The first porcine kidney transplant (in a live recipient)
It’s been a year, and like many, I have been waiting for the details to be published in the NEJM (where else – especially since this was done at MGH). Here are the key elements that caught my eye but if you are truly interested, read the paper. (1) At the time of the xenotransplant, the patient’s disease was very advanced: 30 years of diabetes, 10+ years of dialysis, one previous cadaveric transplant that failed (BK virus), and at this point was running out of vascular access points. (2) The patient did become free from dialysis. (3) The patient died suddenly at home 52 days post discharge likely from a cardiac arrhythmia: autopsy confirmed extensive heart disease, and a functioning xenograft without signs of rejection. (4) The immunosuppressive regimen was complex: 9 drugs used in total including 2 for an episode of acute T-cell mediated rejection early on that resolved. All in all, a lot of promise for the 500,000+ patients on dialysis in the US and those in the rest of the world. Xenotransplantation of a Porcine Kidney for End-Stage Kidney Disease
An allogeneic stem-cell based alternative to islet transplants for hard to manage Type 1 diabetes
The ability to manage type 1 diabetes has improved substantially over the last decades with ever more sophisticated continuous monitors and pumps, but it continues to be a heavy burden, especially for individuals with brittle diabetes who easily swing, unaware, between hyperglycemic and hypoglycemic episodes. For those individuals, the option of transplantation from cadaveric islets exists but availability is sparse. This is why the prospect of a reliable source of islets based on differentiation of pluripotent embryonic stem cells is so interesting. Here Vertex reports on the first 12 Type 1 patients infused with full dose zimislecel with at least 12 months of follow-up. Ten patients became insulin independent, the remaining two had a lower requirement than pre-infusion. All were free from severe hypoglycemic events. Two patients died, one from unrelated causes, the other from cryptococcus meningitis that was related to immunosuppression but with very significant additional risk factors.
These results are encouraging, but it is unfortunate that the article is sparse on details on what the maintenance immunosuppressive regimen was like. We have no idea about what the level of variation across subjects was (did anyone go off immunosuppression?), and what biomarkers were used to modulate immunosuppression (even the protocol is silent on that). Since this is a core element of the applicability of the therapy, I am surprised the referees did not demand that this information be included. Another thought; would it be possible to make the process autologous via iPSC technology? Stem Cell–Derived, Fully Differentiated Islets for Type 1 Diabetes
Cells as a multivalent therapeutic platform
When it came to the fore in the early 2010s, CAR-T therapy was one of the most exciting developments in medicine in a generation, not just because it brought back/cured (some) patients who were literally at death’s door from their leukemia or lymphoma, but because it was opening a new world of therapeutics. Cells are factories, with the flexibility that comes from a full complement of molecular machinery, and therefore have the potential to become therapeutic effectors through multiple parallel processes. Now after years of refining the base CAR-T approach, the community is moving toward taking advantage of this with a new report from the Penn group developing “armored” CAR-Ts that secrete IL18 for additional immune stimulation on top of targeting CD19. The other major advance is that the Penn group has developed a 3-day manufacturing process, so that the manufacturing timeline is no longer the bottleneck to therapy.
As to the clinical results, 21 lymphoma patients who had previously failed CAR-T therapy received huCART19-IL18: most had a response, and some had a durable response which considering this was in very advanced disease counts as remarkable. But a key element is that this opens the door to a different model of therapeutic development which is more “device like” and less like the “all-or-nothing” traditional drug model. One could imagine a whole new approach based on incremental improvements on an existing backbone cell therapy. Will a platform regulatory framework enable / allow it? We shall see. Enhanced CAR T-Cell Therapy for Lymphoma after Previous Failure
Very long-term outcomes for gene therapy in Hemophilia B
The disappointing commercial performance of gene therapy in Hemophilia A (Roctavian) has several drivers, but one of them was that the durability of the therapeutic effect seemed to be limited, at least in a subset of patients. Here, an update on an early cohort of patients treated with Hemgenix (etranacogene dezaparvovec, CSL/uniQure) shows that, 11-14 years post therapy, 7 of the 10 patients are stable and do not need Factor IX prophylaxis, while 3 do though their annual bleeding rate remains much lower than it was pre-gene therapy. There were no cases of gene therapy-related malignancy. In most patients, titers against AAV8 remained very high even 10+ years out.
This persistence of efficacy may explain why most analysts forecast higher revenues for Hemgenix than for Roctavian despite there being 5x hemophilia A patients relative to hemophilia B (and also the fact that subcutaneous Hemlibra in hemophilia A is so convenient to patients). It also one of the few studies that show outcomes very far out from gene therapy, and overall, it’s reassuring, and shows remarkable value for most of the patients who were treated. Sustained Clinical Benefit of AAV Gene Therapy in Severe Hemophilia B
Gene therapy for an ultra-rare disease
Leukocyte adhesion deficiency type 1 (LAD-1) is a very rare autosomal recessive disease that typically leads to death from infections in the first years of life, unless an allogenic hematopoietic stem cell transplant is performed (which has its own morbidity and mortality implications – when a matched donor is available). A series of 9 children were treated with ex-vivo lentiviral gene therapy inserting a working copy ITGB2 into autologous hematopoietic stem cells. As far as I can tell, 8 of the 9 children were essentially cured (the 9th appeared to have other concomitant abnormalities). Given that the insertion can occur anywhere, malignant transformation is always a concern, but sequential analysis did not show any particular clone of the transfected cells emerging as dominant which is reassuring. The effect also seemed durable at 2+ years. We will know more over time as the plan is to follow those kids for 15 years, but meanwhile the FDA appears poised to approve this therapy.
Though I have not seen independent estimates numbers from the company boil down to an incidence around 1/200,000 births (note that when I do a back of the envelope Hardy-Weinberg calculation based on the carrier rate in the general population, this comes out closer to 1/1,000,000, but perhaps there are mixing effects). It will be an important test case whether this program ends-up with reasonable economics for the developer, Rocket Pharmaceuticals – I hope so, the gene therapy and rare disease communities need it. Lentiviral Gene Therapy for Severe Leukocyte Adhesion Deficiency Type 1
An N-of-1 therapy platform, and Peter Marks’ legacy at the FDA
As was widely reported in the mainstream media, a case report of a tailor-made base editing therapeutic specifically designed to correct a single base truncating mutation (labeled as Q335X) in the gene encoding CPS1, an enzyme involved in urea metabolism (actually, both alleles of CPS1 were affected in the infant, but only one was corrected). A lipid encapsulated CRISPR-Cas9n was administered at 7 months of life and a couple months later when the report was issued, the patient was doing well. Behind this was an incredible effort: 1) to properly characterize the genetic defect in the patient; 2) to create, screen and select for the optimal construct to correct the defect in a cultured human cell line modified to have mutation Q335X; 3) to create a mouse model with the Q355X mutation and test efficacy of the selected construct; 4) to assess the safety of the finalized formulation of the drug in cynomolgus monkeys. Some people must not have slept much during this period. The outcome is great but is this scalable? In a poignant companion editorial, a valediction to his impactful career at the FDA, Peter Marks writes that he believes it can be, having championed for years a platform approach that would streamline this the design of individualized treatment for the multitude of mutations that cause a galaxy of rare diseases. Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease; Progress in the Development of N-of-1 Therapy
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