore would not differ in the non-malignant population.

Conclusion

Bellicum presented excellent data for BPX-501 and should it continue as it appears, would set the standard for mortality and morbidity in HSCT. Importantly, the results are early but appear better than current protocols that dominate the allogeneic HSCT landscape (MUD, MRD, haploHSCT w/PostCy). The Company is planning an end of Phase II (EoP2) meeting around mid-year and BPX-501 should be in pivotal trials after that. With several CAR-T programs and TCR programs entering the clinic, 2016 is likely to be an active year for Bellicum.

Citations:

1. O’Donnell PV, Luznik L, Jones RJ, Vogelsang GB, Leffell MS, Phelps M et al. Nonmyeloablative bone marrow transplantation from partially HLA-mismatched related donors using posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2002; 8: 377–386. | Article | PubMed | ISI | CAS |

2. Luznik L, O’Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2008;14: 641–650. | Article | PubMed | ISI | CAS |

3. Kasamon YL, Luznik L, Leffell MS, Kowalski J, Tsai HL, Bolanos-Meade J et al. Nonmyeloablative HLA-haploidentical bone marrow transplantation with high-dose posttransplantation cyclophosphamide: effect of HLA disparity on outcome. Biol Blood Marrow Transplant 2010; 16: 482–489. | Article | PubMed | ISI |

4. Brunstein CG, Fuchs EJ, Carter SL, Karanes C, Costa LJ, Wu J et al. Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood 2011; 118: 282–288. | Article | PubMed | ISI | CAS |

5. Burroughs LM, O’Donnell PV, Sandmaier BM, Storer BE, Luznik L, Symons HJet al. Comparison of outcomes of HLA-matched related, unrelated, or HLA-haploidentical related hematopoietic cell transplantation following nonmyeloablative conditioning for relapsed or refractory Hodgkin lymphoma.Biol Blood Marrow Transplant 2008; 14: 1279–1287. | Article | PubMed | ISI |

6. Raiola A, Dominietto A, Varaldo R, Ghiso A, Galaverna F, Bramanti S et al. Unmanipulated haploidentical BMT following non-myeloablative conditioning and post-transplantation CY for advanced Hodgkin’s lymphoma. Bone Marrow Transplant 2013; 49: 190–194. | Article | PubMed |

7. Bashey A, Zhang X, Sizemore CA, Manion K, Brown S, Holland HK et al. T-cell-replete HLA-haploidentical hematopoietic transplantation for hematologic malignancies using post-transplantation cyclophosphamide results in outcomes equivalent to those of contemporaneous HLA-matched related and unrelated donor transplantation. J Clin Oncol 2013; 31: 1310–1316. | Article | PubMed |

8. Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, Holland HK et al. Haploidentical Transplantation Using T Cell Replete Peripheral Blood Stem Cells and Myeloablative Conditioning in Patients with High-Risk Hematologic Malignancies Who Lack Conventional Donors is Well Tolerated and Produces Excellent Relapse-Free Survival: Results of a Prospective Phase II Trial. Biol Blood Marrow Transplant 2012; 18: 1859–1866. | Article | PubMed |

9. A. Raiola, A. Dominietto, R. Varaldo et al. Unmanipulated haploidentical BMT following non-myeloablative conditioning and post-transplantation CY for advanced Hodgkin’s lymphoma. Bone Marrow Transplantation, vol. 49, no. 2, pp. 190–194, 2014. | Article |

10. A. Di Stasi, D. R. Milton, L. M. Poon et al. Similar transplantation outcomes for acute myeloid leukemia and myelodysplastic syndrome patients with haploidentical versus 10/10 human leukocyte antigen-matched unrelated and related donors. Biology of Blood and Marrow Transplantation, vol. 20, no. 12, pp. 1975–1981, 2014. | Article |

11. R Devillier, S Bramanti, S Fürst, B Sarina, J El-Cheikh, R Crocchiolo, et. al. T-replete haploidentical allogeneic transplantation using post-transplantation cyclophosphamide in advanced AML and myelodysplastic syndromes. Bone Marrow Transplantation 2015, (9 November) | doi:10.1038/bmt.2015.270 | Article |

12. 11.S. R. McCurdy, J. A. Kanakry, M. M. Showel, et al. Risk-stratified outcomes of nonmyeloablative HLA-haploidentical BMT with high-dose posttransplantation cyclophosphamide. Blood, vol. 125, no. 19, pp. 3024–3031, 2015. | Article |

13. A. Bashey, X. Zhang, K. Jackson, et al. Comparison of outcomes of hematopoietic cell transplants from T-replete haploidentical donors using post-transplantation cyclophosphamide with 10 of 10 HLA-A, -B, -C, -DRB1, and -DQB1 allele-matched unrelated donors and HLA-identical sibling donors: a multivariable analysis including disease risk index. Biology of Blood and Marrow Transplantation, 2015. | Article |

14. S. O. Ciurea, M. J. Zhang, A. A. Bacigalupo, et al. Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood, vol. 126, no. 8, pp. 1033–1040, 2015. | Article |

15. Bacigalupo A, Dominietto A, Ghiso A, Di Grazia C, Lamparelli T, Gualandi F et. al. Unmanipulated haploidentical bone marrow transplantation and post-transplant cyclophosphamide for hematologic malignanices following a myeloablative conditioning: an update. Bone Marrow Transplant. 2015 Jun;50 Suppl 2:S37–9. doi: 10.1038/bmt.2015.93. | Article |