Nearly a year since Sangamo Therapeutics (SGMO) stock price plunged below $1 a share, the genetic medicines developer very briefly returned to that benchmark on Friday, two days after joining partner Pfizer (PFE) to report positive Phase III data for their hemophilia A gene therapy candidate.
The companies reported that giroctocogene fitelparvovec met its primary endpoint in the Phase III AFFINE trial (NCT04370054) by achieving non-inferiority, as well as superiority, of total annualized bleeding rate (ABR) from Week 12 through at least 15 months of follow up post-infusion compared with routine Factor VIII (FVIII) replacement prophylaxis treatment.
Giroctocogene fitelparvovec demonstrated a statistically significant 74% reduction in mean total ABR compared to the pre-infusion period (1.24 vs 4.73) following a single 3e13 vg/kg dose, Pfizer and Sangamo shared.
Pfizer and Sangamo also announced results on secondary endpoints that showed superiority compared to prophylaxis:
- 84% of participants maintained FVIII activity >5% at 15 months post-infusion, with most participants having FVIII activity ≥15%.
- The mean treated ABR showed a statistically significant 98.3% reduction from 4.08 in the pre-infusion period to 0.07 post-infusion (from Week 12 up to at least 15 months [15–44 months].
De-risking Sangamo stock
Maury Raycroft, PhD, an equity research analyst with Jefferies, noted that the Pfizer/Sangamo results were comparable to those of BioMarin Pharmaceutical (BMRN)’s Roctavian®(valoctocogene roxaparvovec or “val rox”), approved by the FDA last year as the first adeno-associated virus vector (AAV)-based gene therapy indicated to treat hemophilia A.
Roctavian showed an 84% reduction in mean total ABR with 71.6 weeks follow-up, as well as 88% of participants maintaining FVIII activity >5% at 49–52 weeks follow-up.
“The Phase III succeeded w/ ABR that looks competitive/better vs BMRN. We see good chance for safety (w/ minimal need for prophy[lactic] steroid) to look better vs BMRN, and comments in PFE’s press release and from SGMO mgmt indicate PFE is fully committed to advancing the program, which helps de-risk SGMO stock,” Raycroft wrote in a research note.
Raycroft maintained Jefferies’ “Buy” rating and 12-month price target of $8 on Sangamo shares. He was one of two analysts to weigh in on the shares this past week. Patrick Trucchio of H.C. Wainwright & Co. reiterated his firm’s “Buy” rating and $5 price target Wednesday.
Last year, a team of Morningstar analysts raised durability issues with the Pfizer/Sangamo gene therapy, based on two-year data on five patients taking the highest 3×10^13 vg/kg dose. That data, shared at the 63rd American Society of Hematology Annual Meeting and Exposition (ASH 2021) held in Atlanta and virtually, showed a mean factor VIII activity of 25%, down from the 49% seen at 18 months.
“Combined with bleeds in two patients during year two and liver enzyme elevations, we’re less enthused about this program,” concluded a team of Morningstar analysts led by Karen Andersen CFA, strategist, biotechnology; and Damien Conover, CFA, director, pharmaceuticals.
The team is also watching another hemophilia A gene therapy candidate in the clinic: SPK-8011, being developed by Roche-owned Spark Therapeutics, is under study in a Phase III trial (NCT06297486) with an estimated primary completion date of May 2027.
Pfizer acknowledged that 49.3% of dosed participants in AFFINE showed transient elevated factor VIII levels of 150% or greater—but quickly added that the higher levels had no significant impact on the gene therapy’s safety and efficacy. In 2022, the FDA lifted a clinical hold placed on the AFFINE trial after the Factor VIII levels of some patients treated with the gene therapy reached >150%, posing a potential thrombosis risk. The hold allowed the agency to enable implementation of a protocol amendment covering clinical management of elevated factor VIII levels.
“We are thrilled with the positive topline results from the Phase III AFFINE trial, which demonstrated the potential of giroctocogene fitelparvovec as a one-time gene therapy for people with hemophilia A and provide a potential alternative to the current burden of disease management,” Nathalie Dubois-Stringfellow, PhD, Sangamo’s Chief Development Officer, said in a statement.
More than doubling
Investors initially shared that enthusiasm, sending Sangamo shares more than doubling, zooming 120% at the start of trading on Wednesday, to 88 cents a share from Tuesday’s closing price of 40 cents.
Sangamo shares yo-yoed Wednesday before settling for a 40% gain and a price of 56 cents at the closing bell. However, shares continued climbing through the week, rising another 20% to 67 cents Thursday—then another 70% to $1.14 cents in early trading Friday as of 10:10 a.m. before trading around 90 cents a share later that morning, lowering the gain to the 30% range.
A likely reason for the initial yo-yo: Investors saw separately issued statements from Pfizer and from Sangamo that offered little insight about the road ahead for giroctocogene fitelparvovec. Both companies simply said that Pfizer “will discuss these data with regulatory authorities in the coming months.”
Back in March, however, Sangamo offered some more specificity about the regulatory path for the hemophilia A gene therapy, by disclosing in its Form 10-K annual report for 2023 that Pfizer was “anticipating submitting a Biologics License Application, or BLA, in the U.S. and a marketing authorization application, or MAA, in Europe in early 2025 if the pivotal readout is supportive.”
Sangamo has significant cash riding on the outcome of giroctocogene fitelparvovec’s path from clinic to approvals—namely up to $220 million in milestone payments the company could receive from Pfizer, tied to achieving specified regulatory and commercial milestones for giroctocogene fitelparvovec and product sales royalties of 14–20% if the gene therapy is approved and commercialized, subject to reductions due to patent expiration, entry of biosimilar products to the market and payment made under certain licenses for third‑party intellectual property.
Raycroft and Jefferies estimate that Sangamo is eligible for about $70 million in first milestone payments upon BLA filings in three territories starting in early’25, with additional commercial milestone payments tied to the first patient dosed.
“Now that the [Phase] III results are out, they can start discussing monetizing royalties for hemA to extend cash runway,” Raycroft said.
Potentially Longer Runway
Sangamo finished the first quarter with $54.417 million in cash and cash equivalents, just enough to fund planned operations into the third quarter of this year—but down 33% from $81.002 million as of December 31, 2023. If Sangamo receives all $220 million in milestones, its runway would be extended into 2026, Raycroft added.
Cash is no small concern to Sangamo, which last year announced two rounds of layoffs, the second eliminating about 40% of its U.S. workforce, and shut down its headquarters/AAV manufacturing site in Brisbane, CA. The company shifted its HQ within the San Francisco Bay Area to its Sangamo Research Center facility in Richmond, CA.
Sangamo’s workforce has shrunk from 483 full-time employees as of February 1, 2023, to 405 as of December 31, 2023. In March, the company began shutting down its Valbonne, France, cell therapy manufacturing facility and research labs, through a restructuring expected to eliminate its entire 95-person French workforce by year’s end.
Pfizer shares rose 2% on the positive Phase III trial news, from $29.50 on Tuesday to $29.98 Wednesday. Arguably, that increase reflected news unrelated to Sangamo and the gene therapy, as the U.K.’s Medicines and Healthcare products Regulatory Agency (MHRA) approved an adapted version of the COVID-19 vaccine co-developed with BioNTech (BNTX) that targets the JN.1 COVID-19 subvariant.
Pfizer said analyses of the full Phase III dataset from AFFINE remain ongoing, with researchers planning to present additional data from the trial at unspecified upcoming medical meetings.
Sangamo had initially developed giroctocogene fitelparvovec under the name SB-225 before starting in 2017 to partner with Pfizer on the gene therapy, which Sangamo formerly called SB-525, and Pfizer initially renamed PF-07055480). Two years later, Sangamo earned a $25 million milestone payment from Pfizer after completing its transfer of the manufacturing technology and its IND application for giroctocogene fitelparvovec to the pharma giant.
And in 2020, Pfizer and Sangamo reported positive Phase I/II results showing that giroctocogene fitelparvovec showed sustained factor VIII (FVIII) activity levels, no bleeding events, and no required FVIII infusions in all five patients within one of the study’s four dose cohorts. The companies ended that year by advancing the gene therapy into AFFINE.
“ I think this is a moment for gene therapy, because hemophilia A isn’t an ultra-rare disease, and it isn’t a lethal disease in small children, which is what the approved products have been so far,” Sangamo CEO Sandy Macrae, PhD, told GEN in 2021.
“An important moment”
“This is an important moment in the first wave of genomic medicines,” Macrae added. “If you look at the total lifetime cost, it’s $25–30 million by the time you include all the hospital visits and consequences of their disease. If a simple once-and-done treatment that lasts for many years can take that away, it’s a benefit to the patient, it’s a benefit to society, and it’s a benefit to the whole community of hemophilia.”
AFFINE (NCT04370054) is an open-label, multicenter, single-arm trial designed to assess the efficacy and safety of a single 3e13 vg/kg dose of giroctocogene fitelparvovec via IV infusion in 75 adult men with moderately severe to severe hemophilia A. Fifty of the men were included in assessments of key endpoints in the primary efficacy analysis, after they completed a minimum six months of routine FVIII replacement prophylaxis therapy during a lead-in study (NCT03587116) that was intended to provide data to compare with post giroctocogene fitelparvovec treatment.
AFFINE participants will be evaluated over five years—and up to a total of 15 years as part of a long-term follow-up study.
Dubois-Stringfellow added that the results of AFFINE “further validate the power of our genomic technologies and take us one step closer towards what could become Sangamo’s first medicine commercially available to patients.”
Giroctocogene fitelparvovec is the most advanced of three Sangamo programs outside its core neurology pipeline of five preclinical programs. The other non-core neurology candidates are isaralgagene civaparvovec, a Phase I/II Fabry disease gene therapy candidate; and TX200, a Phase I/II chimeric antigen receptor-modified regulatory T-cell (CAR-Treg) therapy designed to prevent rejection in kidney transplant patients.
Giroctocogene fitelparvovec’s Phase III success comes about a year and a half after the FDA approved the first AAV gene therapy indicated for Hemophilia B, Hemgenix® (etranacogene dezaparvovec-drlb). uniQure led the research and clinical development of Hemgenix, then in 2021 licensed global commercial rights to CSL Behring, which won FDA approval for the gene therapy in November 2022. uniQure manufactures Hemgenix in Lexington, MA.
The positive results from AFFINE marks Pfizer’s latest milestone in building a portfolio of gene therapy treatments for hemophilia and other disorders.
In April, Pfizer won FDA approval for BEQVEZ™ (fidanocogene elaparvovec), an AAV-based gene therapy designed to treat adults with moderate to severe hemophilia B. BEQVEZ has also won approval in Canada and is awaiting a decision from the European Commission following a positive opinion in May from the European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use.
However, in May, Pfizer paused enrollment in the Phase III CIFFREO trial (NCT04281485) assessing its Duchenne muscular dystrophy (DMD) gene therapy candidate fordadistrogene movaparvovec, after acknowledging the sudden death of a young boy who received the treatment last year in a Phase II study (NCT05429372). Pfizer has since said it is evaluating next steps for fordadistrogene movaparvovec after it failed CIFFREO.
Leaders & laggards
- 10x Genomics (TXG) shares rose 14% from $16.70 to $18.97 between July 22 and Wednesday, after Jefferies upgraded the company’s stock from “Hold” to “Buy,” while leaving unchanged at $24 its 12-month price target on the company’s shares. “Our Buy-rated thesis is predicated on conviction in return to growth in single cell and continuation of favorable market dynamics in spatial. We like TXG’s strong competitive position, which offers superior technology and customer stickiness, given technological consistency is crucial in the field,” Jefferies equity analyst Tycho Peterson wrote in a research note. The upgrade comes two weeks after Deutsche Bank analyst Justin Bowers downgraded 10x’s shares from “Buy” to “Hold” on July 10 and slashed his firm’s price target by 55%, from $55 to $25, sparking a 14% price drop from $18.25 to $15.71.
- Cassava Sciences (SAVA) shares surged 27% from $10.08 to $12.83 on July 22 after Richard (Rick) Barry, the company’s executive chairman and principal executive officer, issued an open letter to “shareholders, employees, principal investigators, patients, and their loved ones” disclosing that its first Phase III trial of its Alzheimer’s disease candidate simufilam (formerly PTI-125) is expected to release data by December, with 804 patients randomized 1:1 between simufilam and placebo. “The second Phase 3 trial of 1,125 patients (randomized 1:1:1 between two dose levels of simufilam and placebo) is expected to conclude by June 2025,” Barry added. Barry was appointed July 17 to succeed chairman, president, and CEO Remi Barbier, who departed along with his wife Lindsay Burns, senior vice president of neuroscience.
- MEI Pharma (MEIP) shares jumped 21% from $2.86 to $3.47 on June 22 after the company announced plans to eliminate an unspecified percentage of its workforce “as soon as practicable” in phases to conserve cash, as well as end clinical development of voruciclib, while continuing to conduct specified non-clinical activities related to its drug candidates. MEI’s board agreed to evaluate strategic alternatives that include unspecified “potential transactions” and an orderly wind-down of operations “if appropriate.” MEI also plans to consider out-licensing opportunities for existing programs, as well as merger and acquisition opportunities. President and CEO David M. Urso and chief medical officer Richard Ghalie, MD, will step down effective August 1, with Urso also leaving the board, though he and Ghalie were expected to sign consulting agreements with MEI. Board chairperson Charles V. Baltic III agreed to step down immediately.
- MIRA Pharmaceuticals (MIRA) shares multiplied seven-fold, rocketing 626% from 69 cents to $5.01 on July 22, then tumbled 53% over the two following days, to $2.56 Tuesday and $2.35 Wednesday, after the company announced positive preclinical results for its oral ketamine analog Ketamir-2. MIRA said its key areas of recent data investigation included Ketamir-2’s greater convenience and improved patient compliance, brain penetration, drug resistance, oral bioavailability, and potential for lower dosing. Ketamir-2 is under study to treat neurological and neuropsychiatric disorders including depression, treatment-resistant depression, and post-traumatic stress disorder (PTSD). MIRA said it plans to submit an Investigational New Drug (IND) application to the FDA by year’s end.
- Pieris Pharmaceuticals (PIRS) shares zoomed 90% from $7.94 to $15.05 Wednesday, after the company announced it had joined privately-held Palvella Therapeutics in agreeing to an all-stock merger deal. The combined company is expected to have about $80.5 million of cash and cash equivalents at closing, including approximately $78.9 million from an oversubscribed $78.9 million concurrent private financing co-led by existing investor BVF Partners and new investor Frazier Life Sciences. The cash and cash equivalents are expected to provide the combined company with a cash runway stretching into the second half of 2027. During that time, the combined company is expected to achieve multiple clinical trial milestones, including pivotal Phase III results from a single-arm, baseline-controlled trial of QTORIN™ 3.9% rapamycin anhydrous gel (QTORIN™ rapamycin) to treat microcystic lymphatic malformation.
